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Prowle J.R.,The Royal London Hospital | Chua H.-R.,National University of Singapore | Bagshaw S.M.,University of Alberta | Bellomo R.,Austin Health
Critical Care | Year: 2012

Intravenous fluids are widely administered to maintain renal perfusion and prevent acute kidney injury (AKI). However, fluid overload is of concern during AKI. Using the Pubmed database (up to October 2011) we identified all randomised controlled studies of goal-directed therapy (GDT)-based fluid resuscitation (FR) reporting renal outcomes and documenting fluid given during perioperative care. In 24 perioperative studies, GDT was associated with decreased risk of postoperative AKI (odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.39 to 0.89) but additional fluid given was limited (median: 555 ml). Moreover, the decrease in AKI was greatest (OR = 0.47, 95% CI = 0.29 to 0.76) in the 10 studies where FR was the same between GDT and control groups. Inotropic drug use in GDT patients was associated with decreased AKI (OR = 0.52, 95% CI = 0.34 to 0.80, P = 0.003), whereas studies not involving inotropic drugs found no effect (OR = 0.75, 95% CI = 0.37 to 1.53, P = 0.43). The greatest protection from AKI occurred in patients with no difference in total fluid delivery and use of inotropes (OR = 0.46, 95% CI = 0.27 to 0.76, P = 0.0036). GDT-based FR may decrease AKI in surgical patients; however, this effect requires little overall FR and appears most effective when supported by inotropic drugs. © 2012 BioMed Central Ltd.


