Vienna, Austria

The Medical University of Vienna is a university located in Vienna, Austria. It is the direct successor of the faculty of medicine of the University of Vienna, founded in 1365 by Rudolf IV, Duke of Austria. Thus it is the oldest medical school in the German–speaking world, and it was the second medical faculty in the Holy Roman Empire, after the Charles University of Prague.The Medical University of Vienna is the largest medical organisation in Austria, as well as one of the top-level research institutions in Europe and provides Europe's largest hospital, the Vienna General Hospital, with all of its medical staff.It consists of 31 university clinics and clinical institutes, 12 medical-theoretical departments which perform around 48,000 operations each year. The Vienna General Hospital has about 100,000 patients treated as inpatients and 605,000 treated as outpatients each year.There have been seven Nobel prize laureates affiliated with the medical faculty, and fifteen in total with the University of Vienna. These include Robert Bárány, Julius Wagner-Jauregg and Karl Landsteiner, the discoverer of the ABO blood type system and the Rhesus factor. Sigmund Freud qualified as a doctor at the medical faculty and worked as a doctor and lecturer at the General Hospital, carrying out research into cerebral palsy, aphasia and microscopic neuroanatomy.In the 2014-15 Times Higher Education Rankings, Medical University of Vienna is listed among the top 15 medical schools in Europe and 49th in the world. .In 2014, there were 6,016 candidate applications for 660 places in medicine proper and 80 in dentistry, which corresponds to an admission rate of about 12 percent. Admission is based upon ranking in an admission test, called "MedAT", which is carried out every summer in conjunction with the two other public medical schools of Austria, Medical University of Graz and Innsbruck Medical University. Wikipedia.

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Medical University of Vienna | Date: 2014-12-19

The invention relates to an aortic catheter (1) for insertion into the aorta (A), having a flexible tube (2), two occlusion balloons (3, 4), which are spaced part from one another and each of which is connected to a supply line (5, 6) for supplying a pumping medium (7) for inflating the occlusion balloons (3, 4), having at least one opening (8) arranged between the occlusion balloons (3, 4) in the tube (2) for supplying a cooling medium (9), which at least one opening (8) is connected to a first cooling medium supply line (10) running in the tube (2), and also relates to a resuscitation set (22) with such an aortic catheter (1), and a distal port (13) for supplying a cooling medium (9) in the direction of cerebral vessels is disposed in the tube (2), which distal port (13) is connected to a second cooling medium supply line (14) running in the tube (2).

Whittle N.,University of Innsbruck | Hauschild M.,University of Innsbruck | Lubec G.,Medical University of Vienna | Holmes A.,U.S. National Institutes of Health | Singewald N.,University of Innsbruck
Journal of Neuroscience | Year: 2010

Fear extinction is impaired in neuropsychiatric disorders, including posttraumatic stress disorder. Identifying drugs that facilitate fear extinction in animal models provides leads for novel pharmacological treatments for these disorders. Zinc (Zn) is expressed in neurons in a cortico-amygdala circuit mediating fear extinction, and modulates neurotransmitter systems regulating extinction. We previously found that the 129S1/SvImJ mouse strain (S1) exhibited a profound impairment in fear extinction, coupled with abnormalities in the activation of the extinction circuit. Here, we tested the role of Zn in fear extinction in S1 and C57BL/6N reference strain (B6) by feeding the mice a Zn-restricted diet (ZnR) and testing for fear extinction, as well as neuronal activation of the extinction circuit via quantification of the immediate-early genes c-Fos and Zif268. Results showed that (preconditioning or postconditioning) ZnR completely rescued deficient extinction learning and long-term extinction retrieval in S1 and expedited extinction learning in B6, without affecting fear acquisition or fear expression. The extinction- facilitating effects of ZnR were associated with the normalization of Zif268 and/or c-Fos expression in cortico-amygdala regions of S1. Specifically, ZnR increased activity in infralimbic cortex, lateral and basolateral amygdala nuclei, and lateral central amygdala nucleus, and decreased activity in prelimbic and insular cortices and medial central amygdala nucleus. ZnR also increased activation in the main intercalated nucleus and decreased activation of the medial paracapsular intercalated mass in S1. Our findings reveal a novel role for Zn in fear extinction and further support the utility of the S1 model for identifying extinction facilitating drugs. Copyright © 2010 the authors.

Hoivik M.L.,University of Oslo | Reinisch W.,Medical University of Vienna | Cvancarova M.,University of Oslo | Moum B.,University of Oslo
Alimentary Pharmacology and Therapeutics | Year: 2014

Background The point prevalence estimates of anaemia in patients with inflammatory bowel disease (IBD) range between 6% and 74%. The variation is probably due to differences in the definition of anaemia and the study populations. Aim To retrospectively determine the prevalence of anaemia at diagnosis and at the 1-, 5-and 10-year follow-ups in patients with IBD from a prospectively followed, population-based inception cohort (the IBSEN Study). To compare the prevalence of anaemia after a 10-year disease course with the prevalence of anaemia in the background population, and to assess clinical factors associated with anaemia at diagnosis and during follow-up. Methods Newly diagnosed IBD patients were included in a population-based, prospective cohort. Follow-up was performed at 1, 5 and 10 years. All visits included clinical examinations and blood samples. Anaemia was defined according to the WHO. Results A total of 756 patients (UC, n = 519 and CD, n = 237) were included; 48.8% of CD and 20.2% of UC patients were anaemic at diagnosis (P < 0.001). The proportion of patients with anaemia decreased during the disease course in all patients, except in women with CD. After 10 years of disease, the relative risk for anaemia was increased in all groups, except for women with UC. The variables associated with anaemia were generally unchanged during the disease course, and elevated CRP was the strongest predictor of risk. Conclusions Anaemia was more common in CD than in UC. The prevalence of anaemia decreased during the disease course. Women with CD were at high risk for anaemia. Elevated CRP was independently associated with anaemia. © 2013 John Wiley & Sons Ltd.

Kamada T.,Japan National Institute of Radiological Sciences | Tsujii H.,Japan National Institute of Radiological Sciences | Blakely E.A.,Lawrence Berkeley National Laboratory | Debus J.,University of Heidelberg | And 9 more authors.
The Lancet Oncology | Year: 2015

Charged particle therapy is generally regarded as cutting-edge technology in oncology. Many proton therapy centres are active in the USA, Europe, and Asia, but only a few centres use heavy ions, even though these ions are much more effective than x-rays owing to the special radiobiological properties of densely ionising radiation. The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. So far, more than 8000 patients have had this treatment at NIRS, and the centre thus has by far the greatest experience in carbon ion treatment worldwide. A panel of radiation oncologists, radiobiologists, and medical physicists from the USA and Europe recently completed peer review of the carbon ion therapy at NIRS. The review panel had access to the latest developments in treatment planning and beam delivery and to all updated clinical data produced at NIRS. A detailed comparison with the most advanced results obtained with x-rays or protons in Europe and the USA was then possible. In addition to those tumours for which carbon ions are known to produce excellent results, such as bone and soft-tissue sarcoma of the skull base, head and neck, and pelvis, promising data were obtained for other tumours, such as locally recurrent rectal cancer and pancreatic cancer. The most serious impediment to the worldwide spread of heavy ion therapy centres is the high initial capital cost. The 20 years of clinical experience at NIRS can help guide strategic decisions on the design and construction of new heavy ion therapy centres. © 2015 Elsevier Ltd.

Carbone D.P.,Ohio State University | Gandara D.R.,University of California at Davis | Antonia S.J.,H. Lee Moffitt Cancer Center and Research Institute | Zielinski C.,Medical University of Vienna | Paz-Ares L.,Institute Biomedicina Of Seville
Journal of Thoracic Oncology | Year: 2015

As the leading cause of cancer death worldwide, lung cancer continues to impose a major burden on healthcare systems and cause significant challenges for clinicians and patients. Most patients present with advanced disease at the time of diagnosis and have a poor prognosis, with the vast majority surviving less than 5 years. Although new therapies have been introduced in recent years that target molecular disease drivers present in a subset of patients, there is a significant need for treatments able to improve response and extend survival while minimizing effects on quality of life. Recent evidence of clinical efficacy for immunotherapeutic approaches for lung cancer suggests that they will become the next major therapeutic advance for this disease. Non-small-cell lung cancer, which accounts for approximately 85% of lung cancer cases, has historically been considered a nonimmunogenic disease; however, as with several other malignancies, recent data show that much of this lack of immune responsiveness is functional rather than structural (i.e., possible to overcome therapeutically). This review explores the key elements of the immune system involved in non-small-cell lung cancer and briefly examines immunotherapeutic strategies in development to shift the balance of immune activity away from a tumor-induced immune-suppressive state toward an active antitumor immune response. © 2015 by the International Association for the Study of Lung Cancer.

Range F.,Medical University of Vienna | Range F.,Wolf Science Center | Viranyi Z.,Medical University of Vienna | Viranyi Z.,Wolf Science Center
PLoS ONE | Year: 2014

Domestication is thought to have influenced the cognitive abilities of dogs underlying their communication with humans, but little is known about its effect on their interactions with conspecifics. Since domestication hypotheses offer limited predictions in regard to wolf-wolf compared to dog-dog interactions, we extend the cooperative breeding hypothesis suggesting that the dependency of wolves on close cooperation with conspecifics, including breeding but also territory defense and hunting, has created selection pressures on motivational and cognitive processes enhancing their propensity to pay close attention to conspecifics' actions. During domestication, dogs' dependency on conspecifics has been relaxed, leading to reduced motivational and cognitive abilities to interact with conspecifics. Here we show that 6-month-old wolves outperform same aged dogs in a two-action-imitation task following a conspecific demonstration. While the wolves readily opened the apparatus after a demonstration, the dogs failed to solve the problem. This difference could not be explained by differential motivation, better physical insight of wolves, differential developmental pathways of wolves and dogs or a higher dependency of dogs from humans. Our results are best explained by the hypothesis that higher cooperativeness may come together with a higher propensity to pay close attention to detailed actions of others and offer an alternative perspective to domestication by emphasizing the cooperativeness of wolves as a potential source of dog-human cooperation. © 2014 Range, Virányi.

Cosyns B.,UZ Brussel | Droogmans S.,UZ Brussel | Rosenhek R.,Medical University of Vienna | Lancellotti P.,University of Liège
Heart | Year: 2013

Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, ' Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management.

Stanek G.,Medical University of Vienna | Wormser G.P.,New York Medical College | Gray J.,University College Dublin | Strle F.,University of Ljubljana
The Lancet | Year: 2012

Lyme borreliosis (Lyme disease) is caused by spirochaetes of the Borrelia burgdorferi sensu lato species complex, which are transmitted by ticks. The most common clinical manifestation is erythema migrans, which eventually resolves, even without antibiotic treatment. However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient's skin, nervous system, joints, or heart. The incidence of this disease is increasing in many countries. Laboratory evidence of infection, mainly serology, is essential for diagnosis, except in the case of typical erythema migrans. Diagnosed cases are usually treated with antibiotics for 2-4 weeks and most patients make an uneventful recovery. No convincing evidence exists to support the use of antibiotics for longer than 4 weeks, or for the persistence of spirochaetes in adequately treated patients. Prevention is mainly accomplished by protecting against tick bites. There is no vaccine available for human beings. © 2012 Elsevier Ltd.

Schuhmacher A.J.,Sloan Kettering Cancer Center | Sibilia M.,Medical University of Vienna
Cancer Cell | Year: 2012

Clinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, development of pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53-defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic. © 2012 Elsevier Inc.

Donnez J.,Catholic University of Leuven | Tomaszewski J.,Prywatna Klinika Polozniczo Ginekologiczna | Bouchard P.,University Paris - Sud | Lemieszczuk B.,Gabinet Lekarski Specjalistyczny Sonus | And 8 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: The efficacy and side-effect profile of ulipristal acetate as compared with those of leuprolide acetate for the treatment of symptomatic uterine fibroids before surgery are unclear. METHODS: In this double-blind noninferiority trial, we randomly assigned 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral ulipristal acetate (at a dose of either 5 mg or 10 mg) or once-monthly intramuscular injections of leuprolide acetate (at a dose of 3.75 mg). The primary outcome was the proportion of patients with controlled bleeding at week 13, with a prespecified noninferiority margin of -20%. RESULTS: Uterine bleeding was controlled in 90% of patients receiving 5 mg of ulipristal acetate, in 98% of those receiving 10 mg of ulipristal acetate, and in 89% of those receiving leuprolide acetate, for differences (as compared with leuprolide acetate) of 1.2 percentage points (95% confidence interval [CI], -9.3 to 11.8) for 5 mg of ulipristal acetate and 8.8 percentage points (95% CI, 0.4 to 18.3) for 10 mg of ulipristal acetate. Median times to amenorrhea were 7 days for patients receiving 5 mg of ulipristal acetate, 5 days for those receiving 10 mg of ulipristal acetate, and 21 days for those receiving leuprolide acetate. Moderate-to-severe hot flashes were reported for 11% of patients receiving 5 mg of ulipristal acetate, for 10% of those receiving 10 mg of ulipristal acetate, and for 40% of those receiving leuprolide acetate (P<0.001 for each dose of ulipristal acetate vs. leuprolide acetate). CONCLUSIONS: Both the 5-mg and 10-mg daily doses of ulipristal acetate were noninferior to oncemonthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes. (Funded by PregLem; number, NCT00740831.) Copyright © 2012 Massachusetts Medical Society.

Bechmann L.P.,University of Duisburg - Essen | Hannivoort R.A.,University of Groningen | Gerken G.,University of Duisburg - Essen | Hotamisligil G.S.,Harvard University | And 2 more authors.
Journal of Hepatology | Year: 2012

It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer. Alterations in insulin response, β-oxidation, lipid storage and transport, autophagy and an imbalance in chemokines and nuclear receptor signaling are held accountable for these changes. Furthermore, recent studies revealed a role for lipid accumulation in inflammation and ER stress in the clinical context of liver regeneration and hepatic carcinogenesis. This review focuses on novel findings related to nuclear receptor signaling - including the vitamin D receptor and the liver receptor homolog 1 - in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of NAFLD, liver regeneration, and cancer. © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

van Duijn E.,Medical University of Vienna | van Duijn E.,University of Oslo | van Duijn E.,University of Ulm
Journal of neurology, neurosurgery, and psychiatry | Year: 2014

BACKGROUND: The majority of Huntington's disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods.METHODS: The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis.RESULTS: Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association.CONCLUSIONS: A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

Schaap F.G.,Maastricht University | Trauner M.,Medical University of Vienna
Nature Reviews Gastroenterology and Hepatology | Year: 2014

The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications. © 2014 Macmillan Publishers Limited. All rights reserved.

Mulec J.,Karst Research Institute | Vaupotic J.,Jozef Stefan Institute | Walochnik J.,Medical University of Vienna
Microbial Ecology | Year: 2012

Bioaerosols in cave air can serve as natural tracers and, together with physical parameters, give a detailed view of conditions in the cave atmosphere and responses to climatic changes. Airborne microbes in the Postojna Cave system indicated very dynamic atmospheric conditions, especially in the transitory seasonal periods between winter and summer. Physical parameters of cave atmosphere explained the highest variance in structure of microbial community in the winter and in the summer. The airborne microbial community is composed of different microbial groups with generally low abundances. At sites with elevated organic input, occasional high concentrations of bacteria and fungi can be expected of up to 1,000 colony-forming units/m3 per individual group. The most abundant group of airborne amoebozoans were the mycetozoans. Along with movements of air masses, airborne algae also travel deep underground. In a cave passage with elevated radon concentration (up to 60 kBq/m3) airborne biota were less abundant; however, the concentration of DNA in the air was comparable to that in other parts of the cave. Due to seasonal natural air inflow, high concentrations of biological and inanimate particles are introduced underground. Sedimentation of airborne allochthonous material might represent an important and continuous source of organic material for cave fauna. © 2012 Springer Science+Business Media, LLC.

Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital | Emery P.,University of Leeds | Emery P.,Leeds Teaching Hospitals NHS Trust | And 9 more authors.
The Lancet | Year: 2014

Background Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy. Methods This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7 · 5 mg/week, increased by 2 · 5 mg every 1-2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28] (<3 · 2 at weeks 22 and 26) were randomised to adalimumabcontinuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with, number NCT00420927. Findings The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2-28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. Interpretation Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate.

Patel C.B.,Duke University | Zuckermann A.,Medical University of Vienna
Journal of Heart and Lung Transplantation | Year: 2014

Mechanical circulatory support has seen numerous advances in the recent years, with important observations made to guide patient selection for the therapy, indications for use, and management of devices after implantation. There is rapid growth in the use of left ventricular assist device therapy (LVAD) for advanced heart failure, with a movement to pursue device intervention earlier in the disease spectrum before comorbidities escalate. With this increase in LVAD use have come new challenges, including unanticipated adverse events and high readmission rates. Simultaneously, complications encountered during LVAD support and an increased number of patients supported with a goal for transplant have had an important effect on the allocation of cardiac allografts. Still, the field continues to evolve and address these challenges in systematic fashion to provide novel solutions and meet the needs of a growing population with advanced heart failure. This has led to an extensive body of literature, ranging from case reports to multicenter clinical trials, which will enhance the future of LVAD technology and patient outcomes. This review summarizes important publications in mechanical circulatory support during the past 24 months. © 2014 International Society for Heart and Lung Transplantation.

Zeuzem S.,Goethe University Frankfurt | Dusheiko G.M.,University College London | Salupere R.,University of Tartu | Mangia A.,Casa Sollievo Della Sofferenza Hospital | And 12 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection. METHODS: We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval [CI], 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus. CONCLUSIONS: Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. Copyright © 2014 Massachusetts Medical Society.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.23M | Year: 2012

Novel transplant regimens are currently being developed to improve beneficial GvL effects and reduce GvHD and infections via several new forms of cellular therapies. This newly emerging supra-disciplinary field of cellular therapy and regenerative medicine is also being used to improve outcomes in autoimmune disease (such as Rheumatoid Arthritis) and cancers. The goal of this research programme is to gain insight into the mechanisms of action of GvL and GvHD in order to improve current therapies and develop and test novel ones via clinical trials and/or animal model experiments. The research is therefore necessarily multidisciplinary including clinical medicine, immunology, genomics, proteomics, molecular biology and pathology. In order to implement cellular therapies across Europe the current EU Directive 2001/83/EC applies. These regulations stipulate that the cellular therapies which are advanced therapeutic medical products (ATMP) must be produced under current Good Manufacturing Practice (cGMP). Not only is there a lack of understanding of GvL vs. GvHD effects but there is also a lack of training in cGMP for both clinical and non-clinical scientists. We aim to re-address these basic current needs, as well as those of industry, which include lack of access to clinical tissue for validation of bio-markers prior to commercialisation.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.4.5-2 | Award Amount: 15.74M | Year: 2010

Chronic kidney disease (CKD) affects up to 10% of the population. Besides eventual progression towards end stage renal disease CKD impacts the patients quality of life by causing serious comorbidities including cardiovascular complications and bone metabolism disorders. On the everyday clinical level early stage diagnosis and tailored treatment of CKD are still inadequate. In addition, CKD seems not to have reached its appropriate emplacement in an epidemiological and healthcare perspective yet, and the pathophysiology of the disease on a molecular and cellular level is not well enough understood. Our sysKID consortium was installed for precisely addressing these issues: To unravel the molecular and cellular mechanisms of chronic kidney disease development, combine this information with clinical risk factors, and on this basis delineate chronic kidney disease biomarkers. These markers will allow us to perform preclinical studies of novel therapy approaches for halting disease progression, and will provide us with the materials for development and clinical evaluation of tools for early stage diagnosis as well as prognosis and treatment monitoring. sysKID assures a successful implementation of these goals by a truly international consortium of 27 leading research groups. We combine clinical know how, provide access to a huge chronic kidney disease sample and clinical data pool, and build a Systems Biology framework for chronic kidney disease by integrating molecular and cellular biology, computational biology, statistics and epidemiology. Our expert group is further complemented by a high level advisory board covering science, product development, and the patients perspective. sysKID implementation is structured for completing pre-clinical Proof of Concept studies of novel chronic kidney disease therapy regimes, and further for completing clinical evaluation of an epidemiological screening tool as well as of early stage chronic kidney disease diagnostic kits.

Agency: Cordis | Branch: H2020 | Program: COFUND-EJP | Phase: NFRP-07-2015 | Award Amount: 29.25M | Year: 2015

The proposed European Concerted Programme on Radiation Protection Research (acronym: CONCERT) aims to contribute to the sustainable integration of European and national research programmes in radiation protection. It will do so by focusing resources and efforts in five key directions: Bring together the elements of the European scientific communities in the fields of radiation effects and risks, radioecology, nuclear emergency preparedness, dosimetry and medical radiation protection, whose joint expertise is essential to continue the development of radiation protection knowledge in a multidisciplinary mode to reduce further the uncertainties in radiation protection. Strengthen integrative activities between the various areas of expertise, in particular biology, biophysics, epidemiology, dosimetry and modelling as well as fostering the use of existing infrastructures and education and training activities in radiation protection. Stimulate and foster scientific excellence, by setting up and co-funding advanced research programmes with the potential to enhance current knowledge and the scientific evidence base for radiation protection. Exchange and communicate with all stakeholders, including the professional organizations concerned with radiation protection, the regulatory organizations across Europe, the public and media where necessary, and the international community of scientific, technical, legal and other professional experts in radiation protection. Foster the harmonious application of available scientific basis for radiation protection practices across Europe, by bringing together scientific and technical expertise in radiation protection issues, standard setting know how, particularly with respect to the implementation of the Euratom Basic Safety Standards (BSS) at the legal, administrative and operational level. To reach its goals, CONCERT will have seven Work Packages each of which will focus on each of the key directions.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2011.9.7 | Award Amount: 7.86M | Year: 2012

Future advancements in ICT domain are closely linked to the understanding about how multi-level complex systems function. Indeed, multi-level dependencies may amplify cascade failures or make more sudden the collapse of the entire system. Recent large-scale blackouts resulting from cascades in the power-grid coupled to the control communication system witness this point very clearly. A better understanding of multi-level systems is essential for future ICTs and for improving life quality and security in an increasingly interconnected and interdependent world. In this respect, complex networks science is particularly suitable for the many challenges that we face today, from critical infrastructures and communication systems, to techno-social and socio-economic networks.MULTIPLEX proposes a substantial paradigm shift for the development of a mathematical, computational and algorithmic framework for multi-level complex networks. Firstly, this will lead to a significant progress in the understanding and the prediction of complex multi-level systems. Secondly, it will enable a better control, and optimization of their dynamics. By combining mathematical analyses, modelling approaches and the use of massive heterogeneous data sets, we shall address several prominent aspects of multi-level complex networks, i.e. their topology, dynamical organization and evolution.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2011.5.6 | Award Amount: 4.57M | Year: 2011

In his opening address to the ECB Central Banking Conference, Jean-Claude Trichet said that in the face of the crisis, we felt abandoned by conventional tools, and went on to call for the development of complex systems based approaches to augment existing ways of understanding the economy. This project proposes to address this need by creating an integrated set of complex systems-based ICT tools for modeling the economy, of practical use to policy makers, to be used in both simulation and gaming modes.\nThe core element of our project will be a pair of coupled agent-based models of the European economy, one for the financial system and one for the macro-economy. The European model will in turn be coupled to a corresponding American model developed in an independently funded sister project. These models will be carefully calibrated using a comprehensive data set. The models will be constructed around the available data, so that the resulting model can be placed in the existing state of the real economy at any given point in time, and used to simulate that economy going forward. The decision making components of the model will also be calibrated using laboratory experiments with human subjects. The final result will include a sophisticated graphical user interface with open-source software. This model will allow us to do research to better understand the combined European and American economies, freed from the constraint of unrealistic assumptions such as perfect rationality and representative agents.\nThe output of the research will be used to provide new insights for policy makers and evaluate quantitatively policy measures at the European level.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.1-3 | Award Amount: 7.82M | Year: 2014

The eSMART programme of work will demonstrate the effects of a real-time, mobile phone based, remote patient monitoring intervention on key patient outcomes and delivery of care provided to people with cancer during and after chemotherapy. Utilising the remote patient monitoring system, the Advanced Symptom Management System (ASyMS), will reduce the symptom burden experienced by patients receiving chemotherapy, improve their quality of life (QoL) during acute treatment and survivorship, and result in changes in clinical practice and improved delivery of care for patients with cancer. eSMART involves 11 European and one American partner as well as cancer care clinicians from all partner countries. A two-group, multicentre, repeated-measures randomised controlled trial (RCT) will be conducted across 16 sites in Europe, 1108 patients will be recruited. Adult (>18 years) patients diagnosed with breast, colorectal cancer or haematological cancers, commencing first-line chemotherapy and planned to receive at least 4 cycles of chemotherapy will be invited to participate. Work will take place in four consecutive phases. Members of the European Cancer Patient Coalition have an integral role as advisors at every stage of the programme to provide advice and feedback and ensure that work is conducted in line with patients perspectives and needs. eSMART will demonstrate how delivering patient focused, anticipatory care via technology can improve outcomes for people with cancer whilst simultaneously addressing the increasing demands on acute services across Europe by; enhancing patient outcomes and quality-of-life improvement; promoting of advances in cancer care; reducing social and economic barriers in cancer care; accelerating interoperability and collaboration across Europe and enhancing the economic stimulation of the National Health markets.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2013-ITN | Award Amount: 3.59M | Year: 2013

ImResFun shall provide state-of-the-art training in infectious disease research and medical immunology targeting the most common human fungal pathogens, the opportunistic Candida species. The key objectives of ImResFun are: (i) to understand how immune cells and infected organs respond to invasion by Candida spp, (ii) to decipher host-defense mechanisms mediating pathogen elimination, and (iii) to identify genetic networks driving the dynamics of host-pathogen interplay. ImResFun will exploit cutting-edge technologies to unravel the basic mechanisms of fungal pathogenesis and host immunity, and to improve diagnosis and identify novel biomarkers of infection. Importantly, ImResFun will translate research into clinical practice and identify potential targets for antifungal drug discovery. ImResFun has seven WPs. In addition to coordination (WP7), research will cover molecular mechanisms of host-pathogen interactions using dual-system infection biology in vitro and in vivo (WP1), clinical patient setting and age-related infections (WP2), chemical biology and antifungal drug development (WP3), and bioinformatics and genome-wide data analysis (WP4). A compulsory and tailor-made practical course (WP5) and complementary skills (WP6) program will boost hypothesis-driven projects. Meaningful exposure to the private sector is ensured by extensive secondments of all ESRs/ERs. The resulting reciprocal technology transfer will be beneficial for both SMEs and ESR/ER hosts and sustain collaborations among partners. ImResFun will use personalized career development plans for each ESR/ER to train entrepreneurial scientists capable of translating frontier research into clinical practice, biotechnology and drug discovery. Taken together, ImResFun offers a best-practice example for interdisciplinary, intersectorial and supradisciplinary training in understanding the immunology of microbial infectious diseases, since most approaches are amenable to other microbial pathogens.

Agency: Cordis | Branch: FP7 | Program: CSA | Phase: ICT-2011.4.4 | Award Amount: 1.59M | Year: 2012

VISCERAL is a support action that will organize two competitions on information extraction and retrieval involving medical image data and associated text that will benchmark the state of the art and define the next big challenges in large scale data processing in medical image analysis.The increasing amounts of medical imaging data acquired in clinical practice hold a tremendous body of diagnostically relevant information. Only a small portion of these data are accessible during clinical routine or research due to the complexity, richness, high dimensionality and size of the data.There is consensus in the community that leaps in this regard are hampered by the lack of large bodies of data shared across research groups and an associated definition of joint challenges on which development should focus. VISCERAL will provide the means to jump-start this process with two competitions (1) providing access to unprecedented amounts of real world imaging data annotated through experts and (2) using a community effort to generate a large corpus of automatically generated standard annotations. The goal of the project is to formulate relevant and challenging tasks, to provide the necessary data for research and evaluation, and to conduct competitions for identifying successful computational strategies and highlighting directions of future research.To this end, VISCERAL will conduct two competitions. The first competition will focus on automatic identification, localization and segmentation of anatomical structures in medical imaging data, the second competition will comprise retrieval tasks that aim at identifying similar cases relevant for diagnosis. In addition to the direct evaluation, the project will result in two data corpora - one gold corpus of expert manual annotations, and a silver corpus that will be computed from the competition entries. Both data sets will be made available to challenge participants and, afterwards, to the scientific community.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-15-2015 | Award Amount: 6.83M | Year: 2016

CLINICAL PROBLEM AND UNMET NEED There are 11,827 patients with severe structural airway disease in Europe. Even with the current standard of care, when hospitalised this group of patients has a 22% risk of dying. Patients are currently subjected to repeated surgical interventions (stent insertion) which have a high failure rate. Other therapeutic strategies under development include synthetic tracheal scaffolds seeded with patients own stem cells. Preliminary data show that these scaffolds are poorly integrated and are susceptible to infection. TETRA PROJECT Our SME-led project will address the limitations of standard clinical care and competitor products under development and will: - Build on our successful compassionate use experience using autologous stem cell seeded scaffold-tracheal transplants in 48 patients - Follow on from our Phase I 4 patient INSPIRE clinical trial which will improve on the clinical prototype used in compassionate use cases - Conduct a 48 patient Phase II pivotal clinical trial to provide robust, quality data with validated GMP manufacturing processes to support an accelerated route to market for commercial exploitation in this orphan indication - Prepare a dossier for MAA submission BENEFITS Our product, an ATMP, aims to eliminate the need for repeated surgical interventions of high risk and limited efficacy, reduce deaths and improve the quality of life for surviving patients. If treating 20% of the patients with severe structural airway disease, we estimate that in Europe our technology will improve the quality and length of patient lives and result in savings of 517 million per year. We plan to further develop our platform technology to generate other complex tissues/organs such as bowel and liver replacements for clinical applications which will impact the lives of tens of thousands of patient in the EU with bowel and liver diseases.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: ICT-27-2015 | Award Amount: 4.90M | Year: 2016

Silicon photonics is expected to leverage-off many of the advances made in CMOS electronics. International R&D efforts in this field have so far been mainly focused on the silicon-on-insulator (SOI) photonic integrated circuit (PIC) technology platform because it is predestined for datacom, high-performance computing and telecom applications. However, SOI based integrated optical waveguides cannot be used for the VIS/NIR <1.1m wavelength region, which is important for life sciences and health related applications and, thus, offers a huge potential for PIC technology. To this end, a novel CMOS compatible low-loss silicon nitride waveguide based PIC technology platform will be developed in OCTCHIP and directly applied to the a strong business case in the field of optical coherence tomography (OCT) for ophthalmology. OCT is a revolutionizing in-vivo 3D imaging technique for non-invasive optical biopsy addressing medical needs with early diagnosis and reduction of healthcare cost. OCT has proven its value primarily in ophthalmology and cardiology but recently also in a variety of other medical fields. However, wide adoption has not taken place due to size and cost limitations as well as non-existence of miniaturized devices. The PIC technology developed in OCTCHIP will make a new generation of OCT systems possible with step-changes in size and cost beyond state-of-the-art. The monolithic integration of silicon nitride optical waveguides, silicon photodiodes and electronics combined with the hybrid integration of a III-V laser source will enable a compact, low-cost and maintenance free solution. OCTCHIP will contribute to radically transform OCT towards widespread adoption in point-of-care diagnostics for the early diagnosis of retinal pathologies, which are leading causes for blindness. The endeavor is strongly driven by company partners with strong expertise in the fields of silicon foundry process technology, miniaturized laser sources, and OCT system integration.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-18-2015 | Award Amount: 6.31M | Year: 2016

Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of death or long-term disability in infants born at term in the western world, affecting about 1-4 per 1.000 life births and consequently about 5-20.000 infants per year in Europe. Hypothermic treatment became the only established therapy to improve outcome after perinatal hypoxic-ischemic insults. Despite hypothermia and neonatal intensive care, 45-50% of affected children die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective interventions, beside hypothermia, are warranted to further improve their outcome. Allopurinol is a xanthine oxidase inhibitor and reduces the production of oxygen radicals and brain damage in experimental, animal, and early human studies of ischemia and reperfusion. This project aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to near-term infants with HIE in addition to hypothermic treatment. Beyond this primary objective, the project will provide information on the effect of hypothermia on pharmacokinetics of drugs with a similar metabolism as allopurinol in neonates. Furthermore it will give the opportunity to further develop and validate biomarkers for neonatal brain injury using advanced magnetic resonance imaging, biochemistry, and electroencephalogramms, which will then be available for future studies testing neuroprotective interventions. Finally, this trial will extend our knowledge about incidence of and risk factors for perinatal asphyxia and HIE possibly enabling generation of more preventive strategies for the future.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.1.1-5 | Award Amount: 14.64M | Year: 2008

Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimers and Parkinsons, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function. A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2011-1.1.5. | Award Amount: 10.83M | Year: 2012

ECRIN is a distributed ESFRI-roadmap pan-European infrastructure designed to support multinational clinical research, making Europe a single area for clinical studies, taking advantage of its population size to access patients. Servicing multinational trials started during its preparatory phase, and it now applies for an ERIC status by 2011. The ERIC budget will be restricted to core activities required to enable provision of services, and the ECRIN-IA project is designed to expand ECRIN partnerships and impact beyond this core activity. Networking activities will promote pan-European expansion, capacity building, and partnership with other world regions, and address the funding issue (WP2). ECRIN-IA will develop e-services, education material to train professionals and patients associations, and communication with users, patients, citizens and policymakers (WP3). It will support the structuring and connection to ECRIN of disease-, technology-, or product-oriented investigation networks and hubs focusing on specific areas: rare diseases (WP4), medical device (WP5), nutrition (WP6). Transnational access activities will support the cost of multinational extension of clinical trials on rare diseases, medical device and nutrition selected by the ECRIN scientific board (WP7). Joint research activities are designed to improve the efficiency of ECRIN services, through the development of tools for risk-adapted monitoring (WP8), and the upgrade of the VISTA data management tool (WP9). This project will build a consistent organisation for clinical research in Europe, with ECRIN developing generic tools and providing generic services to multinational studies, and supporting the construction of pan-European disease-oriented networks, that will in turn act as ECRIN users and provide the scientific content. Such organisation will improve Europes attractiveness for industry trials, boost its scientific competitiveness, and result in better healthcare for European citizens.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.2.4.5-1 | Award Amount: 15.66M | Year: 2010

Causes explaining the epidemic of IgE-associated (allergic) diseases are unclear. MeDALL (Mechanisms of the Development of Allergy) aims at generating novel knowledge on mechanisms of allergy initiation, in particular in childhood. To understand how a complex network of genetic and environmental factors leads to complex allergic phenotypes, a novel stepwise, large and integrative translational approach is needed. MeDALL includes experts in allergy, epidemiology, genetics, immunology, biology, animal models, biochemistry and systems biology combining strengths of ongoing EU projects. Classical phenotypes (expert-based) and novel phenotypes of allergy (hypothesis-free statistical modelling) are compared. Population-based data are collected from a cross-sectional study (Karelia) and existing birth-cohorts followed using a common protocol. IgE to foods and inhalants are tested using component-resolved diagnosis across Europe in populations. Biomarker profiles (fingerprints) are extensively assessed using epigenetics, targeted proteomics and unbiased transcriptomics in a subsample of the study population. Those associated with allergic phenotypes are validated in large study populations. Relevant fingerprints are combined into network biomarker phenotype handprints using a systems biology approach and validated in a sufficiently powered sample. Animal studies and in vitro human immunology reinforce the validation. This information coupled with classical and novel phenotypes characterize environmental protective and susceptibility factors of allergy and risk groups. Results are fitted into new integrative complex mathematical models to establish suitable biomarkers for early diagnosis, prevention and targets for therapy of allergy-associated diseases such as asthma and atopic dermatitis. Ethics and gender are considered. MeDALL aims at improving health of European citizens, Europe competitiveness and innovative capacity while addressing global health issues.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: NMP-2008-4.0-1 | Award Amount: 6.64M | Year: 2009

NANOFOL proposes to develop a new diagnostic/therapy approach using folate based nanobiodevices (FBN) able to provide a new type of cost efficient treatment for chronic inflammatory diseases such as Atherosclerosis and Rheumatoid Arthritis with low side effects that will constitute a more advantageous solution than current therapies. NANOFOL will achieve all that by fulfilling the following objectives: Design , development and production of nanobiodevices (FBN) targeting directly effector cells Proof of concept in vitro and in vivo of a folate based nanodevice targeting activated macrophages in chronic inflammation not affecting bystander cells Proof of concept in vitro and in vivo of a nanodevice containing a bispecific antibody (against folate receptor and another macrophage marker) targeting activated macrophages in chronic inflammation not affecting bystander cells Proof of concept of FBN delivery therapeutic agents (by small interfering ribonucleic acid molecules (siRNA) or lipophylic molecules) targeting inflammatory signaling pathways In vitro and in vivo testing of cellular toxicity caused by the novel nanobiodevices in cells other than activated macrophages Design of models that will enable to minimize animal experimentation. Development of a strategy to assess potential risks in order to ensure nanobiodevice safe delivery. NANOFOL has adopted a specific risk strategy to attain objectives in a step by step approach allowing improving gradually the concept (specificity, stability, side effects efficacy) from the lower to the higher risky solutions ensuring reduced experimental animal testing and high human safety. The NANOFOL project will combine expertise in nanotechnologies, biology, chemistry, materials science, biotechnology, engineering, risk analysis, medical and pharmaceutical sciences.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-11-2015 | Award Amount: 5.98M | Year: 2016

Bladder cancer is among the most expensive diseases in oncology in terms of treatment costs; each procedure requires days of hospitalisation and recurrence rates are high. Current unmet clinical needs can be addressed by optical methods due to the combination of non-invasive and real-time capture of unprecedented biomedical information. The MIB objective is to provide robust, easy-to-use, cost-effective optical methods with superior sensitivity and specificity to enable a step-change in point-of-care diagnostics of bladder cancer. The concept relies on combining optical methods (optical coherence tomography, multi-spectral opto-acoustic tomography, shifted excitation Raman difference spectroscopy, and multiphoton microscopy) providing structural, biochemical and functional information. The hypothesis is that such combination enables in situ diagnosis of bladder cancer with superior sensitivity and specificity due to unprecedented combined anatomic, biochemical and molecular tissue information. The step-change is that this hybrid concept is provided endoscopically for in vivo clinical use. The project relies on development of new light sources, high-speed imaging systems, unique imaging fibre bundles, and endoscopes, combined and applied clinically. The consortium comprises world-leading academic organisations in a strong partnership with innovative SMEs and clinical end-users. Through commercialization of this novel imaging platform, MIB is expected to reinforce leading market positions in medical devices and healthcare for the SMEs in areas where European industry is already strong. The impact is that improved diagnostic procedures facilitate earlier onset of effective treatment, thus recurrence and follow-up procedures would be reduced by 10%, i.e., reducing costs. Using MIB technology, healthcare cost savings in the order of 360M are expected for the whole EU. Equally important, prognosis and patient quality of life would improve drastically.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: ICT-24-2015 | Award Amount: 4.34M | Year: 2016

The MURAB project has the ambition to revolutionise the way cancer screening and muscle diseases are researched for patients and has the potential to save lives by early detection and treatment. The project intends to create a new paradigm in which, the precision of great medical imaging modalities like MRI and Ultrasound are combined with the precision of robotics in order to target the right place in the body. This will be achieved by identifying a target using Magnetic Resonance Imaging (MRI) and then use a robot with an ultrasound (US) probe to match the images and navigate to the right location. This will be done thanks to a new innovative technique, which will be developed in the project and called Tissue Active Slam (TAS) which will use different techniques and modalities, like elastography, in order to cope with the deformation of the tissues. Such a procedure has the potential to drastically improve the clinical workflow and save lives by ensuring an exact targeting of (small) lesions, which are visible under MRI and not under US. Technologies developed within MURAB also have the potential to improve other clinical procedures. Clinically, two applications will be targeted and validated in the project: breast cancer diagnostics (MUW and ZGT) and muscle disease diagnostics (UMCN). Considering the potential for the market, industrial partners are involved with expertise in the delivery of safe robotics components and applications (KUKA), as well as with great knowledge and ambition in pushing innovation to the medical market (SIEMENS).

The present invention relates to a pharmaceutical composition for stimulating angiogenesis and/or the treatment or prevention of hypovascularity and/or the prevention and/or treatment of an angiogenic disorder/disease, whereby the composition comprises specific compounds which may be obtained from Leontopodium alpinum Cass, (Edelweiss). These compounds relate to lignan compounds as shown in herein disclosed formula I. A preferred compound in this context is leologinIUPAC name [(2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)tetxahydrofuran-3-yl]methyl (2Z)-2-methylbut-2-enoat], and even more particularly 5-methoxy-leoligin (IUPAC name: [(25,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4,5-trimethoxyphenyl)tetrahydrofuran-3-yl]methyl-(2Z)-2-methylbut-2-enoat) and derivatives thereof. Corresponding means and methods in respect of medical uses of these compounds are described. The compounds provided herein may particularly be useful in the treatment of wound healing, in particular traumatic wounds (like, but not limited to surface and skin wounds), non-diabetic retinopathy, vascular obliteration. The compounds derived from Leontopodium alpinum Cass. (Edelweiss) as described herein are also useful in the re-vascularization of tissue after amputation as well during or after transplantation of tissues or organs. These compounds are also useful in the medical intervention of arterio- and veno-microvasculopathy of blood vessels, in particular retinal microvasculopathy, arterio- and veno-microangiopathy that preferably cannot be treated by surgery, in ischemic diseases or ischemic disorders or in the treatment or prevention of necrosis/necrotic events, in particular of ischemic diseases or necrosis/necrotic events that cannot be treated by surgery. These compounds may also be used in the treatment or prevention of stable angina abdominalis, vascular dementia, impotence or penile dysfunction and the like and they may be employed in the reactivation of necrotisising tissue or in the reactivation of hibernating tissue.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-1.2-4 | Award Amount: 9.31M | Year: 2010

Following the pioneering experiences which lasted several decades, particle therapy has become a recognized way of curing cancer. 2 new European dual-ion facilities (Heidelberg, Pavia) will soon become operational, followed by several others which are today at different stages of planning and construction. Hadron therapy faces the challenge of improving treatment outcomes with tools able to provide on-line a 4 dimensional feedback of the irradiation to enhance the dose conformation to the cancer volume and improve the treatment of moving organs. ENVISION is set up by 15 leading European research organisations, and 1 leading industrial partner IBA , to respond to these challenges. CERN is project coordinator and the majority of the key European experts in this field are involved, as well as the Hadron Research Facilities (Heidelberg, Pavia) who will immediately benefit from the developments foreseen in this project. A valorisation committee with members of the industrial partners has been established to maximally exploit the results. ENVISION tackles the problems of on-line Dose Monitoring and of performing accurate Quality Assurance tests by developing novel imaging modalities related to dose deposition and allow assessing the treated volume and deriving reliable indicators of the delivered dose. It concentrates on the detection of nuclear reaction products produced by the interaction of the beam with atomic nuclei of the tissue (positron emitting nuclides for ibPET, photons or light charged particles for ibSPAT). The methods are applicable to all therapy relevant ion species. The application of TOF techniques with superior time resolution to beam delivery integrated double head ibPET scanners has the potential for improving ibPET image quality. Furthermore, the real-time observation of the dose delivery process will become feasible for the 1st time, substantially reducing intervention times in case of treatment mistakes or incidents.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.2.2.2-2 | Award Amount: 3.88M | Year: 2012

The increasing number of elderly people will have a major impact on the prevalence of age-related diseases, which will pose major challenges to keep health systems in Europe sustainable. Current knowledge is insufficient to identify the transition of normal brain ageing into Alzheimer`s Disease (AD)-like brain damage. Elucidation of the genes and pathways contributing to the earliest stages of AD pathology and associated neurodegeneration should be instrumental to allow intervention when the condition is still reversible. The aim of the DEVELAGE project is to characterise shared molecular pathways between early developmental processes in the brain and brain ageing. Our concept is based on the hypothesis that disorders of neural development contribute to age-related neurodegeneration, that developmentally essential proteins might have a role in neurodegeneration, and that neurodegeneration-related proteins and genes are important during the development of the brain. The DEVELAGE approach is unique in that it is brain tissue-based, derived from neuropathological diagnosis with detailed molecular analysis of the spectrum of developmental and ageing changes in the very same brain samples used for a comprehensive array of investigations in humans as well as in experimental models at genetic, epigenetic, transcription and protein levels. DEVELAGE contributes to the understanding of biological variation by examining relevant number of cases with different phases of ageing and neurodegeneration as well as developing brains with or without developmental disorders. Pathways examined in humans will be validated in animal models, including a non-human primate, and vice versa. The combination of human samples and animal models susceptible to experimental manipulation will promote the translation of clinically relevant data into experimentally testable predictions and promotes the exploitation of therapeutically relevant targets to reverse or halt disease progresssion.

