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The invention describes phosphonates of acetylenic betulin derivatives with anticancer activity,with Formula 2


Grant
Agency: European Commission | 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


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.


Goniewicz M.L.,Queen Mary, University of London | Goniewicz M.L.,Medical University of Silesia, Katowice | Zielinska-Danch W.,Medical University of Silesia, Katowice
Pediatrics | Year: 2012

BACKGROUND: Electronic cigarettes (e-cigarettes) are battery-powered devices developed with the goal of mimicking the action of smoking, including nicotine delivery, without the toxic effects of tobacco smoke. Little is known about the uptake of e-cigarettes among young people. METHODS: A survey was conducted with a cluster sample of 20 240 students enrolled at 176 nationally representative Polish high schools and universities between September 2010 and June 2011. We estimated national e-cigarette prevalence among various demographic groups by using population weights. Multiple logistic regression was used to evaluate which demographic factors were independent predictors of 2 outcomes: ever use of e-cigarettes and use in the previous 30 days. RESULTS: Among high school students, aged 15 to 19 years, 23.5% had ever used e-cigarettes and 8.2% had done so within the previous 30 days. Among those in universities, aged 20 to 24 years, 19.0% had ever used an e-cigarette and 5.9% had done so in the previous 30 days. In multivariate analyses that controlled for covariates, smoking cigarettes, male gender, living in an urban area, and having parents who smoke were associated with ever use of e-cigarettes. Overall, 3.2% of never smoking students reported ever use of e-cigarettes. CONCLUSIONS: About one-fifth of Polish youth have tried e-cigarettes; most of them had previously smoked cigarettes. It is unclear whether e-cigarettes are just a novelty that young people try only once or whether they have potential to compete in the marketplace with conventional cigarettes. Copyright © 2012 by the American Academy of Pediatrics.


Buldak R.J.,Medical University of Silesia, Katowice
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society | Year: 2013

Visfatin has recently been established as a novel adipokine that is predominantly expressed in visceral fat. Recombinant visfatin has immunomodulating properties, which can activate human leukocytes in vitro to induce cytokine production (IL-1β, TNF-α, and IL-6). Only few studies have investigated the effect of visfatin on prostate, breast, ovarian cancer as well as astrocytoma cell biology. There have been no studies on the cytokine secretion in human melanoma cells in response to visfatin stimulation along with intracellular protein kinases inhibitors. ELISA assay was performed in supernatants of Me45 cells stimulated with visfatin in the presence or the absence of specific pharmacological inhibitors of the indicated protein kinases (p38, MEK 1, PI3k and JAK kinase) and nuclear factor kappa B (NK-κB) inhibitor. Intracellular reactive oxygen species level was measured in 2', 7'-dichlorodihydrofluorescein diacetate (H2DCF-DA)-loaded cells using a fluorescent measurement system. For determination of NF-κB activation, activated NF-κB p65 subunit was determined using an EZ-TFA-detect chemiluminescent transcription factor assay. We report that visfatin led to the significant increase in IL-6 and IL-8 level in culture supernatants of human malignant melanoma Me45 cells. Additionally visfatin resulted in the increase of the intracellular reactive oxygen species level. PI3k and NF-κB pathways were activated upon visfatin stimulation. The results may reflect the fact that PI3k pathway stimulation by visfatin may further lead to NF-κB activation and pro-inflammatory response.


Soltysik K.,Medical University of Silesia, Katowice
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society | Year: 2013

The functions of estrogens are relatively well known, however the molecular mechanism of their action is not clear. The classical pathway of estrogen action is dependent on ERα and ERβ which act as transcription factors. The effects of this pathway occur within hours or days. In addition, so-called, non-classical mechanism of steroid action dependent on membrane estrogen receptors (mER) was described. In this mechanism the effects of estrogen action are observed in a much shorter time. Here we review the structure and cellular localization of mER, molecular basis of non-classical mER action, physiological role of mER as well as implications of mER action for cancer biology. Finally, some concerns about the new estrogen receptor - GPER and candidates for estrogen receptors - ER-X and ERx, are briefly discussed. It seems that mER is a complex containing signal proteins (signalosome), as IGF receptor, EGF receptor, Ras protein, adaptor protein Shc, non-receptor kinase c-Src and PI-3K, what rationalizes production of second messengers. Some features of membrane receptors are almost identical if compared to nuclear receptors. Probably, membrane and nuclear estrogen receptors are not separate units, but rather the components of a complex mechanism in which they both cooperate with each other. We conclude that the image of the estrogen receptor as a simple transcription factor is a far-reaching simplification. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors.