WALTHAM, Mass. & STOCKHOLM--(BUSINESS WIRE)--Bioverativ Inc. NASDAQ: BIVV) and Swedish Orphan Biovitrum AB (publ) (Sobi™) (STO: SOBI) today announce that interim results from the B-YOND extension trial, which studies ALPROLIX® [Coagulation Factor IX (Recombinant), Fc Fusion Protein] in previously-treated subjects with severe hemophilia B, were published in the March 2017 issue of Thrombosis and Haemostasis. The study results reinforce the long-term safety and efficacy of prophylactic treatment with ALPROLIX over a median duration of more than three years in adults/adolescents and more than a year and a half in children under 12 years of age. The primary outcome measure was development of inhibitors (neutralizing antibodies that can interfere with activity of the therapy); no patients treated with ALPROLIX in the study developed inhibitors. “ The interim data from B-YOND confirm the safety profile of ALPROLIX, and show that adult, adolescent and pediatric subjects maintained low annual bleed rates with prophylactic dosing of ALPROLIX every 1-2 weeks,” said John Pasi, MD, PhD, principal investigator of the study, Professor of Haemostasis and Thrombosis at The Royal London Hospital, Barts and the London School of Medicine and Dentistry, London. “ These results come from the longest-term study of an extended half-life therapy for hemophilia B and provide physicians across the globe with important insights and information about the treatment of hemophilia B.” B-YOND is an ongoing open-label, non-randomized extension study, and eligible previously-treated patients who completed B-LONG or Kids B-LONG could enroll in one of three treatment groups: weekly prophylaxis, individualized prophylaxis, and modified prophylaxis. An episodic treatment arm is also available only to adult and adolescent participants. At the time of the interim data cut, 116 male subjects (93 from B-LONG and 23 from Kids B-LONG) were enrolled in the study. “ These results confirm the long-term safety and efficacy profile of ALPROLIX and show that a majority of the participants in the study were able to dose once weekly or less frequently while maintaining adequate protection,” said Maha Radhakrishnan, MD, senior vice president of medical at Bioverativ. In the individualized prophylaxis treatment group, as of the B-YOND interim data cut, a total of 26 adolescent/adult subjects out of 30 (86.7%) had a dosing interval longer than one week with a median dosing interval of 13.7 days, and pediatric subjects aged 6 to <12 years had a median dosing interval of 10.0 days. Fifteen of 26 (57.7%) adult/adolescent subjects in the individualized prophylaxis treatment group had a dosing interval of every 14 days or longer. “ Together with Bioverativ, we remain focused on advancing research to better understand the underlying science and potential benefits of ALPROLIX for people with hemophilia B,” said Krassimir Mitchev, MD, PhD, vice president and medical therapeutic area head of Haemophilia at Sobi. Growing Body of Evidence Further Reinforces the Safety and Efficacy of ALPROLIX The overall median annualized bleeding rate (ABR) at the time of the B-YOND interim data cut was 2.3 for adult/adolescent participants in both the weekly and individualized prophylaxis treatment groups, and 2.4 for those in the modified prophylaxis study arm. Participants receiving on-demand therapy, or treatment when a bleeding episode occurred, had a median ABR of 11.3. Among children under age six (n=9), the median ABR in the weekly prophylaxis group was zero. For children between six and 12 years old, the median ABR was similar in the weekly (2.7; n=10) and individualized (2.4; n=5) prophylaxis groups. The one participant from the 6 to <12 years cohort who was in the modified prophylaxis group had an ABR of 3.1. In the B-YOND study as of the interim data cut, ALPROLIX was well tolerated and adverse events (AEs) were typical of the hemophilia B populations studied. The most common AEs were headache (n=14, 12.1%) and common cold (n=13, 11.2%), and the majority of AEs were considered by the investigator to be unrelated to ALPROLIX treatment. A total of 39 serious AEs (SAEs) were reported in 23 participants (19.8%) treated with ALPROLIX. All SAEs were assessed by the investigator as unrelated to ALPROLIX, with the exception of one SAE of renal colic in an adult/adolescent participant with a medical history of previous clot colic; the event resolved and did not lead to study discontinuation. In the study as of the interim data cut, there were no reports of serious allergic reactions or anaphylaxis associated with ALPROLIX, no vascular thrombotic events, and no deaths. The full publication is available online at https://th.schattauer.de. About the B-YOND Extension Study B-YOND enrolled 116 previously-treated males, including 93 participants (81%) who completed B-LONG, and 23 (100%) of those who completed Kids B-LONG. The primary outcome measure is development of inhibitors. Secondary endpoints include the annualized number of bleeding episodes per subject (including spontaneous joint bleeding rates), ALPROLIX exposure days per participant, ALPROLIX consumption (total IU/kg per subject per year), and the participant’s assessment of response to treatment of a bleeding episode. From the start of B-LONG to the B-YOND interim data cut, adult/adolescent subjects had a median of 39.5 months of cumulative ALPROLIX treatment, and a median of 162 cumulative ALPROLIX exposure days. From the start of Kids B-LONG to the B-YOND interim data cut, pediatric subjects had a median of 21.9 months of cumulative ALPROLIX treatment, and a median of 94 cumulative ALPROLIX exposure days. About ALPROLIX® ALPROLIX® [Coagulation Factor IX (Recombinant), Fc Fusion Protein] is a recombinant clotting factor therapy developed for hemophilia B using Fc fusion technology to prolong circulation in the body. It is engineered by fusing factor IX to the Fc portion of immunoglobulin G subclass 1, or IgG1 (a protein commonly found in the body), enabling ALPROLIX to use a naturally