Agency: Cordis | Branch: FP7 | Program: CP-TP | Phase: KBBE.2012.2.5-01 | Award Amount: 11.91M | Year: 2013

The AQUAVALENS consortium has brought together SMEs, Industries, Universities and Research Institutes with the mission of protecting the health of European Citizens from contaminated drinking water and water used in food processing. We will achieve this by developing sustainable technologies to enable water system managers whether in large or small water systems or within food growers or manufacturers to better control the safety of their water supplies. The work of the project is divided into four main clusters of work packages that sequentially lead to the development of appropriate technologies. These four clusters are: 1. Platform targets, 2. Platform development, 3. Field studies in European drinking water systems, and 4. Improving Public Health through safer water. In cluster 1 we shall generate new knowledge on the molecular genetics of viral, bacterial and parasitic waterborne pathogens. This will enable us to identify gene targets for the identification, and characterisation of these pathogens, that will also enable the determination of their virulence for humans. In cluster 2 we shall use the knowledge gained to develop new technologies that integrate sample preparation and detection into a single platform. These platforms will then be subject to a rigorous process of validation and standardisation. In cluster 3 we will use the validated platforms to undertake a series of field studies in large and small drinking water systems, and in food production. These field studies will generate new knowledge about the risk to public health from waterborne pathogens in Europe and also test the value of the technologies in the field. Finally in cluster 4 we test how these technologies can be used to protect human health, though improving the effectiveness of Water Safety Plans, adaptation to climate change, and control of outbreaks of infectious disease. We will also determine the sustainability and potential economic impacts of these technologies.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 3.66M | Year: 2016

The calcium sensing receptor (CaSR) is a class C Gprotein-coupled receptor that plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary Ca excretion. Abnormal CaSR function is implicated in calciotropic disorders, and in non-calciotropic disorders such as Alzheimers disease (AD), cardiovascular disease (CVD), diabetes (DM), sarcopenia and cancer, which account for >25% of the global disease burden. The CaSR is a unique GPCR whose principal physiological ligand is the Ca2\ ion; it is expressed almost ubiquitously; interacts with multiple G subtypes regulating highly divergent downstream signalling pathways, depending on the cellular context. The CaSR Biomedicine is a fully translational project that utilises the concept of a single molecule, the CaSR, influencing a range of physiological and disease processes, to develop a unique, strong multidisciplinary and intersectoral scientific training programme preparing 14 young scientists to become specialists in GPCR biology and signalling. The objectives of CaSR Biomedicine are: 1. Educate and train Early Stage Researchers to become highly innovative scientists to enhance their career perspective. 2. Elucidate ligand- and tissue-dependent differences in CaSR physiology by examining its functions at cellular level and thus to contribute to the understanding of GPCR signalling in general. 3. Assess how CaSR function is altered in AD, CVD, DM, sarcopenia, and cancer, and to find innovative CaSR-based therapeutic approaches for these major, age-related disorders. 4. Establish long-lasting interdisciplinary and intersectoral cooperation among researchers and between researchers and industry, to strengthen the European Research Area. Therefore the CaSR Biomedicine will investigate the complexity of CaSR signalling and function to identify CaSR-based therapeutic approaches to diseases linked to changes in CaSR expression or function (AD, CVD, DM, sarcopenia, and cancer).

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.1.2-1 | Award Amount: 15.44M | Year: 2008

The overall objective of UNICELLSYS is a quantitative understanding of fundamental characteristics of eukaryotic unicellular organism biology: how cell growth and proliferation are controlled and coordinated by extracellular and intrinsic stimuli. Achieving an understanding of the principles with which bio-molecular systems function requires integrating quantitative experimentation with simulations of dynamic mathematical models. UNICELLSYS bring together a consortium of leading European experimental and computational systems biologists that will study cell growth and proliferation at the levels of cell population, single cell, cellular network, large-scale dynamic systems and functional module. Building computational reconstructions and dynamic models will involve different precise quantitative measurements as well as complementary approaches of mathematical modelling. A major challenge will be the generation of comprehensive dynamic models of the entire control system of cell growth and proliferation, which will require integration of smaller sub-models and reduction of complexity. Implementation of the models will allow observing responses to altered growth conditions zooming in seamlessly from populations consisting of cells of different replicative age and cell cycle stage via genome-wide molecular networks, large dynamic systems to detailed functional modules. Employing computational simulations combined with experimentation will allow discovering new and emerging principles of bio-molecular organisation and analysing the control mechanisms of cell growth and proliferation. The project will deliver new knowledge on fundamental eukaryotic biology as well as tools for quantitative experimentation and modelling. Detailed plans for dissemination and exploitation will ensure that UNICELLSYS will have major impact on the development of Systems Biology in Europe ensuring a competitive advantage of Europe in dynamic quantitative modelling of bio-molecular processes.

Agency: Cordis | Branch: FP7 | Program: CSA-SA | Phase: HEALTH-2007-4.1-7 | Award Amount: 385.37K | Year: 2008

This project aims primarily at analysing and measuring the impact of Directive 2001/20/EC (Clinical Trials Directive, CTD) and related legislation on the industry and academic clinical research with medicinal products but also on their impact on clinical research in the broader sense. This initiative fits with the need to provide evidence for a potential reconsideration of certain aspects of the current legislation and the elaboration of suitable approaches to national implementation of the CTD. The CTD was adopted with the objective of harmonising the EU regulatory environment for medicinal products, of improving the protection of participants, of optimising the use of safety information, and of ensuring the credibility of data through a strengthened responsibility of the sponsors and Member States. 3.5 years after implementation of the CTD it appears that some of these aims have been reached more than others. The aim of harmonisation, however, has clearly not been reached. As this Directives scope is limited to medicinal products it does not harmonise all other areas of clinical research in a consistent way, especially as some EU Member States choose to implement the CTD in new clinical research legislation with wider scope than the Directives. As a result, also other types of clinical research face now different conditions in different EU Member States. Especially the performance of large multi-national clinical trials suffers from this lack of harmonisation. This raises concern on the competitiveness and attractiveness of the EU for clinical research. In an attempt to achieve the same quality standards almost similar procedures for all types of clinical trials with medicinal products are required from registration trials with innovative treatments to trials comparing treatment strategies using marketed drugs and minimally invasive trials. Especially SMEs and academic institutions face major difficulties in fulfilling their sponsor responsibilities. This ICREL project is designed to create objective and reliable data on the impact of the CTD and related legislation on clinical research in Europe by measuring clinical research activities and conditions for clinical trials sponsored by big Pharmaceutical Industry and SMEs as well as non-commercial institutions, and by analysing its direct and indirect consequences on all types of clinical research and stakeholders through validated methods of information compilation and surveys: WP 2: Impact on big Phamaceutical Industry and SME sponsored clinical trials: WP 3: Impact on non-commercially sponsored clinical trials; WP4: Impact on clinical trials other than clinical trials on medicinal products; WP 5: Impact on Competent Authorities, pharmacovigilance, monitoring, clinical trials infrastructure and funding; WP 6: Impact on ethics committees an don participant protection The results of this project will be discussed during a final meeting with all involved stakeholders and broadly disseminated. The participants are institutions involved in various aspects of clinical research at the EU level, able to collect data from experts and organisations all over Europe, to analyse and interpret the results and to disseminate the consolidated conclusions to their communities (industry, academic research, competent authorities, ethics committees) and the public at large e.g. through publications, conferences and web pages.

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2007-2.2-01 | Award Amount: 8.06M | Year: 2008

European clinical research needs an integrated and distributed infrastructure able to provide efficient support to multinational clinical trials, taking advantage of the European population and competencies, unlocking latent expertise and patients scattered across the EU member states. ECRIN (European Clinical Research Infrastructures Network) is designed to bridge the fragmentation of clinical research in Europe through the connection of national networks of clinical research centres and clinical trial units. Participants are currently Austria, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, Switzerland, the United Kingdom, and the EORTC. It will provide integrated, one-stop shop services to investigators and sponsors in multinational studies (patient recruitment and investigation, data management, GMP manufacturing of biotherapy products, quality assurance, monitoring, ethics, regulatory affairs and adverse event reporting). With this objective, the preparation phase will consist of - WP2: selection of a legal status and of the governance structure - WP3: agreement on a financial plan leading to a long-term sustainability during the construction step and the operation phase - WP4: survey on needs in terms of GMP facilities for biopharmaceuticals and biotherapy, and their design. - WP5: education programme for multinational clinical studies - WP6: extension to other EU member states - WP7: capacity building to help national networks fulfil the sponsors tasks - WP8: update and upgrade of the quality assurance system - WP9: internal and external communication - WP10: accreditation of data centres - WP11: support to pilot projects Users will be investigators and sponsors in the academic and SME sector. Participants will be the national coordination of clinical research infrastructures, and national ministries and funding agencies in order to reach an agreement ensuring the long-term sustainability of the infrastructure.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: ICT-29-2016 | Award Amount: 4.00M | Year: 2017

More than 450.000 people are diagnosed with esophageal cancer (EC) each-year worldwide and approximately 400.000 die from the disease. Esophageal cancer is the eighth most commonly diagnosed cancer, but it is the sixth leading cause of cancer-related death, with incidence rates steeply rising. Risk factors, including gastroesophageal reflux disease and Barretts esophagus, may diagnostically implicate more than 300 million people worldwide. Nevertheless, the disease is detected late due to limitations in current diagnostic procedures leading to adverse prognosis and high treatment costs. ESOTRAC will change the landscape of esophageal diagnosis, over existing methods, based on cross-sectional optoacoustic and optical coherence endoscopy. The dual-modality system delivers a set of early-cancer imaging features necessary for improving early diagnosis, saving lives and leading to 3-5 Billion annual savings for the healthcare system. OCT provides micron scale subsurface morphological information based on photon scattering and optoacoustics provides deeper penetration and complementary pathophysiological features based on photon absorption. ESOTRAC develops novel photonic components (light sources, optical/optoacoustic scopes) and innovates novel medical system designs. Then, it performs pilot studies to investigate the functionality of the new endoscope and deliver a novel imaging-feature portfolio offering improved and earlier diagnosis. A central ESOTRAC ambition is that the new endoscope will become the new EC diagnostic standard by enabling quantitative and label-free three-dimensional endoscopy of early cancer with tremendous potential to impact esophageal care. ESOTRAC leverages European investment and know-how and strengthens the prospects of economic growth by leading the market position in endoscopic imaging.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-24-2015 | Award Amount: 14.94M | Year: 2016

Pharmacogenomics is the study of genetic variability affecting an individuals response to a drug. Its use allows personalized medicine and reduction in trial and error prescribing leading to more efficacious, safer and cost-effective drug therapy. The U-PGx consortium will investigate a pre-emptive genotyping approach (that is: multiple pharmacogenomic variants are collected prospectively and embedded into the patients electronic record) of a panel of important pharmacogenomic variants as a new model of personalised medicine. To meet this goal we combine existing pharmacogenomics guidelines and novel health IT solutions. Implementation will be conducted at a large scale in seven existing European health care environments and accounts for the diversity in health system organisations and settings. Feasibility, health outcome and cost-effectiveness will be investigated. We will formulate European strategies for improving clinical implementation of pharmacogenomics based on the findings of this project.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-11-2015 | Award Amount: 5.86M | Year: 2016

Breast cancer represents a leading cause of cancer death in women and a major socio-economic issue. With currently available methods, early diagnosis frequently fails. Moreover, beyond mere detection, there is an ever-increasing need for improved non-invasive characterisation of cancer. Targeted therapies require an in-depth analysis of cancer to select and guide appropriate treatment. Both, PET and MRI can provide molecular and functional information that may be of pivotal importance for tailoring therapy. However, current whole-body PET/MRI systems lack the necessary sensitivity and resolution for this task. HYPMED addresses this by engineering an innovative imaging tool. HYPMED will integrate an innovative fully-digital MRI-transparent PET-detector into a novel multi-channel PET-transparent MRI surface coil. The PET-RF insert will allow unprecedented imaging of breast cancer with high-resolution/ultra-high sensitivity PET, combined with high-level structural and functional MRI, and allow minimal-invasive MR- and PET-guided targeted biopsy. Moreover with such PET-RF inserts, every regular clinical MR-system can, upon demand, be turned into a hybrid system. We will evaluate the impact of this technology on breast cancer diagnosis, prediction, and monitoring/assessment of treatment response by a carefully designed clinical study that employs established and novel PET tracers in 250 patients. Imaging data will be correlated with established and novel molecular biomarkers; results will be compared to those obtained from whole-body PET/MRI and PET/CT. A multidisciplinary consortium of clinical scientists, 3 SMEs and an industry partner will pave the way for commercialization of HYPMED products for advanced clinical decision making in cancer patients. Once HYPMED is successful, we will expand this approach to other applications such as prostate cancer or cardiac hybrid imaging, and thus introduce a paradigm shift in the field of PET/MR hybrid imaging as a whole.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2011.5.2 | Award Amount: 5.17M | Year: 2013

Breast cancer is frequent and life threatening, but curable if detected early. Early detection and comprehensive characterisation of findings require optimized imaging and image understanding to maximise detection of significant disease while preventing overdiagnosis. Personalised predictive modeling of breast cancer allows treatment stratification, preventing unnecessary and unsuccessful treatments. VPH-PRISM addresses these key topics with integrated multidisciplinary, multi-scale ICT modeling of breast tissue microstructure in the context of environmental, genetic, and clinical factors.Key challenges include establishment of combined biomarkers from the automated analysis and spatial correlation of digital pathology and advanced breast imaging. Tissue characterisation includes the peritumoral stroma, a key in tumour progression and therapy response. Comprehensive clinical breast cancer phenotypes are extracted from prospectively collected multidisciplinary data. Interactions of environmental and genetic factors with specific breast tissue patterns are analysed in three large ongoing population-based imaging cohorts. A standard breast model enables efficient, combined statistical modeling of sparsely sampled and heterogeneous, large-scale data across disciplines, scales, structures, time and patients.Using the developed tools and models, and the data collected, we will: improve estimates of tumour spread to aid surgery and assess chemo- and radiotherapeutic response optimise multi-modal imaging methods through biophysical forward modeling of image formation for more efficient phenotyping and imaging biomarkers predict personal risks for cancer progression and select optimal treatment strategiesVPH-PRISM will provide a proof of concept for multidisciplinary model based discovery of environment-tissue interactions, quantitative drug efficacy assessment, surgery planning, and treatment outcome prediction at early and advanced stages of breast cancer.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-3.1-5 | Award Amount: 3.63M | Year: 2009

The APRES project aims at providing information and recommendations on the appropriateness of prescribing antibiotics in primary care. The appropriateness of prescribing antibiotics is the extent to which the pattern of prescribed antibiotics is congruent with the antibiotic resistance pattern of bacteria. More than 90% of antibiotics in Europe is prescribed to non-hospitalized patients, but existing information on the antibiotic resistance pattern is exclusively based on samples from hospitalized patients. Guidelines for prescribing antibiotics to outpatients cannot be based on empirical evidence about antibiotic resistance of bacteria circulating in the community because this evidence is lacking. The APRES project contains 4 work packages. WP1 includes a) a systematic review on the relationship between outpatient consumption of antibiotics and patterns of antibiotic resistance of pathogens circulating in the community; b) the establishment of a database of information sources and databases in nine European countries on outpatient consumption of antibiotics and antibiotic resistance patterns of pathogens circulating in the community. In WP2 the antibiotic resistance pattern of S. aureus and S. pneumoniae will be established in nine European countries, based on samples from healthy persons consulting in primary care practices participating in nationally representative networks. In WP3 we will establish the 5-year pattern of prescribed antibiotics the same practices and its variation between nine European countries. The data will be retrieved from electronic medical records in the same primary care practices. WP4 includes the integrative analyses by linking the antibiotic prescribing data with the antibiotic resistance patterns obtained in the same practices to establish the appropriateness of prescribing antibiotics. On the basis of these results, country specific guidelines will be formulated for appropriate prescribing of antibiotics.

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2008-1.1.2 | Award Amount: 11.23M | Year: 2009

ULICE is a 4-year project set up by 20 leading European research organisations, including 2 leading European industrial partners (Siemens and IBA), to respond to the need for greater access to hadron therapy facilities for particle therapy research. Project coordinator is the Italian Research Infrastructure Facility CNAO (Milan). Both existing European Hadron Research Facilities in Heidelberg and Milan are partner and together with the next operational centre (Philipps-Universitt Marburg; yr4) they will provide 624 hours of beam-time (141 users, 52 projects) to external researchers. Future facilities like MedAustron, Etoile and Archade also participate in ULICE, which will result in a strong integrated network. Full exploitation of all different resources, unrestricted spread of information and the improvement of existing and upcoming facilities are provided by using grid-based data sharing. The project is built around 3 pillars with measurable outputs. These outputs will be exploited by the (future) facilities and (partly by) the industrial partners: 1. JRA - focus on development of instruments and protocols: new gantry design, improvement of four-dimensional particle beam delivery, adaptive treatment planning, mechanisms for patient selection to the whole European Community and database development for specific tumours which can best be treated using carbon ion. 2. Networking - increasing cooperation between facilities and research communities wanting to work with the research infrastructure. Outputs will be (among others): a report on recommendations for strategically optimal locations for future RIs throughout Europe, training to new users 3. Transnational access: 2-step approach, using a combination of pre-defined (within ULICE) clinical trial programmes to allow researchers with patients to visit the facility, and radiobiological and physics experiments to take place.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-1.2-3 | Award Amount: 9.09M | Year: 2008

We aim develop in-vivo imaging biomarker of multidrug transporter function as a generic tool for the prediction, diagnosis, monitoring and prognosis of major CNS diseases, as well as to provide support and guidance for therapeutic interventions. Multidrug transporters actively transport substrates (including multiple CNS drugs) against concentration gradients across the blood-brain barrier (BBB). Overactivity of these efflux transporters results in inadequate access of CNS drugs to their targets and hampers the build up of adequate tissue levels of these drugs in the brain, greatly limiting their therapeutic efficacy. As such, this transporter hypothesis of drug resistance is applicable to a broad range of CNS drugs and patients with a variety of CNS diseases who critically depend on these drugs. Efflux transporters may also influence brain elimination of A, the hallmark of Alzheimers disease (AD). Impaired multidrug transporter function with reduced clearance of A could lead to accumulation within the extracellular space, contributing to the pathogenesis of AD. We will determine the contribution of multidrug transporters to impaired brain uptake of drugs for the prediction of therapeutic responses, or the contribution of impaired transporter function to reduced clearance of toxic substances for the early in-vivo diagnosis of AD. Circumvention of pharmacoresistance, or increasing clearance, may involve inhibitors of multidrug transporters or sophisticated alternative therapies, but demonstration of overexpression or underactivity of transporter function is an essential and necessary first step. An in-vivo imaging biomarker of multidrug transporter function is essential for identifying altered transporter activity in individual patients. If a relation between overexpression and therapy resistance, or underactivity and AD, can be demonstrated, such a biomarker will provide the means for predicting treatment response, or early diagnosis, in individual patients.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.31M | Year: 2012

Chronic liver diseases (CLD) and their end-stages, cirrhosis and hepatocellular carcinoma (HCC), are leading causes of morbidity and mortality worldwide with enormous socio-economic costs. Patients with liver cirrhosis are at high risk of deadly hepatic failure and over 80% of HCC develop on a cirrhotic background. HCC ranks as the 5th most common cancer and with >600,000 deaths per annum it constitutes a major global health problem. The main etiologies of CLD are chronic HCV and HBV infections, alcohol abuse and nonalcoholic steatohepatitis (NASH) as a result of the metabolic syndrome taking epidemic proportions. Liver transplantation is currently the only available therapy for terminal liver failure. It is well recognized that the cytokine TGF-Beta plays a pivotal role in the sequence of events leading to end-stage CLD, but the complexity of the underlying aberrant responses in the cells and the organ that lead to the drastic changes seen in CLD and HCC is poorly understood. A broad spectrum of scientific and technological capacities is needed to accomplish the goal of discovering drugs and treatment modalities for CLD and HCC.As a result, there is a lack in academia and industry alike - of internationally oriented researchers and research leaders, capable of seamless and bi-directional transfer of goal-oriented scientific knowledge and technologies between the basic, translational and clinical research and industrial capacities; a conditio sine qua non for effectively and efficiently combating CLD and HCC and alleviate its medical and socio-economic burdens. Consequently, the ITN formulated the mission to provide a multidisciplinary and intersectorial Research Training Programme for talented young researchers, so as to prepare them for leading roles in CLD research and drug discovery in European industry and academia.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.4.2-3 | Award Amount: 2.92M | Year: 2014

The HEALTH.2013.4.2-3 call identifies a need for new or improved statistical methodology for clinical trials for the efficient assessment of safety and/or efficacy of treatment for small population groups. This project brings together international experts in innovative clinical trial design methodology in these specific areas along with key stakeholders including regulatory authorities, industry, clinicians and patient groups to address this need. Our aim is the development novel methodology for the design and analysis of clinical trials in small populations. We will focus on four specific areas where we believe there are particular challenges: (i) early phase dose-finding studies in small populations, (ii) decision-theoretic methods for clinical trials in small populations, (iii) confirmatory trials in small populations and personalised medicines, (iv) use of evidence synthesis in the planning and interpretation of clinical trials in small populations and rare diseases. We will build on recent research advances, of our own and of others in this area. In the rare disease setting, we will focus on Bayesian and decision-theoretic methods that formally enable comparison of the gain in information with the cost, both in economic and opportunity terms, of clinical experimentation, and assess how information from outside the trial can formally be incorporated in the design and decision-making processes. In the personalised medicine setting, we will develop methods that allow evaluation of efficacy in a number of sub-populations simultaneously in a confirmatory clinical trial without any reduction in scientific or statistical rigour.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.3.1-1 | Award Amount: 3.73M | Year: 2011

This project is concerned with optimising the delivery of primary healthcare to European citizens who are migrants who experience language and cultural barriers in host countries. We focus on the implementation of evidence-based health information (e.g. guidelines to enhance communication in cross-cultural consultations) and interventions (e.g. training initiatives on interculturalism and the use of paid interpreters) designed to address language and cultural barriers in primary care settings. We explore how these are translated (or not) into routine practice in primary care settings. We will investigate and support implementation processes for these using a unique combination of contemporary social theory, the Normalisation Process Theory and a participatory research methodology. Our five study objectives are to determine: What guidelines and/or training initiatives are currently available in our partner countries that have been generated by primary care research in a way that was inclusive of all key stakeholders? How are the guidelines and/or training initiatives translated into practice by primary care staff? What are the processes of implementation, on the ground in routine practice? What is the capacity of primary care settings in different countries (and, therefore, different organisational contexts) to incorporate implementation processes within their current organisational arrangement? Is the implementation work for guidelines and/or training initiatives sustainable - leading to normalised use of these technologies in routine practice? What are the benefits (if any) of using NPT and PLA to investigate and support implementation processes? There will be co-operation between an inter-disciplinary team of experienced researchers, across 6 European health care settings with different organizational contexts and capacities to respond to this implementation work.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.2.4.1-2 | Award Amount: 3.96M | Year: 2012

About 75% of advanced epithelial ovarian cancer (EOC) patients respond to first-line surgery and chemotherapy but most relapse and ultimately acquire platinum resistance which soon leads to death. Relapsed high grade serous ovarian cancer (HGSOC) is the single main cause of EOC-related morbidity and mortality (despite the fact that HGSOC is highly chemosensitive). We hypothesize that the primary tumour includes a small population of resistant cells that are ultimately responsible for relapse and that by targeting this population front-line we may prolong disease-free survival or even achieve cure. OCTIPS will use unique retrospective and novel prospective paired tumour samples collected at the time of diagnosis and relapse to identify and validate molecules and pathways responsible for relapse. This identification will employ cutting edge high throughput multiplatform analyses such as next generation sequencing, mRNA and miRNA expression arrays and SNP array. Known and newly defined molecules or pathways will be evaluated in innovative integrated cancer model systems, utilising cell lines and avian egg and murine xenografts. New therapies to target these molecules and pathways will be developed and validated in these model systems. In order to translate these findings into patient benefit, agents that target the relapsing cell population will be tested for tolerability, efficacy, ability to combine with first line chemotherapy and then in randomised first line trials by the OCTIPS consortium. By translating the clinical observation of treatment failures into innovative cancer models that mimic relapsed ovarian cancer, we will validate improved front-line therapeutic strategies to help prolong patient survival. The impact of this application is that it defines a highly rigorous approach to integrate the bedside to bench to bedside paradigm, leading to novel prognosis-changing strategies for the treatment of ovarian cancer patients.

CytoThreat addresses the need to assess the risks of pharmaceuticals released in the environment, focusing on cytostatic drugs because they are highly hazardous compounds due to their genotoxic properties which may cause unexpected long term effects. Their release in the environment may lead to systemic ecological effects and increased cancer incidence, reduced fertility and malformations in the offspring in humans. The occurrence, distribution and fate of selected widely used cytostatics in different aquatic matrices, their acute and chronic toxicity and impact on the stability of the genetic material in a variety of aquatic organisms representing different trophic levels is addressed to provide data sets necessary for scientifically based risk assessment. Special emphasis is put on the combined effects of environmentally relevant mixtures. A combination of state-of-the art analytical chemistry, in vivo and in vitro systems, and OMICS technologies is applied. In vivo studies with zebrafish models aim at identifying linkages between the genomic profiles, exposure conditions and adverse effects in vertebrates to identify molecular biomarkers for adverse effects of specific groups of cytostatics to be used as diagnostic markers and for predicting synergistic effects of combined exposures. Comparative in vitro genotoxicity and transcriptomic studies with zebrafish and human derived cells will provide additional information for the extrapolation of toxicological data to humans. Comparisons with the hazardous effects of other groups of pharmaceuticals will provide knowledge on the magnitude of the problem. CytoThreat will generate new knowledge on environmental and health risks of cytostatics and provide objective arguments for recommendations and regulations. Partners form 5 member states and 2 associated countries with complementary expertise in analytical chemistry, aquatic and genetic toxicology, and genomics and bioinformatics are involved.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: ENV.2008. | Award Amount: 6.08M | Year: 2009

The rapid worldwide increase in mobile phone use in adolescents and, more recently, children has generated considerable interest in the possible health effects of exposure to radio frequency (RF) fields. The current project aims to assess the potential carcinogenic effects of childhood and adolescent exposure to RF and ELF from mobile telephones on tumours of the central nervous system. The study will include approximately 1,000 cases of malignant and benign brain tumours aged 10 to 24 years and their respective controls from 15 countries (7 of which have funding under this contract). The project will build upon the methodological experience (both in terms of exposure assessment and epidemiological design) collected within the INTERPHONE study. Particular attention will be paid to issues of: potential selection bias related to the very low response rates of population-based controls by selecting hospitalized controls with specific diagnoses, representative of the general population and unrelated to mobile phone use ; and potential recall errors by validating questionnaire responses with the help of network operators and repeat questionnaires. Improved exposure indices for RF will be derived taking into account spatial distribution of energy in the brain at different ages; ELF from the phones will also be considered, as well as other important sources of EMF in the general environment of young people. The proposed age range is the most cost efficient to answer the question (because of latency) of brain cancer risk from exposure in childhood and adolescence. The timing of the project is optimal (2010-2014) because of the increasing prevalence of heavy use among adolescents and, in the last 5-10 years, children, without hands-free kits, particularly in Southern European countries and Israel.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2011.3.5 | Award Amount: 13.40M | Year: 2012

Biophotonics offers low-cost, non-invasive, accurate, rapid alternatives to conventional diagnostic methods and has the potential to address medical needs with early detection and to reduce the cost of healthcare. FAMOS will develop a new generation of light sources with step-changes in performance beyond the state-of-the-art to radically transform biophotonic technologies for point-of-care diagnosis and functional imaging. This will enable optical diagnostics with superior sensi-tivity, specificity, reliability and clinical utility at reduced cost, heralding an imaging renaissance in Europe.FAMOS addresses optical imaging from molecular over (sub)cellular to individual organs, with no gap in the arsenal of diagnostic tools for medical end-users. The world-class multidisciplinary FA-MOS team of 7 leading academic institutions and 10 top SMEs has unique complementary knowledge of optical coherence tomography, adaptive optics, photoacoustic tomography, coherent anti-stokes Raman scattering, multiphoton tomography as well as swept-source, diode-pumped ultrafast and tuneable nanosecond pulse lasers. Combinations of some techniques will offer multi-modal solutions to diagnostic needs that will exploit and enhance the benefits of each modality. FAMOS technologies have wide applicability, but our specific focus is on diagnosis in ophthalmol-ogy and oncology. Partnerships with leading innovative clinical users will enable preclinical evalua-tion.The objectives of FAMOS are:\tDevelop new light sources with a step-change in performance (2-3 times more compact and up to 3-4 times cheaper diode pumped Ti:sapphire, 4-10 times faster swept sources and tuneable nanosecond pulse sources)\tIntegrate these with optical imaging for a step-change in diagnosis (2-5 times better resolution cellular retinal imaging with more than 10 times larger field of view, up to 10 times enhanced penetration single source subcellular morphologic imaging, increased selectivity of intrinsic mo-lecular sensing as well as several frames per second deep tissue functional tomography\tPerform preclinical studies to demonstrate novel or improved ophthalmic and skin cancer diag-nosis establishing novel biomarkers (melanocyte shape, NADPH, melanin concentration, Hb/HbO2 as well as lipid, water and DNA/RNA concentration)\tEnable exceptional commercial opportunities for SMEs\tProvide state-of-the-art academic training

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-1.4-7 | Award Amount: 3.91M | Year: 2009

The success of stem cell therapy is highly dependent on a safe and reliable supply of human stem cells and stem cell-derived differentiated cells, which must be assured by efficient and robust culture methods. Current culture of human embryonic and adult stem cells is not optimised (with regards to e.g. media, growth factors, supporting biomaterials, differentiation techniques) and is far from fulfilling the demands in terms of reproducibility and preciseness. Additionally, current methods do not allow fast screening of culture conditions for their systematic optimisation. These limitations currently slow down the development of stem cell applications and will be addressed and overcome by the Hyperlab project. To reach the overall aim of developing new and improved culture methods, media and protocols for stem cell cultivation and differentiation, Hyperlab will adapt novel microfluidics-based cell cultivation technologies to the specific needs of stem cell culture. The developed culture systems will have two major advantages over existing approaches: on the one hand, they will improve stem cell culture in terms of microenvironment control, reproducibility, robustness and efficiency. On the other hand, these microscale technologies, together with developed transgenic readout systems, will allow medium to high throughput screening of culture conditions, enabling determination of optimal protocols in shorter time. Once established, technologies, protocols and conditions will be evaluated for their upscalability and will be made GMP-compliant to form a solid basis for progress in human stem cell therapy. To implement this innovative strategy, Hyperlab follows an integrated approach, bringing together renowned experts from stem cell biology, microsystem technologies, biomaterial design and relevant regulatory bodies. Hyperlab is thus in a position to provide standardised, reproducible methods and tools to advance therapeutic stem cell research.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2009.4.3 | Award Amount: 10.56M | Year: 2010

In KHRESMOI, we will build a multi-lingual multi-modal search and access system for biomedical information and documents. This will be achieved by:- Effective automated information extraction from biomedical documents, including improvement using crowd sourcing and active learning, and automated estimation of the level of trust and target user expertise- Automated analysis and indexing for medical images in 2D (X-Rays), 3D (MRI, CT), and 4D (fMRI)- Linking information extracted from unstructured or semi-structured biomedical texts and images to structured information in knowledge bases- Support of cross-language search, including multi-lingual queries, and returning machine-translated pertinent excerpts- Adaptive user interfaces to assist in formulating queries and display search results via ergonomic and interactive visualizationsThe research will flow into several open source components, which will be integrated into an innovative open architecture for robust and scalable biomedical information search.The system will be evaluated in use cases by three well-defined user groups:1. Members of the general public want access to reliable and understandable medical information in their own language2. Clinicians and general practitioners need accurate answers rapidly a search on PubMed requires on average 30 minutes, while clinicians typically have 5 minutes available. Furthermore, over 40% of searches fail to provide relevant information3. Radiologists are drowning in images at larger hospitals over 100GB (over 100000 images) are produced per dayRepresentative groups of end users are available for sizable evaluations, accessed through a medical search engine with 11000 queries per day, a professional association of 2700 medical doctors, and two radiology departments with 175 radiologists.KHRESMOI is directed at Objective ICT-2009.4.3: Intelligent Information Management. It will focus on target outcome (a) capturing tractable information.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: SPA.2009.1.1.01 | Award Amount: 7.17M | Year: 2010

Air quality is a crucial environmental factor, e.g. evidenced by the fact that particles in the air are estimated to reduce the lifetime of the average European citizen by 8 months. Assessing and monitoring air quality are thus fundamental to improve Europes welfare. PASODOBLE will develop and demonstrate user-driven downstream information services for the public, regional and local air quality sectors by combining space-based and in-situ data with models in 4 thematic service lines: (1) Health community support for hospitals, pharmacies, doctors and people at risk, (2) public information for regions, cities, tourist industry and sporting event organizers, (3) compliance monitoring support on particulate matter for regional environmental agencies and (4) local forecast model evaluation support for local authorities and city bodies. Continuing on the achievements of the ESA GSE PROMOTE project, PASODOBLE will stimulate the development of quality-assured air quality services towards their application market by increasing the implementation efficiency of demonstrated and operational services in the future (new regions, users or parameter combinations, additional service providers). PASODOBLE objectives are: (1) evolution of existing and development of new sustainable air quality services for Europe on regional and local scales, (2) development and testing of a generic service framework for coordinated input data acquisition and customizable user-friendly access to services, (3) utilization of multiple cycles of delivery, use and assessment versus requirements and market planning in cooperation with users and (4) promotion and harmonisation of best practise tools for air quality communities. PASODOBLE comprises an initial phase of requirement analysis, service design, development and implementation, followed by 2 annual demonstration and evaluation cycles in which the services and the generic framework with regard to user needs and business planning will be assessed.

News Article | February 21, 2017

(Vienna, February 21, 2017) The lung is an important interface between the body and the outside environment: with each breath, a surface of roughly 100 square meters exchanges oxygen for carbon dioxide. More than 10,000 liters of air pass adult lungs every day and with this come numerous viruses, bacteria and pollutants, which need to be prevented from entering the body. To defend the organism from these intruders, the lungs harbor their own arsenal of highly specialized immune cells that are equipped to maintain the balance between host defense and tissue quiescence. However, how this balanced immune homeostasis in lungs emerged after birth, was largely unexplored. Now, for the first time, the group of Sylvia Knapp, Director of Medical Affairs at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor of Infection Biology at the Medical University of Vienna showed with the help of mouse models that the very first breath of a newborn releases crucial signals that shape the lifelong immunological milieu of lungs. The study, published in Cell Reports (DOI:10.1016/j.celrep.2017.01.071), reveals that the mechanical forces of spontaneous ventilation at birth lead to the release of interleukin (IL)-33, a cytokine with a wide-range of effects: So-called "type 2 innate lymphoid cells" (ILC2s) follow the IL-33 signal and migrate into the lung tissue, where they release IL-13, another cytokine. This second signal determines the faith of alveolar macrophages by inducing the anti-inflammatory M2 phenotype. "ILC2-cells are crucial in defending the lungs against parasites or influenza viruses, but little was known about their role in lung homeostasis", first author Simona Saluzzo, PhD Student at CeMM and the Medical University of Vienna, explains. "Now we understand that right after birth, ILC2 are responsible for the differentiation of alveolar macrophages into specialized cells that keep the immune system in check and ensure that the lungs stay calm and healthy to ensure proper gas exchange." These ILC2-induced effects protect the lungs from excessive inflammation to daily encountered environmental triggers - but there is a catch, senior author Sylvia Knapp emphasizes: "We could show in our study that the described mechanisms are crucial in achieving lung quiescence after the first contact with the outside world. However, these processes at the same time increase the susceptibility to bacterial infections, such as caused by pneumococci. In other words: The mechanism that maintains the lung function of gas exchange at the same time explains why bacterial pneumonia is the primary cause of death by an infectious disease in Western countries." Attached pictures: 1. Fluorescent staining of IL-33 in a newborn mouse lung; 2. Graphical abstract of the study; 3. Senior author Sylvia Knapp and first author Simona Saluzzo The study "First-breath induced type-2 pathways shape the lung immune environment" was published in Cell Reports on February 21, 2017. DOI:10.1016/j.celrep.2017.01.071 The study was supported by the Austrian Science Funds (FWF), the Vienna Science and Technology Fund (WWTF) and grants from the Medical Research Council and the Wellcome Trust. Sylvia Knapp is Director of Medical Affairs at CeMM and Professor of Infection Biology at the Medical University of Vienna. She studied Medicine in Vienna and Berlin, is a board-certified Internist and obtained her PhD at the University of Amsterdam. Sylvia's research focuses on the innate immune response to bacterial infections in general, focusing specifically on the comprehensive repertoire of macrophage functions in health, development and disease. The mission of CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is to achieve maximum scientific innovation in molecular medicine to improve healthcare. At CeMM, an international and creative team of scientists and medical doctors pursues free-minded basic life science research in a large and vibrant hospital environment of outstanding medical tradition and practice. CeMM's research is based on post-genomic technologies and focuses on societally important diseases, such as immune disorders and infections, cancer and metabolic disorders. CeMM operates in a unique mode of super-cooperation, connecting biology with medicine, experiments with computation, discovery with translation, and science with society and the arts. The goal of CeMM is to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future. CeMM trains a modern blend of biomedical scientists and is located at the campus of the General Hospital and the Medical University of Vienna. http://www. The Medical University of Vienna is one of the most traditional medical education establishments with nearly 7,500 students and approximately 5,500 staff members, and one of the most important top-level biomedical research institutions in Europe. Its international outlook is one of its most important pillars and the research focus is centered on immunology, cancer research, imaging, brain research and cardiovascular diseases. https:/ For further information please contact Mag. Wolfgang Däuble Media Relations Manager CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 http://www.

News Article | December 1, 2016

(Vienna, the 01.12.2016) It promises to be a simple and elegant strategy to heal diabetes type 1: Replacing the destroyed beta-cells in the bodies of patients with newly-produced insulin-secreting cells. For years, researchers around the globe tried various approaches with stem- or adult cells in order to induce this transformation. Their effort lead to a fundamental understanding of the molecular mechanisms involved in the development of beta cells - however, a compound capable of doing the trick was missing. Then a team coordinated by Stefan Kubicek, Group Leader at CeMM, eventually got a lead: In their latest study, published in Cell (DOI: 10.1016/j.cell.2016.11.010), they showed that artemisinins hit the bulls eye. With a specially designed, fully automated assay, they tested the effects of a representative library of approved drugs on cultured alpha cells and found the malaria drug to do the required job. "With our study, we could show that artemisinins change the epigenetic program of glucagon-producing alpha cells and induce profound alterations of their biochemical function", Stefan Kubicek explains. Alpha- and beta cells form together with at least three other highly specialized cell types the so-called islets of Langerhans in the pancreas, the body's control centers for the regulation of blood sugar. Insulin, the hormone produced by beta cells, signals to reduce blood glucose, while glucagon from alpha cells has the opposite effect. But those cells are flexible: Previous studies showed that alpha cells can replenish insulin producing cells following extreme beta cell loss. The epigenetic master regulator Arx was identified as the key molecular player in the transformation process. "Arx regulates many genes that are crucial for the functionality of an alpha cell," says Stefan Kubicek. "Preceding work of our collaborator, Patrick Collombat's team showed that a genetic knock out of Arx leads to a transformation of alpha cells into beta cells." This effect, however, was only observed in live model organisms - it was completely unknown if additional factors from the surrounding cells or even distant organs play a role. To exclude those factors, Kubicek's team together with the group of Jacob HecksherSorensen at Novo Nordisk designed special alpha and beta cell lines to analyze them isolated from their environment. They proved that loss of Arx is sufficient to confer alpha cell identity and does not depend on the body's influence. With those cell lines, the researchers at CeMM where now able to test their compound library and found artemisinins to have the same effect as an Arx loss. In close collaboration with research groups at CeMM lead by Christoph Bock and Giulio Superti-Furga as well as the group of Tibor Harkany at the Medical University of Vienna they managed to elucidate the molecular mode of action by which artemisinins reshape alpha cells: The compound binds to a protein called gephyrin, that activates GABA receptors, central switches of the cellular signaling. Subsequently, the change of countless biochemical reactions lead to the production of insulin. Another study by Patrick Collombat, published in the same issue of Cell, shows that in mouse models injections of GABA also lead to the transformation of alpha into beta cells, suggesting that both substances target the same mechanism. In addition to the cell line experiments, the effect of the malaria drug was also shown in model organisms: Stefan Kubicek´s team and their collaborators (Martin Distel, CCRI Wien; Dirk Meyer, Leopold-Franzens-Universität Innsbruck; Patrick Collombat, INSERM Nice; Physiogenex, Labege) observed an increased beta cell mass and improved blood sugar homeostasis in diabetic zebrafish, mice and rats upon artemisinin delivery. As the molecular targets for artemisinins in fish, rodents and humans are very similar, chances are high that the effect on alpha cells will also occur in humans. "Obviously, the long term effect of artemisinins needs to be tested," says Stefan Kubicek. "Especially the regenerative capacity of human alpha cells is yet unknown. Furthermore, the new beta cells must be protected from the immune system. But we are confident that the discovery of artemisinins and their mode of action can form the foundation for a completely new therapy of type 1 diabetes." The Study "Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity" is published in Cell on 1st of December 2016; DOI:10.1016/j.cell.2016.11.010. Funding: This work was partially funded by the Juvenile Diabetes Research Foundation (JDRF), the European Research Council (ERC), the Medical University of Vienna, the European Molecular Biology Organization (EMBO), the NovoNordisk Foundation, the European Commission FP7 Marie Sk?odowska-Curie Actions, the Austrian Science Fund (FWF), the Austrian Academy of Sciences (ÖAW); the INSERM AVENIR program; the INSERM, the FMR, the ANR/BMBF, LABEX SIGNALIFE, the Max-Planck-Society, Club Isatis, Mr. and Mrs. Dorato, Mr. and Mrs. Peter de Marffy-Mantuano, the Fondation Générale de Santé and the Foundation Schlumberger pour l'Education et la Recherche. Stefan Kubicek studied organic chemistry in Vienna and Zürich. He received his Ph.D. in Thomas Jenuwein's group at the Institute for Molecular Pathology (IMP) in Vienna followed by postdoctoral work with Stuart Schreiber at the Broad Institute of Harvard and MIT in the U.S. He joined CeMM in 2010. He is the Head of the Chemical Screening and Platform Austria for Chemical Biology (PLACEBO) and the Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives. The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. http://www. For further information please contact Mag. Wolfgang Däuble Media Relations Manager CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 http://www.

News Article | December 21, 2016

Diet-related diseases like non-alcoholic fatty liver disease (NAFLD) are known to have a major inflammatory component. However, the molecular pathways linking diet-induced changes with inflammation remained elusive. In a new study, scientists at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna identified crucial inflammatory processes in NAFLD. Moreover, the study published in Hepatology shows that malondialdehyde (MDA), a biomarker for oxidative stress, plays a key role in the development of NAFLD and can be neutralized by specific natural antibodies - a novel approach towards a potential therapy for the prevalent disease. The combination of a nutrient rich, western diet and a lack of exercise is a lifestyle which can lead to serious health issues: Worldwide, the incidences of obesity, hypertension or insulin resistance are alarmingly high. As a consequence, risk of developing inflammation-associated diseases like type 2 diabetes, NAFLD and cardiovascular disease increased accordingly. However, the exact pathways that link the eating habits with the ensuing inflammation were so far not well understood. The team of Christoph Binder, Professor of Atherosclerosis Research at the Medical University of Vienna and Principal Investigator at CeMM, in collaboration with Ronit Shiri-Sverdlov at the Maastricht University, Christoph Reinhardt at the University Medical Center of the Johannes Gutenberg University Mainz and the German Center for Cardiovascular Research Mainz was not only able to shed light on the biological processes that lead to the development of chronic inflammation upon a nutrient rich diet in mice. Moreover, the scientists found MDA to be a key player in hepatic inflammation which can be neutralized with natural antibodies. Their results were published in Hepatology (DOI: 10.1002/hep.28970). The highly reactive molecule malondialdehyde, a product from lipid decomposition and biomarker for oxidative stress, accumulates on the surface of dying cells in the liver. Chemically bound to membrane proteins or phospholipids, they form so called MDA epitopes - Binder's research group showed that those MDA epitopes induce cytokine secretion as well as leukocyte recruitment and thereby propagate existing inflammation and render it chronic. "We were able to show in cell culture as well as in model organisms that those MDA epitopes play a major role in diet-induced hepatic inflammation," says Clara Jana-Lui Busch, one of the co-first authors of the study and PhD student at CeMM and the Medical University of Vienna. This was not the only insight of the study: "With intravenous injection of a specific MDA antibody which binds MDA epitopes selectively, we could ameliorate the inflammation in mice" Tim Hendrikx, the other co-first author and PostDoc in the group of Christoph Binder adds. This study shows how the close collaboration of CeMM and the Medical University of Vienna fosters the development of a future precision medicine, says senior author Christoph Binder. "With cutting edge RNA sequencing methods and bioinformatic analyses of transcriptome data, we discovered key mechanisms in some of the most prevalent diseases and we confirmed those findings in mice models." Binder explains, and adds: "Above that, the administration of specific antibodies for MDA epitopes provide a promising new approach for the development of therapeutic strategies." The study "Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice" was published in Hepatology online in advance on December 16 2016. DOI: 10.1002/hep.28970 The study was funded by The Austrian Science Fund (FWF, SFB Lipotox F30), Boehringer Ingelheim (PhD Fellowship), Austrian Academy of Sciences (Doc Fellowship), EMBO (Short Term Fellowships), The Netherlands Organisation for Scientific Research (NWO), German Center for Cardiovascular Research (DZHK), German Federal Ministry of Education and Research, and the German Research Foundation (DFG). Christoph Binder obtained his MD degree at the University of Vienna in 1997 and received his Ph.D. in Molecular Pathology at the University of California San Diego (UCSD) in 2002. Following a postdoctoral training period at UCSD, he joined the Institute for Laboratory Medicine of the Medical University of Vienna and became Principal Investigator at CeMM in 2006. In 2009 he was appointed Professor of Atherosclerosis Research at the Medical University of Vienna. Christoph Binder is dually affiliated with CeMM and the Medical University of Vienna. http://cemm. The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. http://www. The Medical University of Vienna is one of the most traditional medical education establishments with nearly 8,000 students and approximately 5,500 staff members, and one of the most important top-level biomedical research institutions in Europe. Its international outlook is one of its most important pillars and the research focus is centered on immunology, cancer research, imaging, brain research and cardiovascular diseases. https:/ For further information please contact CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 http://www.

