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News Article | November 17, 2016
Site: www.sciencedaily.com

Researchers at University of California San Diego School of Medicine have shown that ustekinumab, a human antibody used to treat arthritis, significantly induces response and remission in patients with moderate to severe Crohn's disease. Results of the clinical trial will appear in the November 16 issue of the New England Journal of Medicine. "A high percentage of the patients in the study who had not responded to conventional therapies were in clinical remission after only a single dose of intravenous ustekinumab," said William J. Sandborn, MD, professor of medicine at UC San Diego School of Medicine and director of the Inflammatory Bowel Disease Center at UC San Diego Health. "Finding effective new treatment options for this patient population is critical because Crohn's disease can dramatically impact a person's quality of life. Patients suffering from this disease may go to the bathroom up to 20 times a day and experience abdominal pain, ulcers and a reduced appetite." Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that affects approximately 700,000 people in the United States. It can affect any part of the GI tract but it is more commonly found at the end of the small intestine (the ileum) where it joins the beginning of the large intestine (or colon). Crohn's disease is usually treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists or integrin inhibitors. "The drawbacks of these therapies include an increased risk of infection and cancer, and limited efficacy," said Sandborn. "Ustekinumab has not been associated with an increased risk of serious adverse events." The rates of remission response in the randomized study at week six among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving a placebo. The study also found subcutaneous (injected) ustekinumab every 8 to 12 weeks maintained remission in patients. "This study indicates that ustekinumab may have a long duration of action, a likelihood that may become better understood in future trials," said Sandborn. "Our current findings offer hope for those suffering from this debilitating gastrointestinal tract disease." The Inflammatory Bowel Disease (IBD) Center at UC San Diego Health is dedicated to diagnosing and treating people with IBD from around the world. The center's leadership in IBD medical research means patient access to clinical trials for the newest therapies and advanced surgical techniques for the treatment of this challenging condition. Care is provided by a multidisciplinary team of specialists in gastroenterology, endoscopy, oncology, surgery, transplantation and radiology. Co-authors of the study include: Brian Feagan, Robarts Clinical Trials, Robarts Research Institute, Western University, London; Subrata Ghosh, University of Calgary; Levinus Dieleman, University of Alberta; Stephan Targan, Cedars-Sinai Medical Center; Christopher Gasink, Douglas Jacobstein, Yinghua Lang, Joshua Friedman, Jewel Johanns, Long‑Long Gao, Ye Miao, and Omoniyi Adedokun, Janssen Research and Development; Marion Blank, Janssen Scientific Affairs; Bruce Sands, Jean‑Frédéric Colombel, Icahn School of Medicine; Seymour Katz, New York University School of Medicine; Stephen Hanauer, Feinberg School of Medicine; Severine Vermeire, Paul Rutgeerts, University of Hospitals; Willem de Villiers, Stellenbosch University; Zsolt Tulassay, Semmelweis University; Ursula Seidler, Hannover Medical School; Bruce Salzberg, Atlanta Gastroenterology Specialists; Pierre Desreumaux, Hopital Claude Huriez; Scott Lee, University of Washington Medical Center; and Edward Loftus,Jr., Mayo Clinic. This study was funded by Janssen Research and Development (NCT01369329, NCT01369342, NCT01369355).