occurring pathway to extend the time the therapy remains in the body (half-life). While Fc fusion technology has been used for more than 15 years, Bioverativ and Sobi have optimized the technology and are the first companies to utilize it in the treatment of hemophilia. ALPROLIX is manufactured using a human cell line in an environment free of animal and human additives. ALPROLIX is approved and marketed by Bioverativ for the treatment of hemophilia B in the United States, Japan and Canada. It is also approved in Australia, New Zealand, Brazil and other countries, and Bioverativ has marketing rights in these regions. It is also authorized in the European Union, Iceland, Liechtenstein, Norway and Switzerland, where it is marketed by Sobi. Allergic-type hypersensitivity reactions and development of inhibitors have been observed with ALPROLIX in the treatment of hemophilia B, including in previously-untreated patients. For more information, please see the full U.S. prescribing information for ALPROLIX. Note that the indication for previously-untreated patients is not included in the EU Product Information. About Hemophilia B Hemophilia B is caused by having substantially reduced or no factor IX activity in the blood, which is needed for normal blood clotting.1 The World Federation of Hemophilia estimates that approximately 28,000 people are currently diagnosed with hemophilia B worldwide.2 People with hemophilia B may experience bleeding episodes in joints and muscles that cause pain, decreased mobility and irreversible joint damage. In the worst cases, these bleeding episodes can cause organ bleeds and life-threatening hemorrhages. Infusions of factor IX temporarily replace clotting factors necessary to resolve bleeding and, when used prophylactically, to prevent new bleeding episodes.1 About the Bioverativ and Sobi Collaboration Bioverativ and Sobi collaborate on the development and commercialization of ALPROLIX and ELOCTATE®/Elocta® [Antihemophilic Factor (Recombinant), Fc Fusion Protein]. Bioverativ has final development and commercialization rights in North America and all other regions in the world excluding the Sobi territory, and has manufacturing responsibility for ELOCTATE and ALPROLIX. Sobi has final development and commercialization rights in the Sobi territory (essentially Europe, North Africa, Russia and most Middle Eastern markets). About Bioverativ Bioverativ is a global biotechnology company dedicated to transforming the lives of people with hemophilia and other rare blood disorders through world-class research, development and commercialization of innovative therapies. Launched in 2017 following separation from Biogen Inc., Bioverativ builds upon a strong heritage of scientific innovation and is committed to actively working with the blood disorders community. The company’s mission is to create progress for patients where they need it most and its hemophilia therapies when launched represented the first major advancements in hemophilia treatment in more than two decades. For more information, visit www.bioverativ.com or follow @bioverativ on Twitter. Bioverativ was created as a spin-off from Biogen’s hemophilia business and separated from Biogen effective February 1, 2017. Bioverativ is an independent, publicly-traded company, headquartered in Waltham, Massachusetts. During a temporary transition period, which includes time to allow Bioverativ to establish certain licenses and consents related to ELOCTATE and ALPROLIX, each of Bioverativ and Biogen will have a relationship to the products. About Sobi™ Sobi is an international specialty healthcare company dedicated to rare diseases. Sobi’s mission is to develop and deliver innovative therapies and services to improve the lives of patients. The product portfolio is primarily focused on Haemophilia, Inflammation and Genetic diseases. Sobi also markets a portfolio of specialty and rare disease products across Europe, the Middle East, North Africa and Russia for partner companies. Sobi is a pioneer in biotechnology with world-class capabilities in protein biochemistry and biologics manufacturing. In 2016, Sobi had total revenues of SEK 5.2 billion (USD 608 M) and about 760 employees. The share (STO:SOBI) is listed on Nasdaq Stockholm. More information is available at www.sobi.com. Bioverativ Safe Harbor This press release contains forward-looking statements, including statements about the potential benefits, safety profile, and efficacy of ALPROLIX in hemophilia B and the potential of the Fc Fusion technology. These forward-looking statements may be accompanied by such words as “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “potential,” “project,” “target,” “will” and other words and terms of similar meaning. You should not place undue reliance on these statements. These statements involve risks and uncertainties that could cause Bioverativ’s actual results to differ materially from those reflected in such statements, including, without limitation, risks related to development of early stage programs, unexpected concerns that may arise from additional data or analysis, regulatory authorities may require additional information or further studies, regulatory authorities may fail to expand product labeling, and other risks and uncertainties associated with Bioverativ’s drug development and commercialization activities described in the Risk Factors section of Bioverativ’s filings with the Securities and Exchange Commission. These statements are based on Bioverativ’s current beliefs and expectations and speak only as of the date of this press release. Bioverativ does not undertake any obligation to publicly update any forward-looking statements. 1 World Federation of Hemophilia. About Bleeding Disorders – Frequently Asked Questions. Available at: http://www.wfh.org/en/page.aspx?pid=637#Difference_A_B. Accessed on: January, 13, 2017. 2 World Federation of Hemophilia. Report on the Annual Global Survey 2013. Available at: http://www1.wfh.org/publications/files/pdf-1591.pdf. Accessed on: January 13, 2017.