AOP Orphan Pharmaceuticals AG (AOP Orphan) and PharmaEssentia Corporation (Taipei Exchange: 6446) announced results from the PROUD-PV study, a pivotal phase III clinical study in Polycythemia Vera (PV) presented at ASH 2016. The PROUD-PV is a phase III, randomized, open-label, multicenter, controlled, parallel arm study assessing the efficacy and safety of ropeginterferon alfa-2b versus HU in patients with Polycythemia Vera. This study is part of the development program to support marketing authorizations of ropeginterferon alfa-2b (AOP2014/P1101) in Europe and in the United States (U.S.). Ropeginterferon alfa-2b, a novel, long-acting, mono-pegylated proline interferon, uniquely administered once every two weeks is expected to be the first interferon approved for PV worldwide, and the only approved first-line treatment for PV in the U.S. In PROUD-PV, a study sponsored and conducted by AOP Orphan, 254 PV patients from 48 centers across Europe were treated either once every two weeks with ropeginterferon alfa-2b or daily with the cytoreductive therapy hydroxyurea (HU). The study included both treatment-naive and HU-pretreated patients with characteristics of an 'early, first-line' PV population. At 12 months, Complete Hematologic Response[1] (CHR) was achieved in a high proportion of patients and non-inferiority was demonstrated (43.1% for ropeginterferon alfa-2b versus 45.6% for HU in the intent-to-treat-population, p=0.0028). The pre-specified primary endpoint, which was a composite of CHR and spleen length normality, was confounded by the fact that the median spleen length was almost normal at baseline and the observed change was not clinically relevant (21.3% for ropeginterferon alfa-2b versus 27.6% for HU in the intent-to-treat-population, p=0.2233). Ropeginterferon alfa-2b showed significantly better tolerability than HU. Overall, 59.6% of the patients in the ropeginterferon alfa-2b arm experienced treatment related adverse events compared to 75.6 % of the patients treated with HU (p<0.05). There was no difference in adverse events of special interest concerning interferons (auto-immune, psychiatric), or concerning PV (cardiovascular disorders). Most importantly, throughout the phase III program (PROUD-PV and CONTINUATION-PV) five related secondary malignancies were observed, all in the HU cohort (two acute leukemias, two basal carcinomas and one melanoma). Professor Heinz Gisslinger from the Medical University of Vienna, presenting the results at ASH said, "We did already know from several smaller studies that interferons can be a valuable treatment option for myeloproliferative diseases, however this is the first and largest prospective controlled trial. This trial confirms the expected efficacy, while the observed safety and tolerability appears superior to previously reported data." Professor Jean-Jacques Kiladjian from the Saint-Louis Hospital & Paris Diderot University in France, added, "The potential to improve progression-free survival holds promise for long-term patient benefit, in line with the unique disease modification capabilities of interferon." Ko-Chung Lin, Ph.D., founder and CEO of PharmaEssentia, added, "The founding cornerstone of PharmaEssentia was to solve the discontinuity of long acting interferon beyond the weekly dosing regimen. We have been able to do this with ropeginterferon alfa-2b. The advantages provided by ropeginterferon alfa-2b as shown by this promising Phase III trial study and in prior studies, along with our state-of-the-art manufacturing facility in Taiwan, collectively bring us closer to making our treatment available to PV patients in the United States. We are proud to discover, develop, manufacture and eventually market ropeginterferon alfa-2b. This is fully in line with our mission to offer efficacious, safe and cost effective therapies for the treatment of myeloproliferative neoplasms such as PV, myelofibrosis, chronic myeloid leukemia, as well as hepatitis and other diseases." "AOP Orphan has continuously invested over many years into development of treatments in the field of MPNs. Our clinical development of ropeginterferon alfa-2b and today's release of the PROUD-PV data mark another milestone in our mission to provide innovative solutions for patients with rare diseases," said Rudolf Widmann, Ph.D. founder and CEO of AOP Orphan. Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon with improved pharmacokinetic properties allowing once every two weeks administration offering improved tolerability and convenience. Ropeginterferon alfa-2b was discovered by PharmaEssentia. Ropeginterferon alfa-2b has Orphan Drug designation in the United States of America and the European Union. PharmaEssentia plans to commercialize ropeginterferon alfa-2b in North and South America, as well as Asia. PharmaEssentia has exclusively licensed the rights to ropeginterferon alfa-2b to AOP Orphan for European, Commonwealth of Independent States (CIS), and Middle Eastern markets for the development and commercialization in the field of Myeloproliferative Neoplasms (MPNs). Polycythemia Vera (PV) is a cancer of the blood-building cells in the bone marrow resulting in a chronic increase of red blood cells, white blood cells and platelets. This condition may result in circulatory disorders such as thrombosis and embolism, as well as malignant transformation to myelofibrosis or leukemia. AOP Orphan is a multinational company with headquarters in Vienna, Austria focusing on clinical research, development and distribution of medicines for rare and complex diseases. The company also provides individualized and customized services to meet and accommodate the needs of physicians and patients across Central Europe, the Middle East & Asia. Currently AOP Orphan is concentrating on orphan and complex diseases in Hematology & Oncology, Cardiology & Pulmonology, and CNS & Gastroenterology. PharmaEssentia Corporation (Taipei Exchange:6446) is a global biopharmaceutical company delivering efficacious, safe and cost-effective therapeutic products for the treatment of human diseases while aiming to bring long lasting value to stakeholders. PharmaEssentia was founded in 2003 by a group of Taiwanese-American executives and high-ranking scientists from leading U.S. biotechnology and pharmaceutical companies in order to develop treatments for myeloproliferative neoplasms, hepatitis and other diseases. The company is committed to the improvement of health and quality of life for patients suffering from these diseases. The Company's world-class cGMP biologics facility in Taichung is certified by the Taiwan Food and Drug Administration (TFDA) and is designed and operated to be compliant with all U.S. FDA and EMA requirements.

Agency: Cordis | Branch: FP7 | Program: CSA | Phase: ICT-2009.8.0 | Award Amount: 1.08M | Year: 2011

Our society is organized around a positive feedback dynamic that produces innovation cascades. In these cascades, new artifacts are inextricably linked with transformations in social organization and the generation of new needs for individual and society. Besides desired effects, these cascades produce disruptive changes in the environment and in society itself, ultimately leading to sustainability crises. The usual, but inadequate, response to these is more innovation, unleashing new cascades, and new crises. The core challenge in improving our responses is to link current, reductionist, models of past causalities with novel approaches to increase the number of dimensions in which phenomena are perceived, so that we may get better at anticipating the unanticipated consequences of innovation cascades. INSITE will pave the way for novel ICT approaches that will do so, since only through ICT can complex dynamics be grasped in sufficient detail to allow us to do the reverse of customary science: anticipate and complexify, rather than reduce and simplify.To further INSITEs main objective to build a community dedicated to meeting the challenge described above, we will recruit people from a variety of fields to join us in working groups to (1) prepare case studies that illuminate the dynamics of innovation cascades involving ICT, from printing to the internet, (2) develop a roadmap indicating the kinds and uses of models to understand and guide these dynamics in the direction of sustainability, (3) devise experiments to elucidate innovation dynamics, in the context of multiplayer online computer games, (4) envision practices and technologies to enable networks of innovators to engage in experiments in participatory policy, and (5) explore the implications in theory and practice of reconceptualizing technology to include its social dimensions, leading to a notion of generalized ICT that includes such diverse things as cities, urban systems and museums.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: INFRADEV-4-2014-2015 | Award Amount: 14.84M | Year: 2015

The social and economic challenges of ageing populations and chronic disease can only be met by translation of biomedical discoveries to new, innovative and cost effective treatments. The ESFRI Biological and Medical Research Infrastructures (BMS RI) underpin every step in this process; effectively joining scientific capabilities and shared services will transform the understanding of biological mechanisms and accelerate its translation into medical care. Biological and medical research that addresses the grand challenges of health and ageing span a broad range of scientific disciplines and user communities. The BMS RIs play a central, facilitating role in this groundbreaking research: inter-disciplinary biomedical and translational research requires resources from multiple research infrastructures such as biobank samples, and resources from multiple research infrastructures such as biobank samples, imaging facilities, molecular screening centres or animal models. Through a user-led approach CORBEL will develop the tools, services and data management required by cutting-edge European research projects: collectively the BMS RIs will establish a sustained foundation of collaborative scientific services for biomedical research in Europe and embed the combined infrastructure capabilities into the scientific workflow of advanced users. Furthermore CORBEL will enable the BMS RIs to support users throughout the execution of a scientific project: from planning and grant applications through to the long-term sustainable management and exploitation of research data. By harmonising user access, unifying data management, creating common ethical and legal services, and offering joint innovation support CORBEL will establish and support a new model for biological and medical research in Europe. The BMS RI joint platform will visibly reduce redundancy and simplify project management and transform the ability of users to deliver advanced, cross-disciplinary research.

FOR MEDICAL AND TRADE MEDIA ONLY Anti-Interleukin-6 Monoclonal Antibody Sirukumab Efficacy and Safety Findings from SIRROUND-H and SIRROUND-T Trials Presented for the First Time at the 2016 ACR/ARHP Annual Meeting Janssen Research & Development, LLC (Janssen) announced today results from two pivotal Phase 3 studies evaluating subcutaneous (SC) sirukumab, a human anti-interleukin (IL)-6 monoclonal antibody in development for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). Data from the Janssen-sponsored head-to-head study, SIRROUND-H, showed patients receiving sirukumab monotherapy demonstrated significantly greater improvement in Disease Activity Score (DAS28), the first of two co-primary endpoints, when compared with Humira® (adalimumab) monotherapy. Investigators also reported results from a second study (SIRROUND-T), which showed that patients refractory to or intolerant to one or more anti-tumor necrosis factor (TNF) treatments receiving sirukumab demonstrated significant improvement in ACR 20 response compared with placebo.[1] Sirukumab is currently being evaluated by health authorities in Europe, the U.S. and Japan as a SC therapy for the treatment of adult patients with moderately to severely active RA. "We are focused on developing a range of therapeutic options to help meet the needs of people living with RA, including individuals who are still searching for an effective option having not experienced success with other advanced therapies," said Newman Yeilding, M.D., Head of Immunology Development, Janssen Research & Development, LLC. "We believe the sirukumab data generated to date show the potential of this IL-6-targeted therapy to benefit adults living with moderately to severely active RA in the future, and we look forward to continuing to work with global health authorities on the applications that have been submitted." SIRROUND-H: Efficacy and Safety of Monotherapy with Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, Compared with Adalimumab Monotherapy in Biologic-Naive Patients with Active Rheumatoid Arthritis[2] The Phase 3 SIRROUND-H trial is a randomised, double-blind, parallel-group study that included 559 biologic-naive patients with moderately to severely active RA who were intolerant to methotrexate (MTX), considered inappropriate for MTX treatment for safety reasons or were inadequate responders to MTX. Patients were randomised evenly to receive sirukumab 50 mg q4w or sirukumab 100 mg q2w or adalimumab 40 mg q2w as monotherapy. In addition to the co-primary endpoints evaluated, a clinically relevant proportion of patients in all three treatment groups attained the major secondary endpoints of DAS28 remission at week 24 (sirukumab 50 mg q4w, 13 percent; sirukumab 100 mg q2w, 20 percent; adalimumab 40mg q2w, 8 percent [P = 0.086 and P < 0.001, respectively]) and ACR20 response at week 24 (sirukumab 50 mg q4w, 54 percent; sirukumab 100 mg q2w, 59 percent; adalimumab 40mg q2w, 57 percent [P > 0.05]). "We saw significant improvements in disease activity among patients receiving both doses of sirukumab compared with those receiving adalimumab, and while sirukumab-treated patients demonstrated clinically relevant ACR50 improvements, the difference in ACR50 response ratesresults did not reach statistical significance," said Peter Taylor, Ph.D., Norman Collisson Professor of Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford and lead SIRROUND-H investigator. "As not all patients are appropriate candidates for TNF blocker therapy or methotrexate, and many are intolerant to methotrexate, the clinical improvements observed with sirukumab in this study provide important insights when evaluating available data for this IL-6 inhibitor in the treatment of moderately to severely active rheumatoid arthritis." The incidence of patients reporting adverse events (AEs) was 57 percent, 64 percent and 55 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab q2w groups, respectively. The incidence of patients reporting serious AEs was 7 percent, 3 percent and 4 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab q2w groups, respectively. The rate of reported infections was 20 percent, 24 percent and 19 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab 40mg q2w groups, respectively, and there were few serious infections reported (sirukumab 50 mg q4w, 3 percent; sirukumab 100 mg q2w, 0 percent; adalimumab, 1 percent). The reported incidence of injection-site reactions was dose-related and greater with sirukumab 100 mg q2w (21 percent) compared with sirukumab 50 mg q4w (11 percent) and adalimumab (8 percent). No injection-site reactions were considered serious, and there were no deaths reported through week 24.[2] SIRROUND-T: Efficacy and Safety of Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, in Patients with Active Rheumatoid Arthritis Despite Anti-TNF and Other Biologic Therapy[1],[3] The Phase 3 SIRROUND-T trial is a randomised, double-blind, placebo-controlled study that included 878 patients refractory to anti-TNF therapy, approximately 40 percent of whom had prior exposure to non-TNF biologic therapies. Patients were randomised evenly to receive sirukumab 50 mg q4w or sirukumab 100 mg q2w or placebo. Patients receiving placebo with less than 20 percent improvement from baseline in both swollen and tender joint counts at weeks 18, as well as those still on placebo at week 24, were re-randomised to receive SC injections of sirukumab 50 mg q4w or 100 mg q2w through week 52. In addition to meeting the primary endpoint (ACR20 at week 16), patients receiving sirukumab also demonstrated statistically significant improvements across secondary endpoints compared with placebo. These included a change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI), percentage of patients achieving ACR50 and percentage of patients achieving DAS28 remission at week 24 (P ≤ 0.001 for all measures). These improvements were seen as early as week four and were maintained with sirukumab therapy through week 52. Additionally, the efficacy of sirukumab was similar in patients who had previously received both anti-TNF therapy as well as other biologic therapy and in patients who had taken only TNF inhibitors. "These Phase 3 results-the first of an IL-6 cytokine inhibitor in RA-showed significant improvements in the signs and symptoms of patients with moderately to severely active RA whose disease remains active despite treatment with anti-TNF therapy, a typically difficult to treat group," said Daniel Aletaha, Consultant Physician, Division of Rheumatology, Medical University of Vienna and lead SIRROUND-T investigator. "Improvements in pain and inflammation were seen within four weeks and were maintained with sirukumab treatment through one year." The incidence of patients reporting AEs at week 24 was 62 percent, 69 percent and 62 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and placebo groups, respectively. Incidence of patients reporting serious AEs was 8 percent, 8 percent and 5 percent in the sirukumab 50 mg q4w, sirukumab100 mg q2w and placebo groups, respectively. Through week 52, the incidences of AEs and serious AEs were comparable between sirukumab 50 mg q4w (80 percent and 14 percent, respectively) and sirukumab 100 mg q2w (81 percent and 13 percent, respectively). No deaths were reported through week 24; there were five deaths reported through week 52 (two in the sirukumab 50 mg q4w group and three in the sirukumab 100 mg q2w group).[1] The Phase 3 clinical program in patients with active RA includes five studies investigating subcutaneously administered sirukumab 50 mg every four weeks and sirukumab 100 mg every two weeks in combination with conventional disease-modifying antirheumatic drugs (DMARDs) or as monotherapy. The comprehensive development program involves more than 3,000 patients encompassing the following five studies: Sirukumab is a human monoclonal IgG1 kappa antibody that targets the cytokine IL-6, a naturally occurring protein that is believed to play a role in autoimmune conditions like RA. It is not approved as a treatment for RA or any other indication anywhere in the world. In December 2011, Janssen and GSK entered into a licensing and co-development agreement with respect to sirukumab. Under the terms, Janssen retains exclusive rights to commercialise sirukumab in Europe, the Middle East, Africa and Asia Pacific, while GSK has commercialisation rights in North, Central and South America. The agreement gives both companies the option to investigate sirukumab for other indications beyond RA. Sirukumab is currently being evaluated by health authorities in Europe, the U.S. and Japan as a SC therapy for the treatment of adult patients with moderately to severely active RA. Rheumatoid arthritis is a chronic, systemic inflammatory condition that is characterised by pain, joint swelling, stiffness, joint destruction and disability. It is estimated that approximately 6.2 million Europeans are affected by the condition, for which there is no cure.[4] At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science. We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at Follow us at This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding new product development including ongoing clinical studies. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; competition, including technological advances, new products and patents attained by competitors; challenges to patents; manufacturing difficulties or delays; product efficacy or safety concerns resulting in product recalls or regulatory action; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 3, 2016, including in Exhibit 99 thereto, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at, or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. Humira® is a registered trademark of AbbVie Inc. 1. Aletaha, D., et al. Efficacy and Safety of Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, in Patients with Active Rheumatoid Arthritis Despite Anti-TNF Therapy: Results from a Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study. Annual Meeting of the American College of Rheumatology/Association for Rheumatology Health Professionals Meeting (ACR/ARHP 2016), Abstract 59233. 2. Taylor, P., et al. Efficacy and Safety of Monotherapy with Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, Compared with Adalimumab Monotherapy in Biologic-Naive Patients with Active Rheumatoid Arthritis: Results of a Global, Randomized, Double-Blind, Parallel-Group, Phase 3 Study. Annual Meeting of the American College of Rheumatology/Association for Rheumatology Health Professionals Meeting (ACR/ARHP 2016), Abstract 57374. 3. Tanaka, Y., et al. Efficacy of Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, Based upon Prior Use of Non-Anti-TNF Biologics in Patients with Active Rheumatoid Arthritis Despite Anti-TNF Therapy: Results from a Global Phase 3 Study, Annual Meeting of the American College of Rheumatology/Association for Rheumatology Health Professionals Meeting (ACR/ARHP 2016), Abstract 59315. 4. World Health Organization. "The Global Burden of Disease: 2004 Update," p. 32. Available at: . Accessed 08 November 2016.

Wiedermann U.,Medical University of Vienna | Davis A.B.,Truman State University | Zielinski C.C.,Medical University of Vienna
Breast Cancer Research and Treatment | Year: 2013

Immunologic interventions in a subset of breast cancer patients represent a well-established therapeutic approach reflecting individualized treatment modalities. Thus, the therapeutic administration of monoclonal antibodies targeting tumor-associated antigens (TAA), such as Her-2/neu, represents a milestone in cancer treatment. However, passive antibody administration suffers from several drawbacks, including frequency and long duration of treatment. These undesirables may be avoidable in an approach based on generating active immune responses against these same targets. Only recently has the significance of tumors in relation to their microenvironments been understood as essential for creating an effective cancer vaccine. In particular, the immune system plays an important role in suppressing or promoting tumor formation and growth. Therefore, activation of appropriate triggers (such as induction of Th1 cells, CD8+ T cells, and suppression of regulatory cells in combination with generation of antibodies with anti-tumor activity) is a desirable goal. Current vaccination approaches have concentrated on therapeutic vaccines using certain TAA. Many cancer antigens, including breast cancer antigens, have been described and also given priority ranking for use as vaccine antigens by the US National Cancer Institute. One of the TAA antigens which has been thoroughly examined in numerous trials is Her-2/neu. This review will discuss delivery systems for this antigen with special focus on T and B cell peptide vaccines. Attention will be given to their advantages and limitations, as well as the use of certain adjuvants to improve anti-cancer responses. © 2013 Springer Science+Business Media New York.

Yanez-Cuna J.O.,Research Institute of Molecular Pathology IMP | Dinh H.Q.,Gregor Mendel Institute of Molecular Plant Biology | Dinh H.Q.,Medical University of Vienna | Kvon E.Z.,Research Institute of Molecular Pathology IMP | And 2 more authors.
Genome Research | Year: 2012

The regulation of gene expression is mediated at the transcriptional level by enhancer regions that are bound by sequence-specific transcription factors (TFs). Recent studies have shown that the in vivo binding sites of single TFs differ between developmental or cellular contexts. How this context-specific binding is encoded in the cis -regulatory DNA sequence has, however, remained unclear. We computationally dissect context-specific TF binding sites in Drosophila, Caenorhabditis elegans, mouse, and human and find distinct combinations of sequence motifs for partner factors, which are predictive and reveal specific motif requirements of individual binding sites. We predict that TF binding in the early Drosophila embryo depends on motifs for the early zygotic TFs Vielfaltig (also known as Zelda) and Tramtrack. We validate experimentally that the activity of Twist-bound enhancers and Twist binding itself depend on Vielfaltig motifs, suggesting that Vielfaltig is more generally important for early transcription. Our finding that the motif content can predict context-specific binding and that the predictions work across different Drosophila species suggests that characteristic motif combinations are shared between sites, revealing context-specific motif codes ( cis-regulatory signatures), which appear to be conserved during evolution. Taken together, this study establishes a novel approach to derive predictive cis-regulatory motif requirements for individual TF binding sites and enhancers. Importantly, the method is generally applicable across different cell types and organisms to elucidate cis-regulatory sequence determinants and the corresponding trans-acting factors from the increasing number of tissue- and cell-type-specific TF binding studies.

Skolarikos A.,Sismanoglio Hospital | Straub M.,TU Munich | Knoll T.,University of Tübingen | Sarica K.,Dr Lutfi KIrdar Research and Teaching Hospital | And 4 more authors.
European Urology | Year: 2015

Context An optimum metabolic evaluation strategy for urinary stone patients has not been clearly defined. Objective To evaluate the optimum strategy for metabolic stone evaluation and management to prevent recurrent urinary stones. Evidence acquisition Several databases were searched to identify studies on the metabolic evaluation and prevention of stone recurrence in urolithiasis patients. Special interest was given to the level of evidence in the existing literature. Evidence synthesis Reliable stone analysis and basic metabolic evaluation are highly recommended in all patients after stone passage (grade A). Every patient should be assigned to a low- or high-risk group for stone formation. It is highly recommended that low-risk stone formers follow general fluid and nutritional intake guidelines, as well as lifestyle-related preventative measures to reduce stone recurrences (grade A). High-risk stone formers should undergo specific metabolic evaluation with 24-h urine collection (grade A). More specifically, there is strong evidence to recommend pharmacological treatment of calcium oxalate stones in patients with specific abnormalities in urine composition (grades A and B). Treatment of calcium phosphate stones using thiazides is only highly recommended when hypercalciuria is present (grade A). In the presence of renal tubular acidosis (RTA), potassium citrate and/or thiazide are highly recommended based on the relative urinary risk factor (grade A or B). Recommendations for therapeutic measures for the remaining stone types are based on low evidence (grade C or B following panel consensus). Diagnostic and therapeutic algorithms are presented for all stone types based on the best level of existing evidence. Conclusion Metabolic stone evaluation is highly recommended to prevent stone recurrences. Patient summary In this report, we looked at how patients with urolithiasis should be evaluated and treated in order to prevent new stone formation. Stone type determination and specific blood and urine analysis are needed to guide patient treatment. © 2014 European Association of Urology. All rights reserved.

MacCarrone M.,Biomedical University of Rome | MacCarrone M.,European Center for Brain Research | Guzman M.,Complutense University of Madrid | MacKie K.,Indiana University | And 3 more authors.
Nature Reviews Neuroscience | Year: 2014

Among the many signalling lipids, endocannabinoids are increasingly recognized for their important roles in neuronal and glial development. Recent experimental evidence suggests that, during neuronal differentiation, endocannabinoid signalling undergoes a fundamental switch from the prenatal determination of cell fate to the homeostatic regulation of synaptic neurotransmission and bioenergetics in the mature nervous system. These studies also offer novel insights into neuropsychiatric disease mechanisms and contribute to the public debate about the benefits and the risks of cannabis use during pregnancy and in adolescence. © 2015 Macmillan Publishers Limited.

Bonderman D.,Medical University of Vienna | Ghio S.,University of Pavia | Felix S.B.,University of Greifswald | Ghofrani H.-A.,Justus Liebig University | And 7 more authors.
Circulation | Year: 2013

BACKGROUND - : Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction. METHODS AND RESULTS - : Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (-6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min·m; 95% confidence interval, 0.2-0.5; P=0.0001) and stroke volume index (5.2 mL·m; 95% confidence interval, 2.0-8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (-46.6 dynes·s·cm; 95% confidence interval, -89.4 to -3.8; P=0.03) and systemic vascular resistance (-239.3 dynes·s·cm; 95% confidence interval, -363.4 to -115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups. CONCLUSIONS - : Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance. © 2013 American Heart Association, Inc.

Reinisch W.,Medical University of Vienna | Staun M.,Copenhagen University | Bhandari S.,Hull and East Yorkshire Hospitals NHS Trust | Munoz M.,University of Malaga
Journal of Crohn's and Colitis | Year: 2013

Iron deficiency anemia (IDA) frequently occurs in patients suffering from inflammatory bowel disease (IBD) and negatively impacts their quality of life. Nevertheless, the condition appears to be both under-diagnosed and undertreated. Regular biochemical screening of patients with IBD for anemia by the gastroenterology community has to be advocated. Oral iron is a low cost treatment however its effectiveness is limited by low bioavailability and poor tolerability. Intravenous (IV) iron rapidly replenishes iron stores and has demonstrated its safe use in a number of studies in various therapeutic areas. A broad spectrum of new IV iron formulations is now becoming available offering improved tolerability and patient convenience by rapidly restoring the depleted iron status of patients with IBD. The following article aims to review the magnitude of the problem of IDA in IBD, suggest screening standards and highlight existing and future therapies. © 2012.

Mechtler T.P.,Medical University of Vienna | Stary S.,Medical University of Vienna | Metz T.F.,Medical University of Vienna | De Jesus V.R.,Centers for Disease Control and Prevention | And 5 more authors.
The Lancet | Year: 2012

Background: The interest in neonatal screening for lysosomal storage disorders has increased substantially because of newly developed enzyme replacement therapies, the need for early diagnosis, and technical advances. We tested for Gaucher's disease, Pompe's disease, Fabry's disease, and Niemann-Pick disease types A and B in an anonymous prospective nationwide screening study that included genetic mutation analysis to assess the practicality and appropriateness of including these disorders in neonatal screening panels. Methods: Specimens from dried blood spots of 34 736 newborn babies were collected consecutively from January, 2010 to July, 2010, as part of the national routine Austrian newborn screening programme. Anonymised samples were analysed for enzyme activities of acid β-glucocerebrosidase, α-galactosidase, α-glucosidase, and acid sphingomyelinase by electrospray ionisation tandem mass spectrometry. Genetic mutation analyses were done in samples with suspected enzyme deficiency. Findings: All 34 736 samples were analysed successfully by the multiplex screening assay. Low enzyme activities were detected in 38 babies. Mutation analysis confirmed lysosomal storage disorders in 15 of them. The most frequent mutations were found for Fabry's disease (1 per 3859 births), followed by Pompe's disease (1 per 8684), and Gaucher's disease (1 per 17 368). The positive predictive values were 32 (95 CI 16-52), 80 (28-99), and 50 (7-93), respectively. Mutational analysis detected predominantly missense mutations associated with a late-onset phenotype. Interpretation: The combined overall proportion of infants carrying a mutation for lysosomal storage disorders was higher than expected. Neonatal screening for lysosomal storage disorders is likely to raise challenges for primary health-care providers. Furthermore, the high frequency of late-onset mutations makes lysosomal storage disorders a broad health problem beyond childhood. Funding: Austrian Ministry of Health, Family, and Women. © 2012 Elsevier Ltd.

Gohring J.,Medical University of Vienna | Fulcher N.,Gregor Mendel Institute of Molecular Plant Biology | Jacak J.,Johannes Kepler University | Jacak J.,Upper Austria University of Applied Sciences | Riha K.,Gregor Mendel Institute of Molecular Plant Biology
Nucleic Acids Research | Year: 2014

Telomeres comprise the protective caps of natural chromosome ends and function in the suppression of DNA damage signaling and cellular senescence. Therefore, techniques used to determine telomere length are important in a number of studies, ranging from those investigating telomeric structure to effects on human disease. Terminal restriction fragment (TRF) analysis has for a long time shown to be one of the most accurate methods for quantification of absolute telomere length and range from a number of species. As this technique centers on standard Southern blotting, telomeric DNA is observed on resulting autoradiograms as a heterogeneous smear. Methods to accurately determine telomere length from telomeric smears have proven problematic, and no reliable technique has been suggested to obtain mean telomere length values. Here, we present TeloTool, a new program allowing thorough statistical analysis of TRF data. Using this new method, a number of methodical biases are removed from previously stated techniques, including assumptions based on probe intensity corrections. This program provides a standardized mean for quick and reliable extraction of quantitative data from TRF autoradiograms; its wide application will allow accurate comparison between datasets generated in different laboratories. © 2013 The Author(s) 2013. Published by Oxford University Press.

Pifl C.,Medical University of Vienna | Kish S.J.,Center for Addiction and Mental Health | Hornykiewicz O.,Medical University of Vienna
Movement Disorders | Year: 2012

The thalamus occupies a pivotal position within the corticobasal ganglia-cortical circuits. In Parkinson's disease (PD), the thalamus exhibits pathological neuronal discharge patterns, foremost increased bursting and oscillatory activity, which are thought to perturb the faithful transfer of basal ganglia impulse flow to the cortex. Analogous abnormal thalamic discharge patterns develop in animals with experimentally reduced thalamic noradrenaline; conversely, added to thalamic neuronal preparations, noradrenaline exhibits marked antioscillatory and antibursting activity. Our study is based on this experimentally established link between noradrenaline and the quality of thalamic neuronal discharges. We analyzed 14 thalamic nuclei from all functionally relevant territories of 9 patients with PD and 8 controls, and measured noradrenaline with high-performance liquid chromatography with electrochemical detection. In PD, noradrenaline was profoundly reduced in all nuclei of the motor (pallidonigral and cerebellar) thalamus (ventroanterior: -86%, P =. 0011; ventrolateral oral: -87%, P = 0010; ventrolateral caudal: -89%, P = 0014): Also, marked noradrenaline losses, ranging from 68% to 91% of controls, were found in other thalamic territories, including associative, limbic and intralaminar regions; the primary sensory regions were only mildly affected. The marked noradrenergic deafferentiation of the thalamus discloses a strategically located noradrenergic component in the overall pathophysiology of PD, suggesting a role in the complex mechanisms involved with the genesis of the motor and non-motor symptoms. Our study thus significantly contributes to the knowledge of the extrastriatal nondopaminergic mechanisms of PD with direct relevance to treatment of this disorder. © 2012 Movement Disorder Society.

De Wit M.P.T.,Medical Center | Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital | Gossec L.,University of Paris Descartes | Van Der Heijde D.M.F.M.,Leiden University
Annals of the Rheumatic Diseases | Year: 2011

To transcribe the treat-to-target (T2T) recommendations into a version that can be easily understood by patients. A core group of physicians and patients involved in the elaboration of the T2T recommendations produced a draft version of the T2T recommendations in lay language. This version was discussed, changed and reworded during a 1-day meeting with nine patients with rheumatoid arthritis (RA) from nine different European countries. Finally, the level of agreement with the translation and with the content of the recommendations was assessed by the patient participants. The project resulted in a patient version of the T2T recommendations. The level of agreement with the translation and the content was high. The group discussion revealed a number of potentialbarriers for the implementation of the recommendations in clinical practice, such as inequalities in arthritis healthcare provision across Europe. An accurate version of the T2T recommendations that can be easily understood by patients is available and can improve the shared decision process in the management of RA.

Kim N.H.,University of California at San Diego | Delcroix M.,University Hospitals of Leuven | Jenkins D.P.,Papworth Hospital | Channick R.,Massachusetts General Hospital | And 7 more authors.
Journal of the American College of Cardiology | Year: 2013

Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France. © 2013 by the American College of Cardiology Foundation. Published by Elsevier Inc.

Graf A.C.,Medical University of Vienna | Graf A.C.,University of Bremen | Posch M.,Medical University of Vienna | Koenig F.,Medical University of Vienna
Biometrical Journal | Year: 2015

If the response to treatment depends on genetic biomarkers, it is important to identify predictive biomarkers that define (sub-)populations where the treatment has a positive benefit risk balance. One approach to determine relevant subpopulations are subgroup analyses where the treatment effect is estimated in biomarker positive and biomarker negative groups. Subgroup analyses are challenging because several types of risks are associated with inference on subgroups. On the one hand, by disregarding a relevant subpopulation a treatment option may be missed due to a dilution of the treatment effect in the full population. Furthermore, even if the diluted treatment effect can be demonstrated in an overall population, it is not ethical to treat patients that do not benefit from the treatment when they can be identified in advance. On the other hand, selecting a spurious subpopulation increases the risk to restrict an efficacious treatment to a too narrow fraction of a potential benefiting population. We propose to quantify these risks with utility functions and investigate nonadaptive study designs that allow for inference on subgroups using multiple testing procedures as well as adaptive designs, where subgroups may be selected in an interim analysis. The characteristics of such adaptive and nonadaptive designs are compared for a range of scenarios. © 2014 The Authors. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Lichtenberger B.M.,Medical University of Vienna | Tan P.K.,Medical University of Vienna | Niederleithner H.,Medical University of Vienna | Ferrara N.,Genentech | And 2 more authors.
Cell | Year: 2010

It is established that tumor cell-derived VEGF acts on endothelial cells to promote angiogenesis and tumor growth. Here, we demonstrate that in K5-SOS-dependent mouse skin tumors, autocrine VEGF is required for tumor cell proliferation in a cell-autonomous and angiogenesis-independent manner. VEGF is upregulated in SOS-expressing tumors, and its deletion in epidermal cells delays tumorigenesis by suppressing angiogenesis and tumor cell proliferation. Epidermis-specific Flt1 deletion also impairs tumorigenesis and proliferation. Surprisingly, complete tumor inhibition occurs in the absence of VEGF in EGFR mutant mice, demonstrating that VEGFR and EGFR synergize in neoplastic cells to promote tumor growth. Mechanistically, K5-SOS upregulates VEGF, Flt1, and Neuropilin-1 in an Erk-dependent manner, thereby activating an autocrine proliferation loop, whereas EGFR prevents tumor cells from apoptosis. Moreover, Flt1 is upregulated in human SCC, and its inhibition in SCC cells impairs proliferation. Thus, in addition to regulating angiogenesis, VEGF has to be considered as a potent growth factor for epidermal tumors. © 2010 Elsevier Inc. All rights reserved.

Pahnke J.,Otto Von Guericke University of Magdeburg | Pahnke J.,German Center for Neurodegenerative Diseases | Langer O.,AIT Austrian Institute of Technology | Langer O.,Medical University of Vienna | Krohn M.,Otto Von Guericke University of Magdeburg
Neurobiology of Disease | Year: 2014

Much has been said about the increasing number of demented patients and the main risk factor 'age'. Frustratingly, we do not know the precise pattern and all modulating factors that provoke the pathologic changes in the brains of affected elderly. We have to diagnose early to be able to stop the progression of diseases that irreversibly destroy brain substance. Familiar AD cases have mislead some researchers for almost 20. years, which has unfortunately narrowed the scientific understanding and has, thus, lead to insufficient funding of independent approaches. Therefore, basic researchers hardly have been able to develop causative treatments and clinicians still do not have access to prognostic and early diagnostic tools.During the recent years it became clear that insufficient Aβ export, physiologically facilitated by the ABC transporter superfamily at the brain's barriers, plays a fundamental role in disease initiation and progression. Furthermore, export mechanisms that are deficient in affected elderly are new targets for activation and, thus, treatment, but ideally also for prevention. In sporadic AD disturbed clearance of β-amyloid from the brain is so far the most important factor for its accumulation in the parenchyma and vessel walls. Here, we review findings about the contribution of ABC transporters and of the perivascular drainage/glymphatic system on β-amyloid clearance. We highlight their potential value for innovative early diagnostics using PET and describe recently described, effective ABC transporter-targeting agents as potential causative treatment for neurodegenerative proteopathies/dementias. © 2014 Elsevier Inc.

Aletaha D.,Medical University of Vienna | Martinez-Avila J.,Medical University of Vienna | Kvien T.K.,Diakonhjemmet Hospital | Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital
Annals of the Rheumatic Diseases | Year: 2012

Background: The simplified disease activity index (SDAI) and the clinical disease activity index (CDAI) are established instruments to measure disease activity in rheumatoid arthritis (RA). To date, no validated response definitions for the SDAI and CDAI are available. Objective: The authors aimed to define minor, moderate and major response criteria for the SDAI. Methods: The authors used data from two clinical trials on infliximab versus methotrexate in early (ASPIRE) or established (ATTRACT) RA, and identified the three SDAI cutpoints based on the best agreement (by κ statistics) with the American College of Rheumatology (ACR)20/50/70 responses. Cutpoints were then tested for different aspects of validity in the trial datasets and in a Norwegian disease modifying antirheumatic drug prescription dataset (NOR-DMARD). Results: Based on agreement with the ACR response, the minor, moderate and major responses were identified as SDAI 50%, 70% and 85% improvement. These cutpoints had good face validity concerning the disease activity states achieved by the different response definitions. Construct validity was shown by a clear association of increasing SDAI response categories with increasing levels of functional improvement, achievement of better functional states and lower annual radiographic progression. Across SDAI 50/70/85, the sensitivities regarding a patient-perceived improvement decreased (73%/39%/22%) and the specificities increased (61%/89%/96%) in a meaningful way. Further, the cutpoints discriminated the different treatment arms in ASPIRE and ATTRACT. The same cutpoints were used for the CDAI, with similar results in the validation analyses. Conclusion: These new response criteria expand the usefulness of the SDAI and CDAI for their use as endpoints in clinical trials beyond the definition of disease activity categories.

Scheinert D.,University of Leipzig | Schulte K.-L.,Ev. Krankenhaus Konigin Elisabeth Herzberge | Zeller T.,Universitaets Herzzentrum Freiburg Bad Krozingen | Lammer J.,Medical University of Vienna | Tepe G.,Rosenheim Hospital
Journal of Endovascular Therapy | Year: 2015

Purpose: To evaluate the safety and efficacy of the novel Passeo-18 Lux paclitaxel-coated balloon compared with the Passeo-18 uncoated balloon in patients with symptomatic de novo or restenotic femoropopliteal lesions. Methods: Sixty patients (34 men; mean age 70.7±10.1 years) in 5 European centers were enrolled in the BIOLUX P-I trial ( identifier NCT01056120) and randomized 1:1 to either the paclitaxel-coated balloon or the uncoated balloon. The primary endpoint was late lumen loss at 6 months. Secondary endpoints were binary restenosis at 6 months, clinically driven target lesion revascularization (TLR), change in ankle-brachial index and Rutherford classification, and major adverse events at 6 and 12 months. Results: At 6 months, patients treated with paclitaxel-coated balloons had a significantly lower late lumen loss (0.51±0.72 vs. 1.04±1.00 mm, p=0.033) and binary restenosis (11.5% vs. 34.6%, p=0.048) than the control group. Correspondingly, clinically driven TLR was lower in the paclitaxel-coated balloon group at 12 months [15.4% vs. 41.7% (p=0.064) for the intention-to-treat population and 16.0% vs. 52.9%, (p=0.020) for the as-treated population]. No death and one minor amputation were observed compared with two deaths and two minor amputations in the control group. No major amputations or thrombosis were reported. Conclusion: The Passeo-18 Lux paclitaxel-coated balloon has been proven to be safe and effective in patients with femoropopliteal lesions, with superior performance outcomes compared with treatment with an uncoated balloon. © The Author(s) 2015.

Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital Vienna | Van Der Heijde D.,Leiden University | MacHold K.P.,Medical University of Vienna | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2014

In light of the recent emergence of new therapeutics for rheumatoid arthritis, such as kinase inhibitors and biosimilars, a new nomenclature for disease-modifying antirheumatic drugs (DMARDs), which are currently often classified as synthetic (or chemical) DMARDs (sDMARDS) and biological DMARDs (bDMARDs), may be needed. We propose to divide the latter into biological original and biosimilar DMARDs (boDMARDs and bsDMARDs, respectively, such as abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab or tocilizumab, but also emerging ones like clazakizumab, ixekizumab, sarilumab, secukinumab or sirukumab) and the former into conventional synthetic and targeted synthetic DMARDs (csDMARDs and tsDMARDs, respectively). tsDMARDs would then constitute only those that were specifically developed to target a particular molecular structure (such as tofacitinib, fostamatinib, baricitinib or apremilast, or agents not focused primarily on rheumatic diseases, such as imatinib or ibrutinib), while csDMARDs would comprise the traditional drugs (such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts and others). The proposed nomenclature may provide means to group and distinguish the different types of DMARDs in clinical studies and review articles.

Delcroix M.,University Hospitals of Leuven | Noordegraaf A.V.,VU University Amsterdam | Fadel E.,University Paris - Sud | Lang I.,Medical University of Vienna | And 2 more authors.
European Respiratory Journal | Year: 2013

In chronic thromboembolic pulmonary hypertension (CTEPH) increased pulmonary vascular resistance is caused by fibrotic organisation of unresolved thromboemboli. CTEPH mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary artery obliteration, although distal arteriopathy can be observed as a consequence of non-occluded area over-perfusion. Accordingly, there is proportionally more wave reflection in CTEPH, impacting on pressure and flow wave morphology. However, the time constant, i.e. resistance x compliance, is not different in CTEPH and PAH, indicating only trivial effects of proximal wave reflection on hydraulic right ventricular load. More discriminative is the analysis of the pressure decay after pulmonary arterial occlusion, which is more rapid in the absence of significant distal arteriopathy. Structure and function of the right ventricle show a similar pattern to right ventricular hypertrophy, namely dilatation and wall thickening, as well as loss of function in CTEPH and PAH. This is probably related to similar loading conditions. Hyperventilation with hypocapnia is characteristic of both PAH and CTEPH. Ventilatory equivalents for carbon dioxide, as a function of arterial carbon dioxide tension, conform to the alveolar ventilation equation in both conditions, indicating a predominant role of increased chemosensitivity. However, a slight increase in the arterial to end-tidal carbon dioxide tension gradient in CTEPH shows a contribution of increased dead space ventilation. Copyright©ERS 2013.

Jerabek H.,AIT Austrian Institute of Technology | Pabst G.,Austrian Academy of Sciences | Rappolt M.,Austrian Academy of Sciences | Stockner T.,AIT Austrian Institute of Technology | Stockner T.,Medical University of Vienna
Journal of the American Chemical Society | Year: 2010

Anesthetic drugs have been in use for over 160 years in surgery, but their mode of action remains largely unresolved. We have studied the effect of (R)-(-)-ketamine on the biophysical properties of lipid model membranes composed of palmitoyloleoylphosphatidylcholine by a combination of X-ray diffraction and all-atom molecular dynamics simulations. In agreement with several previous studies, we do not find significant changes to the membrane thickness and lateral area per lipid up to 8 mol % ketamine content. However, we observed that the insertion of ketamine within the lipid/water interface caused significant changes of lateral pressure and a pressure shift toward the center of the bilayer. The changes are predicted to be large enough to affect the opening probability of ion channels as derived for two protein models. Depending on the protein model, we found inhibition values of IC50 = 2 mol % and 18 mol % ketamine, corresponding to approximately 0.08 and 0.9 -M concentrations in the blood circulation, respectively. This compares remarkably well with clinical applied concentrations. We thus provide evidence for a lateral pressure mediated mode of anesthesia, first proposed more than 10 years ago. © 2010 American Chemical Society.