Cieslik-Bielecka A.,Medical University of Silesia, Katowice
Journal of biological regulators and homeostatic agents | Year: 2012

Platelets, as main actors of the first stage of the healing process, play an important role in tissue repair. Their granules contain many active substances, particularly over 30 growth factors with significant effects on the resident cells at the site of injury, such as mesenchymal stem cells, chondrocytes, fibroblasts, osteoblasts. This potential may be increased by the concentration of the platelets, using platelet-rich plasma/fibrin products. In the four families of platelet concentrates, 2 families contain also significant concentrations of leukocytes: L-PRP (Leukocyte- and Platelet-Rich Plasma) and L-PRF (Leukocyte- and Platelet-Rich Fibrin). Inductive properties of platelet concentrates were widely described. However, they present also antimicrobial effects. The antibacterial effects of L-PRP were highlighted in only a few in vitro studies. Strong activity comparable to gentamicin and oxacillin for L-PRP against methicillin susceptible Staphylococcus aureus (MSSA) was already demonstrated. L-PRP also inhibited the growth of methicillin resistant Staphylococcus aureus (MRSA) and Escherichia coli. Some authors also reported clinical observations about the reduction of infections and the induction of healing processes after the use of platelet concentrates in cardiac, orthopaedic, oral and maxillofacial surgery. However, very little is yet known about the antibacterial effects of these concentrates. In this manuscript, the current data about the antimicrobial agents and cells present in the platelet-rich plasma/fibrin are highlighted and discussed, in order to introduce this new key chapter of the platelet concentrate technology history.


Adamczak M.,Medical University of Silesia, Katowice | Wiecek A.,Medical University of Silesia, Katowice
Seminars in Nephrology | Year: 2013

During the past 2 decades, results of both basic science and clinical studies have changed the physicians' views about adipocyte pathophysiology. Since leptin was discovered in 1994, white adipose tissue was recognized as an endocrine organ and an important source of biologically active substances with local and/or systemic action called adipokines. Inappropriate secretion of several adipokines by the excessive amount of white adipose tissue seems to participate in the pathogenesis of obesity-related pathologic processes including endothelial dysfunction, inflammation, atherosclerosis, diabetes mellitus, and chronic kidney disease. In this review endocrine action of selected adipokines (mainly leptin and adiponectin) in the context of kidney diseases is discussed. Specifically, the role of these adipokines in malnutrition, chronic kidney disease progression, and pathogenesis of cardiovascular complications is presented. © 2013 Elsevier Inc..


Kukla M.,Medical University of Silesia, Katowice
Hepatology International | Year: 2013

It has become increasingly clear that angiogenesis occurring during chronic wound healing and fibrogenesis provides a key contribution to disease progression and complications. The association of fibrogenesis and angiogenesis should be regarded as crucial in the modern evaluation of liver disease progression and in the search for therapeutic targets. Physiological hepatic angiogenesis occurs during liver regeneration, contributing to the formation of new functional sinusoids. Pathological angiogenesis in liver is characterized by intrahepatic vascular remodeling with capillarization of the sinusoids and development of intrahepatic shunts, which lead to increased hepatic resistance and decreased effective hepatocyte perfusion. The problem of angiogenesis in chronic hepatitis C and nonalcoholic fatty liver disease has not been fully resolved. This manuscript briefly describes pathogenesis of new blood vessel formation in chronic hepatitis and potential role of angiogenesis in disease progression. © 2012 Asian Pacific Association for the Study of the Liver.


Kasperska-Zajac A.,Medical University of Silesia, Katowice
Journal of the European Academy of Dermatology and Venereology | Year: 2012

The patterns of acute-phase response (APR) biomarkers differ upon various inflammatory conditions. Little information is available on the systemic inflammatory response in urticaria/angio-oedema. It has been shown that concentrations of circulating APR biomarkers, IL-6 and C-reactive protein (CRP), are elevated more in severe chronic urticaria (CU) than in patients showing milder urticarial symptoms. It is not clear whether the increase of IL-6 and CRP is merely an epiphenomenon or may contribute to the pathogenesis of CU. It is tempting to speculate that mediators of APR may enhance urticarial inflammation. In addition, there is some association between APR and activation of coagulation/fibrinolysis in CU. It is well known that even slight elevation in CRP baseline concentration is enough to produce significant increase in cardiovascular risk. In this light, one should ask whether CU patients, in particular those showing stronger systemic inflammatory response and long-lasting course are more vulnerable to the cardiovascular events. Apart from highly troublesome symptoms and low quality of life, CU may then involve some remote, serious systemic consequences. Taken together, CU can be identified as a mast cell- and basophil-dependent inflammatory disorder of the skin, which is accompanied by APR. Characterization of APR in CU may appear essential for an insight into the activity of this disease and for assessment of the inflammation degree. Moreover, measurement of these biomarkers might be particularly relevant while assessing CU patients demanding an anti-inflammatory or immunosuppressive therapy. This review summarizes information regarding APR in the course of urticaria/angio-oedema. © 2011 European Academy of Dermatology and Venereology.

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