News Article | November 17, 2016
Site: www.eurekalert.org

Researchers at University of California San Diego School of Medicine have shown that ustekinumab, a human antibody used to treat arthritis, significantly induces response and remission in patients with moderate to severe Crohn's disease. Results of the clinical trial will appear in the November 16 issue of the New England Journal of Medicine. "A high percentage of the patients in the study who had not responded to conventional therapies were in clinical remission after only a single dose of intravenous ustekinumab," said William J. Sandborn, MD, professor of medicine at UC San Diego School of Medicine and director of the Inflammatory Bowel Disease Center at UC San Diego Health. "Finding effective new treatment options for this patient population is critical because Crohn's disease can dramatically impact a person's quality of life. Patients suffering from this disease may go to the bathroom up to 20 times a day and experience abdominal pain, ulcers and a reduced appetite." Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that affects approximately 700,000 people in the United States. It can affect any part of the GI tract but it is more commonly found at the end of the small intestine (the ileum) where it joins the beginning of the large intestine (or colon). Crohn's disease is usually treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists or integrin inhibitors. "The drawbacks of these therapies include an increased risk of infection and cancer, and limited efficacy," said Sandborn. "Ustekinumab has not been associated with an increased risk of serious adverse events." The rates of remission response in the randomized study at week six among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving a placebo. The study also found subcutaneous (injected) ustekinumab every 8 to 12 weeks maintained remission in patients. "This study indicates that ustekinumab may have a long duration of action, a likelihood that may become better understood in future trials," said Sandborn. "Our current findings offer hope for those suffering from this debilitating gastrointestinal tract disease." The Inflammatory Bowel Disease (IBD) Center at UC San Diego Health is dedicated to diagnosing and treating people with IBD from around the world. The center's leadership in IBD medical research means patient access to clinical trials for the newest therapies and advanced surgical techniques for the treatment of this challenging condition. Care is provided by a multidisciplinary team of specialists in gastroenterology, endoscopy, oncology, surgery, transplantation and radiology. Co-authors of the study include: Brian Feagan, Robarts Clinical Trials, Robarts Research Institute, Western University, London; Subrata Ghosh, University of Calgary; Levinus Dieleman, University of Alberta; Stephan Targan, Cedars-Sinai Medical Center; Christopher Gasink, Douglas Jacobstein, Yinghua Lang, Joshua Friedman, Jewel Johanns, Long?Long Gao, Ye Miao, and Omoniyi Adedokun, Janssen Research and Development; Marion Blank, Janssen Scientific Affairs; Bruce Sands, Jean?Frédéric Colombel, Icahn School of Medicine; Seymour Katz, New York University School of Medicine; Stephen Hanauer, Feinberg School of Medicine; Severine Vermeire, Paul Rutgeerts, University of Hospitals; Willem de Villiers, Stellenbosch University; Zsolt Tulassay, Semmelweis University; Ursula Seidler, Hannover Medical School; Bruce Salzberg, Atlanta Gastroenterology Specialists; Pierre Desreumaux, Hopital Claude Huriez; Scott Lee, University of Washington Medical Center; and Edward Loftus,Jr., Mayo Clinic.


The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder. Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) throughput. To elucidate ketamine’s mechanism of action, we tested whether the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/N-methyl-D-aspartate receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex at 1 and 24 h post infusion with magnetic resonance spectroscopy at 7 T. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared with placebo, specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.Neuropsychopharmacology advance online publication, 19 October 2016; doi:10.1038/npp.2016.184. © 2016 American College of Neuropsychopharmacology


Millan M.J.,Institute Of Recherche Servier | Fone K.,University of Nottingham | Steckler T.,Janssen Research and Development | Horan W.P.,University of California at Los Angeles
European Neuropsychopharmacology | Year: 2014

Schizophrenia is a complex and multifactorial disorder generally diagnosed in young adults at the time of the first psychotic episode of delusions and hallucinations. These positive symptoms can be controlled in most patients by currently-available antipsychotics. Conversely, they are poorly effective against concomitant neurocognitive dysfunction, deficits in social cognition and negative symptoms (NS), which strongly contribute to poor functional outcome. The precise notion of NS has evolved over the past century, with recent studies - underpinned by novel rating methods - suggesting two major sub-domains: "decreased emotional expression", incorporating blunted affect and poverty of speech, and "avolition", which embraces amotivation, asociality and "anhedonia" (inability to anticipate pleasure). Recent studies implicate a dysfunction of frontocortico-temporal networks in the aetiology of NS, together with a disruption of cortico-striatal circuits, though other structures are also involved, like the insular and parietal cortices, amygdala and thalamus. At the cellular level, a disruption of GABAergic-glutamatergic balance, dopaminergic signalling and, possibly, oxytocinergic and cannibinoidergic transmission may be involved. Several agents are currently under clinical investigation for the potentially improved control of NS, including oxytocin itself, N-Methyl- d-Aspartate receptor modulators and minocycline. Further, magnetic-electrical "stimulation" strategies to recruit cortical circuits and "cognitive-behavioural-psychosocial" therapies likewise hold promise. To acquire novel insights into the causes and treatment of NS, experimental study is crucial, and opportunities are emerging for improved genetic, pharmacological and developmental modelling, together with more refined readouts related to deficits in reward, sociality and "expression". The present article comprises an integrative overview of the above issues as a platform for this Special Issue of European Neuropsychopharmacology in which five clinical and five preclinical articles treat individual themes in greater detail. This Volume provides, then, a framework for progress in the understanding - and ultimately control - of the debilitating NS of schizophrenia. © 2014 Elsevier B.V. and ECNP.