Bauer M.,Jena University Hospital | Press A.T.,Jena University Hospital | Trauner M.,Medical University of Vienna
Current Opinion in Critical Care | Year: 2013

Purpose of Review: Sepsis elicits profound changes in the concentrations of plasma proteins synthesized by liver parenchymal cells referred to as acute-phase proteins. Mechanisms controlling this orchestrated response include release of cytokines that induce acute-phase proteins, while other 'house-keeping' genes are downregulated. Recent Findings: Although some acute-phase proteins help to control damage, functions of many other acute-phase reactants remain obscure. Changes in acute-phase gene expression are primarily subject to transcriptional regulation and can be comprehensively monitored by array techniques. Emerging evidence from such strategies implies that in addition to a 'common host response' also highly specific pathways are induced in specific disease contexts. Applying a systems biology approach to the integrated response of the hepatocyte to infection would suggest that the reprogramming of metabolic functions occurs in parallel with a severity-dependent disruption of phase I and II biotransformation and canalicular transport, that is, excretory failure. Although traditionally bilirubin serves to monitor excretion, emerging evidence suggests that bile acids indicate liver dysfunction with higher sensitivity and specificity. Summary: Sepsis induces reprogramming of the hepatic transcriptome. This includes induction of adaptive acute-phase proteins but also repression of phase I, II metabolism and transport with important implications for monitoring and pharmacotherapy. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Akin C.,University of Michigan | Valent P.,Medical University of Vienna | Metcalfe D.D.,National Institute of Allergy and Infectious Diseases
Journal of Allergy and Clinical Immunology | Year: 2010

The term mast cell activation syndrome (MCAS) is finding increasing use as a diagnosis for subjects who present with signs and symptoms involving the dermis, gastrointestinal track, and cardiovascular system frequently accompanied by neurologic complaints. Such patients often have undergone multiple extensive medical evaluations by different physicians in varied disciplines without a definitive medical diagnosis until the diagnosis of MCAS is applied. However, MCAS as a distinct clinical entity has not been generally accepted, nor do there exist definitive criteria for diagnosis. Based on current understanding of this disease "syndrome" and on what we do know about mast cell activation and resulting pathology, we will explore and propose criteria for its diagnosis. The proposed criteria will be discussed in the context of other disorders involving mast cells or with similar presentations and as a basis for further scientific study and validation. © 2010 American Academy of Allergy, Asthma & Immunology.

Radonjic-Hoesli S.,University of Bern | Valent P.,Medical University of Vienna | Klion A.D.,National Institute of Allergy and Infectious Diseases | Wechsler M.E.,National Jewish Health | Simon H.-U.,University of Bern
Annual Review of Pharmacology and Toxicology | Year: 2015

Eosinophil-associated diseases often present with life-threatening manifestations and/or chronic organ damage. Currently available therapeutic options are limited to a few drugs that often have to be prescribed on a lifelong basis to keep eosinophil counts under control. In the past 10 years, treatment options and outcomes in patients with clonal eosinophilic and other eosinophilic disorders have improved substantially. Several new targeted therapies have emerged, addressing different aspects of eosinophil expansion and inflammation. In this review, we discuss available and currently tested agents as well as new strategies and drug targets relevant to both primary and secondary eosinophilic diseases, including allergic disorders. ©2015 by Annual Reviews. All rights reserved.

Singh A.S.G.,Medical University of Vienna | Anand A.,M. S. University of Baroda | Leitgeb R.A.,Medical University of Vienna | Javidi B.,University of Connecticut
Optics Express | Year: 2012

A lateral shearing interferometer is used for direct holographic imaging of microorganisms. This is achieved by increasing the shear to be larger than the object size and results in a very simple and inexpensive common-path imaging device that can be easily coupled to the output of an inverted microscope. The shear is created by reflections from the front and back surface of a glass plate. Stability measurements show a standard deviation of the phase measurements of less than 1nm over 8 min. without any vibration compensation. The setup is applied to imaging both microorganisms in a microfluidic channel and red blood cells and reconstructions are presented. © 2012 Optical Society of America.

Agency: Cordis | Branch: FP7 | Program: CSA-CA | Phase: HEALTH-2007-2.4.5-7 | Award Amount: 1.39M | Year: 2008

Hearing loss is one of the most common chronic health conditions in the elderly population with important implications for patient quality of life. The diminished ability to hear and to communicate is frustrating in and of itself, but the strong association of hearing loss with depression and functional decline adds further to the burden on individuals who are hearing impaired. Hearing loss can limit communications skills: not to hear means not to understand what is being said. Hence deafness does not produce compassion but do often produce a sense of irritation. Despite the prevalence and burden of hearing loss, hearing impairment is largely underdiagnosed in older persons and undertreated. The reason for this is that one of the most conspicuous signs of a hearing loss is that it cannot be seen! Actually, this is the reason why deafness does not receive the necessary attention. Too often, the public and still too many health care professionals underestimate the dramatic effects of deafness. Novel strategies should be explored to make screening and early intervention a feasible part of routine care. Project AHEAD III has been specifically designed to: - Provide evidence of the effects of hearing impairment in adults and particularly in the elderly - Analyse costs associated with the implementation of integrated large scale programmes of hearing screening and intervention in the elderly - Provide quality standards and minimum requirements for screening methods and related diagnostic techniques - Develop guidelines and recommendations on how to implement successful screening programmes to be tuned to the local, social, and economical conditions of a country.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2010-ITN | Award Amount: 3.50M | Year: 2011

In the understanding of the initiation and development of several diseases revolutionary changes are currently taking place. Cancer and brain diseases are examples of medical fields where new technologies are finding their way into research and applications, radically altering the way the diseases are being diagnosed and treated. Especially methods that yield information on molecular and cellular mechanisms open up the way for novel effective therapies for disease prevention and disease curing. The aim of this ITN is to conduct training and research in the field of novel bio-analytical methods and tools for cell based diseases, in specific for severe cancers and brain diseases. These methods and tools should allow faster and more reliable diagnosis, but are also of great importance for therapy research leading to novel treatment methods. This ITN combines disciplines such as engineering, biotechnology, medicine, and chip-technology and the consortium covers universities, hospitals and industry. The functionality of the devices is determined by the type of measurements that need to be performed, therefore we will focus on a few specific diseases: our cancer research will be aimed at skin cancer (melanoma) and blood cancer (leukaemia), and the part on brain diseases will focus on schizophrenia. Although we will direct our activities towards these three diseases in particular, we expect that the research (methods, devices, and technology) will also have impact on the understanding of other cancer types and other brain diseases.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2011-ITN | Award Amount: 3.45M | Year: 2012

The greatest challenge for radiation therapy is to reach the highest probability of cure with the least morbidity. In practice, some difficulties remain to identify cancer cells, target them with radiation and minimize collateral damage. Over the last decades, remarkable progress has been made thanks to modern advances in computer and imaging technologies. Currently, the radiotherapy has reached a point where, besides 3D tumour morphology, time variations and biological variability within the tumour can also be taken into account. The SUMMER project is devised to produce unique software using several imaging sources (CT, MRI, PET, MR spectroscopy, fMRI, 4D PET-CT) for biological target volume delineation, based on spatial co-registration of multimodal morphologic and functional images. Furthermore, it will make additional biological information concerning tumour extension and tumour response available to radiotherapy, essential for patient treatment follow-up. Finally, radiation area will be more focused leading to less side-effect for the patient. Radiation oncology is now more dependent on medical imaging than it has ever been - and that dependence is only going to become greater. Therefore, convergence and collaboration of radiation oncology, nuclear medicine, diagnostic imaging and also computer science is the underlying driver to integrate efficiently and cost-effectively all information coming from various imaging technologies into the radiation therapy workflow. The design challenge is to combine the different level and kind of information into one interface, while currently doctors need to mentally do this operation. SUMMER will contribute to renew and strengthen this relationship through cross-disciplinary research, common workshops, and collaboration on training and education.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2013.8.1 | Award Amount: 3.54M | Year: 2013

Current ICT technology provides new capabilities to measure the functional activity of the brain and to compute in real-time stimuli that can be applied to the brain itself in order to train and modify its activity. This new frontier of research is made possible by a dramatic increase in cheap computing power, novel design methodologies for high-performance software, integrated circuits and systems for sensors and actuators, and algorithms and software environments for collaborative interaction of people cooperating on solving a specific problem. This project will explore the consequences of exploiting these novel technologies in a deliberate attempt to improve a higher-order task such as creativity.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 3.85M | Year: 2015

This ETN is embedded into an established international research programme; The European Research Initiative on Anaplastic Lymphoma Kinase (ALK)-related malignancies (ERIA; is an existing and functional network of 13 partners, which will cosset and nurture a cohort of early stage researchers to become confident, competent, independent and well-connected European scientists with excellent career perspectives. ERIA was instigated to coordinate research into ALK-related malignancies to facilitate the development of less-toxic and more efficacious therapies. ALK is increasingly recognised as a prevalent oncogene in a number of human malignancies and therefore poses a prominent clinical problem, which requires coordinated research into its oncogenic mechanisms. ERIA now conducts a collaborative multidisciplinary research programme at the interface of biomedical and bio-mechanistic approaches, which will be an excellent environment to train the next generation of European scientists. The 15 recruited fellows will be incorporated into international academic study groups (all partners of the ERIA network) to perform high calibre research and also will be exposed to environments from other sectors to broaden their experience. Secondments will include technical training within individual laboratories and SMEs (TissueGnostics, Galkem, Cambridge Life Sciences, Sofigen and Varionostics) as well as large Pharma (Roche). Training through research will be complemented with a balanced programme of transferable skills and access to local courses. The training of each fellow will be guided by a personal career development plan and supervised by a PhD committee panel. The primary goal of the network is to train the recruited fellows by participation in an internationally competitive research programme and integrating them into an international network. Thereby providing competence in state-of-the-art research and development at the forefront of translational science.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.53M | Year: 2012

In the research part we will deal with the basic principles of the innate immune defense used to control tumors and viral infections with a focus on NK and NK/T cells, including analysis of NK receptor genomics/epigenetics, gene polymorphisms/disease linkage, differentiation of hitherto unrecognized NK cell subpopulations and novel ligands for NK receptors exposed by tumor and/or virally infected cells. We will investigate the mechanisms installed by tumors and viruses to avoid or subvert immune defenses. This will include the investigation of the role of NK/T cell subpopulations in the defense against tumors and infections by herpes virus family members, some being involved in tumor formation, in the development of inflammatory diseases and/or constituting a frequent complication during tumor therapy. The project will support anti-tumor and anti-viral therapies by developing novel technology for NK cell generation from cord blood stem cells for NK cell infusions in patients, by genetic engineering of NK cells and by using NK receptors and their ligands to develop novel reagents for amplifying anti-tumor and -viral activities of NK/T cells. It will further undertake basic studies on the potential of the newly emerging iPS cell technology for reconstituting immune systems including NK cells in patients with hematologic cancers. All students of this ITN will be trained in state-of-the-art immunotechnology including wider aspects of molecular medicine at the individual partner universities. An exchange of students between the different partners will be organized to ensure that every participant will be trained in several laboratories/universities with different expertise. It will further include network-wide training modules with cutting-edge lectures of internationally recognized research experts in the field, state-of-the-art seminars in the front-line technologies used in this project as well as courses in genome-wide bioinformatics, business and patent rights.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-15-2014 | Award Amount: 6.00M | Year: 2015

Stem Cell therapy in IschEmic Non-treatable Cardiac diseasE (SCIENCE) With more than 17 million deaths worldwide each year, ischemic heart disease (IHD) caused by coronary artery disease is the most common cause of death and a major cause of hospital admissions in industrialised countries. IHD caused over four million deaths in Europe in the year 2012 constituting 47% of all deaths. Today IHD is the main cause of death among women throughout Europe and the main cause of death among men in all but six European countries. Conventional therapies have reduced mortality of IHD significantly, but have left an increasing number of patients with chronic IHD and/or heart failure without further treatment options. An increasing morbidity rate of this nature in an ageing population is a huge burden for society. The overall aim of the SCIENCE project is to implement an effective stem cell-based therapy with allogeneic adipose derived stromal cells to improve myocardial function in patients with ischemic heart disease and heart failure. This goal will be achieved by conducting a multicentre clinical trial in a strong consortium of experienced international scientists and experts as well as significant representatives of the biomedical industry within translational medicine and a close collaboration with relevant authorities. The consortium will ensure feasibility of treatment by simplifying and rationalising cell production and distribution using state-of-the art manufacturing technology that makes cell therapy a realistic option for clinical practise. The consortium expects the SCIENCE project to pave the way for future approval of this treatment by national authorities throughout Europe as the standard form of care for patients with ischemic heart disease and heart failure. This concept will establish a new platform for growth and consolidation of innovative small and medium-size companies within stem cell research and development. Such a platform will ease implementati

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: FETPROACT-01-2016 | Award Amount: 4.94M | Year: 2017

This consortium will pioneer disruptive technology for bio-electronic medicine to provide much needed therapies for cardiorespiratory and functional neurological disease. The technology implements small neural networks known as central pattern generators (CPG) to deliver fit-and-forget bio-electronic implants that respond to physiological feedback in real time, are safer, simpler, non-invasive, and have autonomy exceeding the patient lifespan. Multichannel neurons will be made to compete on analogue chips to obtain flexible motor sequences underpinned by a wide parameter space. By building large scale nonlinear optimization tools and using them to assimilate electrophysiological data, we will develop a method for automatically finding the network parameters that accurately reproduce biological motor sequences and their adaptation to multiple physiological inputs. In this way, we will have resolved the issue of programming analogue CPGs which has long been the obstacle to using neural chips in medicine. An adaptive pacemaker will be constructed, tested, validated and trialled on animal models of atrio-ventricular block and left bundle branch block to demonstrate the benefits of heart rate adaptation, beat-to-beat cardiac resynchronization and respiratory sinus arrhythmia. By providing novel therapy for arrhythmias, heart failure and their comorbidities such as sleep apnoea and hypertension, CResPace will extend patients life and increase quality of life.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: FETOPEN-01-2016-2017 | Award Amount: 3.76M | Year: 2017

The physical laws of diffraction generally limit the spatial resolution of optical systems, being about 200 nm for light in the visible range. Within ChipScope we want to overcome this limit by developing the scientific and technological basis for a completely new approach to optical superresolution, based on semiconductor nano Light Emitting Diode (nanoLED) arrays with individual pixel operation. The core idea of ChipScope is to use spatially resolved illumination instead of spatially resolved detection for achieving microscopy functionality with superresolution. This will be made possible by developing chip-based nanoLED arrays with light emitting diode (LED) dimensions and distances much smaller than the wavelength of visible light (i.e. <50 nm). Thus, ChipScope will develop the highest resolution LED arrays in the world. These new devices will enable novel science in general and superresolution in particular. Making optical superresolution ubiquitously available is expected to lead to foundational breakthroughs in virtually every field of research and technology that makes use of optical microscopes. Within the project, the first chip-sized ChipScope microscopes will be developed, tested, calibrated and compared with state-of-the-art microscopy systems. During the course of the project, a game changing real-time imaging device for scientific investigation of living tissue will be used to study the in-cell mechanisms in Chronic Obstructive Pulmonary Disease (COPD) syndrome as a proof-of-concept of the new science and applications that will follow.

Agency: Cordis | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-IAPP-2008 | Award Amount: 1.48M | Year: 2009

The main objective of this project is to develop a research network that includes both private and public institutions focused on the exchange of expertise in imaging, genomics and bioinformatics to be utilized in monitoring therapies and disease progression in severe allergic asthma (AA): Aeirtec, a research-service SME with Hu-SCID in vivo models of AA that would benefit from academic expertise in high tech imaging and immunology Marinomed, an SME with novel compounds potentially relevant to AA, in need of in vivo models as well as genomics and imaging technologies aimed at validating its compounds CBM, an SME with expertise in genomics as well as IP exploitation and business development, managing a biotech cluster, in need of furthering its imaging expertise as well as its competence in AA models UMG-GOE is a university which provides strong expertise in the imaging field, in need of bioinformatics support as well as specific expertise on AA models MUW is an academic partner with expertise in in vivo models of AA and in the basic immunology underlying the disease that will advance their research objectives with novel therapeutics to study and from expertise in genomics and imaging. The combined expertise and transfer of knowledge between academic and industrial partners will have an impact on the scientific community and on exploitation and commercialization.The main scientific and technological objectives will encompass: 1. Development of novel optical imaging techniques and genomic biomarkers for severe AA 2. Identification of potential biomarkers useful for clinical monitoring of therapeutic efficacy of novel compounds in ththe treatment of severe AA 3. Development of novel high resolution molecular imaging techniques in animal models of AA 4. Bioinformatics support in the acquisition, management, archiving, and analysis of imaging and genomics data

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.2.1-2 | Award Amount: 15.03M | Year: 2010

The aim of EU-GEI is to identify the interactive genetic, clinical and environmental determinants involved in the development, severity and outcome of schizophrenia (EU-GEI, Schiz. Res. 2008; 102: 21-6). In order to identify these interactive determinants, EU-GEI will employ family-based, multidisciplinary research paradigms, which allow for the efficient assessment of gene-environment interactions. In order to go beyond old findings from historical convenience cohorts with crude measures of environmental factors and clinical outcomes, the focus in EU-GEI will be on recruitment of new, family-based clinical samples with state-of-the-art assessments of environmental, clinical and genetic determinants as well as their underlying neural and behavioural mechanisms. New statistical tools will be developed to combine the latest multilevel epidemiological with the latest genome-wide genetic approaches to analysis. Translation of results to clinical practice will be facilitated by additional experimental research and risk assessment bioinformatics approaches. This will result in the identification of modifiable biological and cognitive mechanisms underlying gene-environment interactions and the construction of Risk Assessment Charts and Momentary Assessment Technology tools which can be used for (i) early prediction of transition to psychotic disorder in help-seeking individuals with an at-risk mental state and (ii) early prediction of course and outcome after illness onset. In order to reach these goals, EU-GEI has assembled a multidisciplinary team of top schizophrenia researchers who have the range of skills required to deliver a program of research that meets all the calls requirements and who have access to / will collect a number of unique European samples. The partners in EU-GEI represent the nationally funded schizophrenia / mental health networks of the UK, Netherlands, France, Spain, Turkey and Germany as well as other partners.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.5-2 | Award Amount: 7.86M | Year: 2010

Chronic inflammatory diseases associated with allergy, including asthma and rhinitis, constitute a major and continuously growing public health concern for Europe. However, the causative factors and mechanisms converting a physiological inflammatory reaction to a chronic response triggering allergic disease remain elusive. Viral infections, particularly those caused by human rhinoviruses (RV) are the most frequent triggers of acute asthma exacerbations. RV infections have more recently been associated with asthma initiation; there is evidence suggesting that such infections may also contribute to respiratory allergy persistence. The strategic aims of PreDicta are to evaluate the hypothesis that repeated infections reprogram the immune system towards a persistent inflammatory pattern leading to respiratory allergies by (i) dissecting the molecular and cellular mechanisms involved in the lack of resolution of inflammation in the context of a human disease, (ii) identifying specific infectious agents and underlying altered host-pathogen interactions, and develop relevant prognostic and therapeutic strategies. PreDicta follows three interconnected workflows: models, mechanisms and translational output. Models include a longitudinal cohort in children, mouse models of repeated virus infection, primary epithelial cultures from patients, viral-bacterial interaction models, and models of epithelial-T-cell-dendritic cell interactions. These will be used to look into disease persistence, inflammation patterns, dysbiosis, immune regulation and resolution of inflammation. Translational outputs include prognostic use of subtype-specific antiviral antibodies, DNAZymes for therapeutic use and delivery technologies targeted to the bronchial epithelium. This interdisciplinary Consortium with strong track record, unique resources and strong translational focus, aims to produce new knowledge and technologies that can rapidly and effectively reach clinical care.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-1.4-3 | Award Amount: 4.16M | Year: 2008

The FAST project aims at the development of safe and effective treatment of food allergies. It targets persistent and severe allergy to fish and fruit. Besides persistence and severity, this choice is based on prevalence and the importance of these foods for a healthy diet. Classical allergen-specific immunotherapy (SIT) for treatment of food allergy using subcutaneous injections with food extracts has proven to be effective but too dangerous due to anaphylactic side-effects. FAST will therefore develop a safe alternative by replacing food extracts with hypo-allergenic recombinant major allergens, the active ingredients of SIT. Both severe fish and fruit allergy are caused by a single major allergen, parvalbumin for fish and lipid transfer protein for fruit. This makes development of a novel biotechnological product feasible. Two approaches will be evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypo-allergenic versions of parvalbumin and lipid transfer protein will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models), Phase I and II randomized double-blind placebo-controlled multi-center clinical trials will be performed. Two routes of administration will be evaluated, subcutaneous in case of fish and sublingual in case of fruit. The primary read-out will be the double-blind placebo-controlled food challenge. To understand the underlying immune mechanisms of subcutaneous and sublingual immunotherapy, these trials will be accompanied by in depth serological and cellular immune analyses, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST will improve the quality of life of food allergic patients by providing a safe and effective curative treatment that will end their dependence on avoidance and rescue medication.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.3-1 | Award Amount: 3.86M | Year: 2010

Europe is facing a rapidly growing threat from Type 2 diabetes mellitus (T2D), which is undoubtedly associated with an unhealthy diet and a more sedentary lifestyle. Evidence is accumulating that gestational diabetes mellitus (GDM) may be playing a role in this process. Thus it provides a significant opportunity for preventing future T2D. Not only is GDM prevalence on the rise, but intrauterine exposure to hyperglycaemia predisposes the offspring to diabetes and obesity. Another putative contributing factor is a low vitamin D status, which is also increasing in prevalence and may have causal links with both obesity and decreased glucose tolerance. The main aims of this project are: 1) to establish the current status of the prevalence of GDM in Europe and facilitate the adoption of a single diagnostic approach and 2) to deliver the best strategy that prevents GDM. The latter was deemed as not fully feasible within the scope of this call and our decision was to test the most relevant approaches (diet, exercise, vitamin D, alone or in combination) against surrogate variables of GDM (fasting blood glucose, insulin sensitivity, pregnancy weight gain) to come up with the best intervention for entry into a definitive GDM prevention trial. Deliverables include the sample size and modus operandi for such a trial. Value will be added to the project by 1) Assessing variables modifying the uptake of preventive interventions, 2) Exploring health costs of GDM and potential savings of preventive approaches, 3) Improving pathophysiological understanding by assessing intervention effect on several parameters in mother and foetus and 4) Facilitating future research through a well defined cohort of mother-offspring pairs and comprehensive biobanking.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-23-2014 | Award Amount: 6.15M | Year: 2015

The evidence base of Internet-based interventions in the prevention and treatment of mental health conditions has rapidly grown in the past decade. Yet many European countries (e.g., Germany, Austria, Switzerland, Great Britain, The Netherlands, Spain) have not implemented these promising approaches into health systems. Individuals with risk conditions or distinct mental health problems interested in using online interventions are often unable to access appropriate and evidence-based online interventions. The aim of this proposal is to establish a comprehensive model of health promotion, risk detection, disease prevention, and treatment facilitation for the most prevalent mental health problems and disorders (depression, anxiety, adjustment disorders, eating disorders/weight management and substance abuse) that assists individuals and mental health professionals in selecting and using evidence-based, online interventions. To reach this aim, the project partners bring together over 30 evidence-based, online interventions spanning the mental health intervention spectrum from universal and targeted prevention, self-help to treatment for the respective conditions applicable to children, adolescents and adults. Following a stakeholder needs survey, the model will be integrated into existing health care and other settings in Germany, Great Britain, Switzerland, Austria, The Netherlands, and Spain by 1. developing valid and economic, online screenings to allocate individuals to interventions, 2. developing technology for a common e-Health intervention platform, 3. developing implementation plans, 4. implementing evidence-based interventions into health care, and 5. evaluating and comparing their feasibility, acceptability, reach, efficacy and (cost)-effectiveness, adoption, and dissemination including moderators of interventions. Our proposal aims at the sustained implementation of the ICare model into health services and collaborations with health care providers across different EU countries.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.4.5-12 | Award Amount: 14.81M | Year: 2008

Objective: To delineate the biological and molecular pathways that initiate and drive chronic inflammatory disease and to transform the knowledge obtained into the development of novel anti-inflammatory interventions. Focus will be given to Rheumatoid Arthritis (RA) since longitudinal data indicate that intensive treatment can prevent persistency and chronicity. State of the Art and beyond: The first generation of targeted therapies in chronic inflammatory disease used RA as prototype disease for clinical development. These therapies are now also used in other inflammatory disorders. Although treatments have been developed that are effective in a proportion of patients, they are aspecific, relatively toxic and do not mediate cure. Currently, it is unknown which molecular effects need to be induced and/or targeted to prevent induction or persistency of RA. However, this is within reach through a strong international consortium of world-leading European groups that cover both basic- and translational research. Work plan: The general strategy for the project is to enable parallel studies that are focussed on critical switch moments in the biological processes that drive chronicity of inflammation. As the consortium consists of a multidisciplinary team with basic- and clinical expertise, translational research will be conducted to delineate the molecular basis of dysregulated inflammation, the RA-specific autoimmune-response and organ specific pathobiology. The final aim is to develop novel- and specific anti-inflammatory therapies. Impact of the project: This project will (i) identify the molecular networks underlying chronic inflammation and thereby (ii) will define novel targets for drug-development as well as (iii) algorithms that will predict outcome of therapy. Moreover, within this project European SMEs will evaluate new interventions (iv) and this project will (v) offer a platform to rapidly develop ideas and patents into new therapies.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.3-4 | Award Amount: 3.86M | Year: 2008

The TOBI project aims to analyse mechanisms provoking adipokine-mediated crosstalk and an inflammatory drift in obese patients. It will be the remit of this project to develop novel strategies to reduce or reverse major adipokine-mediated adverse interactions in peripheral tissues and by periorganic adipose tissue, namely insulin resistance and vascular dysfunction, respectively. Special attention will be given to the study of novel lipid-derived adipokines and the identification of targets for drug development that could interfere with the obesity-associated inflammatory drift. TOBI research focuses on molecular mechanisms initiating and promoting inflammatory signalling pathways in adipocytes and adipose tissue macrophages that cause a shift to inflammatory adipokines to interfere with insulin sensitivity and vascular function. Adipocyte dysfunction by alterations in ER stress signalling and lipolysis will be analysed as probable starting points of adipocyte inflammatory alterations. Signalling pathways and transcription factors controlling expression of inflammatory adipokines and anti-inflammatory adipokines will be studied. TOBI will particularly investigate lipid-derived adipokines that have been little studied to date. Key molecules of pathophysiological relevance will be validated for their potential as targets for drug development. The TOBI consortium will mount a comprehensive collaborative program for analysing the molecular mechanisms underlying regulation of adipokine production and their function in target tissues using genetic, molecular and biochemical approaches. The consortium combines all necessary expertise to investigate the basis of the obesity-associated inflammatory drift. A TOBI toolbox will be developed that strengthen collaboration and comparability of results. In addition the consortium includes relevant partners to exploit the results by translating them into new treatment strategies for obesity-associated adipokine-mediated disorders.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-1 | Award Amount: 8.18M | Year: 2013

The Fibro-Targets project is a multi-disciplinary 4 years program involving 10 partners ambitioning the identification, characterisation and validation of in vitro and in vivo models of novel therapeutically relevant targets for myocardial interstitial fibrosis (MIF) in heart failure. The project is based on the hypothesis that the intervention on novel fibrosis-related targets involved in the processes of fibroblast differentiation to myofibroblasts, the predominance of collagen synthesis over degradation and/or collagen maturation may allow for interstitial repair, thus providing a new strategy for the prevention and treatment of adverse cardiac remodeling involved in the transition to and the progression of heart failure. From a large body of existing multi-omics, literature data and previous hypothesis-driven research conducted by members of the consortium, a number of specific extracellular and intracellular targets have been identified whose involvement in MIF is beginning to be understood and that may be targeted by specific therapies. The specific aims of the Fibro-Targets are: (i) To provide further evidence on the mechanisms of action of the above targets (ii) To validate experimentally that new anti-fibrotic strategies can be developed based on the above targets (iii) To approach the potential clinical scenario of the above targets for HF therapy To reach these aims the following studies will be performed: (i) Observational and interventional experimental studies in already existing and/or de novo generated appropriate in vitro and in vivo models. (ii) Clinical studies, stratifying large scale populations of patients available to the consortium, at risk to develop HF and likely to be responsive to specific novel and/or exiting anti-fibrotic therapies. The stratification will be based on specific fibrogenetic phenotypic profiles using multi-panel imaging and circulating markers descriptive of mechanisms involving the proposed novel targets.

Agency: Cordis | Branch: FP7 | Program: CP-FP-SICA | Phase: HEALTH.2010.3.4-1 | Award Amount: 4.26M | Year: 2011

Multiple reports have documented the important deficit in human resources in health (HRH) in Africa. The causes are multiple and relate to a combination of underproduction, internal mal-distribution and inappropriate task allocation, working conditions and brain drain. The HURAPRIM-project will develop innovative interventions and policies and address the HRH crisis. The objectives of the projects are to analyze the actual situation of HRH in Africa, to understand the complexity of the causes for the actual shortages in primary health care, to test interventions, strategies and policies that may improve the situation and to maximise networking and synergies. In order to achieve these goals, the project will assess the scope of the deficit in human resources and analyse the process of recruitment, undergraduate and postgraduate training, professional retention and unemployment and this for a variety of primary health care workers. The known complexity of the problem will prevent us from applying a one size fits all-approach. Therefore, the project consortium brings together three experienced and committed European partners and five African partners, representing different parts of Africa and specific situations in HRH. The designed interventions will be tested out through case-studies in these partner countries. The interventions will target different levels (capacity building, recruitment and retention, task differentiation and cooperation with informal sector/traditional healers), will addresses (in various degrees of importance) aspects at the micro-, meso and macro-levels and will be designed with involvement of all stakeholders, political authorities, NGOs and especially the local population. The frame of reference for the analysis will look at relevance, equity, quality, efficiency, acceptability, sustainability, participation and feasibility. Acceptance by policy makers, in close cooperation with stakeholders and of the local communities will be a main focu

So far, there are no effective treatments for neuropathic pain (NP), and current treatments suffer from serious unwanted side effects. The NGF ligand-receptor system has recently emerged as a novel target for NP of great therapeutic potential, a master regulator, controlling both neuropathic and inflammatory components. Besides being a multi-component system, it also modulates the endocannabinoid (EC) signalling. Blocking the NGF signaling system is therefore a rational and thoroughly validated approach to pain therapy. Extensive evidence for potent analgesic efficacy of antiNGF mAbs has been obtained in preclinical models and in clinical trials,showing remarkable analgesic efficacy and creating great expectations for this new class of analgesic compounds.However, potential safety concerns related to off-target side effects have been raised and recently the FDA called for more preclinical research. To fully exploit the huge therapeutic potential of NGF system, we built a consortium of leading researchers in the NGF, EC and pain scientific arena.The innovative proposal will investigate new strategies for the treatment of different NP forms, based on the NGF system and its interplay with EC signalling, focussing at different levels of the pain transmission and perception systems. The project results will provide solid, mechanism-based grounds for the development of already identified second-generation therapeutics, based on the NGF target system, as well as for the identification and validation of new druggable targets emerging from the elucidated mechanisms. It will also identify biomarkers for NP, validated in animal models and clinical samples, that could result in future clinical benefits, for the stratification of patients suffering from different neuropathies and their treatment. The project will contribute to the understanding and controlling NP mechanisms, with an interdisciplinary approach, leading to the development of next-generation NGF targeting drugs.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.3.3-4 | Award Amount: 8.32M | Year: 2010

The 2009 H1N1 pandemic and the ongoing threat of highly pathogenic H5N1 strains have focused attention worldwide on the urgent need for effective anti-influenza drug options when the public is not protected by vaccination. The need is pressing since several circulating strains are resistant to currently stock-piled anti-neuraminidase drugs. In this project, we will exploit our recent advances in the detailed mechanistic understanding of the structure and function of the viral polymerase, the replication machine of the virus, to develop new drug candidates that inhibit viral replication in infected cells. The polymerase is an excellent drug target as it is highly conserved in all influenza A strains, whether of avian, swine or human origin. The project consortium includes 12 academic and SME partners from 6 European countries chosen for their expertise and complementarity. The focused drug design programme will start with already existing patented small molecule hits against two different polymerase active site targets and use structure-based medicinal chemistry expertise to arrive at optimized leads to enter preclinical studies. The aim is to take one preclinical candidate to phase 1 clinical trials, with contingency plans in place to cover setbacks. In parallel, a world-leading network of European academic labs will continue fundamental research on influenza polymerase atomic structure, cellular function and role in inter-species transmission, which will feed back into the drug design programme with enhanced assays for polymerase inhibitors, improved understanding of how the inhibitors work in the cellular context and potential resistance mechanisms, as well as providing new targets for future anti-influenza drug-design. If successful, the project will provide new opportunities to treat both seasonal and pandemic flu and thus can have an enormous impact on world-wide public health and well-being as well as the competitiveness of the European pharmaceutical sector

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.2.2-2 | Award Amount: 14.17M | Year: 2008

RESOLVE has been outlined to better understand the regulatory networks that control the devel-opmental processes in organ repair and to identify mechanisms which cause the termination of regu-lar organ development leading to fibroproliferative wound healing. Fibroproliferative wound healing represents a major pathology in elderly people shifting regular organ development into progressive organ fibrosis with complete loss of organ function. Based on the identification of valuated molecu-lar targets of fibroproliferative repair, RESOLVE aims to create suitable treatment strategies to achieve healthy ageing in the elderly. In doing so, RESOLVE will create a significant impact on life quality of elderly people. RESOLVEs outcomes will strengthen the competitiveness of European science and biotechnology industry and contribute to cost saving strategies in the health care sector. RESOLVEs structured scientific approach combines as yet fragmented fields of research using model organisms which represent (a) different forms of wound healing, (b) different human diseases and (c) different genetic backgrounds, guaranteeing social and scientific relevance, modularity of re-search and the integration of existing biological knowledge, technical expertise and medical experi-ence. In addition, sequential generation of data during improvement or worsening ensures clinical relevance and leads to a stringent exploitation strategy. The sustainable outcomes of RESOLVEs efforts will be: (A) the urgently needed diagnostic tool for fibroproliferative wound healing in various organs, (B) highly valuable transgenic animals offering test systems for fibroproliferative wound healing, and (C) a characterization of compounds capable of interfering with targets involved in fibroprolifera-tive repair.

Agency: Cordis | Branch: FP7 | Program: CSA-SA | Phase: HEALTH.2013.4.1-4 | Award Amount: 554.66K | Year: 2013

Diabetes, Cardiovascular and Chronic kidney (DCC) -diseases are relentlessly increasing globally, causing enormous human suffering, premature deaths and unsustainable costs. Leading European research has indisputably pointed that the kidney filtration barrier and its epithelial cell, the podocyte, is a common denominator for the DCC-diseases. However, European excellence and expertise have remained uncoordinated in separate pockets and, consequently, underutilised for full societal benefits and capacity creation to combat the challenges of diabetic, hypertensive and primary kidney diseases. Notably, these diseases are of major healthcare interest and of key importance for discovery intensive biopharma industry. KidneyConnect brings together teams of excellence to underpin nationally funded programs under a) Discovery and Future Technologies b) New Research Platforms c) Translational and d) Clinical Podocyte Research to create connected capacities, access to well trained talents and to optimize strategies for industry-academia cowork. In addition to resource maps, KidneyConnect supports international congresses, training courses, talent coaching, special seminars and builds systematically relations to key stakeholders. Due to the limited funds available, main aims are to provide roadmaps for future efforts, outlines for shared data -and sample repositories, targeted training, societal outreach and, as a result, competitive European funded programs. Our events are arranged as satellites of established meetings and supported by in-kind contribution from partners. The goal is to establish faster translation from discovery to clinical practices by creating dynamic networks, sustainable capacities and outlines for improved kidney disease management. High cohesion and shared resources together with the most prominent European authorities included will guarantee optimized resource usage. Substantial benefits and competitiveness in the huge global markets are to be expected

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.11M | Year: 2015

Drug development is a long and costly process which suffers from the major shortcoming that frequently failure is often only determined during the final stage. Recently, it has been recognised that more care needs to be taken during the early stages of development to avoid going into lengthy and costly confirmatory studies with ineffective or harmful treatments. To achieve this goal it is essential to implement efficient methods for the design and analysis of such early development studies. The expertise in this area is, however, limited at the moment and adequate methodology is only partially available. Using a cross-sectorial, transnational approach, the IDEAS network brings together leading public and private sector researchers in the field with ample experience in training to educate, promote and support the future leaders in medical statistics in general and in the design and analysis of early developmental studies in particular. Within the network, cross-sectorial, transnational teams will support young researchers with individual methodological projects and devise an individually tailored training programme for them. Clinical advisors supplement the input of the supervisory team and ensure practical relevance and uptake of the methods devised. The training activities are comprised of a well-rounded mix of specialist, methodological components and generic, transferable skills. A mandatory set of networkwide training activities is supplemented by individual training components and cross-sectorial secondments, and particular attention is given to interaction and collaboration between researchers and supervisors across public and private sector partners. At the end of their training the researchers will be uniquely qualified with expertise in the field, benefit from experience in both public and private sector and can rely on a wide network of experts in the field in the future.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2011-ITN | Award Amount: 3.19M | Year: 2011

Peritoneal dialysis (PD) and haemodialysis (HD) are life-saving renal replacement therapies for more than 200,000 patients with chronic kidney disease in Europe, and this number increases annually. Although PD and HD have similar mortality rates, PD offers major advantages in terms of quality of life, costs, home-based treatment opportunities and early patient survival. Moreover, PD, rather than HD, offers opportunities for improvements. Nevertheless, only 10% of patients in Europe are treated with PD. Presently, PD research faces a significant shortage in workforce, probably through competition with other specialisations, the absence of a coherent training program and limited trans-European collaboration. The EuTRiPD consortium consists of eight research institutes, an SME and a large private company throughout eight of the EU Member States. Additionally, one multi-national company and three (inter)national organizations that promote education, scholarly excellence and public awareness will be associate partners. Each partner has internationally recognized expertise in PD, ranging from basic to bedside research and from raising awareness on kidney diseases to commercialisation of project results. By providing an inter-disciplinary and intersectoral long lasting training programme in PD research, EuTRiPD will address this need for researchers and clinicians in renal diseases. The scientific goal of EuTRiPD is to advance the current state of the art in PD by carrying out bench to bedside research, focused on the identification of biomarkers and interventions that promote survival and function of the peritoneal membrane. This will finally result in the clinical implementation of new therapeutic approaches. EuTRiPD will deliver twelve skilled ESRs with excellent career opportunities in nephrology and PD research. The unique set up of this training program will equip them with the skills to pursue a career in other disciplines and sectors should they choose to do so.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: NMP.2010.2.3-1 | Award Amount: 8.02M | Year: 2011

The importance of developing novel approaches for bone repair is underscored by the heavy burden on health care costs and patient suffering caused by traumatic, osteoporotic and osteolytic metastatic bone lesions. To address these health challenges, we will develop optimally performing bioinspired biomaterials mimicking the natural physiological processes underlying bone repair. Our overall approach is to produce smart bioactive 3D scaffolds to fit within bone lesions, which we will then inject with functional, genetically-engineered self-solidifying elastin-like polymers with absolute-controlled molecular architecture and sequences containing specific domains for cell attachment, growth factors and calcium phosphate nanoparticles. The resulting bioactive, biodegradable scaffolds, biogels and regenerated bone will be analysed for biomaterial effects on bone growth, healing, foreign body reactions using cutting-edge in vitro assays, BioMEMS technology, in vivo animal models, non-invasive imaging and gene expression profiling for discovery of biomarkers associated with bone repair. Biomaterials will also be tested with biodynamic assays to assess strength, durability, toxicology, sterilisation reaction, eco-toxicology and risk assessment. Our multidisciplinary consortium with its extensive, state-of-the-art expertise consisting of private and public partners, cellular and molecular biologists, immunologists, physicists, bioengineers, and orthopaedic surgeons will tackle serious bone lesions with a comprehensive work plan to develop a prototype, evaluate it in vivo and in vitro, upscale its production and prepare the final material for clinical phase trials and commercialisation of the dual component product. Our ultimate aims are to ensure strong, healthy bone regeneration, reduce pain and suffering and to become a competitor in the biomaterials market of Europe.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: DRS-14-2015 | Award Amount: 4.96M | Year: 2016

Modern critical infrastructures are becoming increasingly smarter (e.g. cities). Making the infrastructures smarter usually means making them smarter in normal operation and use: more adaptive, more intelligent But will these smart critical infrastructures (SCIs) behave equally smartly and be smartly resilient also when exposed to extreme threats, such as extreme weather disasters or terrorist attacks? If making existing infrastructure smarter is achieved by making it more complex, would it also make it more vulnerable? Would this affect resilience of an SCI as its ability to anticipate, prepare for, adapt and withstand, respond to, and recover? These are the main questions tackled by this proposal. The proposal envisages answering the above questions in several steps. (#1) By identifying existing indicators suitable for assessing resilience of SCIs. (#2) By identifying new smart resilience indicators (RIs) including those from Big Data. (#3) By developing a new advanced resilience assessment methodology (TRL4) based on smart RIs (resilience indicators cube, including the resilience matrix). (#4) By developing the interactive SCI Dashboard tool. (#5) By applying the methodology/tools in 8 case studies, integrated under one virtual, smart-city-like, European case study. The SCIs considered (in 8 European countries!) deal with energy, transportation, health, water Results #2, #3, #4 and #5 are a breakthrough innovation. This approach will allow benchmarking the best-practice solutions and identifying the early warnings, improving resilience of SCIs against new threats and cascading and ripple effects. The benefits/savings to be achieved by the project will be assessed by the reinsurance company participant. The consortium involves 7 leading end-users/industries in the area, 7 leading research organizations, supported by academia and lead by a dedicated European organization. External world leading resilience experts will be included in the CIRAB.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2016 | Award Amount: 2.54M | Year: 2017

The EN-ACTI2NG program (European Network on Anti-Cancer Immuno-Therapy Improvement by modification of CAR and TCR Interactions and Nanoscale Geometry) emanates from the recent clinical evidence that T cells expressing engineered tumor-specific immune receptors can eradicate certain tumors that do not respond to conventional treatment. To obtain T cells with reactivity to a wider array of tumors and to improve efficiency and on- and off-target toxicity are current challenges Therefore the EN-ACTI2NG program aims 1) to train PhD students with expertise in development of new and improved T cell-mediated cancer immuno-therapies; 2) to endow the PhD students with the ability to establish efficient communication between the academic and industrial research environments and between scientists and the general public; 3) to improve T cell mediated anti-cancer immuno-therapy by the identification and development of new cancer-specific immune receptors and enhancing their function by identifying and modifying their molecular mechanism of action. To reach these objectives we have designed individual research projects ranging from biophysical analysis of immune receptors, via molecular modification of their structure and testing their tumor killing capacity in cell-based and pre-clinical assays to product development. Secondments will assure that each PhD student will be exposed to these complementary approaches and that there will be synergic feedback between the projects, producing innovative results that could otherwise not be achieved. Extensive training in research-specific skills, career development and a continuous training in communication skills will allow the PhD students to become facilitators of the process of transformation of scientific innovation into products with social and economic value. As such, the EN-ACTI2NG program should contribute to overcoming the more general challenge of converting the European Community into an innovation-driven society.

ELASTISLET aims to create a breakthrough development in encapsulation technology and its use in cell and tissue therapies for the treatment of type 1 and 2 diabetes. ELASTISLET will combine leading technologies in biomaterial design, production and processing, cross-linking/grafting technology and cell therapy, to synergistically integrate them into a new immune-isolation and biomimetic scaffolding approach for islet and cell transplantation in diabetes treatment. ELASTISLETs starting point is a highly innovative and versatile family of superior biomaterials, the Elastin-like Recombinamers (ELRs). Those innovative materials will be combined with the most cutting-edge encapsulation technologies, such as reactive LbL. ELASTISLET relies on the most innovative ideas taken from synthetic biology, nanobiotechnology and molecular and cellular biology to build the ideal niche for islet/cell encapsulation and transplantation. ELASTISLET main objective is to achieve a functional coating that fulfils, first, the basic requirements of optimal biocompatibility and physical properties (permselectivity) but, second, generate a capsule that can promote an intense and directed cross talk through all cell-material interfaces involved: the implant-surrounding tissue (outer) interface and cargo cells-capsule (inner) interface. At the end, a capsule that is able not only to cloak its content and isolate it from the immune rejection but that it is able to biologically interact with the surrounding tissues and its cargo simultaneously in a way that the implanted capsule will immediately interact and fuse with the surrounding tissues creating a real continuity of the extracellular matrix from the core of the capsule to the surrounding hosts tissues and procuring adequate nutrient supply. That will provide a physiologically ideal biomimetic environment for the implanted islets/cells to survive and function in the long term without perceiving a foreign, unusual or hostile environment.

Siller-Matula J.M.,Medical University of Vienna | Trenk D.,Universitaets Herzzentrum Freiburg Bad Krozingen | Krahenbuhl S.,University of Basel | Michelson A.D.,Dana-Farber Cancer Institute | Delle-Karth G.,Medical University of Vienna
Journal of Thrombosis and Haemostasis | Year: 2014

Polypharmacy in patients undergoing coronary artery stenting or in those presenting with an acute coronary syndrome is common. Nevertheless, the risk of drug-drug interactions in patients treated simultaneously with P2Y12 receptor inhibitors is less well considered in routine clinical practice. Whereas the irreversible P2Y12 receptor inhibitors clopidogrel and prasugrel are prodrugs requiring cytochrome P450 (CYP) enzymes for metabolic activation, such activation is not necessary for the direct-acting reversible P2Y12 receptor inhibitor ticagrelor. Several drugs frequently used in cardiology have been shown to interact with the metabolism of P2Y12 receptor inhibitors in pharmacodynamic studies. Whereas several drug-drug interactions have been described for clopidogrel and ticagrelor, prasugrel seems to have a low potential for drug-drug interactions. The clinical implications of these interactions have raised concern. In general, concomitant administration of P2Y12 receptor antagonists and strong inhibitors or inducers of CYP3A/CYP2C19 should be performed with caution in patients treated with clopidogrel/ticagrelor. Under most circumstances, clinicians have the option of prescribing alternative drugs with less risk of drug-drug interactions when used concomitantly with P2Y12 receptor inhibitors. © 2013 International Society on Thrombosis and Haemostasis.