News Article | December 21, 2016
Site: www.nature.com

From established anti-inflammation agents and steroids to the latest biological drugs, people with inflammatory bowel disease (IBD) are benefiting from a growing arsenal of treatments. But the complicated network of genetic, epigenetic and environmental factors that trigger the disease is not well understood, and IBD is difficult to model in the lab. There is no cure, and for some people all therapies eventually fail. “There is still a significant minority of patients who have truly refractory, chronic active disease, and new biologics are not likely to help these patients,” says James Lindsay, who is head of the adolescent and adult IBD service at The Royal London Hospital. “These patients are in and out of hospital, they may be on intravenous nutrition, they're not working, they have morbidity from steroids and they have a truly atrocious quality of life.” Enter cell-based therapies. Among the many treatments being investigated, the furthest advanced involve the transplantation of haematopoietic stem cells, which make the body's blood cells, and treatments based on mesenchymal stem cells — adult stem cells that can differentiate into a variety of cell types. In earlier stages of investigation are efforts to construct 3D tissues called organoids using intestinal stem cells, as well as work to modify the cells that regulate the immune system. The ultimate goal of these treatments is to provide a cure for IBD. After years of study in the lab, some have reached clinical trials, although results have so far been mixed. The road to approval may well be long, but cell-based therapies offer hope to people for whom conventional treatments have failed. Found in bone marrow, haematopoietic stem cells make all of the body's blood cells, including the immune cells that overreact in IBD. For decades, people with blood cancers such as leukaemia and multiple myeloma have undergone a treatment that wipes out their haematopoietic stem cells with chemotherapy and replaces them with donated, cancer-free cells — a tough and highly toxic programme, but one that is often effective in ridding people of these cancers. Similar transplants that reboot the immune system have been shown to work in autoimmune diseases such as multiple sclerosis. In the 1990s, gastroenterologists began to notice that some people with Crohn's disease — one of the major forms of IBD — who were given transplants to treat blood cancers were also relieved of their IBD symptoms. Although these observations raised interest in cell transplants, many were concerned about the lack of evidence for a treatment that can be lethal. “There was a worry that loads of people would go through a very risky procedure, whether it was of benefit or not,” says Lindsay. That worry was the motivation behind the Autologous Stem Cell Transplantation for Crohn's Disease (ASTIC) trial, the first and so far only phase III trial designed to test the technique. Transplants in the ASTIC trial followed a similar procedure to that used for blood cancers, but instead of using cells from a donor, a patient's own stem cells were harvested and reinfused. ASTIC involved 11 centres across Europe, and enrolled 45 people with refractory Crohn's disease. In the first year, 23 volunteers were given transplants; the others received standard care (C. J. Hawkey et al. J. Am. Med. Assoc. 314, 2524–2534; 2015). Transplants were then offered to those in the control group as well. “We had two questions,” says Christopher Hawkey, ASTIC lead researcher and a gastroenterologist at the University of Nottingham, UK. “How often is Crohn's 'cured' by stem-cell transplants, and more broadly, is it effective in these people who have run out of treatment options?” The trial's main endpoint was a difficult one: sustained clinical remission after one year, which was defined as no evidence of active disease on endoscopic imaging, and patients able to stop standard medication. “It was probably unwise of me to set it like that,” says Hawkey. Such a high bar — designed to reflect the risk associated with the treatment — meant that only two people in the treatment group reached the endpoint, compared with one in the control group. As expected, the procedure resulted in many serious adverse events, including one death. Given that so few participants reached ASTIC's demanding endpoint, the researchers concluded that the trial had failed, leading some to write off these transplants for IBD. But Hawkey points out that some participants did benefit. “Half the patients had no signs of active Crohn's disease at least a year after transplant, and just over a quarter had no signs of disease all,” he says. Preliminary results from a four-year follow-up of the participants have confirmed the treatment's positive effects. “It changed people's lives,” says Lindsay, who was one of the investigators on the trial. “I had a chap who was dependent on intravenous nutrition and couldn't work. He's now off IV nutrition, he's working; he's got incomplete remission, but his life has been revolutionized.” By labelling ASTIC a failure, researchers are ignoring the potential of these transplants to help people who have exhausted the available treatments — those who cannot undergo any more surgery or cope with the toxicity of any more drugs — says Daniel Hommes, gastroenterologist and director of the Center for Inflammatory Bowel Diseases at the University of California, Los Angeles. “It definitely can be a lifesaver. The trial's very strange endpoint doesn't reflect the potency of this strategy.” Hawkey, Lindsay and other investigators have proposed a follow-up transplant trial that uses much less toxic treatment regimes. “We're not trying to kill every cancer cell in a patient,” Lindsay says. They have also suggested adopting a more modest endpoint. “If we had used the primary endpoint that the [US] Food and Drug Administration would require for a new biologic, the trial would have been very strongly positive,” he says. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that can become bone, cartilage, muscle and fat cells. They are found in bone marrow, as well as other tissues such as cord blood, dental pulp and fat. The cells have long been the subject of investigation, owing to their apparent potent ability to heal wounds without unduly alarming the immune system, says Hommes. The biggest trial success for MSCs in IBD has come in the form of local injections to help rare, but hard-to-treat, anal fistulas — a hole that is usually the result of an infection. “The MSC is a potential one-cell army to repair a fistula, to both downregulate inflammation and to regenerate the wound,” says Hommes. “And there's a lot of evidence saying that it is an effective therapy.” In a phase III randomized clinical trial of fat-derived MSCs to treat anal fistulas in those with Crohn's disease, injections of the cells resulted in the closure of fistulas in around 16% more patients than controls (J. Panés et al. Lancet 388, 1281–1290; 2016). “That's a signal to follow up on with these patients, who can be refractory to any treatment,” says one of the investigators Gert Van Assche, head of gastroenterology and hepatology at the University Hospitals Leuven, Belgium. On the basis of the results, the biotechnology firm that sponsored the trial, TiGenix in Leuven, is applying to the European Medicines Agency for approval of the treatment, which it hopes to receive in the second half of 2017. Despite this success, significant unknowns remain. “It's still largely a black box as to what was happening mechanistically inside the patient,” says Van Assche. “We can't take a biopsy, and we have to interpret results in mice with caution.” Systemic MSC treatments for IBD, which help to hit inflammation caused by the disease wherever it appears, typically elicit even greater caution from experts. Although results in mice have been tantalizing, many of the clinical trials of intravenous MSCs for IBD, and a number of other conditions, “were largely failures”, says Van Assche. “The trouble with MSCs if you administer them through a drip is that you basically count on them finding the areas of inflammation, but there's a long way for them to go,” says Hommes. “Most are lost before arriving at the site of inflammation.” Despite the lack of clinical proof, the essentially unregulated nature of stem-cell procedures in the United States means that systemic MSC treatments for conditions such as IBD are already available to patients determined to find them. For adaptive immune systems, simplicity is not a virtue. Human systems are equipped with many types of T cell. Certain regulatory T cells (T cells) that can block other inflammation-producing T cells are crucial for protecting against IBD. The Crohn's And T Cells Study (CATS1), which was sponsored by biotechnology company TxCell in Sophia Antipolis, France, examined whether activating T cells is an effective treatment for refractory Crohn's disease ( et al. Gastroenterology 143, 1207–1217; 2012). In 20 participants, T cells were isolated, primed to respond to ovalbumin — a protein that is the main component of egg whites — and reinfused. When the patients later ate a meringue cake packed with ovalbumin, their T cells were activated, which the researchers hoped would dampen the Crohn's inflammation. Six of the eight people who received a million cells showed an improvement in Crohn's symptoms at eight weeks, including two who were seemingly in remission. Encouraged by the results, the company is moving forward with a follow-up trial, which will enrol 56 patients. First results are expected in 2018. “From a basic science point of view, immune regulatory cells are very promising,” Van Assche says. “But we have to see confirming data from the larger trial.” In addition, TxCell is looking into whether T cells can be modified. The company is drawing on techniques used to engineer T cells to produce surface proteins (chimeric antigen receptors) that allow the cells to better target tumour cells in people with blood cancers. This research also benefits from recent advances in gene-editing capabilities. Re-engineering T cells could allow the specific inflammatory signals that drive IBD at an individual level to be targeted and dampened, Hommes says. But first researchers need to fully identify the specific signals involved in IBD inflammation. For example, although multiple biological drugs for IBD successfully target the protein tumour necrosis factor-α (TNF-α), “TNF-α itself has never been a distinct target for IBD”, Hommes says. It has proved to be a potent strategy, but why is unclear. Obstacles such as these keep T -cell therapy a long way from clinical use at present. “Theoretically, these treatments could be good,” says Stephan Targan at Cedars-Sinai Medical Center in Los Angeles, California, “but they're in their infancy.” Scientists have hunted for IBD treatments based on intestinal stem cells — the adult cells that keep the intestine in good repair — for the best part of a decade. Interest in these stem cells soared when, in 2009, Hans Clevers, a molecular geneticist at the Hubrecht Institute in Utrecht, the Netherlands, used the cells to build 3D tissue models called organoids. Work is at a very early stage, but organoids can now also be generated by modifying other types of cell to become induced pluripotent stem cells, which are then coaxed into becoming fully differentiated adult cells. Researchers at Cedars-Sinai Medical Center have developed intestinal organoids using stem cells derived from the cells of people with IBD, says Targan, director of the institution's Inflammatory Bowel Disease Center. When these IBD stem cells are placed in a 3D cell-culture matrix, they orient themselves and differentiate into all the cell types of the intestinal lining. Researchers can infect these organoids with bacteria or fungi, and study how the intestinal cells interact with immune cells such as macrophages derived from the same IBD cell lines. “In a year or two this technology will really make an impact,” Targan says. His ultimate goal is to use these organoids therapeutically, including as material for transplantation, “but that's a little bit down the line”, he says. David Hackam, chief of paediatric surgery at Johns Hopkins University in Baltimore, Maryland, is leading an effort to build an 'artificial intestine' with stem cells on a biodegradable scaffold. He hopes that this will eventually help to treat necrotizing enterocolitis, a rare disease among babies born prematurely in which the intestine becomes inflamed and starts to die, as well as IBD. One major hurdle was replicating the intestine's finger-like microvilli, which grab sugar, fat and protein molecules in the gut, Hackam says. To overcome this, he teamed up with John March, a biological and environmental engineer at Cornell University in Ithaca, New York, who, with his colleagues, has fabricated a scaffold with synthetic microvilli made out of collagen. “Then the trick was to take this scaffold,” says Hackam, “fold it beautifully and grow intestinal stem cells on it.” Human intestinal stem cells grew and covered the microvilli. The researchers implanted the biodegradable scaffolds in mice, where the grafts developed blood supplies ( et al. Regen. Med. 11, 45–61; 2016). The team has duplicated the feat in piglets, and is working to make the scaffold more biocompatible and more commercially viable, as well as to see whether the scaffolds can absorb nutrients. The scaffold also needs to be able to contract, because this is the process that moves the intestine's contents along. Hackam's group is studying how the organ's nerve network coordinates these contractions and how this network might be replicated from stem cells. Along with bioengineers at Johns Hopkins, the team is also pursuing a method that combines nerve cells with a device, similar to a pacemaker, that produces contractions and has a miniaturized external power supply.