Cheng Y.,Pennsylvania State University | Ren X.,Pennsylvania State University | Hait W.N.,Janssen Research and Development | Yang J.-M.,Pennsylvania State University
Pharmacological Reviews | Year: 2013

Autophagy, a process of self-digestion of the cytoplasm and organelles through which cellular components are recycled for reuse or energy production, is an evolutionarily conserved response to metabolic stress found in eukaryotes from yeast to mammals. It is noteworthy that autophagy is also associated with various pathophysiologic conditions in which this cellular process plays either a cytoprotective or cytopathic role in response to a variety of stresses such as metabolic, inflammatory, neurodegenerative, and therapeutic stress. It is now generally believed that modulating the activity of autophagy through targeting specific regulatory molecules in the autophagy machinery may impact disease processes, thus autophagy may represent a new pharmacologic target for drug development and therapeutic intervention of various human disorders. Induction or inhibition of autophagy using small molecule compounds has shown promise in the treatment of diseases such as cancer. Depending on context, induction or suppression of autophagy may exert therapeutic effects via promoting either cell survival or death, two major events targeted by therapies for various disorders. A better understanding of the biology of autophagy and the pharmacology of autophagy modulators has the potential for facilitating the development of autophagy-based therapeutic interventions for several human diseases. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Talpos J.,Janssen Research and Development | Steckler T.,Janssen Research and Development
Cell and Tissue Research | Year: 2013

During the last decade, the idea of a translational approach has become commonplace within the field of neuroscience. Despite the rapid adaptation of this theoretical framework, few examples of hypothesis-driven translation start with a pre-clinical finding and end with a positive clinical result and no examples of a novel medication have been developed in this way for the treatment of cognition-related disorders. Whereas instances of successful translation exist, most of these are the result of post-hoc hypothesis testing, rather than a priori hypothesis creation. Indeed, part of this disconnection between pre-clinical and clinical results has been driven by paradigms used at both the pre-clinical level (measurement of behaviors that might not be relevant to a patient population) and the clinical level (use of test batteries that cannot be modeled in a pre-clinical environment). However, automated cognition batteries that require responses to stimuli displayed upon a video monitor are decreasing the distance between pre-clinical and clinical behavioral studies. In the last 5 years, numerous papers have been published demonstrating that cognitive functions can be measured in a similar manner in the rodent as in a clinical setting via touch-screen-equipped operant boxes. Here, we argue that the touch-screen approach has the potential of being a powerful tool for the translation of pre-clinical hypotheses into positive clinical findings. © 2013 Springer-Verlag Berlin Heidelberg.


Cheng H.N.,U.S. Department of Agriculture | Neiss T.G.,Janssen Research and Development
Polymer Reviews | Year: 2012

Many polysaccharides are allowed for direct food use, where they serve a number of useful functions including dietary fiber, bulking agent, thickener, encapsulant, gelling agent, foam and emulsion stabilizer, protective colloid, emulsifier and suspending agent, adhesive and binder, flocculant, swelling agent, film/coat former, or syneresis inhibitor. Many of these polysaccharides have complex structures or are mixtures with different components. Over the years, NMR has been a premiere technique for characterizing thesematerials. NMRcharacterization can help identify the materials in question, quantify the different functional groups present, and detect minor components and impurities. Above all, the high resolution achieved in solution NMR can provide detailed structural information on composition, sequence distribution, substitution pattern, and molecular weights (in some cases) for individual polysaccharides. Concurrent application of other analytical techniques, such as methylation, esterification, fractionation, mass spectrometry, and chromatographic methods, has enabled structural information on even complex polysaccharides or mixtures to be obtained. In this article a review is given of the solution NMR of food polysaccharides, with emphasis on papers published in the past 20 years. Included in the review is a survey of 21 common food polysaccharides, the current understanding of their structures, and the techniques used for their determination. © 2012 Taylor & Francis Group, LLC.