Agency: Cordis | Branch: H2020 | Program: CSA | Phase: INFRASUPP-3-2014 | Award Amount: 2.00M | Year: 2015

There has never been a greater need for skilled managers and operators of research infrastructure (RI). Europe must develop the workforce that will turn ~50 nascent RIs with sites in different countries into powerhouses of support for major projects comparable to understanding the blueprint of life or discovering new subatomic particles. RItrain will develop a flagship training programme enabling RIs across all domains to gain expertise on governance, organisation, financial and staff management, funding, IP, service provision and outreach in an international context. It will be designed and delivered by experts who have set up and managed RIs from concept to maturity. We will define competencies required by RIs through consultation with their senior managers. The resulting competency framework will underpin a Bologna-compliant degree, the Master in Research Infrastructure Management, with three delivery routes. (1) Professionals working in RIs (or organisations representing them) can dip into the content, focusing on areas where there is most need. (2) Management teams can take the course as an organisation, dividing modules between them to gain a certificate for the RI. This will flag the RI as an organisation that values staff development, improving its attractiveness as an employer. (3) Recent graduates and others wishing to enhance their employability can take a full masters degree. Course content will include webinars led by senior managers of RIs. A staff-exchange programme will catalyse exchange of best practice and foster cooperation to develop a mobile work force effective across many RIs. By the end of the project we will be delivering a masters curriculum funded through course fees. Others with an interest in adopting it will be encouraged to do so, providing a means of expanding the programme. Europes research community and global collaborators will gain from world-class facilities to support excellent, high-impact research to benefit humankind.

News Article | December 14, 2016

ATLANTA, GA--(Marketwired - Dec 14, 2016) -  GeoVax Labs, Inc. ( : GOVX), a biotechnology company specializing in developing human vaccines, announced today that Farshad Guirakhoo, PhD, has been promoted to the role of Chief Scientific Officer, effective January 1, 2017. Dr. Guirakhoo joined GeoVax in 2015 as Senior Vice President of Research and Development. Robert T. McNally, PhD, GeoVax's President and Chief Executive Officer, commented, "For the past year, Farshad has been a driving force behind the growth of our vaccine development pipeline, and we are pleased to expand his role at this critical time for our company. In the role of Chief Scientific Officer, Dr. Guirakhoo will lead the scientific advancement of GeoVax's technology pipeline as the Company identifies and pursues new opportunities to address significant medical needs." Dr. McNally continued, "Harriet Robinson, PhD, will continue to hold an instrumental position with GeoVax as Chief Scientific Officer Emeritus. In this role, she will continue to direct our HIV vaccine program as well as continuing to serve as principal investigator on grants to GeoVax from the National Institutes of Health. Dr. Robinson, a co-founder of GeoVax, will also continue to serve as a member of our Board of Directors." Before joining GeoVax in 2015, Dr. Guirakhoo served in senior management and scientific roles within the biotechnology industry with Vaxess Technologies, Hookipa Biotech, Sanofi Pasteur, Acambis, Inc. and OraVax, Inc. He earned his Ph.D. in Virology at the Medical University of Vienna, Vienna, Austria, holds a M.Sc. degree in Genetics and a B.Sc. degree in Biology. He conducted his Post-Doctoral training at the Medical University of Vienna and at the US National Centers for Disease Control and Prevention (CDC), Division of Vector-Borne Infectious Diseases in Fort Collins, CO. In his scientific career, Dr. Guirakhoo has filed over 90 patent applications and is author/co-author of more than 80 peer reviewed publications, including book chapters. He was instrumental in the development and commercialization of the Imojev Japanese encephalitis virus vaccine and the Dengvaxia vaccine for Dengue virus. In 2014, he was named as one of the 50 Most Influential People in Vaccines. About GeoVax GeoVax Labs, Inc., is a clinical-stage biotechnology company developing human vaccines against infectious diseases using its Modified Vaccinia Ankara-Virus Like Particle (MVA-VLP) vaccine platform. The Company's development programs are focused on vaccines against HIV, Zika, and hemorrhagic fever viruses (Ebola, Sudan, Marburg, and Lassa). GeoVax recently began programs to evaluate the use of its MVA-VLP platform in cancer immunotherapy and for therapeutic use in chronic Hepatitis B infections. GeoVax's vaccine platform supports in vivo production of non-infectious VLPs from the cells of the very person receiving the vaccine, mimicking a natural infection, stimulating both the humoral and cellular arms of the immune system to recognize, prevent, and control the target infection. For more information, visit

News Article | December 6, 2016

New clinical trials in a type of cancer considered to be 'undruggable' may lead to a therapy for up to 10 percent of lung cancer patients A subset of lung tumours is exquisitely sensitive to a class of recently approved anti-cancer drugs. Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Ludwig Institute for Cancer Research in Oxford published this finding in the journal Nature Communications. It opens the way for new clinical trials in a type of cancer considered to be "undruggable" and may lead to a therapy for up to 10% of lung cancer patients. (Vienna, 6th of December 2016) Lung cancer remains the leading cause of cancer-related deaths worldwide. In contrast to other tumour types, lung tumours present a high number of genomic alterations - this is a consequence of exposure to carcinogenic substances found in tobacco smoke, which is the main cause of lung cancer. About 10% of lung tumours carry mutations in a gene called ATM. However, there are no drugs available in the clinic to treat ATM mutant lung cancer. With cutting edge high-throughput drug screens that analyse how the genetic makeup of the patient affects their response to drugs, the team of Sebastian Nijman, CeMM Adjunct PI and Group Leader at the Ludwig Institute for Cancer Research in Oxford made a surprising discovery: Cancer cells with ATM mutations are sensitive for drugs that inhibit an enzyme called MEK. The study was published in Nature Communications (DOI: 10.1038/NCOMMS13701) MEK is part of a biochemical pathway which is responsible for supporting proliferation and survival of the cell, while ATM plays a central role during the DNA damage response. In ATM deficient lung cancer cells, Nijman's team found that MEK inhibition results in cells being unable to keep proliferating and leads to apoptosis. An unexpected finding, as MEK inhibitors have so far been approved for the treatment of a type of skin cancer but not for lung cancer. "Normally lung cancer cells are resistant to MEK inhibition as they activate compensatory signals," Ferran Fece, one of the two first authors on the study and former PhD student at CeMM, explains. "In contrast, ATM mutant cells fail to do this and subsequently cannot cope with the blocking of MEK and die. We call this type of unexpected drug sensitivity synthetic lethality". Michal Smida, the other shared first author on the article and former PostDoc at CeMM, adds: "We knew that cancer mutations can lead to extreme sensitivity to some drugs. But finding these cancer Achilles' heels is very difficult as they are difficult to predict and extremely rare. We screened a large number of gene and drug combinations and got lucky." The study constitutes a substantial contribution for the development of a future precision medicine: ATM mutations could be used as a potential biomarker to stratify lung cancer patients to receive a MEK inhibitor. ATM is found to be mutated in 8-10% of lung adenocarcinomas - given that this type of tumour is among the most prevalent for both men and women worldwide, a significant number of patients could benefit from a MEK inhibitor based treatment. The study "MEK inhibitors block growth of lung tumors with mutations in Ataxia Telangiectasia Mutated" is published in Nature Communications on 6th of December 2016, 10:00h London Time; DOI: 10.1038/NCOMMS13701 Funding: This study was supported by the European Research Council (ERC), the Moffitt Lung Cancer Center of Excellence, research grants from the Austrian Science Fund (FWF), the Vienna Science and Technology Fund (WWTF) and the European Union FP7 Career Integration Grant, fellowships from the Austrian Academy of Sciences as well as by the Ministry of Education, Youth and Sports of the Czech Republic. Sebastian Nijman studied Medical Biology at the University of Utrecht and received his Ph.D. at the Netherlands Cancer Institute in 2005 in the group of René Bernards. He was a postdoctoral fellow at The Broad Institute of MIT and Harvard, in the laboratory of Todd Golub and started his own group in 2007 in Vienna at CeMM. There, he discovered the first mechanism of resistance to PI3K/mTOR inhibitors and developed isogenic cell models to discover novel drug-gene interactions. In November 2014, he joined the Ludwig Institute for Cancer Research and Target Discovery Institute in Oxford. Sebastian Nijman retains an adjunct PI position at CeMM. The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. http://www. For further information please contact CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 http://www.

Hadji P.,University of Marburg | Coleman R.,Weston Park Hospital | Gnant M.,Medical University of Vienna | Green J.R.,Novartis
Annals of Oncology | Year: 2012

Recent data from the AZURE, ABCSG-12, and ZO-FAST clinical trials have challenged our understanding of the potential anticancer activity of zoledronic acid (ZOL). Although the results of these studies may appear to be conflicting on the surface, a deeper look into commonalities among the patient populations suggest that some host factors (i.e. patient age and endocrine status) may contribute to the anticancer activity of ZOL. Indeed, data from these large clinical trials suggest that the potential anticancer activity of ZOL may be most robust in a low-estrogen environment. However, this may be only part of the story and many questions remain to be answered to fully explain the phenomenon. Does estrogen override the anticancer activity of ZOL seen in postmenopausal women? Are hormones other than estrogen involved that contribute to this effect? Does the role of bone turnover in breast cancer (BC) growth and progression differ in the presence of various estrogen levels? Here, we present a review of the multitude of factors affected by different endocrine environments in women with BC that may influence the potential anticancer activity of ZOL. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Varadkar S.,University College London | Bien C.G.,Epilepsy Center Bethel | Kruse C.A.,University of California at Los Angeles | Jensen F.E.,University of Pennsylvania | And 5 more authors.
The Lancet Neurology | Year: 2014

Rasmussen's encephalitis is a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. Neuropathological and immunological studies support the notion that Rasmussen's encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. Careful analysis of the association between histopathology and clinical presentation suggests that initial damage to the brain is mediated by T cells and microglia, suggesting a window for treatment if Rasmussen's encephalitis can be diagnosed early. Advances in neuroimaging suggest that progression of the inflammatory process seen with MRI might be a good biomarker in Rasmussen's encephalitis. For many patients, families, and doctors, choosing the right time to move from medical management to surgery is a real therapeutic dilemma. Cerebral hemispherectomy remains the only cure for seizures, but there are inevitable functional compromises. Decisions of whether or when surgery should be undertaken are challenging in the absence of a dense neurological deficit, and vary by institutional experience. Further, the optimum time for surgery, to give the best language and cognitive outcome, is not yet well understood. Immunomodulatory treatments seem to slow rather than halt disease progression in Rasmussen's encephalitis, without changing the eventual outcome. © 2014 Elsevier Ltd.

Gryglewski G.,Medical University of Vienna | Lanzenberger R.,Medical University of Vienna | Kranz G.S.,Medical University of Vienna | Cumming P.,Friederich Alexanders University
Journal of Cerebral Blood Flow and Metabolism | Year: 2014

The success of serotonin-selective reuptake inhibitors has lent support to the monoamine theory of major depressive disorder (MDD). This issue has been addressed in a number of molecular imaging studies by positron emission tomography or single-photon emission computed tomography of serotonin reuptake sites (5-HTT) in the brain of patients with MDD, with strikingly disparate conclusions. Our meta-analysis of the 18 such studies, totaling 364 MDD patients free from significant comorbidities or medication and 372 control subjects, revealed reductions in midbrain 5-HTT (Hedges' g=-0.49; 95% CI: (-0.84, -0.14)) and amygdala (Hedges' g=-0.50; 95% CI: (-0.78, -0.22)), which no individual study possessed sufficient power to detect. Only small effect sizes were found in other regions with high binding (thalamus: g=-0.24, striatum: g=-0.32, and brainstem g=-0.22), and no difference in the frontal or cingulate cortex. Age emerged as an important moderator of 5-HTT availability in MDD, with more severe reductions in striatal 5-HTT evident with greater age of the study populations (P<0.01). There was a strong relationship between severity of depression and 5-HTT reductions in the amygdala (P=0.01). Thus, molecular imaging findings indeed reveal widespread reductions of ∼10% in 5-HTT availability in MDD, which may predict altered spatial-temporal dynamics of serotonergic neurotransmission. © 2014 ISCBFM.

Malmstrom A.,Linköping University | Gronberg B.H.,Norwegian University of Science and Technology | Marosi C.,Medical University of Vienna | Stupp R.,University of Lausanne | And 9 more authors.
The Lancet Oncology | Year: 2012

Background: Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. Methods: Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m 2 on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. Findings: 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1-9·5; n=93] vs 6·0 months [95% CI 5·1-6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52-0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5-8·6; n=98], HR 0·85 [0·64-1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3-9·4; n=119] vs 7·4 months [6·4-8·4; n=123]; HR 0·82, 95% CI 0·63-1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21-0·56], p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 [95% CI 0·37-0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0-11·4] vs 6·8 months [5·9-7·7]; HR 0·56 [95% CI 0·34-0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69-1·38]; p=0·81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. Interpretation: Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide. Funding: Merck, Lion's Cancer Research Foundation, University of Umeå, and the Swedish Cancer Society. © 2012 Elsevier Ltd.

Schmitt J.,TU Dresden | Langan S.,University of Pennsylvania | Stamm T.,Medical University of Vienna | Williams H.C.,University of Nottingham
Journal of Investigative Dermatology | Year: 2011

There is wide variation in the use of outcome measures for eczema. We performed a three-stage web-based international Delphi exercise to develop consensus-based sets of core outcome domains for eczema for controlled trials and clinical recordkeeping. A total of 57 individuals from four stakeholder groups (consumers, clinical experts, regulatory agency representatives, and journal editors) representing 13 countries were asked to rate the importance of 19 outcome domains for eczema and to choose which domains should be included in two core sets of outcomes. Forty-six individuals (81%) participated. Participants received standardized feedback, including the group median, interquartile range, and previous responses, and the assessment was repeated in two subsequent rounds. We defined consensus a priori if at least 60% of the members of at least three stakeholder groups, including consumers, recommended domain inclusion in the core set. Consensus was achieved for inclusion of symptoms, physician-assessed clinical signs, and a measurement for long-term control of flares in the core set of outcome domains for eczema trials. We recommend including these three core outcomes in future eczema trials in order to enhance clinical interpretability and to enable meta-analyses across different studies. For recordkeeping, consensus was reached to regularly monitor eczema symptoms in clinical practice. Future work is needed to select which existing or new scales should be used to measure the domains identified as relevant for the core set. © 2011 The Society for Investigative Dermatology.

Haditsch M.,Austria and Labor Hanover MVZ GmbH | Kunze U.,Medical University of Vienna
Travel Medicine and Infectious Disease | Year: 2013

Tick-borne encephalitis (TBE) is a vector-borne disease that is primarily transmitted to humans by infected ticks and causes infection of the central nervous system. Clinical presentations range from meningitis to encephalitis with or without myelitis, and infection may result in death or long-term neurological sequelae. TBE is endemic in regions of at least 27 European as well as in some Asian countries. Infection and disease, however, can be averted successfully by tick-bite prevention and active vaccination. The risk of infection has shifted from daily life and occupational exposure to leisure-time activities, including travelling. Outdoor activities during the tick season with contact with nature increase the risk of tick bites. Although the number of travel-associated cases is unknown, it is certainly under-estimated because there is hardly any awareness of TBE in non-endemic countries. Therefore, the majority of cases remain undiagnosed, also because of the lack of diagnostic serology, as there is no routine screening for TBE in non-endemic regions. Because of the increasing number of travellers from TBE non-endemic to endemic regions, and in view of the fact that TBE was included in the list of notifiable diseases in the European Union in September 2012, this disease needs to become an important issue in travel medicine. © 2013 Elsevier Ltd. All rights reserved.

Gnant M.,Medical University of Vienna | Dubsky P.,Medical University of Vienna | Hadji P.,University of Marburg
Recent Results in Cancer Research | Year: 2012

Disease recurrence and distant metastases remain challenging for patients with breast cancer despite advances in early diagnosis, surgical expertise, and adjuvant therapy. Bone is the most common site for breast cancer metastasis, and the bone microenvironment plays a crucial role in harboring disseminated tumor cells (DTCs), a putative source of late relapse in and outside bone. Therefore, agents that affect bone metabolism might not only prevent the development of bone lesions but also provide meaningful reductions in the risk of relapse both in bone and beyond. Bisphosphonates bind to mineralized bone surfaces and are ingested by osteoclasts, wherein they inhibit osteolysis, thereby preventing the release of growth factors from the bone matrix. Therefore, the bone microenvironment becomes less conducive to survival and growth of DTCs and bone lesion formation. Recent trials of zoledronic acid in the adjuvant setting in breast cancer have demonstrated reduced disease recurrence in bone and other sites in premenopausal and postmenopausal women with early breast cancer. Based on the proven effect of bone protection during adjuvant endocrine therapy, new treatment guidelines recommend the routine use of bisphosphonates to prevent bone loss during adjuvant therapy, which may likely become the standard practice. © 2012 Springer-Verlag Berlin Heidelberg.

Attems J.,Vitality | Jellinger K.A.,Medical University of Vienna
BMC Medicine | Year: 2014

Recent epidemiological and clinico-pathological data indicate considerable overlap between cerebrovascular disease (CVD) and Alzheimer's disease (AD) and suggest additive or synergistic effects of both pathologies on cognitive decline. The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology. AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds, while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent. Small infarcts in patients with full-blown AD have no impact on cognitive decline but are overwhelmed by the severity of Alzheimer pathology, while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia. Further studies are warranted to elucidate the many hitherto unanswered questions regarding the overlap between CVD and AD as well as the impact of both CVD and AD pathologies on the development and progression of dementia. © 2014 Attems and Jellinger.

Leaper D.,University of Huddersfield | Assadian O.,Medical University of Vienna | Edmiston C.E.,Medical College of Wisconsin
British Journal of Dermatology | Year: 2015

Summary Infection is the likeliest single cause of delayed healing in healing of chronic open wounds by secondary intention. If neglected it can progress from contamination to colonization and local infection through to systemic infection, sepsis and multiple organ dysfunction syndrome, and it can be life-threatening. Infection in chronic wounds is not as easy to define as in acute wounds, and is complicated by the presence of biofilms. There is, as yet, no diagnostic for biofilm presence, but it contributes to excessive inflammation - through excessive and prolonged stimulation of nitric oxide, inflammatory cytokines and free radicals - and activation of immune complexes and complement, leading to a delay in healing. Control of biofilm is a key part of chronic wound management. Maintenance debridement and use of topical antimicrobials (antiseptics) are more effective than antibiotics, which should be reserved for treating spreading local and systemic infection. The continuing rise of antimicrobial resistance to antibiotics should lead us to reserve their use for these indications, as no new effective antibiotics are in the research pipeline. Antiseptics are effective through many mechanisms of action, unlike antibiotics, which makes the development of resistance to them unlikely. There is little evidence to support the theoretical risk that antiseptics select resistant pathogens. However, the use of antiseptic dressings for preventing and managing biofilm and infection progression needs further research involving well-designed, randomized controlled trials. What's already known about this topic? Infection is the most likely cause of stalled healing in chronic wounds. Infection in chronic wounds is a clinical decision-making process; a diagnostic would be useful for practitioners. Presence of biofilm cannot be detected clinically and a diagnostic is needed. What does this study add? Presence of biofilm is the likely cause of persistent infection and requires maintenance debridement at dressing changes, as well as topical antiseptic intervention. Use of antibiotics to treat infections in chronic wounds requires strict antibiotic stewardship. © 2015 British Association of Dermatologists.

Dichlberger A.,Wihuri Research Institute | Kovanen P.T.,Wihuri Research Institute | Schneider W.J.,Medical University of Vienna
Clinical Science | Year: 2013

LDs (lipid droplets) are metabolically highly active intracellular organelles. The lipid and protein profiles of LDs are cell-type-specific, and they undergo dynamic variation upon changes in the physiological state of a cell. It is well known that the main function of the LDs in adipocytes is to ensure energy supply and to maintain lipid homoeostasis in the body. In contrast, LDs in inflammatory cells have been implicated in eicosanoid biosynthesis, particularly under inflammatory conditions, thereby enabling them to regulate immune responses. Human mast cells are potent effector cells of the innate immune system, and the triacylglycerol (triglyceride) stores of their cytoplasmic LDs have been shown to contain large amounts of arachidonic acid, the main precursor of pro-inflammatory eicosanoids. In the present review, we discuss the current knowledge about the formation and function of LDs in inflammatory cells with specific emphasis on arachidonic acid and eicosanoid metabolism. On the basis of findings reported previously and our new observations, we propose a model in which lipolysis of LD-triacylglycerols provides arachidonic acid for lipid mediator generation in human mast cells. © 2013 Biochemical Society.

Gnant M.,Medical University of Vienna | Hadji P.,University of Marburg
Breast Cancer Research | Year: 2010

Treatment options for women with early-stage breast cancer have never been better, and the addition of bisphosphonates to adjuvant therapy is a valuable new tool capable of substantially improving clinical outcomes for these women. Several recent studies demonstrated that the anticancer activity of bisphosphonates is not limited to bone, and can translate into a reduction in disease recurrence, including reductions in locoregional and distant metastases. In addition, bisphosphonates maintain bone health during adjuvant therapy; this may be especially important for women who are at high risk for fracture. © 2010 BioMed Central Ltd.

Ferenci P.,Medical University of Vienna | Reddy K.R.,University of Pennsylvania
Antiviral Therapy | Year: 2011

Boceprevir and telaprevir are the first HCV protease inhibitors to be approved for the treatment of chronic hepatitis C genotype 1 infection. These drugs must be used in combination with pegylated interferon plus ribavirin (P/R) to maximize efficacy and prevent the emergence of resistance-associated variants (RAVs). In randomized, placebo-controlled international studies in treatment-naive and previously treated HCV patients, treatment with either boceprevir- or telaprevir-based triple therapy regimens significantly increased sustained virological response rates compared with placebo plus P/R. Protease inhibitors have the potential, not only to significantly increase cure rates among patients with genotype 1 infection, but also to reduce the duration of treatment for patients who have an extended rapid virological response. Boceprevir is associated with an increased incidence of anaemia and dysgeusia and telaprevir is associated with an increased incidence of rash and anaemia. The emergence of RAVs was associated with an increased risk of virological failure in clinical studies. Although these new drugs bring significant promise, it remains unclear if all genotype 1 patients will need triple therapy. Here, we review some of the complexities uncovered and controversies highlighted by the introduction of HCV protease inhibitors. ©2011 International Medical Press.

Gobert A.,Institute Of Biologie Moleculaire | Gutmann B.,Institute Of Biologie Moleculaire | Taschner A.,Medical University of Vienna | Goringer M.,University of Marburg | And 4 more authors.
Nature Structural and Molecular Biology | Year: 2010

The ubiquitous endonuclease RNase P is responsible for the 5′ maturation of tRNA precursors. Until the discovery of human mitochondrial RNase P, these enzymes had typically been found to be ribonucleoproteins, the catalytic activity of which is associated with the RNA component. Here we show that, in Arabidopsis thaliana mitochondria and plastids, a single protein called′ proteinaceous RNase P′ (PRORP1) can perform the endonucleolytic maturation of tRNA precursors that defines RNase P activity. In addition, PRORP1 is able to cleave tRNA-like structures involved in the maturation of plant mitochondrial mRNAs. Finally, we show that Arabidopsis PRORP1 can replace the bacterial ribonucleoprotein RNase P in Escherichia coli cells. PRORP2 and PRORP3, two paralogs of PRORP1, are both localized in the nucleus. © 2010 Nature America, Inc. All rights reserved.

Di Ieva A.,University of Toronto | Di Ieva A.,Medical University of Vienna | Esteban F.J.,University of Jaén | Grizzi F.,Humanitas Clinical and Research Center | And 2 more authors.
Neuroscientist | Year: 2015

It has been ascertained that the human brain is a complex system studied at multiple scales, from neurons and microcircuits to macronetworks. The brain is characterized by a hierarchical organization that gives rise to its highly topological and functional complexity. Over the last decades, fractal geometry has been shown as a universal tool for the analysis and quantification of the geometric complexity of natural objects, including the brain. The fractal dimension has been identified as a quantitative parameter for the evaluation of the roughness of neural structures, the estimation of time series, and the description of patterns, thus able to discriminate different states of the brain in its entire physiopathological spectrum. Fractal-based computational analyses have been applied to the neurosciences, particularly in the field of clinical neurosciences including neuroimaging and neuroradiology, neurology and neurosurgery, psychiatry and psychology, and neuro-oncology and neuropathology. After a review of the basic concepts of fractal analysis and its main applications to the basic neurosciences in part I of this series, here, we review the main applications of fractals to the clinical neurosciences for a holistic approach towards a fractal geometry model of the brain. © The Author(s) 2013.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: NMP-06-2015 | Award Amount: 4.99M | Year: 2016

FOLSMART will bring to phase I clinical trials novel folate-based nanodevices (FBN) for the treatment of rheumatoid arthritis (RA). These nanodevices for folic acid (FA)-mediated targeting of activated macrophages showed improved clinical scores in a mouse model of RA when compared to methotrexate (MTX), a first-line drug therapy for the treatment of RA. In this way, FBN will be benchmarked against this drug. MTX has significant associated toxicity and second line biological therapies poses a great economic burden to hospital/public health systems. In parallel, nanodevices encapsulating Sulfasalazine (SSZ), will be tested. SSZ is a second line indication for the treatment of RA, unresponsive to MTX or MTXintolerant patients. Furthermore, FOLSMART propose the optimization of mechanisms for the release of the drugs, through pH and temperature sensitive nanodevices. An exploitation and business plans will be elaborated. In parallel, initial economic evaluation of all proposed treatments will be performed to validate these claims. Specific technological objectives of FOLSMART will be: Good Manufacturing Practice (GMP) production of the FBN based therapies which have been positively bench-marked in the previous FP7 European project NANOFOL in comparison with the use of MTX in a RA mouse model: -Liposomal MTX and SSZ with FA-neck domain peptide as targeting agent -Nanoparticles from HSA-FA/MTX conjugates and SSZ -Optimization of mechanisms of drug release and application to other fields Pre-clinical development on RA models -Toxicology and pharmacokinetics, to determine tolerability and efficacy benefit in two animal models rat and dog, under Good Laboratory Practice (GLP) standards -Genotoxicity and Carcinogenicity Phase I clinical trials of the best therapies bench marketed against MTX -Nanodevices with MTX and SSZ will offer improved tolerance and greater efficacy meaning that patients who do not do well on MTX will have cost-effective alternatives

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.1.1-3 | Award Amount: 3.21M | Year: 2011

The main objective of the proposed collaborative project Prot-HiSPRA is to remove time-consuming bottlenecks of existing proteomics technologies (sample preparation, fractionation, proteolysis, separation, data collection, and data mining) and bring the proteome driven analysis into time sensitive clinical practice. Prot-HiSPRA is an objective-driven research project and it aims at generating new knowledge and new technologies which will improve the European competitiveness in the field of applied proteomics. Prot-HiSPRA is planned for the duration of 36 months which is necessary in order to ensure a high-quality validation of the developed high-throughput methodologies. A strong participation of SMEs (partner 2 MAYLAB, partner 3 CELS - left the onsortium, partner 6 RTDs, partner 7 - BIA) will ensure strong innovation and exploitation during HiSPRA. Research activities in the Prot-HiSPRA program can be divided into a technological core project that is tailored to significantly improve on technologies in the fields of proteomics, bioinformatics, and integrated biology. Analytical methods developed with the Prot-HiSPRA project will be exemplified by applying for analysis of clinical samples originating from in vitro fertilization (IVF) procedures. During the IVF process, especially at the moment when decisions are made which embryo can be implanted, decisions must be made so that the process has the greatest chance for success. To further elevate pregnancy rates for IVF a non-invasive, rapid, and robust methods for judging the embryos status is urgently needed to examine the embryos proteome. These methods could not only be applied in the described field of reproductive medicine but also in any the other fields of clinical analysis where fast and reliable diagnosis on a proteomic basis could be made available.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: NMP.2010.2.3-1 | Award Amount: 10.47M | Year: 2011

The use of bioartificial tissue for regenerative medicine offers great therapeutic potential, but also has to meet high demands with respect to the interaction of the bioartificial devices and natural tissues. Key issues for the successful use of bioartifical tissues as natural tissue replacements are their long term functional stability and biocompatible integration. Up to now, various approaches for the generation of bioartificial tissues have not succeeded due to insufficient nutrition and oxygen supply. Therefore, current tissue engineered products have only been realised for non vascularised tissues such as cartilage. ArtiVasc 3D will break new ground and overcome these challenges by providing a micro- and nano-scale based manufacturing and functionalisation technology for the generation of fully vascularised bioartificial tissue that enables entire nutrition and metabolism. The bioartificial vascularised skin engineered in ArtiVasc 3D will, for the first time, allow tissue replacement with optimum properties. ArtiVasc 3D will research and develop an innovative combination of hi-tech engineering such as micro-scale printing, nano-scale multiphoton polymerisation and electro-spinning with biological research on biochemical surface modification and complex cell culture. In a multidisciplinary approach, experts in biomaterial development, cell-matrix interaction, angiogenesis, tissue engineering, simulation, design and fabrication methods work together to generate bioartificial vascularised skin in a fully automated and standardised manufacturing approach. This bioartificial vascularised skin will be of great value in a vast array of clinical treatments, e.g. as a transplant in trauma treatment. In addition, this new bioartificial vascularised skin will be used as an innovative in vitro skin equivalent for pharmaceutical, cosmetics or chemical substance testing, which represents a promising method to reduce expensive, ethically disputed animal testing.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.2.1-4 | Award Amount: 13.02M | Year: 2013

Despite a great progress in the management of epilepsy, still one third of patients is refractory to available medications. The incidence of epilepsy is highest in infancy and 50% of children experience epilepsy-related comorbidities, such as developmental delay and autism. The development of epilepsy (epileptogenesis), extensively studied in animals, is barely studied in humans, as patients usually present AFTER the seizure onset. EPISTOP is the first prospective study of epileptogenesis in humans, beginning BEFORE seizures and continuing through age 2\ years, permitting detailed analysis of the onset, drug-resistance, and comorbidities of epilepsy. To maximize information derived from the study we have chosen homogenous group of patients with prenatal or early infantile diagnosis of Tuberous Sclerosis Complex (TSC). A clinical randomized study of pre-seizure treatment in TSC infants is a part of the project. The aim of EPISTOP is to examine the risk factors and biomarkers of epilepsy and to identify possible new therapeutic targets to block or otherwise modify epileptogenesis in humans. Biomarker analysis will be performed by a multidisciplinary, systematic approach in three clinical settings: 1/ prospective study of epilepsy development in infants with TSC, including analysis of clinical, neuroimaging, and molecular, blood-derived biomarkers at predefined time points: before the onset of seizures, at the onset of epileptiform discharges on EEG, at seizure onset and at the age of 24 months 2/ prospective study of blood-based biomarkers in infants with TSC treated with antiepileptic drugs prior to seizure onset in comparison to children treated only after clinical seizures appearance. 3/ analysis of biomarkers of epileptogenesis and drug-resistant epilepsy in brain specimens obtained from TSC patients who have had epilepsy surgery and TSC autopsy cases. EPISTOP will be carried out by a consortium of 14 partners from 9 countries, including 2 SMEs.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.3.1-2 | Award Amount: 7.63M | Year: 2014

Invasive fungal disease (IFD) is a leading cause of morbidity and mortality in the growing number of immunocompromised individuals, including particularly cancer patients, and bone-marrow or organ transplant recipients. The majority of IFD events are still caused by Candida and Aspergillus species, but there is an increasing incidence of resistant or previously uncommon moulds, yeasts and Zygomycetes. Timely pathogen detection is a prerequisite for effective therapy in patients with IFD. FUNGITECT will focus on this medical priority and develop, validate and market a specific set of novel molecular diagnostic tests for IFD targeting fungal DNA-, RNA- and protein motifs, as well as the enzymatic activity of fungal pathogens. Additionally, FUNGITECT will provide a unique opportunity to establish and implement highly effective diagnostic assays supported by Next-Generation Sequencing and a bioinformatics service platform, facilitating optimized treatment strategies adapted to individual patient requirements with the following paramount aims: i) to provide the diagnostic basis for stratified and timely administration of the most appropriate antifungal therapy permitting improved management of patients with IFD, ii) to decrease the rate of overtreatment and the ensuing adverse side effects including fungal resistance, and iii) to help reduce the enormous healthcare costs for clinical antifungal therapy. The consortium includes leading academic research institutions, SMEs and Industry already successfully positioned in the market.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-03-2015 | Award Amount: 6.47M | Year: 2015

RELENT is multidisciplinary group of scientists and clinical investigators whose goal is to develop individualized treatment for chronic autoimmune diseases, such as rheumatoid arthritis and vasculitis, that cause considerable mortality and morbidity, both from uncontrolled disease and treatment associated co-morbidities, like infection and malignancy. This requires the need to stratify patients by their outcome and to tailor immunosuppression based on much deeper knowledge of the mechanisms that control initiation and persistence of the pathogenic immune responses. The RELENT Consortium has been formed to generate this knowledge with the ultimate goal of developing treatments tailored to the specific needs of individual patients. RELENT combines the resources of seven leading European Investigators and two from US and Australia whose expertise is not available elsewhere in the world but necessary for the ambitious work program. Three SMEs will supply specific reagents and translate the results to biomarker development. This will enable RELENT to deliver its four specific research aims, namely to: i) Combine subset analysis of genome wide association studies with classical cell biology to uncover pathways that influence and ii) use multiplexed antigen arrays, whole proteome analysis and rapid mass analysis to identify protein signatures that predict outcome and response to treatment in chronic autoimmune disease. iii) Characterise T and B cell abnormalities that predispose to autoimmunity and infection by studying the ageing immune system in health and disease. iv) Analyse pathogenic effector T cells and their control by macrophages and dendritic cells and the molecules they secrete using in vivo models. We anticipate to identify common mechanisms responsible for the persistence and outcomes in severe autoimmune and inflammatory diseases in females and males and that the results should be rapidly translatable into clinical practice for the benefit of patients.

Chronic angina pectoris is a debilitating chronic disease, a subgroup of these patients suffers from refractory angina which unfortunately cant be controlled by medical therapy (angioplasty or surgery). Refractory angina is a substantial burden on the individual and healthcare system, in Europe there are 100,000 new cases per year, annual mortality of these patients is relatively low (<4%) thus refractory angina patients suffer multiple hospitalizations and low levels of health-related quality of life. The ReGenHeart project is based on extensive preclinical work and a phase I safety, feasibility and dose-finding clinical study recently completed by the consortium. The project will conduct a multicentre, randomized, placebo-controlled, double-blinded Phase II clinical study to provide proof of concept and clinical validation for a new, percutaneous, cost-efficient therapy for refractory angina patients. Using our optimized catheter-mediated intramyocardial approach with AdenoVEGF-D, which has never been used in man before our phase I trial, we aim to induce regenerative changes supported by therapeutic angiogenesis in the affected area of a patients heart and, in a single procedure, reduce the burden on the individual and their health service. The proposed trial is ready to proceed, subject to final regulatory approval in the six European clinical centres. 180 CCS class 2-3 refractory angina patients will be recruited, which will allow us to assess the benefits of therapy to patients who still have potential to respond to the regenerative therapy. Patients will be randomized 2:1 to either the gene therapy or placebo arms. Trial follow up, at 6 and 12 months, will assess how far they can walk in 6 minutes (primary endpoint) and also by their CCS angina score, quality of life, so-called MACE endpoints and several advanced PET and MRI imaging endpoints.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: KBBE-2007-2-5-01 | Award Amount: 3.42M | Year: 2008

The function of post market monitoring is to further assess possible nutritional and health effects of authorized GM foods on a mixed population of human and animal consumers. Currently, however, little is known about exposure levels, whether adverse effects are predictable, and the occurrence of any unexpected effects following market release of GM foods. Our objective is to identify a panel of anatomic, physiologic, biochemical, molecular, allergenic, and immunogenic biomarkers, which could be used to predict harmful GMO effects after product authorization. Using a prototype allergenic -amylase inhibitor GM-pea, we will extrapolate multiple biomarker databases that correlate GMO effects during gestation, growth, maturation in various animal models with humans. We will establish biomarkers in GMO-fed pigs, salmon, rats, and mice, in addition to indirect effects of GM feeding in the food chain and GMO influence during an underlying allergic disorder. These experiments will yield data on general health with a specific focus on allergy and immunology. To extrapolate our data to humans, we will establish a comparative database with antigenic epitopes and antibody crossreactivity in legume allergic patients and human-mouse chimera in which a human immune system is transplanted into a mouse lacking an immune system. Taken together, these results will yield databases from multiple biological systems that will be used in a mathematical modeling strategy for biomarker discovery and validation. Our consortium consists of partners from Austria, Turkey, Hungary, Ireland, Norway, and Australia and constitutes a diverse interdisciplinary team from veterinary medicine, nutrition, agriculture, immunology, and medicine that is dedicated to the development and validation of biomarkers to be used for post market monitoring of animals and humans consuming newly authorized GMOs.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 3.35M | Year: 2015

ENLIGHT-TEN is a European Network Linking Informatics and Genomics of Helper T cells: our mission is to provide cross-disciplinary training in cellular immunology and big data analysis such that we train a new generation of researchers to fully exploit the power of emerging technological platforms. Our network of TEN beneficiaries combines T cell expertise with state-of-the-art technologies such as next generation sequencing (NGS), bioinformatics, multi-colour flow cytometry, preclinical models and tailored genome editing. Trainees will acquire a comprehensive knowledge in T cell immunology and the capacity to generate and interrogate big data sets as well as expertise in identifying novel biomarkers and developing therapeutic concepts. As such the training programme will provide an ideal stepping-stone for creative and innovative early stage researchers (ESRs) to enter and strengthen Europes academia as well as pharmaceutical and bioinformatics companies. The research focus of the network lies in the identification of extrinsic and intrinsic factors that control development, differentiation and plasticity of helper T cell subsets with particular emphasis on how T cell differentiation impacts on human diseases. The generation of large data sets is an emerging and challenging field, and there is high demand in both the academic sector as well as pharmaceutical companies for researchers to be able to analyse, integrate and exploit this rich source of information. ENLIGHT-TEN will combine the individual strengths of innovative laboratories and enterprises from complementary disciplines to provide unique interdisciplinary training for 13 ESRs, placing them at the forefront of this emerging field. Trainees will be empowered to perform cutting-edge analysis of the steadily increasing number of different T cell subsets, which play highly diverse and critical roles in the development of autoimmune diseases, making them a key target for pharmaceutical companies.

Osman N.I.,Royal Hallamshire Hospital | Chapple C.R.,Royal Hallamshire Hospital | Abrams P.,University of Bristol | Dmochowski R.,Vanderbilt University | And 5 more authors.
European Urology | Year: 2014

Context Detrusor underactivity (DU) is a common cause of lower urinary tract symptoms (LUTS) in both men and women, yet is poorly understood and underresearched. Objective To review the current terminology, definitions, and diagnostic criteria in use, along with the epidemiology and aetiology of DU, as a basis for building a consensus on the standardisation of current concepts. Evidence acquisition The Medline and Embase databases were searched for original articles and reviews in the English language pertaining to DU. Search terms included underactive bladder, detrusor underactivity, impaired detrusor contractility, acontractile detrusor, detrusor failure, detrusor areflexia, raised PVR [postvoid residual], and urinary retention. Selected studies were assessed for content relating to DU. Evidence synthesis A wide range of terminology is applied in contemporary usage. The only term defined by the standardisation document of the International Continence Society (ICS) in 2002 was the urodynamic term detrusor underactivity along with detrusor acontractility. The ICS definition provides a framework, considering the urodynamic abnormality of contraction and how this affects voiding; however, this is necessarily limited. DU is present in 9-48% of men and 12-45% of older women undergoing urodynamic evaluation for non-neurogenic LUTS. Multiple aetiologies are implicated, affecting myogenic function and neural control mechanisms, as well as the efferent and afferent innervations. Diagnostic criteria are based on urodynamic approximations relating to bladder contractility such as maximum flow rate and detrusor pressure at maximum flow. Other estimates rely on mathematical formulas to calculate isovolumetric contractility indexes or urodynamic stop tests. Most methods have major disadvantages or are as yet poorly validated. Contraction strength is only one aspect of bladder voiding function. The others are the speed and persistence of the contraction. Conclusions The term detrusor underactivity and its associated symptoms and signs remain surrounded by ambiguity and confusion with a lack of accepted terminology, definition, and diagnostic methods and criteria. There is a need to reach a consensus on these aspects to allow standardisation of the literature and the development of optimal management approaches.

Raderer M.,Medical University of Vienna | Kiesewetter B.,Medical University of Vienna | Ferreri A.J.M.,San Raffaele Scientific Institute
CA Cancer Journal for Clinicians | Year: 2016

Answer questions and earn CME/CNE Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) accounts for 7% to 8% of newly diagnosed lymphomas. Because of its association with infectious causes, such as Helicobacter pylori (HP) or Chlamydophila psittaci (CP), and autoimmune diseases, it has become the paradigm of an antigen-driven malignancy. MALT lymphoma usually displays an indolent course, and watch-and-wait strategies are justified initially in a certain percentage of patients. In patients with gastric MALT lymphoma or ocular adnexal MALT lymphoma, antibiotic therapy against HP or CP, respectively, is the first-line management of choice, resulting in lymphoma response rates from 75% to 80% after HP eradication and from 33% to 65% after antibiotic therapy for CP. In patients who have localized disease that is refractory to antibiotics, radiation is widely applied in various centers with excellent local control, whereas systemic therapies are increasingly being applied, at least in Europe, because of the potentially systemic nature of the disease. Therefore, the objective of this review is to briefly summarize the clinicopathologic characteristics of this distinct type of lymphoma along with current data on management strategies. © 2015 American Cancer Society.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: AAT.2012.3.3-4.;AAT.2012.3.4-5. | Award Amount: 4.71M | Year: 2012

The project will identify current deficiencies of situational awareness and manual control of modern flight decks, and impact the design of procedures, training and cockpit design in the aerospace industry. Procedures will be developed to help the pilot identify not only the fault, but where the airplane is with respect to its operational envelope and limits. By empowering the pilot to utilize his/her skills more effectively, identifying how to create conditions that increase the likelihood of success, and developing guidelines to train fundamental skills to deal with unexpected events, Man4Gen will directly impact the reduction of fatal accidents such as those caused by LOC-I.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2016 | Award Amount: 3.90M | Year: 2016

FBI fosters education of ESRs on an emerging, multimodal imaging platform and its translation into clinical and biological applications. In FBI, 15 ESRs are trained at world-leading European academic institutions and companies, thus forming strong interdisciplinary relations between industry, technical sciences and clinical end-users. Optical imaging has huge potential to address unmet clinical needs by combining non-invasive and real-time capture of biomedical information; thus enabling earlier onset of treatment, reduced therapy costs, reduced recurrence rates, and improved clinical outcomes. Up to now, optical modalities were applied as standalone techniques each targeting one biomarker. Recently it has been shown that diagnosis is significantly improved by combining different contrast mechanisms simultaneously in a multimodal approach, i.e., staging and grading of lesions is feasible. FBI proposes to combine a selection of modalities depending on the targeted disease. Suspicious lesions are analysed with optical coherence tomography, optoacoustic tomography, multi-photon tomography, and Raman spectroscopy to provide morphological, label-free microangiography, and intrinsic biochemical information, respectively. An important issue is the need for endoscopy: combining said modalities into endoscopes is challenging due to the integration of different imaging concepts, scanning and detection methods, and laser sources. Accordingly, there is a huge need for effectively translating these technical solutions to industry and clinics, which traditionally is restricted by lack of understanding of applications or limited knowledge of new technology. All these barriers are addressed by FBI through research and development of novel photonic components and systems, through educating ESRs in understanding clinical, biological and commercial challenges, and through developing tailored technical solutions and efficient translation of technology within a strong network.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.1.4-1 | Award Amount: 7.38M | Year: 2012

Goals: We propose a regenerative medicine clinical trial of the therapeutic system OSTEOGROW for regenerating bone through harnessing a novel bone device to accelerate and enhance bone repair. The osteogenic device is composed of an autologous carrier and a biologically active recombinant human protein offering a therapeutic solution in bone regeneration superior to currently available options. The autologous carrier is a whole blood-derived coagulum device (WBCD) from the peripheral blood of a patient, which will act as an endogenous biocompatible material causing significantly less inflammatory reactions than currently used bone devices. The bone inducing molecule is the recombinant human bone morphogenetic protein 6 (BMP6) which binds to WBCD and is more potent than other BMPs in stimulating bone formation in preclinical animal models. The consortium members will scale-up the production of BMP6 from an already developed working cell bank to enter clinical trials on bone regeneration. The bone diseases we will treat locally with OSTEOGROW are acute radius fractures and recalcitrant non-unions of the tibia. These conditions are widespread and highly debilitating diseases for which such therapy holds great promise. Workflow: Preliminary pre-clinical data are already available, and clinical grade (GMP) BMP6 will be available before the beginning of the project to perform toxicology studies and to determine the final formulation of OSTEOGROW. Clinical trials will start within 18 months from the start of the project funding. Business strategy: SMEs Genera Research and BioTest will develop and validate the BMP6 production in their facilities. Consortium members from Medical University of Vienna, Sarajevo University Clinical Centre, Linkoping University Faculty of Health Sciences, Zagreb University Trauma Clinic, SMART Medico and Paul Regulatory Services will perform, monitor and coordinate clinical trials. OSTEOGROW will find a wide use in human and veterinary medicine.