Coleman S.J.,Queen Mary, University of London | Chioni A.-M.,Queen Mary, University of London | Ghallab M.,Queen Mary, University of London | Anderson R.K.,Queen Mary, University of London | And 4 more authors.
EMBO Molecular Medicine | Year: 2014

Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion. Synopsis: Chemical or RNAi-mediated inhibition of nuclear FGFR1 and FGF2 leads to disruption of the tumour-supportive microenvironment provided by pancreatic stellate cells thus preventing pancreatic cancer cell invasion. Nuclear FGFR1 and FGF2 are apparent in the stromal fibroblasts at the invasive front of human pancreatic cancer. In vitro FGFR1 and FGF2 co-localise to the nucleus in pancreatic stellate cells but not pancreatic cancer cells and are essential for proliferation and invasion. Blocking nuclear FGFR1 and FGF2 results in a significant reduction in proliferation of pancreatic stellate cells and has a significant effect on invasion of pancreatic cancer cells in a 3D organotypic model of pancreatic cancer. Chemical or RNAi-mediated inhibition of nuclear FGFR1 and FGF2 leads to disruption of the tumour-supportive microenvironment provided by pancreatic stellate cells thus preventing pancreatic cancer cell invasion. © 2014 The Authors.


Dindya S.,The Royal London Hospital | Kyriakides C.,The Royal London Hospital
Recent Patents on Cardiovascular Drug Discovery | Year: 2011

Ultrasound imaging is widely used worldwide principally because it is cheap, easily available and contains no exposure to ionizing radiation. The advent of microbubble ultrasound contrast has further increased the diagnostic sensitivity and specificity of this technique thus widening its clinical applications. The third generation of ultrasound contrast agents consist of sulphur hexafluoride microbubbles encased in a phospholipid shell. This review will elaborate on the pharmacology, safety profile and method of action of these agents. We also aim to discuss the ever expanding uses for contrast enhanced ultrasound in a number of clinical specialities which include the liver, kidney, prostate, sentinel node detection, vascular tree and endovascular stent surveillance. We will also discuss some of the recent patents regarding the future uses of ultrasound microbubble contrast and recent technological advances in clinical applications. © 2011 Bentham Science Publishers Ltd.