News Article | October 26, 2016

The study team was lead by Professor Paolo Maria Matricardi, head of the Molecular Allergology Group at the Department of Pediatric Pulmonology and Immunology of the Charité and included researchers from the Medical University of Vienna, lead by Prof. Rudolf Valenta, and statisticians from Rome, Italy. The team examined the data and blood samples prospectively collected over 20 years from a cohort of 722 German children born in 1990 and monitored since their birth in the framework of the Multicenter Allergy Study (MAS). Purified or engineered molecules of the mite Dermatophagoides pteronyssinus were used with nanotechnology procedures to characterize the origins and evolution of the antibody response during the children's first decades of life. The scientists found that IgE-antibodies against three dust mite molecules (Der p 1, Der p 2 and Der p 23) appeared very early in the children's blood, often before the onset of their disease. In some (but not all) children, this first step was followed by a "cascade" of events involving other mite molecules, through a phenomenon defined as "molecular spreading". Children producing IgE to many molecules ("polymolecular sensitization") had a higher risk of developing allergic rhinitis and asthma. Earlier onset of allergic sensitization, high exposure to house dust mite allergens, and having one or both parents affected by hay fever increased the risk of polymolecular sensitization. Interestingly, healthy pre-school children showing IgE antibodies to Der p 1 or Der p 23 developed more frequently asthma at school age. These and other molecules may be used for disease prevention in early life and to precisely tailor allergen immunotherapy in pediatric and adult patients. "Mite allergy develops in childhood like an avalanche. It starts early with only one or a very few molecules and then grows to many", says Dr Daniela Posa,, first Author of the publication. "The greater the spreading of molecular sensitization, the highest the risk of developing Asthma." PD. Dr. Matricardi adds: "Our findings open new perspectives to the use of mite allergen molecules for prediction, prevention and therapy of allergic rhinitis and asthma caused or triggered by House Dust Mites."

News Article | November 17, 2016

Scientists have established comprehensive maps of the human epigenome, shedding light on how the body regulates which genes are active in which cells. Over the last five years, a worldwide consortium of scientists has established epigenetic maps of 2,100 cell types. Within this coordinated effort, the CeMM Research Center for Molecular Medicine contributed detailed DNA methylation maps of the developing blood, opening up new perspectives for the understanding and treatment of leukemia and immune diseases. One of the great mysteries in biology is how the many different cell types that make up our bodies are derived from a single cell and from one DNA sequence, or genome. We have learned a lot from studying the human genome, but have only partially unveiled the processes underlying cell determination. The identity of each cell type is largely defined by an instructive layer of molecular annotations on top of the genome - the epigenome - which acts as a blueprint unique to each cell type and developmental stage. Unlike the genome the epigenome changes as cells develop and in response to changes in the environment. Defects in the factors that read, write, and erase the epigenetic blueprint are involved in many diseases. The comprehensive analysis of the epigenomes of healthy and abnormal cells will facilitate new ways to diagnose and treat various diseases, and ultimately lead to improved health outcomes. A collection of 41 coordinated papers now published by scientists from across the International Human Epigenome Consortium (IHEC) sheds light on these processes, taking global research in the field of epigenomics a major step forward. These papers represent the most recent work of IHEC member projects from Canada, the European Union, Germany, Japan, Singapore, South Korea, and the United States. Three of these papers have been coordinated by Christoph Bock at CeMM. The latest study from Christoph Bock's team, published today in the journal Cell Stem Cell, charts the epigenetic landscape of DNA methylation in human blood. Led by CeMM scientists Matthias Farlik and Florian Halbritter together with Fabian Müller from Max Plank Institute for Informatics, this study highlights the dynamic nature of the epigenome in the development of human blood. Our body produces billions of blood cells every day, which develop from a few thousand stem cells at the top of a complex hierarchy of blood cells. Using the latest sequencing and epigenome mapping technology, Bock's team now unraveled a blueprint of blood development that is encoded in the DNA methylation patterns of blood stem cells and their differentiating progeny. This success was made possible by close international cooperation of European scientists: Blood donations of British volunteers were sorted by cell type by the team of Mattia Frontini at the University of Cambridge. These samples were shipped to Austria, where CeMM scientists performed the epigenome mapping. All data were then processed in Germany at the Max Plank Institute for Informatics and jointly analyzed by scientists at CeMM and at the Max Plank Institute for Informatics. The result of the combined effort of Bock's team and many other members of IHEC is a detailed map of the human epigenome, similar to a three-dimensional mountain landscape: The stem cells reside on the mountain top, with valleys of cellular differentiation descending in many directions. As the cells differentiate, they pick one of several epigenetically defined routes and follow it downhill, eventually arriving at one specific valley, corresponding to a specialized cell type. Cells cannot easily escape these valleys, which provides robustness and protection against diseases such cancer. Two other studies by Christoph Bock's team were published earlier this year and showcase how researchers are seeking to utilize epigenetic information for medicine. For instance, certain routes of differentiation are jammed in leukemia, such that cells can no longer reach their destination and take wrong turns instead. Surveillance of those cells by epigenetic tests can contribute to a more precise diagnosis of leukemia - clinical tests of this approach are ongoing. „The epigenetic map of the human blood helps us understand how leukemia develops and which cells drive the disease" says Christoph Bock. This is relevant to cancer diagnostics and personalized medicine, and it provides a compass for future efforts aiming to reprogram the epigenome of individual cells, for example by erasing critical epigenetic alterations from leukemia cells. "The collection of manuscripts released by IHEC impressively demonstrates how epigenetic information and analyses can help find answers to pressing questions related to the cellular mechanisms associated with complex human diseases", said Professor Hendrik (Henk) Stunnenberg from Radboud University, The Netherlands, former Chair of the IHEC International Scientific Steering Committee and coordinator of the EU-funded BLUEPRINT project. The Study "DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation" is published on 17 November 2016 in Cell Stem Cell, DOI:10.1016/j.stem.2016.10.019 Funding: This study was partly funded by the BLUEPRINT Project of the European Union. Christoph Bock is a Principal Investigator at CeMM. Trained as a bioinformatician, he leads a team that integrates biology, medicine, and computer science - working on a vision of precision medicine that is driven by large datasets and a deep understanding of disease mechanisms. He is also a guest professor at the Medical University of Vienna's Department for Laboratory Medicine, and he coordinates the genome sequencing activities of CeMM and the Medical University of Vienna. At CeMM, he co-initiated and leads Genom Austria, the Austrian contribution to the International Network of Personal Genome Projects, and he is a principal investigator in the BLUEPRINT project and the International Human Epigenome Consortium. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. The project BLUEPRINT - A BLUEPRINT of Haematopoietic Epigenomes is a large-scale research project receiving close to 30 million Euro funding from the EU. 42 leading European universities, research institutes and industry entrepreneurs participate in what is one of the two first so-called high impact research initiatives to receive funding from the EU. For more information, please visit: The International Human Epigenome Consortium (IHEC) is a global consortium with the primary goal of providing free access to high-resolution reference human epigenome maps for normal and disease cell types to the research community. IHEC members support related projects to improve epigenomic technologies, investigate epigenetic regulation in disease processes, and explore broader gene-environment interactions in human health. Current full members of IHEC include: AMED-CREST/IHEC Team Japan; DLR-PT for BMBF German Epigenome Programme DEEP; CIHR Canadian Epigenetics Environment, and Health Research Consortium (CEEHRC); European Union FP7 BLUEPRINT Project; Hong Kong Epigenomics Project; KNIH Korea Epigenome Project; the NIH/NHGRI ENCODE Project; the NIH Roadmap Epigenomics Program; and the Singapore Epigenome Project. For more information, please visit: For further information please contact Mag. Wolfgang Däuble Media Relations Manager CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 http://www.

News Article | November 29, 2016

"Till death do us part" – for marine bristle worms, these words are invariably true: Shortly after mating, the parent worms die, leaving thousands of newly fertilized eggs to develop in the water. This extreme all-or-nothing mode of reproduction demonstrates a general principle: Animals need to decide if they invest their available energy stores either in growth or in reproduction. Researchers around Florian Raible at the Max F. Perutz Laboratories (MFPL) of the University of Vienna and Medical University of Vienna were now able to solve a 60-year-old riddle and determine the molecule that orchestrates this decision in marine bristle worms. Their results are published in the journal eLife. All organisms need energy, but sources of energy such as food are usually available in limited quantities. Animals therefore need ways to decide on how to best invest their resources. Reproduction is often associated with significant investments, especially when animals produce large quantities of offspring, at the expense of their own growth or well-being. Animal species with an all-or-nothing mode of reproduction have evolved this principle to an extreme: when they reproduce, they invest all available energy into their offspring and then die. For them, reproduction hence becomes a life-or-death decision. The research team of Florian Raible investigates the molecular signals that allow animals to take this central decision. For this, the team takes advantage of the marine bristle worm Platynereis. The brain of these worms had long been known to produce a master hormone that decides on whether the animal should grow, or reproduce and die. The researchers were now able to identify this hormone as the molecule Methylfarnesoate (MF). The hormone was found to directly repress the production of yolk protein in female worms, thereby interfering with an energy-costly step of reproduction. "Identifying MF as a master hormone in the worm brain came as quite a surprise", explains Sven Schenk, first author on the study. "MF and related substances had previously been thought to have evolved only in insects and related animal groups. So our discovery that this substance acts in worms means that this is likely anancient type of hormone that originated much earlier in animal evolution than anyone would have thought." But the discovery also revealed a possible ecological threat: As substances like MF were long thought to be specific to insects, many insecticides have been developed to precisely target this hormone pathway. These include the insecticides currently used on a large scale to fight the tiger mosquito, the animal known to transmit Zika virus. When the team tested these substances in the lab, they turned out to interfere with the hormone signaling of the worms as well. "That finding is concerning", Sven Schenk explains, "because it indicates that after spraying these substances, they may have a wider impact on the ecosystem than intended." The researchers will now focus on determining how widespread this hormone is in other animal groups related to the worms, such as snails or mussels, to get further insight into its role in the animal kingdom. But the team also has another interest. As Florian Raible explains: "The marine bristle worms are long known to respond to moon light and to reproduce only at particular times in the month. Having identified a critical regulator of reproduction, we and our colleagues from the research platform 'Rhythms of Life' are therefore one step closer to decipher how this intriguing timing mechanisms works." To identify the hormone, the team used funds provided by the European Research Council (ERC) and the Austrian Science Fund (FWF). The discovery also relied on the collaboration with the team of Christoph Gerner from the Analytical Chemistry Department. This collaboration was enabled by the interdisciplinary research platform "Rhythms of Life" that is funded by the University of Vienna. More information: Sven Schenk et al. Discovery of methylfarnesoate as the annelid brain hormone reveals an ancient role of sesquiterpenoids in reproduction, eLife (2016). DOI: 10.7554/eLife.17126

News Article | October 28, 2016

Scientists at the Charité -- Universitätsmedizin Berlin found which molecules of the house dust mites are initially targeted by the immune system of children developing, even years later, allergic rhinitis and asthma. The discovery, published in the Journal of Allergy and Clinical Immunology, will open up new avenues not only to novel and more precise therapies, but also to a successful prediction and prevention of chronic rhinitis and asthma caused or aggravated by allergy to house dust mites. The study team was lead by Professor Paolo Maria Matricardi, head of the Molecular Allergology Group at the Department of Pediatric Pulmonology and Immunology of the Charité and included researchers from the Medical University of Vienna, lead by Prof. Rudolf Valenta, and statisticians from Rome, Italy. The team examined the data and blood samples prospectively collected over 20 years from a cohort of 722 German children born in 1990 and monitored since their birth in the framework of the Multicenter Allergy Study (MAS). Purified or engineered molecules of the mite Dermatophagoides Pteronyssinus were used with nanotechnology procedures to characterize the origins and evolution of the antibody response during the children's first decades of life The scientists found that IgE-antibodies against three dust mite molecules (Der p 1, Der p 2 and Der p 23) appeared very early in the children's blood, often before the onset of their disease. In some (but not all) children, this first step was followed by a "cascade" of events involving other mite molecules, through a phenomenon defined as "molecular spreading." Children producing IgE to many molecules ("polymolecular sensitization") had a higher risk of developing allergic rhinitis and asthma. Earlier onset of allergic sensitization, high exposure to house dust mite allergens, and having one or both parents affected by hay fever increased the risk of polymolecular sensitization. Interestingly, healthy pre-school children showing IgE antibodies to Der p 1 or Der p 23 developed more frequently asthma at school age. These and other molecules may be used for disease prevention in early life and to precisely tailor allergen immunotherapy in pediatric and adult patients. "Mite allergy develops in childhood like an avalanche. It starts early with only one or a very few molecules and then grows to many," says Dr Daniela Posa,, first Author of the publication. "The greater the spreading of molecular sensitization, the highest the risk of developing Asthma." PD. Dr. Matricardi adds: "Our findings open new perspectives to the use of mite allergen molecules for prediction, prevention and therapy of allergic rhinitis and asthma caused or triggered by House Dust Mites."

News Article | October 26, 2016

Scientists at the Charité-Universitätsmedizin Berlin have found which molecules from house dust mites are initially targeted by the immune system of children who develop (even years later) allergic rhinitis and asthma. The discovery, published in the Journal of Allergy and Clinical Immunology, will open up new avenues not only to novel and more precise therapies, but also to a successful prediction and prevention of chronic rhinitis and asthma caused or aggravated by allergies to house dust mites. The study team was led by Professor Paolo Maria Matricardi, head of the Molecular Allergology Group at the Department of Pediatric Pulmonology and Immunology of the Charité and included researchers from the Medical University of Vienna, lead by Professor Rudolf Valenta, and statisticians from Rome. The team examined the data and blood samples collected over 20 years from a group of 722 German children born in 1990; they were monitored since their birth in the framework of the Multicenter Allergy Study (MAS). Purified or engineered molecules of the mite Dermatophagoides Pteronyssinus were used with nanotechnology procedures to characterize the origins and evolution of the antibody response during the children’s first decades of life. The scientists found that IgE-antibodies against three dust mite molecules (Der p 1, Der p 2, and Der p 23) appeared very early in the children’s blood, often before the onset of their disease. In some (but not all) children, this first step was followed by a “cascade” of events involving other mite molecules, through a phenomenon defined as “molecular spreading.” Children producing IgE to many molecules (“polymolecular sensitization”) had a higher risk of developing allergic rhinitis and asthma. Earlier onset of allergic sensitization, high exposure to house dust mite allergens, and having one or both parents affected by hay fever increased the risk of polymolecular sensitization. Interestingly, healthy pre-school children showing IgE antibodies to Der p 1 or Der p 23 developed more frequently asthma at school age. These and other molecules may be used for disease prevention in early life and to precisely tailor allergen immunotherapy in pediatric and adult patients. “Mite allergy develops in childhood like an avalanche. It starts early with only one or a very few molecules and then grows to many,” says Dr. Daniela Posa, first author of the publication. "The greater the spreading of molecular sensitization, the highest the risk of developing Asthma." Matricardi adds, “Our findings open new perspectives to the use of mite allergen molecules for prediction, prevention and therapy of allergic rhinitis and asthma caused or triggered by house dust mites.”

Harrison C.,Guys Hospital | Kiladjian J.-J.,University Paris Diderot | Al-Ali H.K.,University of Leipzig | Gisslinger H.,Medical University of Vienna | And 10 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. METHODS: We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. RESULTS: A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. CONCLUSIONS: Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; number, NCT00934544.). Copyright © 2012 Massachusetts Medical Society.

Watanabe H.,University of Heidelberg | Schmidt H.A.,Medical University of Vienna | Kuhn A.,University of Heidelberg | Hoger S.K.,University of Heidelberg | And 4 more authors.
Nature | Year: 2014

In bilaterians, three orthogonal body axes define the animal form, with distinct anterior-posterior, dorsal-ventral and left-right asymmetries. The key signalling factors are Wnt family proteins for the anterior-posterior axis, Bmp family proteins for the dorsal-ventral axis and Nodal for the left-right axis. Cnidarians, the sister group to bilaterians, are characterized by one oral-aboral body axis, which exhibits a distinct biradiality of unknown molecular nature. Here we analysed the biradial growth pattern in the radially symmetrical cnidarian polyp Hydra, and we report evidence of Nodal in a pre-bilaterian clade. We identified a Nodal-related gene (Ndr) in Hydra magnipapillata, and this gene is essential for setting up an axial asymmetry along the main body axis. This asymmetry defines a lateral signalling centre, inducing a new body axis of a budding polyp orthogonal to the mother polyp's axis. Ndr is expressed exclusively in the lateral bud anlage and induces Pitx, which encodes an evolutionarily conserved transcription factor that functions downstream of Nodal. Reminiscent of its function in vertebrates, Nodal acts downstream of β-Catenin signalling. Our data support an evolutionary scenario in which a 'core-signalling cassette' consisting of β-Catenin, Nodal and Pitx pre-dated the cnidarian-bilaterian split. We presume that this cassette was co-opted for various modes of axial patterning: for example, for lateral branching in cnidarians and left-right patterning in bilaterians. © 2014 Macmillan Publishers Limited. All rights reserved.

Blachier M.,University Paris Est Creteil | Leleu H.,University Paris Est Creteil | Peck-Radosavljevic M.,Medical University of Vienna | Valla D.-C.,French Institute of Health and Medical Research | Roudot-Thoraval F.,University Paris Est Creteil
Journal of Hepatology | Year: 2013

To survey the burden of liver disease in Europe and its causes 260 epidemiological studies published in the last five years were reviewed. The incidence and prevalence of cirrhosis and primary liver cancer are key to understand the burden of liver disease. They represent the end-stage of liver pathology and thus are indicative of the associated mortality. About 0.1% of Hungarian males will die of cirrhosis every year compared with 0.001% of Greek females. WHO estimate that liver cancer is responsible for around 47,000 deaths per year in the EU. Harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to overweight and obesity are the leading causes of cirrhosis and primary liver cancer in Europe. Chronic hepatitis B affects 0.5-0.7% of the European population. In the last decade the prevalence of chronic hepatitis C was 0.13-3.26%. It is of great concern that about 90% of people in Europe infected by viral hepatitis are unaware of their status. Available data suggest the prevalence rate of NAFLD is 2-44% in the general European population (including obese children) and 42.6-69.5% in people with type 2 diabetes. Each of these four major causes of liver disease is amenable to prevention and treatment, reducing the burden of liver disease in Europe and saving lives. Further surveys are urgently needed to implement cost-effective prevention programmes and novel treatments to tackle this problem.

Mosti G.,Clinica MD Barbantini | Partsch H.,Medical University of Vienna
European Journal of Vascular and Endovascular Surgery | Year: 2012

Background: Graduated compression is routinely employed as standard therapy for chronic venous insufficiency. Aim: The study aims to compare the haemodynamic efficiency of a multi-component graduated compression bandage (GCB) versus a negative graduated compression bandage (NGCB) applied with higher pressure over the calf. Methods: In 20 patients, all affected by greater saphenous vein (GSV) incompetence and candidates for surgery (Clinical, etiologic, anatomic and pathophysiologic data, CEAP C2-C5), the ejection fraction of the venous calf pump was measured using a plethysmographic method during a standardised walking test without compression, with GCB and NGCB, all composed of the same short-stretch material. Sub-bandage pressures were measured simultaneously over the distal leg and over the calf. Results: NGCBs with median pressures higher at the calf (62 mmHg) than at the distal leg (50 mmHg) achieved a significantly higher increase of ejection fraction (median +157%) compared with GCB, (+115%) with a distal pressure of 54 mmHg and a calf pressure of 28 mmHg (P < 0.001). Conclusions: Patients with severe venous incompetence have a greater haemodynamic benefit from NGCB, especially during standing and walking, than from GCB. © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Mosti G.,Clinica MD Barbantini | Partsch H.,Medical University of Vienna
European Journal of Vascular and Endovascular Surgery | Year: 2014

Background Previous studies have shown that so-called progressive elastic compression stockings (PECS) with a negative pressure gradient have a more pronounced effect on venous pump function than conventional, graduated stockings. The aim of this study was to investigate the effect of higher graduated and non-graduated pressures on the venous calf pump in patients with venous disease. Methods The ejection fraction (EF) of the calf pump was measured by plethysmography under a standardized walking test in 20 patients suffering from chronic venous disease (CEAP C2-C5) without compression, (a) with one and (b) two PECS on top of each other, and (c) with one additional conventional stocking covering only the gaiter area to achieve a graduated high pressure profile. Interface pressure was measured in the gaiter area and on the calf. Results A significant improvement of EF compared with baseline was found with all three compression modalities. The two superimposed PECS, providing median pressures of 33 mmHg in the gaiter area and 46 mmHg at calf level, increased EF significantly up into the normal range. Increasing the gaiter pressure to 56 mmHg without changing the calf pressure did not result in further improvement. Conclusions Two PECS applied on top of each other lead to a maximal improvement of the venous pump function, which cannot be further improved by increasing the pressure in the gaiter area thereby restoring a graduated pressure profile.

Kessler J.,University of Heidelberg | Marhofer P.,Medical University of Vienna | Hopkins P.M.,University of Leeds | Hollmann M.W.,Academic Medical Center Amsterdam
British Journal of Anaesthesia | Year: 2015

Background: Our aim was to review the recent evidence for the efficacy of peripheral regional anaesthesia. Methods: Following a systematic literature search and selection of publications based on prospectively agreed upon criteria, we produced a narrative review of the most commonly performed peripheral regional anaesthetic blocks for surgery on the upper limb, the lower limb, and the trunk. We considered short-term and longer-term benefits and complications among the outcomes of interest. Results: Where good quality evidence exists, the great majority of the blocks reviewed were associated with one or any combination of reduced postoperative pain, reduced opioid consumption, or increased patient satisfaction. For selected surgical procedures, the use of blocks avoided general anaesthesia and was associated with increased efficiency of the surgical pathway. The exceptions were supraclavicular block, where there was insufficient evidence, and transversus abdominis plane block, where the evidence for efficacy was conflicting. The evidence for the impact of the blocks on longer-term outcomes was, in general, inadequate to inform clinical decision making. Permanent complications are rare.Conclusions: The majority of peripheral regional anaesthetic techniques have been shown to produce benefits for patients and hospital efficiency. Further interventional trials are required to clarify such benefits for supraclavicular block and transversus abdominis plane block and to ascertain any longer-term benefits for almost all of the blocks reviewed. Permanent complications of peripheral regional anaesthetic blocks are rare but accurate estimates of their incidence are yet to be determined. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.

Fellinger J.,11 Health | Fellinger J.,Medical University of Vienna | Holzinger D.,11 Health | Holzinger D.,University of Graz | Pollard R.,University of Rochester
The Lancet | Year: 2012

Deafness is a heterogeneous condition with far-reaching effects on social, emotional, and cognitive development. Onset before language has been established happens in about seven per 10 000 people. Increased rates of mental health problems are reported in deaf people. Many regard themselves as members of a cultural minority who use sign language. In this Review, we describe discrepancies between a high burden of common mental health disorders and barriers to health care. About a quarter of deaf individuals have additional disabilities and a high probability of complex mental health needs. Research into factors affecting mental health of deaf children shows that early access to effective communication with family members and peers is desirable. Improved access to health and mental health care can be achieved by provision of specialist services with professionals trained to directly communicate with deaf people and with sign-language interpreters. © 2012 Elsevier Ltd.

Mannon P.,University of Alabama at Birmingham | Reinisch W.,Medical University of Vienna
Gut | Year: 2012

Interleukin 13 (IL-13) is a cytokine of increasing interest to gastroenterologists because of its developing role in ulcerative colitis, eosinophilic oesophagitis (EO) and fibrosis. Recent data show that IL-13 may play an important role in a novel innate immune response since it can be released by signals from an injured or inflamed epithelium, of particular relevance to the gut. Animal models of IL-13-driven inflammation (from asthma to colitis and EO) are being translated to human disease and providing insight into potential strategies for new therapies. In fact, multiple clinical trials using anti-IL-13 drugs are underway in asthma and are being extended to gastrointestinal diseases. This review presents the current knowledge on IL-13 production and function in the gut, including the cells and receptor signalling pathways involved in mediating IL-13 effects, the proposed mechanisms of IL-13 induced gut disease and the many drugs currently being tested that target IL-13 related pathways.

Radad K.,Assiut University | Moldzio R.,Medical University of Vienna | Rausch W.-D.,Medical University of Vienna
CNS Neuroscience and Therapeutics | Year: 2011

Ginsenosides are a special group of triterpenoid saponins attributed to medical effects of ginseng. Therefore, they have been research targets over the last three decades to explain ginseng actions and a wealth of literature has been presented reporting on ginsenosides' effects on the human body. Recently, there is increasing evidence on beneficial effects of ginsenosides to the central nervous system (CNS). Using a wide range of in vitro and in vivo models, researchers have attributed these effects to specific pharmacological actions of ginsenosides on cerebral metabolism, oxidative stress and radical formation, neurotransmitter imbalance and membrane stabilizing effects, and even antiapoptotic effects. Modulating these particular mechanisms by ginsenosides has thus been reported to exert either general stimulatory effects on the brain functions or protecting the CNS against various disease conditions. In this review, we try to address the recently reported ginsenosides' actions on different CNS targets particularly those supporting possible therapeutic efficacies in CNS disorders and neurodegenerative diseases. © 2010 Blackwell Publishing Ltd.

Teperino R.,Max Planck Institute of Immunobiology and Epigenetics | Aberger F.,University of Salzburg | Esterbauer H.,Medical University of Vienna | Riobo N.,Thomas Jefferson University | Pospisilik J.A.,Max Planck Institute of Immunobiology and Epigenetics
Seminars in Cell and Developmental Biology | Year: 2014

Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, Hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease. © 2014 Elsevier Ltd.

Babjuk M.,Charles University | Burger M.,University of Würzburg | Zigeuner R.,Medical University of Graz | Shariat S.F.,Medical University of Vienna | And 8 more authors.
European Urology | Year: 2013

Context The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated. Objective To present the 2013 EAU guidelines on non-muscle-invasive bladder cancer (NMIBC). Evidence acquisition Literature published between 2010 and 2012 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence and grades of recommendation were assigned. Evidence synthesis Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the EORTC scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or by further instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the guidelines is available from the EAU Web site: Conclusions These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated version of their guidelines. Current clinical studies support patient selection into different risk groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystectomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are in the highest risk group for progression. © 2013 European Association of Urology.

Fagiolini A.,University of Siena | Comandini A.,Angelini ACRAF SpA | Dell'Osso M.C.,Marche Polytechnic University | Kasper S.,Medical University of Vienna
CNS Drugs | Year: 2012

Trazodone is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs). The drug is approved and marketed in several countries worldwide for the treatment of major depressive disorder (MDD) in adult patients. In clinical studies, trazodone has demonstrated comparable antidepressant activity to other drug classes, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). Moreover, the SARI action of trazodone may overcome the tolerability issues that are often associated with second-generation antidepressants such as SSRIs (i.e. insomnia, anxiety and sexual dysfunction). Recent focus has been placed on the development of a new prolonged-release once-a-day formulation of trazodone (TzCOAD), which may provide improved tolerability over the conventional immediate-release formulation of trazodone. Clinical studies have led to the recent approval in the USA of TzCOAD (as Oleptro™; Angelini Labopharm LLC, Princeton, NJ, USA), which may see resurgence of interest in the drug for the management of patients with MDD. Although trazodone is approved for the treatment of depression, evidence supports the use of low-dose trazodone as an off-label hypnotic for the treatment of sleep disorders in patients with MDD. The most common adverse effects reported with trazodone are drowsiness (somnolence/sedation), headache, dizziness and dry mouth. Other events reported, albeit with low incidence, include orthostatic hypotension (particularly in elderly patients or those with heart disease), minimal anticholinergic activity, corrected QT interval prolongation and torsade de pointes, cardiac arrhythmias, and rare occurrences of priapism and suicidal ideation. Overall, trazodone is an effective and well tolerated antidepressant (SARI) with an important role in the current treatment of MDD both as monotherapy and as part of a combination strategy. Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants. The recently approved prolonged-release formulation should provide further optimization of this antidepressant and may be useful for enabling an appropriate therapeutic dose to be administered with improved patient compliance. © 2012 The Author(s).

Sharma V.,Institute of Kidney Diseases and Research Center | Margreiter M.,Medical University of Vienna
Current Urology Reports | Year: 2013

Long-term outcome data indicate that open partial nephrectomy has cancer-free survival rates comparable to those of radical surgery, with better preservation of renal function, decreased overall mortality and reduced frequency of cardiovascular events. Open partial nephrectomy is increasingly being challenged by laparoscopic and/or robot assisted partial nephrectomy, which in the hands of experts appears to achieve comparable oncological results, albeit at a higher complication rate. We report a review based on literature published over the past years, which may provide insight into the role of open partial nephrectomy in the present urological practice and in years to come. © 2012 Springer Science+Business Media New York.

Jones H.E.,Johns Hopkins University | Kaltenbach K.,Thomas Jefferson University | Heil S.H.,University of Vermont | Stine S.M.,Wayne State University | And 6 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Methadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy. METHODS: We conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites. Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference. RESULTS: Treatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091), and had a significantly shorter duration of treatment for the neonatal abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance with prespecified thresholds for significance). There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events. CONCLUSIONS: These results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women. (Funded by the National Institute on Drug Abuse; number, NCT00271219.). Copyright © 2010 Massachusetts Medical Society.

Gukovsky I.,University of California at Los Angeles | Li N.,University of California at San Diego | Todoric J.,University of California at San Diego | Todoric J.,Medical University of Vienna | And 2 more authors.
Gastroenterology | Year: 2013

Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research. © 2013 by the AGA Institute.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.5-1 | Award Amount: 7.81M | Year: 2010

Non-alcoholic fatty liver disease (NAFLD) has become one of the top concerns for the practising hepatogastroenterologist due to the obesity epidemic and its potential to progress to advanced liver disease which significantly impacts on overall and liver-related mortality. The aim of the FLIP (Fatty Liver: Inhibition of Progression) project is to understand and prevent the progression of liver disease in NAFLD. FLIP is a consortium of basic scientists and practising clinical hepatologists with an established track record and focus on research into the underlying mechanisms and management of patients with NAFLD. Therefore FLIP provides a unique opportunity to assemble the largest European cohort of patients with histologically diagnosed NAFLD with clinical and epidemiological data and with biobanks of DNA, frozen liver tissue and serum. These will be used in a wide range of collaborative inter-disciplinary research projects aimed at addressing key unanswered questions related to the mechanisms and consequences of liver injury in NAFLD and the development of novel preventive and therapeutic strategies. The main outcomes of FLIP will be new insights in the progression of liver disease in NAFLD in terms of initiating mechanisms and patients at risk, innovative diagnostic methods particularly adapted for large-scale screening and prognostic evaluation, improved implementation of lifestyle changes, collaboration with leading biotechnological or pharmaceutical companies in order to translate to the market diagnostic tests or newly identified molecular targets for pharmacological therapy. By disseminating the projects results, FLIP will further help the European Community to suggest guidelines on the management of this emerging liver disease. The long-term goal is to lay the foundations for the future of NAFLD research in Europe by creating a Collaborative Research Network on NAFLD that will continue the work initiated by the FLIP consortium.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.4-1 | Award Amount: 9.25M | Year: 2010

Leukodystrophies (LDs) are inherited rare neurodegenerative diseases of the white matter and its main component, the myelin, that are affecting predominantly children. Severity of the disease is related to the axonal dysfunction due to myelin deficiency or destruction. Despite the achievement of remarkable advances made in the past decade, there is no current curative therapy. The development of therapeutic approaches for myelin repair and neuroprotection constitutes the main objective of the LeukoTreat project. Indeed LDs constitute prototypic pathologies to tackle myelin formation/destruction issues as well as glial cells dysfunctions in neurodegeneration. The global aim is to promote the development of therapeutic strategies for the largest number of LD affected patients and further applications to more common white matter disorders and finally neurodegenerative diseases. For this purpose, the project will combine the expertise of (i) recognized European research teams in the field of White Matter diseases (COST Myelinet), (ii) high-technology SMEs, (iii) experts in medical ethics and (iv) LD patients and families associations. To develop efficient therapies, the LeukoTreat project is based on 5 complementary approaches consisting in: (i) collecting information on the epidemiology, the natural history, the genotype/phenotype correlation of LDs for at least 500 patients; (ii) validating/identifying biomarkers for therapeutic decisions/follow up to isolate new therapeutic targets; (iii) developing pharmacological strategies with the ultimate objective to launch at least 4 pharmacological clinical trials during 5 years following the project; (iv) developing innovative gene and cell therapies with the ultimate objective to launch at least 3 clinical trials during the next 5 years; (v) tackling ethical impacts of the proposed therapeutic challenges by integrating the participation of patients driven by a well-experienced research team strongly skilled in ethics

Agency: Cordis | Branch: FP7 | Program: CSA-SA | Phase: HEALTH-2007-2.4.4-2 | Award Amount: 1.07M | Year: 2008

This project aims at creating a set of tools intended to facilitate collaborations between academic teams, SMEs and even major companies, in the field of rare diseases (RD). These tools will contribute to building up a community of stakeholders with the ultimate goal of speeding up RD research and development, providing diagnostic tools and therapies as quickly as possible. The specific objectives are to: - identify expert groups in Europe, on-going funded research projects, technological platforms, databases and biobanks relevant to RD research and to release the information in a user-friendly manner on the existing Orphanet website. - identify, among research projects funded at the MS level and at the EU level, those which are in need of partnership with other academic teams and/or which have a potential for market development and may benefit from a partnership with Industry. - release the information on partnership opportunities on the existing OrphanXchange website and adapt the website to meet the needs of all the types of partnerships identified so far. - develop partner search facilities based on the above mentioned databases and on an ad-hoc basis. - develop an electronic newsletter informing the community about newly posted partnership requests and business opportunities. - organise two workshops with top experts to analyse areas in need of collaborative research projects. The new facilities will be developed from three existing RD websites previously funded through EC grants: - serving as a management tool and a follow-up tool between partners. - serving as a tool to facilitate partnership between academic researchers, Industry, and private companies - providing information on on-going research activities in Europe. This project is based on input from four EU projects: Orphanet, OrphanPlatform, E-Rare ( and the RD Task Force (

Agency: Cordis | Branch: FP7 | Program: BSG-SME | Phase: SME-1 | Award Amount: 1.36M | Year: 2010

Colorectal cancer and lung cancer cause millions of death each year. Currently there is no suitable non-invasive method for the early detection of these types of cancer. The tumour suppressor gene BARD1 (BRCA1-associated RING domain protein) is aberrantly expressed in several types of cancer and could be a diagnostic target for early cancer diagnosis in blood samples. The overall objective of the project is to develop blood tests for the early detection of colorectal and lung cancer based on cancer-specific BARD1 isoforms. The outlined tests will analyse BARD1 isoforms at two levels: the expression of isoform-specific RNA in circulating tumour cells (CTC) and the presence of isoform-specific autoantibodies in serum. To reach these objectives, several technological challenges have to be overcome. The BARDiag consortium includes 3 SMEs and 4 research centres, who have excellent expertise, specific knowledge, the required lab infrastructure and necessary clinical materials that will enable to conduct this project. Within the frame of the project, innovative methods for the isolation of CTCs in colorectal and lung cancer patients will be developed, the specific signatures of the BARD1 isoforms at both mRNA and autoimmune levels will be defined, and assays for the detection of these isoforms will be established, validated with clinical samples and tested for their marketability. The results of the proposed project will have extensive impacts. Not only more scientific knowledge on the expression of BARD1 isoforms in colorectal and lung cancer will be obtained and therefore the understanding for cancer will be improved, but also non-invasive methods for the early detection of colorectal and lung cancer will be made broadly available in form of commercial test kits. The SMEs will extend their expertise and knowledge and therefore strengthen their economic power, which will contribute to increase European competitiveness.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: ICT-29-2016 | Award Amount: 3.69M | Year: 2016

The rising life expectancy of EU citizens is creating a dramatic increase in age-related degenerative diseases and associated healthcare costs. The MOON Project (Multi-modal Optical Diagnostics for Ocular and Neurodegenerative Disease) meets this societal challenge by applying photonics to diagnose age-related diseases of the eye and central nervous system. Consistent with the ICT-29-2016: Photonics KET 2016 Work Program, MOON will design and build a multi-band, multimodal and functional imaging platform combining label-free molecularly sensitive Raman spectroscopy with high speed and high-resolution Optical Coherence Tomography (OCT), for in-depth diagnostics of ocular and neurodegenerative diseases. MOON will enhance OCT already the gold standard of retinal imaging - through the development of a disruptive laser technology that enables wide-field structural and functional imaging. MOON will establish a reference database for molecular biomarkers of addressed diseases that enables, for the first time, in-depth molecular-specific diagnosis of retinal diseases and neurodegenerative pathologies based on Raman spectroscopy. The MOON system will be validated in vivo in a clinical setting through close collaboration between clinicians and commercial partners. The clinical validation will establish the diagnostic accuracy of the multi-modal platform, while also verifying the ease-of-use needed for widespread adoption. MOON is driven by unmet medical user needs in diagnostic imaging with a clear business case addressing the highly promising ophthalmic market of early and in-depth molecularly sensitive diagnostics of retinal and neurodegenerative diseases. The three industrial partners cover the complete value/supply chain. MOON aims to bridge the gap between research and product development, thereby expediting the commercialization of the MOON technologies, strengthening the participating companies, and creating a competitive advantage for the European photonics market.

Agency: Cordis | Branch: FP7 | Program: CSA-SA | Phase: HEALTH-2007-3.4-1;HEALTH-2007-3.4-3 | Award Amount: 962.24K | Year: 2009

European Centres of Expertise Networks for rare diseases have been identified by the European Commission as one important area of future activity in the attempt of achieving one of the main objectives across the EC endeavour of Optimising the delivery of health care to European Citizens. It is obvious that especially in rare diseases the joined forces of the experts networking throughout Europe are more likely than national services to meet the needs and expectations of patients. The construction and implementation of European networks of centres of expertise (ENCE) call for input from many different stakeholders: patients and doctors and other care team members, clinical researchers, health administration, and health insurers will have to be heard to come to a model of such networks that can easily be used as blueprint for most of the rare disorders. To achieve this goal first a mapping exercise of existing networks and elements needed for such networking has to be done. We plan to do so for three different rare entities, i.e. cystic fibrosis (CF), pulmonary lymphangioleiomyomatosis (LAM), and lung transplantation (LTX), having in common that they all comply with the EC definition of a rare disease. From the information gathered during this process the areas of activity and a detailed set of criteria for such European networks will be developed. These construction principles will be brought together in a blueprint to be used for other rare disorders. These criteria can then be used for certification, quality control, and funding of a European system of networks. Networking in this European sense will make the best possible use of resources already existing and remaining in the responsibility of the individual member states by interfacing and complementing these present and future elements. This will help the health care system partners to learn from the best and improve the quality of care to the best European level of expertise.

Westbrook A.M.,University of California at Los Angeles | Szakmary A.,Medical University of Vienna | Schiestl R.H.,University of California at Los Angeles | Schiestl R.H.,Medical University of Vienna
Mutation Research - Reviews in Mutation Research | Year: 2010

Chronic inflammation is strongly associated with approximately 1/5th of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With regards to extraintestinal manifestations such as lymphoma, however, more suitable models are required to further investigate the complex and heterogeneous mechanisms that may be at play. © 2010 Elsevier B.V. All rights reserved.

News Article | October 31, 2016

CeMM/MedUni Vienna Researchers discovered how hemolysis causes infections and found a new means to prevent it, paving the way to new treatment possibilities Worldwide, millions of people suffer from hemolysis, the breakdown of red blood cells, such as those afflicted with sickle-cell disease, malaria or sepsis. These patients face an unprecedented risk of death from bacterial infections and the mechanism for this has remained unclear until now. In the latest edition of Nature Immunology, Sylvia Knapp's Group at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna, uncovers the molecular mechanisms that explain how hemolysis escalates the risk for infections. This study puts to rest the old belief that iron availability favors bacterial infections in hemolytic disorders, and moreover reveals a new treatment approach to protect patients with hemolysis from infections. (Vienna, 31. October 2016) For decades, iron has been considered the prime suspect responsible for the high rate of bacterial infections in patients with hemolysis (bursting of red blood cells). Iron is the element, which gives red blood cells their color and moreover, iron has long been established as an essential nutrient for bacteria. Taking that into consideration, the traditional hypothesis predicted that since hemolysis leads to the release of iron-containing heme, the threat of serious bacterial infections in these patients was attributed to the excess availability of circulating iron (heme). A research group led by Sylvia Knapp, Director of Medical Affairs at CeMM and Professor of Infection Biology at the Medical University of Vienna, was able to refute this conventional way of thinking. They revealed that heme was not only failing to act as a willing nutrient to bacteria, heme was instead paralyzing the very innate immune cells sent to protect the host from the bacteria. "Using in vitro and pre-clinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth," explains Rui Martins, PhD student at CeMM and the Medical University of Vienna, and the first author of the study. "In contrast, we found that heme acts on macrophages, the most significant immune cells that are required for mounting an antibacterial response, and it furthermore prevented these cells from eliminating bacteria." The scientists discovered a completely unknown mechanism: The heme molecule interfered with the cytoskeleton of macrophages and thereby immobilized them. Describing the effect of heme, Martins explains further: "Heme causes cells to form numerous spikes, like hair standing on end and then "stuns" the cells within minutes. It is reminiscent of a cartoon character sticking his finger in an electrical outlet." The cytoskeleton is crucial for the basic functions of macrophages. The cytoskeleton consists of long, branching filaments that act as the cell's internal, highly flexible and mobile framework. Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and 'eat' invading bacteria. However, this requires a finely tuned signaling program in which the protein DOCK8 plays a central role. "Through chemical proteomics and biochemical experiments, we discovered that heme interacted with DOCK8, which led to the permanent activation of its downstream target Cdc42, with deleterious effects", explains Sylvia Knapp, the senior author of the study. In the presence of heme, the cytoskeletal resilience is lost, as filaments grow rampant in all directions, resulting in macrophage paralysis--in other words, the cells lose their ability to shape-shift and can no longer chase down and 'eat' the invading bacteria. The resultant impact is that bacteria can multiply virtually unrestricted. The loss of cytoskeletal resilience results in life-threatening conditions for millions of people worldwide, which suffer from hemolysis due to systemic inflammation (sepsis) or disorders such as sickle-cell disease, or malaria. In the recently published study, scientists led by Sylvia Knapp, were not only able to clarify the molecular effect of heme on macrophages but moreover discovered that an already available medication can restore the functionality of affected (paralyzed) macrophages. "Quinine, which is clinically used to treat malaria and is suspected to bind heme, blocks the interaction of heme with DOCK8 and thereby improves the outcome from sepsis", says Sylvia Knapp. "This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically "protect" immune cells and to restore the body's immune defense against bacteria in hemolytic conditions." The Study "Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions" was published online on October 31, 2016 at 1600 London time / 1200 US Eastern time in Nature Immunology, DOI: 10.1038/ni.3590 The research was funded by the Austrian Science Fund (FWF) via the ERA-Infect framework and by the Science Fund of the Austrian National Bank. Sylvia Knapp is Director of Medical Affairs at CeMM and Professor of Infection Biology at the Medical University of Vienna. She studied Medicine in Vienna and Berlin, is a board-certified Internist and obtained her PhD at the University of Amsterdam. Sylvia's research focuses on the innate immune response to bacterial infections in general, focusing specifically on the comprehensive repertoire of macrophage functions in health, development and disease. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. http://www. The Medical University of Vienna is one of the most traditional medical education establishments with nearly 7,500 students and approximately 5,500 staff members, and one of the most important top-level biomedical research institutions in Europe. Its international outlook is one of its most important pillars and the research focus is centered on immunology, cancer research, imaging, brain research and cardiovascular diseases. https:/ For further information please contact: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 http://www.

News Article | November 11, 2016

In people who suffer from pain disorders, painful feelings can severely worsen and spread to other regions of the body. Patients who develop chronic pain after surgery, for example, will often feel it coming from the area surrounding the initial injury and even in some parts of the body far from where it originates. New evidence suggests glia, non-neuronal cells in the brain, may be the culprits behind this effect. Glia were once thought to simply be passive, supporting cells for neurons. But scientists now know they are involved in everything from metabolism to neurodegeneration. A growing body of evidence points to their key role in pain. In a study published today in Science, researchers at the Medical University of Vienna report that glia are involved in long-term potentiation (LTP), or the strengthening of synapses, in pain pathways in the spinal cord. Neuroscientists Timothy Bliss and Terje Lømo first described LTP in the hippocampus, a brain area involved in memory, in the 1970s. Since then scientists have been meticulously studying the role this type of synaptic plasticity—the ability of synapses to change in strength—plays in learning and memory. More recently, researchers discovered that LTP could also amplify pain in areas where injuries or inflammation occur. “We sometimes call this a ‘memory trace of pain’ because the painful insult may lead to subsequent hypersensitivity to painful stimuli, and it was clear that synaptic plasticity can play a role here,” says study co-author Jürgen Sandkühler, a neuroscientist also at the Medical University of Vienna. But current models of how LTP works could not explain why discomfort sometimes becomes widespread or experienced in areas a person has never felt it before, he adds. There are two forms of LTP. In one, synapses strengthen when two neurons transmit signals or “fire” closely in time. The other form, which has long been thought to be dependent on the first, occurs when activity in one circuit reinforces connections in nearby, inactive neural pathways. In their latest study Sandkühler and colleagues show that these two forms of potentiation can, with the help of glial cells, happen independently of each other. To test the role of glia in pain circuits, the researchers conducted a series of experiments in rat spinal cord slices and live rats and found that they could induce both types of LTP between two pain-related neurons—even in the absence of each other—by activating two types of glia, microglia and astrocytes. In a key experiment they induced LTP in one rat and transferred its spinal fluid to another rat; they found that this could induce LTP in the new animal. These results were evidence that the molecules released from glial cells were capable of strengthening synapses between pain-related neurons on their own. Ru-Rong Ji, a neurobiologist studying pain at Duke University who was not involved in the study, praises the work, but adds, “It would be nice to correlate this measurement with behavioral changes—if you see that the animal not only shows LTP but also shows enhanced or prolonged pain behavior.” The Sandkühler group’s study is the most recent addition to a growing body of evidence that glia—and the molecules they release—are involved in long-term potentiation in the spinal cord. This is, however, one of the first studies to provide evidence this effect could be transferable across long distances, although more studies are needed to confirm this. For example, an experiment should be able to demonstrate LTP can, with the help of glia, spread throughout the spinal cord of a single animal. This is something Sandkühler and his colleagues are working on now. “The paper is very provocative because it competes with the idea that LTP is really a single synapse thing [and suggests] a more global process,” says Yves De Koninck, a neuroscientist studying synaptic transmission at Laval University in Quebec. He wonders, however, whether the spreading effect is dependent on the level of neural activation, pointing out that the researchers used a strong electrical stimulus to trigger pain-related neurons and activate glial cells in this study. It is possible, he notes, a small amount of activation could lead to strengthening of specific synapses and that the effect starts to spread as activation increases. The biggest implications of these findings is that molecules released from glial cells in response to a painful stimulus could travel away from the injury site, increasing sensitivity to pain in other parts of the body. Sandkühler also believes glia might be involved in similar mechanisms in the brain, which may explain why physical sickness also has cognitive effects. “I think that the significance of this work is that it will open up the new thinking,” says Min Zhou, a pain neuroscientist at the University of Toronto who did not take part in the work. “Now we [will start] to look if any additional mechanisms may contribute to pain-related emotional changes in the brain.”

Jilma-Stohlawetz P.,Medical University of Vienna | Knobl P.,Medical University of Vienna | Gilbert J.C.,Archemix | Jilma B.,Medical University of Vienna
Thrombosis and Haemostasis | Year: 2012

Blockade of hyperactive von Willebrand factor (VWF) by ARC1779 blunted the platelet drop induced by desmopressin in patients with type 2B von Willebrand disease (VWD). Thus, we hypothesised that ARC1779 may increase VWF levels and correct thrombocytopenia. Three thrombocytopenic patients suffering from type 2B VWD received a loading dose of 0.23 mg/kg ARC1779 followed by 4 μg/kg/min intravenously for 72 hours in a prospective clinical trial. ARC1779 was well tolerated and safe. Plasma concentrations of ARC1779 increased to 76 μg/ml (59-130) leading to an immediate decrease of free VWF A1 domains. VWF/FVIII levels increased as early as 12 h after start of infusion, peaked near the end of infusion, and returned to baseline at follow-up.VWF ristocetin cofactor activity (VWF:RCo) showed a median 10-fold increase 8 hours after end of infusion, while the median VWF-antigen and FVIII increase was less (5-fold and 4-fold, respectively). Most importantly inhibition of hyperactive VWF rapidly increased platelet counts from 40x109/l (38-58 x109/l) to a maximum of 146 x109/l (107-248 x109/l). In conclusion, ARC1779 markedly increases VWF/FVIII levels and most importantly improves or even corrects thrombocytopenia in VWD type 2B patients. This underscores the in vivo potency of ARC1779. © Schattauer 2012.

Gruenberger T.,Medical University of Vienna | Arnold D.,University of Hamburg | Rubbia-Brandt L.,University of Geneva
Surgical Oncology | Year: 2012

For patients with colorectal liver metastases (CLM), hepatic resection currently offers the best chance for long-term survival. Preoperative chemotherapy is now integral to the management of these patients, conferring a disease-free survival advantage over surgery alone in patients with 'upfront' resectable disease and enabling some initially unresectable CLM to become resectable. However, although surgery may improve long-term survival, up to 65.0% of patients will experience disease recurrence at 5 years and reliable prognostic factors are needed to predict those patients who are more likely to experience recurrence after resection. Recently, pathologic tumor response, defined as the 'objective measurement of residual cancer cells in resected tissue,' has been identified as a reliable prognostic factor in patients with colorectal cancer (CRC) receiving preoperative chemotherapy and has been shown to correlate with improved survival after resection of CLM. Addition of the targeted biologic agent bevacizumab to preoperative chemotherapy is associated with an increase in pathologic response rate and an increase in survival compared with chemotherapy alone in patients undergoing hepatic resection. This review discusses the data in support of pathologic response rate as an important new outcome endpoint after hepatic resection of CLM and considers the evidence to date on pathologic response to bevacizumab-containing chemotherapy in metastatic CRC and its correlation with survival. © 2012 Elsevier Ltd. All rights reserved.

Eckhart L.,Medical University of Vienna | Lippens S.,Molecular Signaling and Cell Death Unit | Lippens S.,Ghent University | Tschachler E.,Medical University of Vienna | And 2 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

Epidermal keratinocytes undergo a unique form of terminal differentiation and programmed cell death known as cornification. Cornification leads to the formation of the outermost skin barrier, i.e. the cornified layer, as well as to the formation of hair and nails. Different genes are expressed in coordinated waves to provide the structural and regulatory components of cornification. Differentiation-associated keratin intermediate filaments form a complex scaffold accumulating in the cytoplasm and, upon removal of cell organelles, fill the entire cell interior mainly to provide mechanical strength. In addition, a defined set of proteins is cross-linked by transglutamination in the cell periphery to form the so-called cornified envelope. Extracellular modifications include degradation of the tight linkages between corneocytes by excreted proteases, which allows corneocyte shedding by desquamation, and stacking and modification of the excreted lipids that fill the intercellular spaces between corneocytes to provide a water-repellant barrier. In hard skin appendages such as hair and nails these tight intercorneocyte connections remain permanent. Various lines of evidence exist for a role of organelle disintegration, proteases, nucleases, and transglutaminases contributing to the actual cell death event. However, many mechanistic aspects of kearatinocyte death during cornification remain elusive. Importantly, it has recently become clear that keratinocytes activate anti-apoptotic and anti-necroptotic pathways to prevent premature cell death during terminal differentiation. This review gives an overview of the current concept of cornification as a mode of programmed cell death and the anti-cell death mechanisms in the epidermis that secure epidermal homeostasis. This article is part of a Special Section entitled: Cell Death Pathways. Guest Editors: Frank Madeo and Slaven Stekovic. © 2013 Elsevier B.V.

Duranton F.,RD Nephrologie | Cohen G.,Medical University of Vienna | De Smet R.,Ghent University | Rodriguez M.,University of Cordoba, Spain | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2012

An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articlesmost frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD. Copyright © 2012 by the American Society of Nephrology.

Arock M.,CNRS Laboratory of Biology and Applied Pharmacology | Valent P.,Medical University of Vienna
Expert Review of Hematology | Year: 2010

Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. Organ systems typically involved are the bone marrow, skin, liver and gastrointestinal tract. In most adult patients, the systemic form of mastocytosis (SM) is diagnosed, which includes an indolent subvariant, an aggressive subvariant and a leukemic subvariant, also termed MC leukemia. Whereas in pediatric mastocytosis, which is usually confined to the skin, a number of different KIT mutations and other defects may be detected, the KIT mutation D816V is detectable in most (adult) patients with SM. In a subset of these patients, additional oncogenic factors may lead to enhanced survival and growth of MCs and, thus, to advanced SM. Other factors may lead to MC activation, with consecutive anaphylactic reactions that can be severe or even fatal. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Unfortunately, the prognosis in these patients remains poor, even when treated with novel KIT-targeting agents, polychemotherapy or stem cell transplantation. This article provides a summary of our knowledge on the pathogenesis and on treatment options in SM. © 2010 Expert Reviews Ltd.

Sonderegger S.,Prince Henrys Institute of Medical Research | Pollheimer J.,Medical University of Vienna | Knofler M.,Medical University of Vienna
Placenta | Year: 2010

The family of secreted Wingless ligands plays major roles in embryonic development, stem cell maintenance, differentiation and tissue homeostasis. Accumulating evidence suggests that the canonical Wnt pathway involving nuclear recruitment of β-catenin and activation of Wnt-dependent transcription factors is also critically involved in development and differentiation of the diverse reproductive tissues. Here, we summarise our present knowledge about expression, regulation and function of Wnt ligands and their frizzled receptors in murine and human endometrial and placental cell types. In mice, Wnt signalling promotes early trophoblast lineage development, blastocyst activation, implantation and chorion-allantois fusion. Moreover, different Wnt ligands play essential roles in the development of the murine uterine tract, in cycling endometrial cells and during decidualisation. In humans, estrogen-dependent endometrial cell proliferation, decidualisation, trophoblast attachment and invasion were shown to be controlled by the particular signalling pathway. Failures in Wnt signalling are associated with infertility, endometriosis, endometrial cancer and gestational diseases such as complete mole placentae and choriocarcinomas. However, our present knowledge is still scarce due to the complexity of the Wnt network involving numerous ligands, receptors and non-canonical pathways. Hence, much remains to be learned about the role of different Wnt signalling cascades in reproductive cell types and their changes under pathological conditions. © 2010 Elsevier Ltd. All rights reserved.

Ekmekcioglu C.,Medical University of Vienna | Touitou Y.,Rothschild
Obesity Reviews | Year: 2011

Overweight and obesity are the result of a chronic positive energy balance, and therefore the only effective therapies are a diet which, on the long term, provides lower calories than the daily expended energy and exercise. Because nearly every physiological and biochemical function of the body shows circadian variations it can be suggested that also different chronobiological aspects of food intake, like time of day, meal frequency and regularity, and also circadian desynchronizations like in shift work may affect energy metabolism and weight regulation. The aim of this review is therefore to summarize and discuss studies that have addressed these issues in the past and to also provide an overview about circadian variations of selected aspects of metabolism, gut physiology and also factors that may influence overall energy regulation. The results show that a chronic desynchronization of the circadian system like in shift work and also sleep deprivation can favour the development of obesity. Also, regarding energy balance, a higher meal frequency and regular eating pattern seem to be more advantageous than taking the meals irregularly and seldom. Additional studies are required to conclude whether time of day-dependent food intake significantly influences weight regulation in humans. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.

Kasper S.,Medical University of Vienna | Hajak G.,Foundation Medicine
European Neuropsychopharmacology | Year: 2013

Objective: Post-hoc analysis of two randomized controlled trials with agomelatine was undertaken to compare data on pretreated versus untreated patients with major depressive disorder. Method: Selected trials were Olié and Kasper (2007), a placebo-controlled trial, and Kasper et al. (2010), a randomized, double-blind comparison with sertraline. Results: A total of 40% and 57.7% of patients had been pretreated with antidepressants in the placebo-controlled trial and sertraline-controlled trial, respectively. In the previously-treated patients in the placebo-controlled study, the mean decrease in the total score on the HAM-D17 over 6 weeks was significantly greater with agomelatine than placebo (delta=4.43, P=0.005) and 67.5% of patients were responders. In the previously-treated patients of the sertraline-controlled study, the improvement on the HAM-D17 total score remained numerically higher with agomelatine (delta=1.63, P=0.124), with 55.2% responders. In both studies, agomelatine was well tolerated. Conclusion: Data from the subset of previously treated depressed patients, who can be considered more difficult to treat, indicate that agomelatine, due to its different mode of action, demonstrated antidepressant efficacy, and favorable side effect profile-with proven benefits in first-line treatment-is also an effective candidate for patients with major depressive disorder previously treated with other antidepressants. © 2013 Elsevier B.V. and ECNP.

Merseburger A.S.,Urologic | Herrmann T.R.W.,Urologic | Shariat S.F.,Medical University of Vienna | Kyriazis I.,University of Patras | And 3 more authors.
European Urology | Year: 2013

Context This is a short version of the European Association of Urology (EAU) guidelines on robotic and single-site surgery in urology, as created in 2013 by the EAU Guidelines Office Panel on Urological Technologies. Objective To evaluate current evidence regarding robotic and single-site surgery in urology and to provide clinical recommendations. Evidence acquisition A comprehensive online systematic search of the literature according to Cochrane recommendations was performed in July 2012, identifying data from 1990 to 2012 regarding robotic and single-site surgery in urology. Evidence synthesis There is a lack of high-quality data on both robotic and single-site surgery for most upper and lower urinary tract operations. Mature evidence including midterm follow-up data exists only for robot-assisted radical prostatectomy. In the absence of high-quality data, the guidelines panel's recommendations were based mostly on the review of low-level evidence and expert opinions. Conclusions Robot-assisted urologic surgery is an emerging and safe technology for most urologic operations. Further documentation including long-term oncologic and functional outcomes is deemed necessary before definite conclusions can be drawn regarding the superiority or not of robotic assistance compared with the conventional laparoscopic and open approaches. Laparoendoscopic single-site surgery is a novel laparoscopic technique providing a potentially superior cosmetic outcome over conventional laparoscopy. Nevertheless, further advantages offered by this technology are still under discussion and not yet proven. Due to the technically demanding character of the single-site approach, only experienced laparoscopic surgeons should attempt this technique in clinical settings. Patient summary This work represents the shortened version of the 2013 European Association of Urology guidelines on robotic and single-site surgery. The authors systematically evaluated published evidence in these fields and concluded that robotic assisted surgery is possible and safe for most urologic operations. Whilst laparoendoscopic single-site surgery is performed using the fewest incisions, the balance between risk and benefit is currently unclear. The evidence to support the conclusions in this guideline was generally poor, but best for robotic assisted radical prostatectomy. As such, these recommendations were based upon expert opinion, and further high-quality research is needed in this field. © 2013 European Association of Urology.

Haie-Meder C.,Institute Gustave Roussy | Siebert F.-A.,University of Kiel | Potter R.,Medical University of Vienna
Radiotherapy and Oncology | Year: 2011

Brachytherapy has consistently provided a very conformal radiation therapy modality. Over the last two decades this has been associated with significant improvements in imaging for brachytherapy applications (prostate, gynecology), resulting in many positive advances in treatment planning, application techniques and clinical outcome. This is emphasized by the increased use of brachytherapy in Europe with gynecology as continuous basis and prostate and breast as more recently growing fields. Image guidance enables exact knowledge of the applicator together with improved visualization of tumor and target volumes as well as of organs at risk providing the basis for very individualized 3D and 4D treatment planning. In this commentary the most important recent developments in prostate, gynecological and breast brachytherapy are reviewed, with a focus on European recent and current research aiming at the definition of areas for important future research. Moreover the positive impact of GEC-ESTRO recommendations and the highlights of brachytherapy physics are discussed what altogether presents a full overview of modern image guided brachytherapy. An overview is finally provided on past and current international brachytherapy publications focusing on "Radiotherapy and Oncology". These data show tremendous increase in almost all research areas over the last three decades strongly influenced recently by translational research in regard to imaging and technology. In order to provide high level clinical evidence for future brachytherapy practice the strong need for comprehensive prospective clinical research addressing brachytherapy issues is high-lighted. © 2011 Elsevier Ireland Ltd. All rights reserved.

De Backer D.,Erasme University Hospital | Biston P.,Center Hospitalier University Of Charleroi | Devriendt J.,Free University of Colombia | Madl C.,Medical University of Vienna | And 6 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Both dopamine and norepinephrine are recommended as first-line vasopressor agents in the treatment of shock. There is a continuing controversy about whether one agent is superior to the other. METHODS: In this multicenter, randomized trial, we assigned patients with shock to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure. When blood pressure could not be maintained with a dose of 20 μg per kilogram of body weight per minute for dopamine or a dose of 0.19 μg per kilogram per minute for norepinephrine, open-label norepinephrine, epinephrine, or vasopressin could be added. The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events. RESULTS: The trial included 1679 patients, of whom 858 were assigned to dopamine and 821 to norepinephrine. The baseline characteristics of the groups were similar. There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P = 0.10). However, there were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001). A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1044 patients with septic shock or the 263 with hypovolemic shock (P = 0.03 for cardiogenic shock, P = 0.19 for septic shock, and P = 0.84 for hypovolemic shock, in Kaplan-Meier analyses). CONCLUSIONS: Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. ( number, NCT00314704.) Copyright © 2010 Massachusetts Medical Society.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.1-1 | Award Amount: 7.78M | Year: 2013

Epithelial ovarian cancer (EOC) is the most lethal gyncaecological malignancy causing 41900 deaths annually in Europe. The predominance of aggressive Type II tumours, which are characterised by a high frequency of p53 mutations, and primary or acquired resistance to platinum-based chemotherapy profoundly contribute to the high mortality rate. With current standard therapy the median overall survival of metastatic platinum-resistant (Pt-R) ovarian cancer patients is only 14 month. There is a pressing need for more effective, innovative treatment strategies to particularly improve survival in this subgroup of EOC patients. The GANNET53 trial aims to achieve this goal by applying a highly innovative concept that has grown from solid basic research findings made by members of the GANNET53 consortium. This is a drug strategy targeting a central driver of tumour aggressiveness and metastatic ability, namely mutant p53, via an innovative new Hsp90 (heat shock protein 90) inhibition mechanism. The most advanced, second-generation Hsp90 inhibitor will be used, Ganetespib. The first part (Phase I) of the GANNET53 trial will test the safety of Ganetespib in a new combination with standard chemotherapy (Paclitaxel weekly) in Pt-R Type II EOC patients. The second part (randomised Phase II) will examine the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone in EOC patients with Pt-R Type II tumours. We established a highly efficient consortium with previously proven capability and manpower to perform this multicentre clinical trial and assess our innovative therapeutic concept in this deadly disease. Our consortium consists of national clinical trial groups in gynaecological oncology and high-volume University centres as well as noted p53 scientists and 3 innovative SMEs. Since ovarian cancer is defined as a rare cancer a scale at the European level is crucial for the planned clinical trial.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2011.9.7 | Award Amount: 2.73M | Year: 2012

Thanks to modern ICT, a new generation of large data sets of social, biological, and man-made systems are now available. Many more will be produced at an everincreasing rate in the near future. Such data contain high precision and integrated information on the nature and the evolution -in space and time- of the state of each single component, together with information on different types of interactions between them. Unfortunately, it is extremely difficult to extract meaningful information from this new generation of high-integrated data, since current network theory provides not much more than a static description of single, independent networks. The aim of this project is to provide a novel and coherent theoretical framework for analyzing and modeling these dynamic and multi-layer networks in terms of multi-graphs embedded in space and time. To do this, we will treat time, space and the nature of interactions not as additional dimensions of the problem, but as natural, inherent components of the very same generalized network (GNE) description. The first goal of the project is to devise novel metrics and models, able to capture the interactions between different layers and across different spatio-temporal scales. The second goal is to understand the combined role of spatial distance, time and inter-layer interactions on the dynamics of processes running on GNEs, and on the emergence of collective behaviors, such as synchronization. The third goal is to investigate cases where GNEs are co-evolving with the processes they facilitate. The theory will be validated on real-world applications involving large and heterogeneous data sets of brain networks, on- and off-line social systems, healthcare systems, and transportation flows in cities. Our project will provide new quantitative opportunities in different fields, ranging from the prediction of pathologies to the diffusion of ideas and trends in societies, and for the management of socio-technological systems.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.4.2-3 | Award Amount: 4.14M | Year: 2013

ASTERIX will contribute towards the expected impact listed in the work program by delivering validated innovative statistical design methodologies for cost efficient clinical trials deriving reliable results from trials in small population groups, especially focusing on rare diseases. It directly addresses the rights of the estimated 30 million European patients suffering from rare diseases to the same quality or treatment as other patients. By choosing an integrated approach leveraging statistical methods, smartly combining observational and clinical data as well as improved sequential and adaptive approaches ASTERIX will improve statistical power of clinical trial design in small populations. ASTERIX will systematically include patients and the patient perspective into its research, but moreover develop the approach to involve patients in clinical trial design in a methodological sound manner. Pre-clinical data, historical data on disease characteristics, and benefit and risk as perceived by patients will systematically inform and weigh relevant endpoint measures. Thus the clinical value of trial results will be enhanced considerably. Key methodological innovations include: new standards of evidence that take into account the rare prevalence of disease, leveraging prior information and the availability of multiple endpoints, enabling adaptive designs and sequential meta-analysis using multiple endpoints and providing a blue print to pro-actively share information on trials in the planning stage. The latter will ensure that each new trial in an orphan disease provides the optimum additional knowledge for patient treatment. Relevance and clinical value of the newly designed methodological approaches are validated twofold. Firstly, by cross testing with available clinical trial data of a broad range of highly relevant rare diseases and secondly, by assessing the methods against current and improved regulatory approval strategies.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.4-1 | Award Amount: 3.93M | Year: 2008

In the eurIPFnet consortium, leading European basic and clinical scientists in the field of interstitial lung diseases associate to jointly decipher the natural course and molecular pathomechanisms of Idiopathic Pulmonary Fibrosis (IPF) and to develop new therapeutic strategies for patients with IPF. This devastating disease affects about 360.000 patients in the EU and causes a substantial socioeconomic burden. IPF patients experience a gradual decrease in quality of life due to progressive dyspnoe and coughing, and usually die within 3-5 years upon diagnosis. There is currently no approved treatment available. Our translational research programme includes implementation of a European IPF registry (eurIPFreg), in which data with regard to natural course, familiar background and susceptibility factors of IPF will be collected, and of a European IPF biobank (eurIPFbank) of blood, bronchoalveolar lavage fluid, cells and tissue specimen of IPF. In these samples, we will perform transcriptome, proteome, phosphoproteome and lipidome analysis, cellular studies and genetic analysis to unravel the molecular pathways underlying IPF and to identify and establish new diagnostic and prognostic markers. Candidate gene verification will be performed in cell culture and animal studies, including siRNA and gene transfection technologies and development of genetically altered mice and will result in the development of new animal models of IPF. Identification of new therapeutic targets in these models will be followed by rapid commercial exploitation and early preclinical and early clinical evaluation. Ultimately, we wish to establish a unique, sustainable and internationally unrivalled European infrastructure for investigation and treatment of IPF. Our mission statement is straight-forward and clear: Fighting for improved survival in Idiopathic Pulmonary Fibrosis.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.54M | Year: 2013

Neuroinflammatory disease, in particular multiple sclerosis affects more than 700.000 people within Europe alone. European countries are at the forefront of neuroimmunological research and students in medicine and biology are greatly attracted by the field. Neuroimmunology research further impacts our understanding of the ethiopathology of other CNS-disorders including Alzheimers Dementia and Morbus Parkinson. The ability of inflammatory immune cells to cause tissue damage within the nervous system is largely governed by soluble mediators including cytokines/chemokines, cytolytic molecules and growth factors. The therapeutic targeting of such mediators has proven successful for the treatment of a number of inflammatory diseases, yet is failing for the treatment of neuroinflammatory disorders. Clearly, the rules and regulatory elements, which govern inflammation and tissue injury within the CNS, differ significantly from those of other tissues and a unique CNS-focused research approach to unravel these rules is required. In this ITN proposal, we will train ESRs and ERs specifically in Neuroimmunology by combining prominent laboratories in academia and industry on the task to study the communication networks between immune and CNS-resident cells. Scientifically, we focus particularly on the soluble factors mediating cell-cell communication at the immune-CNS interface. To this end, we combine expertise in molecular and cellular Neuroimmunology with Neuropathology of human and animal models of CNS inflammation. In addition, our goal is to further utilize inflammatory processes for neuroprotection.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: ENV.2011.1.2.1-1 | Award Amount: 4.43M | Year: 2011

There is an urgent need to understand how global and regional climate, land use and air quality changes will impact human health. Our consortium constitutes an innovative and multidisciplinary approach to explore the combined pan-European impact of changes in climate, land use and air pollution on allergen pollen-induced diseases through a chain of quantitative physical and statistical models. We plan to develop integrated and cross-disciplinary approaches to assess the health risks resulting from severe environmental change and to design suitable adaptation policies. We will study vulnerable groups of atopic patients and search for predictive biomarkers, and establish statistical models of disease response to pollen for assessing future trends and risks. We will examine the effects of climate and air quality directly on pollen allergenicity using experimental animals. Furthermore, we will maintain a dialogue with relevant stakeholders and provide recommendations for policy makers. We chose to focus on the invasive and highly allergenic Ambrosia pollen because of the high rate at which it is spreading through Europe and the high frequency at which Europeans are becoming allergic to it with its consequent negative impact on health and the European economy. The outcome of this state-of-the-art project is; 1) improved understanding of the changes of multiple environmental factors and stressors on allergic disease, 2) scenarios of allergic disease risk currently and in the future, 3) useful information for response policies at national and European levels, 4) increased awareness of allergic disease risk in response to multiple environmental changes, 5) improved communication strategies between science and stakeholders, 6) contribution to the Fifth IPCC Assessment Report (AR5) due in 2013-14, and 7) policy-relevant guidance to combat Ambrosia invasion and air pollutant interactions with aeroallergens.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.4.5-2 | Award Amount: 7.61M | Year: 2012

An ideal intervention in a chronic inflammatory disease such as Rheumatoid Arthritis (RA) would be a preventive one. In order to develop preventive strategies and therapies two key developments need to occur: (1) Biomarkers need to be identified that can be used to predict an individuals risk of developing RA. (2) Modifiable disease mechanisms need to be identified and characterized in the early phases of disease. The key objective of the TEAM consortium is to specifically identify diagnostic biomarkers and disease mechanisms operating during the transition from health to rheumatoid arthritis. Our consortium will achieve this by developing a collaborative, integrated programme of work that links researchers with key SMEs involved in biomarker development to produce a personalized predictive bioprofile for patients destined to develop RA. The Euro-TEAM consortium will deliver a step change in the development of biomarkers and diagnostic kits that are timely, strategically important for European SMEs, and based on a disease (RA) in which concrete genetic and environmental risk factors have already been established. Firstly, it will directly compare biomarkers in the preclinical phases of disease with established markers in the clinical phases. Secondly, it will look beyond the synovium interrogating lymphoid, lung and periodontal tissue in a first-in-class approach to measuring systemic changes in the earliest phases of disease. Thirdly, it will place great emphasis on understanding why synovial inflammation resolves in some individuals and develop biomarkers of this reverse phase. Fourthly, it will explore a key cell type (stromal cells) that has been almost completely ignored in current biomarker studies. Finally, it will directly involve patients and other specialists, particularly from the fields of genetics, ethics and patient and public involvement in helping to visualize and communicate risk following a positive biomarker test.

Fonseca J.P.,Institute of Molecular Biotechnology IMBA | Steffen P.A.,Institute of Molecular Biotechnology IMBA | Muller S.,Johann Radon Institute for Computational and Applied Mathematics RICAM | Lu J.,ETH Zurich | And 3 more authors.
Genes and Development | Year: 2012

Epigenetic memory mediated by Polycomb group (PcG) proteins must be maintained during cell division, but must also be flexible to allow cell fate transitions. Here we quantify dynamic chromatin-binding properties of PH::GFP and PC::GFP in living Drosophila in two cell types that undergo defined differentiation and mitosis events. Quantitative fluorescence recovery after photobleaching (FRAP) analysis demonstrates that PcG binding has a higher plasticity in stem cells than in more determined cells and identifies a fraction of PcG proteins that binds mitotic chromatin with up to 300-fold longer residence times than in interphase. Mathematical modeling examines which parameters best distinguish stem cells from differentiated cells. We identify phosphorylation of histone H3 at Ser 28 as a potential mechanism governing the extent and rate of mitotic PC dissociation in different lineages. We propose that regulation of the kinetic properties of PcG-chromatin binding is an essential factor in the choice between stability and flexibility in the establishment of cell identities. © 2012 by Cold Spring Harbor Laboratory Press.

Samwald Dr. M.,Medical University of Vienna | Samwald Dr. M.,Vienna University of Technology | Adlassnig K.-P.,Medical University of Vienna | Adlassnig K.-P.,Medexter Healthcare GmbH
Journal of the American Medical Informatics Association | Year: 2013

A sizable fraction of patients experiences adverse drug events or lack of drug efficacy. A part of this variability in drug response can be explained by genetic differences between patients. However, pharmacogenomic data as well as computational clinical decision support systems for interpreting such data are still unavailable in most healthcare settings. We address this problem by introducing the medicine safety code (MSC), which captures compressed pharmacogenomic data in a twodimensional barcode that can be carried in a patient's wallet. We successfully encoded data about 385 genetic polymorphisms in MSC and were able to decode and interpret MSC quickly with common mobile devices. The MSC could make individual pharmacogenomic data and decision support available in a wide variety of healthcare settings without the set up of large-scale infrastructures or centralized databases.

Berghoff A.S.,Medical University of Vienna | Berghoff A.S.,Comprehensive Cancer Center Vienna | Preusser M.,Medical University of Vienna | Preusser M.,Comprehensive Cancer Center Vienna
Current Opinion in Neurology | Year: 2014

Purpose of review To summarize the current knowledge on v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) aberrations in tumours of the central nervous system. Recent findings BRAF alterations are found in variable frequencies across a wide spectrum of diverse central nervous system neoplasms. BRAF V600 point mutations (most commonly of the V600E type) are most common in pleomorphic xanthoastrocytoma (approximately 60% of cases), gangliogliomas (50%), dysembryoplastic neuroepithelial tumours (30%), Langerhans cell histiocytosis (50%), melanoma brain metastases (50%) and papillary craniopharyngiomas (96%) and are also detectable in a fraction of glioblastomas (overall mutation rate of 2-12%, with a higher rate of approximately 50% in epithelioid glioblastomas). BRAF fusions (most commonly KIAA1549: BRAF) are typical for pilocytic astrocytomas and are almost absent from other tumour types. Clinical trials have established tyrosine-kinase inhibitors of BRAF as feasible treatment option in selected patients with mutation-bearing brain metastases of melanoma. Preclinical studies, some case reports and small patient series have documented tumour responses of primary brain tumours with BRAF aberrations to BRAF inhibition. Summary Molecular testing for BRAF alterations in brain tumours may be of clinical relevance for differential diagnostic considerations in some situations or to guide selection of patients for targeted therapy with specific inhibitors. Prospective clinical trials evaluating the efficacy of BRAF inhibitors in central nervous system tumours are strongly supported by the available evidence. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Schernthaner G.,Rudolfstiftung Hospital | Mogensen C.E.,Aarhus University Hospital | Schernthaner G.-H.,Medical University of Vienna
Diabetes and Vascular Disease Research | Year: 2014

Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. © 2014 The Author(s).

Ramsauer K.,Themis Bioscience GmbH | Schwameis M.,Medical University of Vienna | Firbas C.,Medical University of Vienna | Mullner M.,Themis Bioscience GmbH | And 6 more authors.
The Lancet Infectious Diseases | Year: 2015

Background: Chikungunya is an emerging arthropod-borne disease that has spread from tropical endemic areas to more temperate climates of the USA and Europe. However, no specific treatment or preventive measure is yet available. We aimed to investigate the immunogenicity and safety of a live recombinant measles-virus-based chikungunya vaccine. Methods: We did a randomised, double-blind, placebo-controlled, active-comparator, phase 1, dose-escalation study at one centre in Vienna, Austria. Healthy men and women aged 18-45 years with no comorbidities were randomly assigned, by computer-generated block randomisation (block size of 14), to receive either one of three escalating doses of the measles-virus-based candidate vaccine (low dose [1·5 × 104 median tissue culture infection doses (TCID50) per 0·05 mL], medium dose [7·5 × 104 TCID50 per 0·25 mL], or high dose [3·0 × 105 TCID50 per 1·0 mL]), or the active comparator-Priorix. Participants were additionally block-randomised to receive a booster injection on either day 28 or day 90 after the first vaccination. Participants and study investigators were masked to group allocation. The primary endpoint was the presence of neutralising anti-chikungunya antibodies on day 28, as assessed by 50% plaque reduction neutralisation test. Analysis was by intention to treat and per protocol. This trial is registered with EudraCT, number 2013-001084-23. Findings: Between Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) of the measles-virus-based candidate vaccine, or Priorix (n=6), of whom 36 participants (86%; n=9, n=12, n=10, n=5, respectively) were included in the per-protocol population. The candidate vaccine raised neutralising antibodies in all dose cohorts after one immunisation, with seroconversion rates of 44% (n=4) in the low-dose group, 92% (n=11) in the medium-dose group, and 90% (n=10) in the high-dose group. The immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded. Interpretation: The live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of anti-vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings. Funding: Themis Bioscience GmBH. © 2015 Elsevier Ltd.

Gohring J.,Medical University of Vienna | Jacak J.,Medical University of Vienna | Jacak J.,Johannes Kepler University | Barta A.,Medical University of Vienna
Plant Cell | Year: 2014

Alternative splicing (AS) is an important regulatory process that leads to the creation of multiple RNA transcripts from a single gene. Alternative transcripts often carry premature termination codons (PTCs), which trigger nonsense-mediated decay (NMD), a cytoplasmic RNA degradation pathway. However, intron retention, the most prevalent AS event in plants, often leads to PTC-carrying splice variants that are insensitive to NMD; this led us to question the fate of these special RNA variants. Here, we present an innovative approach to monitor and characterize endogenous mRNA splice variants within living plant cells. This method combines standard confocal laser scanning microscopy for molecular beacon detection with a robust statistical pipeline for sample comparison. We demonstrate this technique on the localization of NMD-insensitive splice variants of two Arabidopsis thaliana genes, RS2Z33 and the SEF factor. The experiments reveal that these intron-containing splice variants remain within the nucleus, which allows them to escape the NMD machinery. Moreover, fluorescence recovery after photobleaching experiments in the nucleoplasm show a decreased mobility of intron-retained mRNAs compared with fully spliced RNAs. In addition, differences in mobility were observed for an mRNA dependent on its origin from an intron-free or an intron-containing gene. © 2014 American Society of Plant Biologists. All rights reserved.

Wesierska-Gadek J.,Medical University of Vienna | Skladanowski A.,Technical University of Gdansk
Future Medicinal Chemistry | Year: 2012

Many anticancer drugs reduce the integrity of DNA, forming strand breaks. This can cause mutations and cancer or cell death if the lesions are not repaired. Interestingly, DNA repair-deficient cancer cells (e.g., those with BRCA1/2 mutations) have been shown to exhibit increased sensitivity to chemotherapy. Based on this observation, a new therapeutic approach termed 'synthetic lethality' has been developed, in which radiation therapy or cytotoxic anticancer agents are employed in conjunction with selective inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). Such combinations can cause severe genomic instability in transformed cells resulting in cell death. The synergistic effects of combining PARP-1 inhibition with anticancer drugs have been demonstrated. However, the outcome of this therapeutic strategy varies significantly between cancer types, suggesting that synthetic lethality may be influenced by additional cellular factors. This review focuses on the outcomes of the combined action of PARP-1 inhibitors and agents that affect the activity of DNA topoisomerases. © 2012 Future Science Ltd.

Fischer G.,Medical University of Vienna | Stover H.,Frankfurt University of Applied Sciences
Heroin Addiction and Related Clinical Problems | Year: 2012

Opioid-dependence treatment varies between countries despite the underlying condition being similar. The European Quality Audit of Opioid Treatment (EQUATOR) project utilised a survey design in 10 European countries to characterise the treatment of opioid dependence from the perspective of treating physicians, patients in treatment, and opioid users currently outside the medication-assisted treatment system. The survey covered topics including treatment goals; knowledge about and experience of treatment; drug use, misuse and diversion; employment; and prison experience. EQUATOR provides the opportunity to generate important new insights to guide treatment policy and practice. This article presents a detailed overview of the study methodology. © Icro Maremmani.

Neubauer A.,National Research Council Canada | Wolfsberger S.,Medical University of Vienna | Wolfsberger S.,University of Calgary
Neurosurgery | Year: 2013

Virtual endoscopy is the computerized creation of images depicting the inside of patient anatomy reconstructed in a virtual reality environment. It permits interactive, noninvasive, 3-dimensional visual inspection of anatomical cavities or vessels. This can aid in diagnostics, potentially replacing an actual endoscopic procedure, and help in the preparation of a surgical intervention by bridging the gap between plain 2-dimensional radiologic images and the 3-dimensional depiction of anatomy during actual endoscopy. If not only the endoscopic vision but also endoscopic handling, including realistic haptic feedback, is simulated, virtual endoscopy can be an effective training tool for novice surgeons. In neurosurgery, the main fields of the application of virtual endoscopy are third ventriculostomy, endonasal surgery, and the evaluation of pathologies in cerebral blood vessels. Progress in this very active field of research is achieved through cooperation between the technical and the medical communities. While the technology advances and new methods for modeling, reconstruction, and simulation are being developed, clinicians evaluate existing simulators, steer the development of new ones, and explore new fields of application. This review introduces some of the most interesting virtual reality systems for endoscopic neurosurgery developed in recent years and presents clinical studies conducted either on areas of application or specific systems. In addition, benefits and limitations of single products and simulated neuroendoscopy in general are pointed out. Copyright © 2012 by the Congress of Neurological Surgeons.

Becattini C.,University of Perugia | Agnelli G.,University of Perugia | Schenone A.,Galliera Hospital | Eichinger S.,Medical University of Vienna | And 8 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: About 20% of patients with unprovoked venous thromboembolism have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy. Extending anticoagulation prevents recurrences but is associated with increased bleeding. The benefit of aspirin for the prevention of recurrent venous thromboembolism is unknown. METHODS:In this multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked venous thromboembolism who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment. The primary efficacy outcome was recurrence of venous thromboembolism, and major bleeding was the primary safety outcome. RESULTS:Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 taking placebo had a recurrence (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups. CONCLUSIONS: Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. (Funded by the University of Perugia and others; WARFASA number, NCT00222677.) Copyright © 2012 Massachusetts Medical Society.

Trnka H.-J.,Orthopaedic Hospital Speising | Krenn S.,Orthopaedic Hospital Speising | Schuh R.,Medical University of Vienna
International Orthopaedics | Year: 2013

This systematic review aims to illustrate the published results of "minimally invasive" procedures for correction of hallux valgus. Based on former systematic reviews on that topic, the literature search was organised by two independent investigators. MEDLINE was systematically searched for available studies. The keywords used were "hallux valgus", "bunion", "percutaneous surgery", "minimally invasive surgery", "arthroscopy", "Bosch" and "SERI". Studies were assessed using the level of evidence rating. A total of 21 papers were included in this review. These studies described a total of 1,750 patients with 2,195 instances of percutaneous, minimally invasive or arthroscopic hallux valgus surgery. Clinical reports of results after minimally invasive hallux valgus surgery at meetings are common. Published results in peer-reviewed journals are less common and the majority of papers are level IV studies according to the level of evidence ratings. We found one level II and three level III studies. Reported complications seem to be less than one may see in one's own clinical practice. This possible bias may be related to the fact that most studies are published by centres performing primarily minimally invasive hallux valgus surgery. © 2013 Springer-Verlag Berlin Heidelberg.

Bauer J.,Medical University of Vienna | Gold R.,Ruhr University Bochum | Adams O.,Heinrich Heine University Düsseldorf | Lassmann H.,Medical University of Vienna
Acta Neuropathologica | Year: 2015

Progressive multifocal leukoencephalopathy is a viral encephalitis induced by the John Cunningham (JC) virus, an ubiquitous neurotropic papovavirus of the genus polyomavirus that in healthy people in latency resides in kidney and bone marrow cells. Activation and entry into the CNS were first seen in patients with malignancies of the hematopoietic system and an impaired immune system. During the 1980 and the 1990s with the appearance of human immunodeficiency virus infection in humans, PML was found to be the most important opportunistic infection of the central nervous system. As a result of highly efficient immunosuppressive and immunomodulatory treatments, in recent years, the number of PML cases again increased. PML is prevented by an intact cellular immune response and accordingly immune reconstitution can terminate established disease in the CNS. However, forced immune reconstitution can lead to massive destruction of virus-infected cells. This may result in clinical exacerbation associated with high morbidity and mortality and referred to as PML with immune reconstitution inflammatory syndrome (PML–IRIS). In the present review, we discuss virological properties and routes of infection in the CNS, but mostly focus on the pathology of PML and PML–IRIS and on the role of the immune system in these disorders. We show that PML and PML–IRIS result from predominant JC virus infection of oligodendrocytes and, to a lesser extent, of infected neurons. Inflammation in these encephalitides seems to be driven by a dominant cytotoxic T cell response which is massively exaggerated during IRIS. © 2015, Springer-Verlag Berlin Heidelberg.

Background: For decades, heparins and vitamin K antagonists (VKAs) have been the gold standards in therapy of venous thromboembolism (VTE). The advent of factor IIa and Xa inhibitors provides new therapeutic options. Th e aim of this analysis is to compare the currently available new oral anticoagulants (NOACs) with VKAs and also indirectly the NOACs with each other, as it is unlikely that a head-to-head comparison will ever be available. Patients and methods: In total, 27,024 patients were included in the RE-COVER, RE-COVER II, EINSTEIN DVT and PE, AMPLIFY and HOKUSAI studies with 13,511 in the VKA arm and 13,513 in the NOAC arm. Efficacy and safety endpoints were assessed by relative risks (RR) and absolute risk reductions (ARR) relative to VKA. Th e indirect comparison between the NOACs was performed according to ISPOR guidelines. Results: No differences between NOACs and VKA were found regarding recurrent VTE and death. Bleeding was significantly reduced by NOACs: major bleeding by rivaroxaban (RR 0.55; 0.38-0.81) and apixaban (RR 0.31; 0.17-0.55); major and clinically relevant non-major bleeding by dabigatran (RR 0.63; 0.51-0.77), apixaban (RR 0.44; 0.36-0.55) and edoxaban (RR 0.81; 0.71-0.93). The ARR for major bleeding was 1 % for rivaroxaban and apixaban; and for the composite bleeding endpoint 3.2 % for dabigatran, 5.4 % for apixaban, and 1.9 % for edoxaban. Regarding efficacy, no differences were found between NOACs. Apixaban reduced incidence of major bleeding more than dabigatran and edoxaban. Regarding occurrence of the composite bleeding endpoint, apixaban performed better than all other NOACs and dabigatran better than rivaroxaban and edoxaban. Conclusions: NOACs are as efficient in the treatment of VTE as VKA but with reduced risk of bleeding complications. Indirect comparisons indicate differences in the risk of clinically relevant bleeding events. Important issues such as monitoring and reversal of anticoagulation are still unresolved, but introduction of NOACs increased the therapeutic spectrum and thereby the potential for individualized therapy. © 2014 Hans Huber Publishers, Hogrefe AG, Bern.

Ricco J.-B.,University of Poitiers | Assadian O.,Medical University of Vienna
Seminars in Vascular Surgery | Year: 2011

In vascular surgery, graft infection remains a serious limb-threatening and often life-threatening complication, despite progress in the last several decades. During the past 3 decades, prevention of surgical site infection predominantly relied on availability of effective perioperative antibiotic prophylaxis or the use of systemic antibiotics for treatment of infections after their clinical manifestation. However, evidence for the prophylactic effect of systemic antibiotics exists only for patients with vein grafts, who are at a lower risk of infection compared to patients receiving prosthetic material. Furthermore, because of the changed epidemiology of bacterial susceptibility against antibiotics today, reliance on the efficacy of systemic antibiotic prophylaxis must be done with caution. The outlook of current trends indicates that maximum effort is needed to maintain the current balance. Simply looking for new antibiotics will not lead to an additional decrease in the rate of infection in vascular surgery. Because of the consequences of infection in vascular surgery and the increasing resistance of causative micro-organisms, the future strategy to deal with infection needs to shift from reliance on systemic antibiotics and treatment of manifest infection to a strong focus on primary prevention of infection, particularly for surgical procedures involving prosthetic materials. This article summarizes current strategies for prevention of surgical site infection in vascular surgery and reviews current literature on antimicrobial vascular grafts using antiseptic agents instead of antibiotics to achieve antimicrobial efficacy. Specific emphasis is put on silver and its use in antimicrobial vascular grafts for prevention and treatment of vascular surgical infection. © 2011 Elsevier Inc.