Wong P.-P.,Queen Mary, University of London | Demircioglu F.,Queen Mary, University of London | Ghazaly E.,Queen Mary, University of London | Alrawashdeh W.,Queen Mary, University of London | And 11 more authors.
Cancer Cell | Year: 2015

Increasing chemotherapy delivery to tumors, while enhancing drug uptake and reducing side effects, is a primary goal of cancer research. In mouse and human cancer models in vivo, we show that coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival. At a molecular level, this strategy alters Gemcitabine transporter and metabolizing enzyme expression levels, enhancing the potency of Gemcitabine within tumor cells in vivo and in vitro. Thus, the dual action of low-dose Cilengitide, in vessels and tumor cells, improves chemotherapy efficacy. Overall, our data demonstrate that vascular promotion therapy is a means to improve cancer treatment. © 2015 Elsevier Inc.


Holmes S.,The Royal London Hospital
Oral and Maxillofacial Surgery Clinics of North America | Year: 2011

Enophthalmos is a complex and unpredictable condition to treat secondarily, and this is likely to remain a difficult challenge. Modern imaging technology and the aggressive stance taken on appropriate primary repair make it likely that surgeons will see fewer minor cases and increased numbers of major cases. The choice of reconstructive material should be evidence-based rather than based on surgical preference. Of crucial importance to the management of all traumas, particularly in revisional surgery, is attention to the soft tissue envelope, which adds to the postoperative result, and may camouflage minor degrees of enophthalmos. © 2011 Elsevier Inc.


Offiah C.,The Royal London Hospital | Hall E.,The Royal London Hospital
Insights into Imaging | Year: 2012

Background: Penetrating trauma of the neck and face is a frequent presentation to acute emergency, trauma and critical care units. There remains a steady incidence of both gunshot penetrating injury to the neck and face as well as non-missile penetrating injury-largely, but not solely, knife-related. Optimal imaging assessment of such injuries therefore remains an on-going requirement of the general and specialised radiologist. Methods: The anatomy of the neck and face-in particular, vascular, pharyngo-oesophageal, laryngo-tracheal and neural anatomy-demands a more specialised and selective management plan which incorporates specific imaging techniques. Results: The current treatment protocol of injuries of the neck and face has seen a radical shift away from expectant surgical exploration in the management of such injuries, largely as a result of advances in the diagnostic capabilities of multi-detector computed tomography angiography (MDCTA), which is now the first-line imaging modality of choice in such cases. Conclusion: This review aims to highlight ballistic considerations, differing imaging modalities, including MDCTA, that might be utilised to assist in the accurate assessment of these injuries as well as the specific radiological features and patterns of specific organ-system injuries that should be considered and communicated to surgical and critical care teams. Teaching points: • MDCTA is the first-line imaging modality in penetrating trauma of the neck and, often, of the face• The inherent deformability of a bullet is a significant factor in its tissue-damaging capabilities• MDCTA can provide accurate assessment of visceral injury of the neck as well as vascular injury• Penetrating facial trauma warrants radiological assessment of key adjacent anatomical structures• In-driven fragments of native bone potentiate tissue damage in projectile penetrating facial trauma © 2012 The Author(s).


Patent
Queen Mary, University of London and The Royal London Hospital | Date: 2013-11-05

Mechanical circulatory supports configured to operate in series with the native heart are disclosed. In an embodiment, a centrifugal pump is used. In an embodiment, inlet and outlet ports are connected into the aorta and blood flow is diverted through a lumen and a centrifugal pump between the inlet and outlet ports.


Al-Nahhas A.,Imperial College London | Jawad A.S.M.,The Royal London Hospital
Annals of the New York Academy of Sciences | Year: 2011

Inflammatory muscle diseases are a group of muscle disorders characterized by muscle weakness, fatigue, and an association with malignancy and paraneoplastic syndrome. A diagnosis of idiopathic inflammatory myopathy is suggested by abnormal myometry and rising creatine kinase, but tissue diagnosis is also needed. Magnetic resonance imaging (MRI) helps localize the appropriate site of biopsy, demonstrate the extent of muscle involvement, and monitor the response to therapy. However, the sensitivity of magnetic resonance (MR) is limited, and whole-body imaging is still far from routine. [ 18F]Fluoro-desoxy-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the ultimate metabolic imaging technique for the management of cancer. It has also been shown to detect inflammatory conditions and to monitor their response to treatment. The use of FDG PET in screening for underlying malignancies is widely reported and recommended in patients with paraneoplastic syndrome. Unfortunately, only a few reports have been published to show the value of FDG PET in inflammatory muscle diseases, which as we show herein, deserve further pursuit. © 2011 New York Academy of Sciences..

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