Nechanitzky R.,Max Planck Institute of Immunobiology and Epigenetics | Davila A.,Max Planck Institute of Immunobiology and Epigenetics | Savarese F.,Max Planck Institute of Immunobiology and Epigenetics | Savarese F.,Medical University of Vienna | And 2 more authors.
Developmental Cell | Year: 2012

Satb1 and Satb2 have been recently described as regulators of embryonic stem (ES) cell pluripotency and as silencing factors in X chromosome inactivation. The influence of the pluripotency machinery on X chromosome inactivation and the lack of an X chromosome inactivation defect in Satb1-/- and Satb2-/- mice raise the question of whether or not Satb proteins are directly and/or redundantly involved in this process. Here, we analyzed X chromosome inactivation in fibroblastic cells that were derived from female Satb1-/-Satb2-/- embryos. By fluorescence in situ hybridization to visualize Xist RNA and by immunohistochemistry to detect H3K27me3 histone modifications, we found that female Satb1-/-Satb2-/- fibroblastic cells contain proper Barr bodies. Moreover, we did not detect an upregulation of X-linked genes, suggesting that Satb proteins are dispensable for X chromosome inactivation in mice.

Qiao R.,Medical University of Vienna | Cabral G.,University of Vienna | Lettman M.M.,Ludwig Institute for Cancer Research | Dammermann A.,University of Vienna | Dong G.,Medical University of Vienna
EMBO Journal | Year: 2012

The centriole is a conserved microtubule-based organelle essential for both centrosome formation and cilium biogenesis. Five conserved proteins for centriole duplication have been identified. Two of them, SAS-5 and SAS-6, physically interact with each other and are codependent for their targeting to procentrioles. However, it remains unclear how these two proteins interact at the molecular level. Here, we demonstrate that the short SAS-5 C-terminal domain (residues 390-404) specifically binds to a narrow central region (residues 275-288) of the SAS-6 coiled coil. This was supported by the crystal structure of the SAS-6 coiled-coil domain (CCD), which, together with mutagenesis studies, indicated that the association is mediated by synergistic hydrophobic and electrostatic interactions. The crystal structure also shows a periodic charge pattern along the SAS-6 CCD, which gives rise to an anti-parallel tetramer. Overall, our findings establish the molecular basis of the specific interaction between SAS-5 and SAS-6, and suggest that both proteins individually adopt an oligomeric conformation that is disrupted upon the formation of the hetero-complex to facilitate the correct assembly of the nine-fold symmetric centriole. © 2012 European Molecular Biology Organization.

Siller-Matula J.M.,Medical University of Vienna | Trenk D.,Universitats Herzzentrum Freiburg Bad Krozingen | Schror K.,Heinrich Heine University Düsseldorf | Gawaz M.,University of Tübingen | And 3 more authors.
JACC: Cardiovascular Interventions | Year: 2013

P2Y12 inhibitors are widely used in patients with acute coronary syndromes and in the secondary prevention of thrombotic events in vascular diseases. Within the past few years, several pharmacological, genetic, and clinical limitations of the second-generation thienopyridine clopidogrel have raised major concerns. High on-treatment platelet reactivity, which is common in clopidogrel-treated patients, and its clinical implications led to the development of the more effective platelet P2Y12 inhibitors prasugrel (a third-generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo- pyrimidine). The pharmacokinetics and pharmacodynamics of prasugrel and ticagrelor indicate that they provide more consistent, more rapid, and more potent platelet inhibition than clopidogrel, which translates into improved ischemic outcomes. Nevertheless, higher efficacy, which is reflected by low on-treatment platelet reactivity, increases the risk of major bleeding events. Therefore, cardiologists might be facing a new challenge in the future: to individualize the level of platelet inhibition in order to decrease thrombotic events without increasing bleeding. The current review focuses on the use of platelet function testing and pharmacogenomic testing in order to identify patients who either do not respond to or are at risk of not responding sufficiently to P2Y12 inhibitors. Moreover, this paper discusses randomized trials, which so far have failed to show that tailored antiplatelet therapy improves clinical outcome, and treatment options for patients with high on-treatment platelet reactivity. © 2013 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.

Karges B.,RWTH Aachen | Rosenbauer J.,Heinrich Heine University Düsseldorf | Kapellen T.,University of Leipzig | Wagner V.M.,University of Lübeck | And 3 more authors.
PLoS Medicine | Year: 2014

Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years.We analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4±3.8 y, range 1–20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19–1.37) to 1.05 (1.00–1.09) and from 1.39 (1.23–1.56) to 1.01 (0.93–1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6–1.7, p<0.001) and 1.9% (0.8–2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%–6.9% (RR 0.96 and 0.90 each year) and 7.0%–7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study.The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients.Please see later in the article for the Editors' Summary. © 2014 Karges et al.

Objective. To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double-blind, placebo-controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX. Methods. Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10-25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]), and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4, 16, and 24. Results. TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and MMP-3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX-I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ-treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders. Conclusion. TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP-3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate-to-severe RA. © 2010, American College of Rheumatology.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.4.2-1 | Award Amount: 7.44M | Year: 2013

Children are often treated as small adultsnot as the special patients they are. Regulations exist to encourage the development of drugs and formulation for children. However, off-patent drugs are often administered to children without appropriate formulations or systematic investigations. Therefore, the paediatric use marketing authorisation (PUMA) has been designed. The EMA Paediatric Working Party has prioritized the unmet need for the cardiovascular off-patent drug enalapril in the European paediatric population. Enalapril is an ACE inhibitor commonly used for cardiac failure in children under 1 year of age, although it is not labelled for any condition in patients <20 kg in European countries. Current problems with the use of enalapril in children include: no appropriate formulation and insufficient stability of the liquid soluble formulation for young paediatric patients; insufficient paediatric pharmacokinetic (PK) data for any formulation; insufficient safety data in neonates, infants, and young children; and limited pharmacodynamics (PD) and efficacy data for paediatric cardiological indications. The aim of the LENA (Labeling of Enalapril from Neonates up to Adolescents) project is to address these shortcomings and provide a basis for a future PUMA of enalapril by developing an age-appropriate solid oral formulation suitable for all paediatric subsets; generating PK and PD data; collecting data on the safety of enalapril in young paediatric patients; and providing dose recommendations based on PK/PD modelling and bridging from adult data. The international collaboration of the LENA investigators will provide the required expertise to develop and evaluate drug formulation, investigate dosing, and recruit paediatric patients for clinical trials while respecting current legislation, regulatory considerations, and ethical aspects, with the aim of applying for a PUMA.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2013.3.3 | Award Amount: 4.67M | Year: 2013

Optical coherence tomography (OCT) is an emerging optical diagnosis that enables in vivo tomographic visualization for non-invasive optical biopsy. OCT has proven its value primarily in ophthalmology, but recently also in dermatology. However, wide adoption has not taken place due to size and cost limitations as well as non-existence of handheld devices.\nHence BIOPSYPEN will develop a new OCT generation with step-changes in size and cost beyond state-of-the-art to radically transform OCT instrumentation for handheld point-of-care diagnosis. In contrast to conventional approaches, BIOPSYPENs OCT is based on integrated optics, more precisely on hybrid integration of silicon photonics with III-V sources, enabling a significantly smaller, low-cost, compact and maintenance free alternative.\nBIOPSYPEN will target complementary research to develop an unprecedented compact (pencil-like), reliable, low-cost, battery-operated, wireless handheld OCT device in combination with an embedded system based external console to receive two-and three-dimensional tomograms for instantaneous post processing and visualization as well as immediate diagnosis.\nBIOPSYPEN will contribute to a significantly wider adoption of OCT in real clinical point of care settings. Early diagnosis of skin cancer and inflammatory skin diseases are envisaged. Skin cancer will be used as a surrogate for other epithelial cancers, e.g. oral, gynaecologic or gastrointestinal cancer. Partnerships with leading innovative clinical users will enable preclinical evaluation.\nThrough the use of integrated optics in combination with complementary cutting-edge technologies, BIOPSYPEN will dramatically reduce cost and size (both at least by one order of magnitude) of currently available OCT commercial systems. It will also eliminate instrumentation maintenance requirements and will reduce training and healthcare costs, paving the way to revolutionize diagnosis for general medicine and primary care.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.2-5 | Award Amount: 3.57M | Year: 2009

A key problem in repair and functional regeneration following myocardial infarction is the inability of heart muscle tissue to regenerate itself and appropriate vascularization under conditions of increased strain caused by the reduced contractibility of the damaged heart. This frequently leads to continuous loss of functional cells, further increase of the infarct area and finally complete loss of heart function. We propose to explore possibilities for cell therapy using different procedures and sources of stem and progenitor cells. First, we will investigate factors stimulatory for stem/progenitor cell release from the bone marrow, their recruitment to the heart and the activation of resident heart stem cells. Second, we will evaluate adoptive transfer of stem/progenitor cells of different sources, from bone marrow, adult and cord blood, adipose tissue and heart tissue itself. The use of ex vivo cultured and differentiated cells including embryonic stem cells will be tested. Third, we will test genetic modification of these cells for improved differentiation, homing and tissue repair. Fourth, we will use a unique artificial scaffold material as a slow release device for factors and as a structural support material for providing the different cell preparations to the damaged areas. This scaffold will aso be used for tissue engineering in vitro followed by insertion of artficial tissue onto the infarct area. This project of high clinical importance is designed to further support the research and development needs of two SMEs, one is determined to become a supplier of growth factor cocktails for clinical stem cell culture, a second is based on the generation and supply of stem cells for clinical use. It will evaluate whether induction of repair by factors, adoptive transfer of stem/progenitor cells or engineered tissue has benefit for heart regeneration and has potential to become a future clinical standard therapy.

Agency: Cordis | Branch: FP7 | Program: MC-IRSES | Phase: FP7-PEOPLE-2013-IRSES | Award Amount: 545.80K | Year: 2014

With the statics of a wealth of model systems in statistical and condensed-matter systems being relatively well understood, an increased effort in research in these fields is channelled towards the understanding of dynamical phenomena. This agenda is even more pressing as dynamic effects are of crucial importance for many experimentally observed and technologically important phenomena. In the first work package, we will use the concerted effort and abundant synergies of the globe-spanning team of research groups to study a wide range of dynamical phenomena in statistical and condensed-matter physics, ranging from magnetic systems, to model systems on complex networks, to complex electronic systems such as graphene, to applications in soft matter and bio-physics. The results and techniques are expected to boost the understanding of dynamical effects in the human model systems in work package 2 which, in turn, is expected to offer new perspectives on the description of the systems investigated here. Socio-economic systems are increasingly studied with tools borrowed from statistical and condensed-matter physics. The theory of complex networks, in particular, has undergone an exciting development and has now found applications in a wide range of fields, including transport problems in modeling traffic systems, disease spreading or models for modeling agents acting in online communities. In the second work package, researchers in the consortium will apply techniques harvested from the wide array of tools used in statistical and condensed-matter physics as exemplified in the work items collected in work package 1 to a range of socio-economic systems with a focus on traffic and public transport models as well as the modeling of human behavior via the proxy of massivley multiplayer online games.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2010-ITN | Award Amount: 2.92M | Year: 2011

The identification of the extracellular calcium sensing receptor (CaSR) was a crucial step in understanding nutrient sensing in mammals. In mammalian organisms the CaSR has multiple roles: besides calcium homeostasis, it is involved in protection against osteoporosis, blood vessel calcification, prevention against colorectal cancer, is involved in metastasis of breast and prostate cancer cells to bone. The proposed ITN will perform basic and multidisciplinary investigations into the role of the CaSR and will provide experimental data for computational modelling. It will use holistic approaches of systems biology to gain knowledge on mechanisms of CaSR function. We will use intersectoral expertise in revealing the significance of CaSR signalling in cancer, and cardiovascular disease. The purpose of this ITN is to: Educate and train Early Stage Researchers to become excellent scientists, enable them to gain a holistic view of their specific research area, prepare them for the challenges of working in a highly competitive environment, be it in Academia or in Industry. Generate a systems biology model for CaSR-dependent signalling in order to find innovative therapeutic approaches and interventions for the natural and synthetic ligands of the CaSR. Establish long lasting interdisciplinary and intersectoral cooperation among basic, clinical and applied researchers, working on the CaSR to strengthen the European Research Area. Being in a research environment that examines the role of one single molecule in many different tissues (e.g. kidney, intestine, blood vessels) and pathologies (cancer and vascular calcification), will increase the awareness of the young researchers for a holistic approach in understanding CaSR-related pathophysiology. Continuous comparison of the function of the CaSR in systems studied by their fellow ESRs, will sensitize the young researchers for the complexities of biomedical research and advantages of multidisciplinarity.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2010-ITN | Award Amount: 3.25M | Year: 2011

The recent identification of tumor initiating (TIC) or cancer stem cells (CSC) has opened a new area of research for scientists interested in cancer. Understanding the biology of cancer stem cells has already unraveled pathways and potential targets. However, accumulating data has underscored the complexity of the CSC research area and prompts hence the need for well-structured networks to provide expert platforms, rapid exchange of information to train future researchers in this new concept. 10 laboratories from 6 member states with 4 expert enterprises, all at the highest level of cancer stem cell research will unit in a European Cancer Stem Cell Training Network (EuroCSCTraining). Partners, from the public and private sector, have complementary expert experience in this new area, are active members of CSC research, and share dedication in training and dissemination. The EuroCSCTraining coordinator is one of the present coordinators of the Paris CSC Consortium and director of the Institute of PhD schools of University Paris-Diderot. The main goal of this Network is to foster translaboratory and transPhD school training in this new area of Cancer Research. The EurosCSCTraining supervisory board will bring together supervisors of the private and public sector along with representatives of PhD schools to provide eligibility criteria of recruitment, monitor training, and set up individual tutorship for PCD. The research projects on cancer stem cells will be advertised simultaneously through the EuroCSCTraining Network and the partners University. It is anticipated that the EuroCSCTraining network will create a multidisciplinary and multisector structure of training for a new area of research in cancer which will develop research in Europe, foster European collaborations and provide the basis to harmonise initial research training in cancer research amongst partner Institutions.

Agency: Cordis | Branch: FP7 | Program: CSA-SA | Phase: HEALTH.2010.4.2-6 | Award Amount: 557.52K | Year: 2010

Advanced Therapy Medicinal Products (ATMPs) are medicinal products for human use, based on gene therapy, somatic cell therapy or tissue engineering. A rapidly growing area in translational research, they represent the next generation of complex medicines for complex diseases and pose particular challenges to medicines regulation. Regulation (EC) No 1394/2007 has been designed to ensure the free movement of ATMPs within the European Union (EU), to facilitate their access to the EU market and to foster the competitiveness of European pharmaceutical companies while guaranteeing the highest level of health protection for patients. The regulation extends standards of current Good Manufacturing Practice (cGMP) to ATMPs to ensure their quality, safety and efficacy. Academic cGMP facilities are major contributors to the development of ATMPs. They respond to clinical needs and provide medicinal products in an environment which, albeit compliant with industrial standards, is by definition not industrial. They find themselves in a challenging position between various, sometimes conflicting interests in the transition of ATMPs from bench to bedside. European investigator-initiated multicenter trials on ATMPs critically depend on academic cGMP facilities. We will assess the impact of Regulation (EC) No 1394/2007 on academic cGMP facilities by: a) conducting a European survey among non-industry facilities in this sector; b) organising workshops and a major conference for targeted, collaborative discourse; c) establishing a web-based platform for information exchange; d) analysing publications and guidance from the perspective of better regulation principles; e) analysing innovation statistics in relation to ATMPs. These activities will yield comprehensive evidence and concrete suggestions to policy makers. The project will in itself foster a dialogue that will strengthen networks of translational research and thus contribute to research excellence in Europe.

French Institute of Health, Medical Research, University of Nantes, French National Center for Scientific Research and Medical University of Vienna | Date: 2013-06-17

The present invention relates to a polypeptide derived from a mite allergen (Der p 2) useful for the prophylactic treatment of allergic asthma.

Olszewski U.,Ludwig Boltzmann Society | Deally A.,University College Dublin | Tacke M.,University College Dublin | Hamilton G.,Ludwig Boltzmann Society | Hamilton G.,Medical University of Vienna
Neoplasia (United States) | Year: 2012

First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cisdiamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non-cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38α mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase α1 (AMPKα1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside. This is in good agreement with previous reports, where AMPKα1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKα1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds. © 2012 Neoplasia Press, Inc. All rights reserved.

Lorenz-Depiereux B.,Helmholtz Center for Environmental Research | Schnabel D.,Charité - Medical University of Berlin | Tiosano D.,Meyer Childrens Hospital | Tiosano D.,Technion - Israel Institute of Technology | And 3 more authors.
American Journal of Human Genetics | Year: 2010

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization. © 2010 The American Society of Human Genetics.

Preusser M.,Medical University of Vienna | Lim M.,Johns Hopkins University | Hafler D.A.,Yale University | Reardon D.A.,Dana-Farber Cancer Institute | Sampson J.H.,Duke University
Nature Reviews Neurology | Year: 2015

Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment - maximal safe resection and combination of radiotherapy with temozolomide chemotherapy - the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies. © 2015 Macmillan Publishers Limited.

Linhart B.,Center for Pathophysiology | Valenta R.,Center for Pathophysiology | Valenta R.,Medical University of Vienna
Current Opinion in Immunology | Year: 2012

Vaccines aim to establish or strengthen immune responses but are also effective for the treatment of allergy. The latter is surprising because allergy represents a hyper-immune response based on immunoglobulin E production against harmless environmental antigens, i.e., allergens. Nevertheless, vaccination with allergens, termed allergen-specific immunotherapy is the only disease-modifying therapy of allergy with long-lasting effects. New forms of allergy diagnosis and allergy vaccines based on recombinant allergen-derivatives, peptides and allergen genes have emerged through molecular allergen characterization. The molecular allergy vaccines allow sophisticated targeting of the immune system and may eliminate side effects which so far have limited the use of traditional allergen extract-based vaccines. Successful clinical trials performed with the new vaccines indicate that broad allergy vaccination is on the horizon and may help to control the allergy pandemic. © 2012 Elsevier Ltd.

Valenta R.,Christian Doppler Laboratory | Valenta R.,Center for Pathophysiology | Linhart B.,Center for Pathophysiology | Swoboda I.,Christian Doppler Laboratory | Niederberger V.,Medical University of Vienna
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

The broad applicability of allergen-specific immunotherapy for the treatment and eventually prevention of IgE-mediated allergy is limited by the poor quality and allergenic activity of natural allergen extracts that are used for the production of current allergy vaccines. Today, the genetic code of the most important allergens has been deciphered; recombinant allergens equalling their natural counterparts have been produced for diagnosis and immunotherapy, and a large panel of genetically modified allergens with reduced allergenic activity has been characterized to improve safety of immunotherapy and explore allergen-specific prevention strategies. Successful immunotherapy studies have been performed with recombinant allergens and hypoallergenic allergen derivatives and will lead to the registration of the first recombinant allergen-based vaccines in the near future. There is no doubt that recombinant allergen-based vaccination strategies will be generally applicable to most allergen sources, including respiratory, food and venom allergens and allow to produce safe allergy vaccines for the treatment of the most common forms of IgE-mediated allergies. © 2011 John Wiley & Sons A/S.

Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital | Weinblatt M.E.,Brigham and Women's Hospital | Sheng S.,Janssen Research and Development LLC | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives: The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: In Part A ( proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12-22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12-24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts. Results: The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm). Conclusions: Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors. Trial registration number: NCT00718718.

Gundacker C.,Medical University of Vienna | Gencik M.,Praxis fur Humangenetik | Hengstschlager M.,Medical University of Vienna
Mutation Research - Reviews in Mutation Research | Year: 2010

The heavy metals mercury and lead are well-known and significant developmental neurotoxicants. This review summarizes the genetic factors that modify their toxicokinetics. Understanding toxicokinetics (uptake, biotransformation, distribution, and elimination processes) is a key precondition to understanding the individual health risks associated with exposure. We selected candidate susceptibility genes when evidence was available for (1) genes/proteins playing a significant role in mercury and lead toxicokinetics, (2) gene expression/protein activity being induced by these metals, and (3) mercury and lead toxicokinetics being affected by gene knockout/knockdown or (4) by functional gene polymorphisms. The genetic background is far better known for mercury than for lead toxicokinetics. Involved are genes encoding L-type amino acid transporters, organic anion transporters, glutathione (GSH)-related enzymes, metallothioneins, and transporters of the ABC family. Certain gene variants can influence mercury toxicokinetics, potentially explaining part of the variable susceptibility to mercury toxicity. Delta-aminolevulinic acid dehydratase (ALAD), vitamin D receptor (VDR) and hemochromatosis (HFE) gene variants are the only well-established susceptibility markers of lead toxicity in humans. Many gaps remain in our knowledge about the functional genomics of this issue. This calls for studies to detect functional gene polymorphisms related to mercury- and lead-associated disease phenotypes, to demonstrate the impact of functional polymorphisms and gene knockout/knockdown in relation to toxicity, to confirm the in vivo relevance of genetic variation, and to examine gene-gene interactions on the respective toxicokinetics. Another crucial aspect is knowledge on the maternal-fetal genetic background, which modulates fetal exposure to these neurotoxicants. To completely define the genetically susceptible risk groups, research is also needed on the genes/proteins involved in the toxicodynamics, i.e., in the mechanisms causing adverse effects in the brain. Studies relating the toxicogenetics to neurodevelopmental disorders are lacking (mercury) or very scarce (lead). Thus, the extent of variability in susceptibility to heavy metal-associated neurological outcomes is poorly characterized. © 2010 Elsevier B.V.

Gutnick T.,Hebrew University of Jerusalem | Byrne R.A.,Medical University of Vienna | Hochner B.,Hebrew University of Jerusalem | Kuba M.,Hebrew University of Jerusalem
Current Biology | Year: 2011

Octopuses are intelligent, soft-bodied animals with keen senses that perform reliably in a variety of visual and tactile learning tasks [1-6]. However, researchers have found them disappointing in that they consistently fail in operant tasks that require them to combine central nervous system reward information with visual and peripheral knowledge of the location of their arms [6-8]. Wells [6] claimed that in order to filter and integrate an abundance of multisensory inputs that might inform the animal of the position of a single arm, octopuses would need an exceptional computing mechanism, and "There is no evidence that such a system exists in Octopus, or in any other soft bodied animal." Recent electrophysiological experiments, which found no clear somatotopic organization in the higher motor centers, support this claim [9]. We developed a three-choice maze that required an octopus to use a single arm to reach a visually marked goal compartment. Using this operant task, we show for the first time that Octopus vulgaris is capable of guiding a single arm in a complex movement to a location. Thus, we claim that octopuses can combine peripheral arm location information with visual input to control goal-directed complex movements. Video Abstract: © 2011 Elsevier Ltd All rights reserved.

Buttgereit F.,Charité - Medical University of Berlin | Smolen J.S.,Medical University of Vienna | Coogan A.N.,National University of Ireland, Maynooth | Cajochen C.,University of Basel
Nature Reviews Rheumatology | Year: 2015

Circadian rhythms are of crucial importance for cellular and physiological functions of the brain and body. Chronobiology has a prominent role in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness being most pronounced in the morning, possibly mediated by circadian rhythms of cytokine and hormone levels. Chronobiological principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients (chronotherapy) could optimize results. Trials of NSAID or methotrexate chronotherapy for patients with RA suggest such an approach can improve outcomes and reduce adverse effects. The most compelling evidence for RA chronotherapy, however, is that coordinating the timing of glucocorticoid therapy to coincide with the nocturnal increase in blood IL-6 levels results in reduced morning stiffness and pain compared with the same glucocorticoid dose taken in the morning. Aside from optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances. Surprisingly, chronobiology is not mentioned in official guidelines for conducting RA drug registration trials. Given the imperative to achieve the best value with approved drugs and health budgets, the time is ripe to translate the 'circadian concept' in rheumatology from bench to bedside. © 2015 Macmillan Publishers Limited. All rights reserved.

Reddy A.S.N.,Colorado State University | Marquez Y.,Medical University of Vienna | Kalyna M.,Medical University of Vienna | Barta A.,Medical University of Vienna
Plant Cell | Year: 2013

Alternative splicing (AS) of precursor mRNAs (pre-mRNAs) from multiexon genes allows organisms to increase their coding potential and regulate gene expression through multiple mechanisms. Recent transcriptome-wide analysis of AS using RNA sequencing has revealed that ASis highly pervasive in plants. Pre-mRNAs from over60%of intron-containing genes undergo AS to produce a vast repertoire of mRNA isoforms. The functions of most splice variants are unknown. However, emerging evidence indicates that splice variants increase the functional diversity of proteins. Furthermore, AS is coupled to transcript stability and translation through nonsense-mediated decay and microRNA-mediated gene regulation. Widespread changes in AS in response to developmental cues and stresses suggest a role for regulated splicing in plant development and stress responses. Here, we review recent progress in uncovering the extent and complexity of the AS landscape in plants, its regulation, and the roles of ASin gene regulation. The prevalence ofASin plants has raised many newquestions that require additional studies.New tools based on recent technological advances are allowing genome-wide analysis of RNA elements in transcripts and of chromatin modifications that regulate AS. Application of these tools in plants will provide significant new insights into AS regulation and crosstalk between AS and other layers of gene regulation. © 2013 American Society of Plant Biologists. All rights reserved.

Dall'Ara E.,Vienna University of Technology | Schmidt R.,Medical University of Vienna | Zysset P.,University of Bern
Bone | Year: 2012

Bone mineral density and microarchitecture was found to predict 70-95% of bone strength. Microdamage, as factor of bone quality, might help to explain the remaining uncertainties. The goal of this study was to investigate whether microindentation can discriminate between intact and severely damaged human vertebral bone tissue in vitro. One portion from each human vertebral slice (N = 35) tested in compression in a previous study was embedded, polished and tested in wet conditions by means of microindentation. The indentation moduli and hardness (HV) of trabecular, osteonal and interstitial bone structural units were computed along the cranio-caudal direction. Each indented region was defined as damaged or intact as seen under a light microscope. A total of 1190 indentations were performed. While both hardness and indentation modulus were independent from gender, both mechanical properties were affected by damage and microstructure. The damaged regions showed 50% lower stiffness and hardness compared to undamaged ones. Interstitial bone was stiffer and harder (13.2 ± 4.4. GPa and 44.7 ± 20.3. HV) than osteonal bone (10.9 ± 3.8. GPa and 37.8 ± 17.3. HV), which was stiffer and harder than trabecular bone (8.1 ± 3.0. GPa and 28.8 ± 11.2. HV) indented in the transverse direction. Moreover, along the axial direction intact trabecular bone (11.4 ± 4.3. GPa) was 16% less stiff than the intact interstitial bone and as stiff as intact osteonal bone. In conclusion microindentation was found to discriminate between highly damaged and intact tissue in both trabecular and cortical bone tested in vitro. It remains to be investigated whether this technique would be able to detect also the damage, which is induced by physiological load in vivo. © 2012 Elsevier Inc.

Marquez Y.,Medical University of Vienna | Hopfler M.,Medical University of Vienna | Hopfler M.,Max Planck Institute of Biochemistry | Ayatollahi Z.,Medical University of Vienna | And 3 more authors.
Genome Research | Year: 2015

Alternative splicing (AS) diversifies transcriptomes and proteomes and is widely recognized as a key mechanism for regulating gene expression. Previously, in an analysis of intron retention events in Arabidopsis, we found unusual AS events inside annotated protein-coding exons. Here, we also identify such AS events in human and use these two sets to analyse their features, regulation, functional impact, and evolutionary origin. As these events involve introns with features of both introns and protein-coding exons, we name them exitrons (exonic introns). Though exitrons were detected as a subset of retained introns, they are clearly distinguishable, and their splicing results in transcripts with different fates. About half of the 1002 Arabidopsis and 923 human exitrons have sizes of multiples of 3 nucleotides (nt). Splicing of these exitrons results in internally deleted proteins and affects protein domains, disordered regions, and various post-translational modification sites, thus broadly impacting protein function. Exitron splicing is regulated across tissues, in response to stress and in carcinogenesis. Intriguingly, annotated intronless genes can be also alternatively spliced via exitron usage. We demonstrate that at least some exitrons originate from ancestral coding exons. Based on our findings, we propose a "splicing memory" hypothesis whereby upon intron loss imprints of former exon borders defined by vestigial splicing regulatory elements could drive the evolution of exitron splicing. Altogether, our studies show that exitron splicing is a conserved strategy for increasing proteome plasticity in plants and animals, complementing the repertoire of AS events. © 2015 Marquez et al.

Valent P.,Medical University of Vienna | Hadzijusufovic E.,Medical University of Vienna | Hadzijusufovic E.,University of Veterinary Medicine Vienna | Schernthaner G.-H.,Medical University of Vienna | And 3 more authors.
Blood | Year: 2015

Vascular safety is an emerging issue in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Whereas imatinib exhibits a well-documented and favorable long-term safety profile without obvious accumulation of vascular events, several types of vascular adverse events (VAEs) have been described in patients receiving secondor third-generation BCR/ABL1 TKIs. Such VAEs include pulmonary hypertension in patients treated with dasatinib, peripheral arterial occlusive disease and other arterial disorders in patients receiving nilotinib, and venous and arterial vascular occlusive events during ponatinib. Although each TKI interacts with a unique profile of molecular targets and has been associated with a unique pattern of adverse events, the mechanisms of druginduced vasculopathy are not well understood. Here, recent data and concepts around VAEs in TKI-treated patients with CMLare discussed, with special reference to potential mechanisms, event management, and strategies aimed at avoiding occurrence of such events in long-term treated patients. (Blood. 2015; 125(6): 901- 906) © 2015 by The American Society of Hematology.

Kavanaugh A.,University of San Diego | Smolen J.S.,Medical University of Vienna
Clinical and Experimental Rheumatology | Year: 2013

There has been great interest lately concerning the possibility that in the treatment of rheumatoid arthritis, biologic agents might be withdrawn for patients who achieve desirable targets, such aslow disease activity or remission. While there are a number of reasons why such a treatment paradigm might be desirable, there is a paucity of relevant data at present to guide clinicians about embarking on such a treatment change. Data is starting to emerge, much of it from controlled trials, that canprovide some guidance as to which patients might be the best candidates for such an approach. These data will provide answers to the key questions that remain concerning this important potential paradigm shift in the treatment of rheumatoid arthritis as well as other systemic inflammatory autoimmune diseases. © Clinical and Experimental Rheumatology 2013.

Partsch H.,Medical University of Vienna | Mortimer P.,University of London
British Journal of Dermatology | Year: 2015

Summary The main points in this scholarly review on the use of compression therapy in leg ulcers are the different modes of action of this treatment and the tools that are available including their practical applicability and use for self management. Due to its effect of counteracting gravity, compression is also suggested for ulcers with aetiologies that are not usually thought to require compression. The clinical evidence reported in ulcer-healing studies are discussed and some considerations are made relating to the cost-effectiveness of this management. In general, the failures of compression therapy are not caused by poor compression material but due to poor knowledge and application techniques of the care providers. Future studies comparing different compression devices should also report details concerning the compression material used and the pressure exerted. © 2015 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Dall'Ara E.,Vienna University of Technology | Pahr D.,Vienna University of Technology | Varga P.,Vienna University of Technology | Kainberger F.,Medical University of Vienna | Zysset P.,Vienna University of Technology
Osteoporosis International | Year: 2012

Summary: While dual energy X-ray absorptiometry (DXA) is considered the gold standard to evaluate fracture risk in vivo, in the present study, the quantitative computed tomography (QCT)-based finite element modeling has been found to provide a quantitative and significantly improved prediction of vertebral strength in vitro. This technique might be used in vivo considering however the much larger doses of radiation needed for QCT. Introduction: Vertebral fracture is a common medical problem in osteoporotic individuals. Bone mineral density (BMD) is the gold standard measure to evaluate fracture risk in vivo. QCT-based finite element (FE) modeling is an engineering method to predict vertebral strength. The aim of this study was to compare the ability of FE and clinical diagnostic tools to predict vertebral strength in vitro using an improved testing protocol. Methods: Thirty-seven vertebral sections were scanned with QCT and high resolution peripheral QCT (HR-pQCT). Bone mineral content (BMC), total BMD (tBMD), areal BMD from lateral (aBMD-lat), and anterior-posterior (aBMD-ap) projections were evaluated for both resolutions. Wedge-shaped fractures were then induced in each specimen with a novel testing setup. Nonlinear homogenized FE models (hFE) and linear micro-FE (μFE) were generated from QCT and HR-pQCT images, respectively. For experiments and models, both structural properties (stiffness, ultimate load) and material properties (apparent modulus and strength) were computed and compared. Results: Both hFE and μFE models predicted material properties better than structural ones and predicted strength significantly better than aBMD computed from QCT and HR-pQCT (hFE: R2 = 0.79, μFE: R2 = 0.88, aBMD-ap: R2 = 0.48-0.47, aBMD-lat: R2 = 0.41-0.43). Moreover, the hFE provided reasonable quantitative estimations of the experimental mechanical properties without fitting the model parameters. Conclusions: The QCT-based hFE method provides a quantitative and significantly improved prediction of vertebral strength in vitro when compared to simulated DXA. This superior predictive power needs to be verified for loading conditions that simulate even more the in vivo case for human vertebrae. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation.

Barta A.,Medical University of Vienna | Kalyna M.,Medical University of Vienna | Reddy A.S.N.,Colorado State University
Plant Cell | Year: 2010

Growing interest in alternative splicing in plants and the extensive sequencing of new plant genomes necessitate more precise definition and classification of genes coding for splicing factors. SR proteins are a family of RNA binding proteins, which function as essential factors for constitutive and alternative splicing. We propose a unified nomenclature for plant SR proteins, taking into account the newly revised nomenclature of the mammalian SR proteins and a number of plant-specific properties of the plant proteins. We identify six subfamilies of SR proteins in Arabidopsis thaliana and rice (Oryza sativa), three of which are plant specific. The proposed subdivision of plant SR proteins into different subfamilies will allow grouping of paralogous proteins and simple assignment of newly discovered SR orthologs from other plant species and will promote functional comparisons in diverse plant species. © 2010 American Society of Plant Biologists.

Lang I.M.,Medical University of Vienna | Pesavento R.,University of Padua | Bonderman D.,Medical University of Vienna | Yuan J.X.-J.,University of Illinois at Chicago
European Respiratory Journal | Year: 2013

All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH. A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, 'sticky' red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelial- mesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel.

Gruenbaum Y.,Hebrew University of Jerusalem | Foisner R.,Medical University of Vienna
Annual Review of Biochemistry | Year: 2015

Lamins are intermediate filament proteins that form a scaffold, termed nuclear lamina, at the nuclear periphery. A small fraction of lamins also localize throughout the nucleoplasm. Lamins bind to a growing number of nuclear protein complexes and are implicated in both nuclear and cytoskeletal organization, mechanical stability, chromatin organization, gene regulation, genome stability, differentiation, and tissue-specific functions. The lamin-based complexes and their specific functions also provide insights into possible disease mechanisms for human laminopathies, ranging from muscular dystrophy to accelerated aging, as observed in Hutchinson-Gilford progeria and atypical Werner syndromes. Copyright © 2015 by Annual Reviews. All rights reserved.

Montgomery S.,University of London | Hansen T.,Lundbeck | Kasper S.,Medical University of Vienna
International Journal of Neuropsychopharmacology | Year: 2011

The aim of this review was to assess the clinical relevance of the relative antidepressant efficacy of escitalopram and citalopram by meta-analysis. Studies in major depressive disorder (MDD) with both escitalopram and citalopram treatment arms were identified. Adult patients had to meet DSM-IV criteria for MDD. The primary outcome measure was the treatment difference in Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 8 (or last assessment if <8 wk). Secondary outcome measures were response (50% improvement from baseline) and remission (MADRS 12). A search of the literature and websites found eight randomized controlled trials (RCTs) and onr naturalistic trial, with a total of 2009 patients (escitalopram, n=995; citalopram, n=1014). Escitalopram was significantly more effective than citalopram in overall treatment effect, with an estimated mean treatment difference of 1.7 points at week 8 (or last assessment if <8 wk) on the MADRS (95% CI 0.8-2.6, p=0.0002) (six RCTs used the MADRS), and in responder rate (8.3 percentage points, 95% CI 4.4-12.3) (eight RCTs) and remitter rate (17.6 percentage points, 95% CI 12.1-23.1) analyses (reported for four RCTs), corresponding to number-needed-to-treat (NNT) values of 11.9 (p<0.0001) for response and 5.7 (p<0.0001) for remission. The overall odds ratios were 1.44 (p<0.0003) for response and 1.86 (p<0.0001) for remission, in favour of escitalopram. In this meta-analysis, the statistically significant superior efficacy of escitalopram compared to citalopram was shown to be clinically relevant. © 2010 CINP.

Kollaritsch H.,Medical University of Vienna | Kundi M.,Medical University of Vienna | Giaquinto C.,University of Padua | Paulke-Korinek M.,Medical University of Vienna
Clinical Microbiology and Infection | Year: 2015

By January 2015, rotavirus vaccination had been implemented in national vaccination programmes in 75 countries worldwide. Two live oral rotavirus vaccines are internationally available: human, monovalent vaccine and human-bovine pentavalent reassortant vaccine. Since January 2014, another live, oral human-bovine monovalent vaccine has been available in India. After implementation of rotavirus vaccines in childhood immunization programmes, there has been an over 90% reduction of rotavirus hospitalizations in industrialized and resource-deprived countries. Additionally, in Latin America, significant reduction of rotavirus-associated deaths has been recorded. Still, numerous countries do not recommend rotavirus mass vaccination because of assumed lack of cost-effectiveness and potential risk of intussusception, which is estimated at 1 per 50 000-70 000 doses of rotavirus vaccines. Cost-effectiveness of vaccination is affected in some countries by high price. Inclusion of herd protection and indirect costs in calculations for cost-effectiveness results in clear benefit: costs saved by health systems due to reduced rotavirus gastroenteritis hospitalizations far exceed the costs for implementation of rotavirus vaccination. There have been objections that high rotavirus vaccination coverage could put selective pressure on certain rotavirus strains against which protection after vaccination is less distinct. However, data now strongly suggest that even if there might be a relative increase of some specific genotypes after the use of rotavirus vaccines, this is not an absolute increase in incidence from certain genotypes and does not affect the overall effectiveness of rotavirus mass vaccination, which resulted in a major decrease of severe cases of rotavirus gastroenteritis in both industrialized and resource deprived countries. © 2015 European Society of Clinical Microbiology and Infectious Diseases.

Richard E.G.,Johns Hopkins University | Honigsmann H.,Medical University of Vienna
Photodermatology Photoimmunology and Photomedicine | Year: 2014

Over 10 years have passed since the first approval of a biologic agent for the treatment of psoriasis. No one can argue that the arrival of this entirely new, highly effective class of medications has not forever changed the therapeutic landscape for psoriasis. Traditional treatments such as phototherapy, however, remain both viable and effective therapies, both as standalone treatments and in combination with biologics. In general, synergistic effects are noted for combinations utilizing phototherapy; however, the long-term impact of these combinations on skin cancer development has yet to be fully determined. Increasing financial pressures for cost-effective therapies augment the appeal of phototherapy and other traditional treatments as compared with the more costly biologics. Phototherapy also remains strong outside the realm of psoriasis, in the management of atopic dermatitis, vitiligo, and cutaneous T-cell lymphoma, among other conditions. Phototherapy will remain a cornerstone in the management of psoriasis as well as nonpsoriatic skin conditions, as its efficacy is well known, its financial cost is reasonable, it is readily compatible with other therapeutics, and its utility is historically proven. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Woehrer A.,Medical University of Vienna | Bauchet L.,Montpellier University | Barnholtz-Sloan J.S.,Case Western Reserve University
Current Opinion in Neurology | Year: 2014

Purpose of review Glioblastoma is the most common malignant brain tumor in adults and carries a particularly poor prognosis. Since 2005, state-of-the-art therapy consists of maximal well tolerated surgical resection followed by combined radiotherapy and chemotherapy with temozolomide. Over the past decade, further advances have been achieved in various disciplines, most prominently including antiangiogenic treatment with bevacizumab. Still, whether these therapeutic innovations have translated to the general population remains unclear. Recent findings Population-based outcome and pattern of care (POC) studies have recently documented the rapid dissemination of the treatment standard to community practice across countries. This has resulted in a modest but significant increase in survival at the population level. However, the increase was significantly less marked in elderly patients in whom undertreatment is a concern. Other serious concerns address diverging POC between academic versus nonacademic centers, patients with high-income versus lowincome, and racial and marital status disparities. With regard to bevacizumab treatment, there is still insufficient evidence of a beneficial impact on population-based survival, so far. Summary Despite the rapid incorporation of the current standard treatment in clinical practice and the thereby achieved modest survival gain at the population-level, prevailing POC needs to be reconsidered and standardized, especially for elderly glioblastoma patients who bear a large disease burden and carry the worst prognosis. Future POC studies are urgently needed and would benefit from the systematic inclusion of quality-of-life data and molecular tumor markers, so that this information could be captured in populationbased cancer registries. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-1.4-2 | Award Amount: 16.06M | Year: 2009

Cardiovascular disease still represents the Killer No.1 in the EU accounting for substantial morbidity/mortality and health care cost. Heart valve replacement represents the most common surgical therapy for valvular heart disease with almost 200.000 annual implantations worldwide. Currently, heart valve prosthesis-associated problems occur in 30-35% of patients within 10 years, frequently necessitating risky re-operations. A particularly severe problem relates to children with congenital heart defects (1% of all newborns) who cannot be treated efficiently due to the lack of growths of the clinically available artificial valve prostheses. The principal objective of the LifeValve project is to develop a new therapeutic strategy to treat heart valve disease patients more efficiently. Two novel life science technologies will be combined: tissue engineering and minimally invasive implantation technology. In particular, the scientific and technological approach of the LifeValve project is to develop a clinically relevant tissue engineered living heart valve, with the capacity of regeneration and growths which can be implanted by minimally invasive catheter technology. First clinical trials will be enrolled in paediatric patients addressing the currently unmet dramatic medical need for growing implants. A highly interdisciplinary approach combines basic sciences, medical research, engineering and clinical practice. In addition, close industry-academia collaborations are integrated. It is expected that new knowledge applicable for a much broader field of cardiovascular diseases will be generated by the unique combination of consortium partners each representing opinion leaders in their fields. The consortium is compact comprising all the necessary expertise and skills to realize the precisely planned work in a short period of time.The close collaboration of the well interconnected LifeValve consortium will most efficiently contribute to an added value for the EU.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-1.2-1;HEALTH-2007-1.2-2 | Award Amount: 7.09M | Year: 2008

The aim of FUN OCT is to expand the non-invasive optical biopsy capability of optical coherence tomography (OCT) and combination of OCT with multiphoton tomography (MT) to develop novel functional capabilities hereby enabling morphofunctional performance, i.e., the fusion of anatomic and functional imaging at the cellular resolution level. These methodologies will enable unprecedented non-invasive detection of depth resolved physiological, metabolic as well as molecular specific tissue information, i.e., forming a novel, powerful medical imaging platform. This novel platform fills an important gap left by todays medical imaging technology. The hypothesis is that the combination of cellular resolution, real time imaging of morphology and depth resolved tissue function could enable a major step forward in early cancer diagnosis and in the early detection of retinal pathologies that are world wide leading causes of blindness. This is accomplished due to a synergistic effect from joining complementary international expertise in the fields of laser sources, OCT, MT and beam delivery system technology. The consortium comprises 6 research groups and 2 SMEs. The consortium will make use of its existing relations to clinical collaborators in order to achieve proof-of-principle validation of the imaging modalities. The outcome contributes directly to improving and to maintaining the quality of life and living conditions of the European aging population through early diagnosis of cancer and of retinal pathologies as well as more efficient therapy monitoring. Moreover, the envisaged imaging modality may in the long term act as a screening device to investigate the prevalence of cancer as a function of geographic (regional) or gender related parameters. Finally, the diagnosis of other age-related diseases in a variety of medical fields, such as cardiology, neurology, gynaecology, and gastroenterology, benefit from this novel diagnostic platform provided by FUN OCT.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2016 | Award Amount: 4.04M | Year: 2016

There is no health without mental health. 27% of our population are young, and mental health disorders are our leading cause of disability. 50% of mental disorders emerge by 14 yrs, 75% by 24 yrs and, untreated, triple odds of having a mental health disorder in later life. TEAMs will build a network of expertise and train a new generation of researchers to deliver more effective, affordable and feasible mental health services for young people. Our interdisciplinary, international, intersectoral network, balanced in skills, experience and perspectives, will train the next generation of researchers to lead Youth Mental Health (YMH) services into the future. Research objectives focus on key challenges in YMH: delivering new technologies to support rapid, large-scale, and early assessment, prevention and treatment.TEAM will also deliver policy directions and guidelines for technology-enabled YMH. 2 themes are covered: how can technology a) increase access, and b) help people to engage more successfully? TEAM will deliver new technology-enabled services that are both accessible and engaging for young people. Our ambitious objectives require individuals with a unique combination of interdisciplinary and intersectoral skills. TEAM ESRs will receive integrated training across three key areas necessary to fully realise the potential of technology-enabled mental health: Mental Healthcare Delivery - the theories and practice of YMH; Computer science - core principles in software engineering and technology infrastructures; Interaction Design - theories and methods including co-designing with young people and active engagement with clinicians, social workers, caregivers (e.g. parents) and teachers. Intersectoral secondments promote interdisciplinary and intersectoral learning and communication, and public engagement and outreach focus on young people, those who play major roles in their lives (e.g. parents and teachers), health care professionals.