Rushforth S.L.,Newcastle University | Steckler T.,Janssen Research and Development | Shoaib M.,Newcastle University
Neuropsychopharmacology | Year: 2011

Ketamine, an NMDA-receptor antagonist, produces cognitive deficits in humans in a battery of tasks involving attention and memory. Nicotine can enhance various indices of cognitive performance, including working memory span capacity measured using the odor span task (OST). This study examined the effects of a sub-chronic ketamine treatment to model cognitive deficits associated with schizophrenia, and to evaluate the effectiveness of nicotine, antipsychotic clozapine, and the novel mGlu2/3 agonist, LY404039, in restoring OST performance. Male hooded Lister rats were trained in the OST, a working memory task involving detection of a novel odor from an increasing number of presented odors until they exhibited asymptotic levels of stable performance. Sub-chronic ketamine exposure (10 and 30 mg/kg i.p. for 5 consecutive days) produced a dose-dependent impairment that was stable beyond 14 days following exposure. In one cohort, administration of graded doses of nicotine (0.025-0.1 mg/kg) acutely restored the performance in ketamine-treated animals, while significant improvements in odor span were observed in control subjects. In a second cohort of rats, acute tests with clozapine (1-10 mg/kg) and LY404039 (0.3-10 mg/kg) failed to reverse ketamine-induced deficits in doses that were observed to impair performance in the control groups. These data suggest that sub-chronic ketamine exposure in the OST presents a valuable method to examine novel treatments to restore cognitive impairments associated with neuropsychiatric disorders such as schizophrenia. Moreover, it highlights a central role for neuronal nicotinic receptors as viable targets for intervention that may be useful adjuncts to the currently prescribed anti-psychotics. © 2011 American College of Neuropsychopharmacology. All rights reserved.


News Article | October 28, 2016
Site: www.prweb.com

When Roger M. Mills, M.D., had the chance to make a late-career change from academic cardiology to the pharmaceutical industry, he had no idea what kind of adventures the next decade would bring. In his new book “Nesiritide: The Rise and Fall of Scios,” Mills gives readers an inside look at the development, early success and subsequent demise of a biotechnology drug that he was personally involved in developing, testing and marketing. “’Nesiritide’ gives the non-medical public an unprecedented insight into the complexity, risk, and competitiveness of drug development,” Mills said. “It demonstrates the devastating impact of media attention to questions of drug safety.” After his time at Scios Inc., the company that developed Nesiritide and after retiring from Janssen Research & Development, LLC as a senior director in clinical research, Mills has adopted the mission of better informing the medical community and the general public about the workings of the often-mysterious pharmaceutical industry. Nesiritide: The Rise and Fall of Scios By Roger M. Mills, M.D. ISBN: 978-1-49179-763-1 Available in softcover, hardcover, e-book Available on Amazon, Barnes & Noble and iUniverse About the author Roger M. Mills, M.D. is a graduate of Amherst College and the University of Pennsylvania medical school. After completing his medical residency, he served in the U.S. Navy before beginning a thirty-year career in academic clinical cardiology as a research fellow at Harvard’s Peter Bent Brigham hospital. He joined Scios Inc., a Johnson & Johnson operating company, in 2005 and later moved to J&J's Janssen Research and Development, LLC. He retired after a 10-year career with J&J, and now lives in Dexter, Mich. with his wife, Katherine, and their Labrador retriever, Posie.


News Article | November 14, 2016
Site: phys.org

In order to make progress for rare diseases, David tells me, he realized that if he didn't drive things forward than no one would. After being given his diagnosis as a medical student concentrating on oncology, David switched gears and made CD his first order of business. When he observed all the hurdles in the way of progress, he decided to get an MBA at Wharton, developing business contacts and funding sources for the network of CD researchers he was building. He created a community for patients and physicians to collaborate and share high-potential research ideas. In parallel, he began to conduct CD research at Penn and identify top experts to conduct other priority projects. More recently, the CDCN launched a registry of people with CD so they could share patient records and unpublished cases of the disease. An immediate consequence of these efforts was a redefinition of the more deadly form of CD disease—the so-called 'multicentric' form that involves several regions of enlarged lymph nodes as opposed to just one. The former consensus held that benign lymph node tumors secreted Interleukin-6 (IL-6), which in turn hyperactivated the immune system and caused widespread organ dysfunction. The new explanation is pretty much the opposite. In other words, an overactive immune system is what seems to cause the tumors, flu-like symptoms and organ system dysfunction in the first place. The job is therefore to first explain the cause of hyperactivation of different proinflammatory cells and proteins (including Il-6), and then identify ways to stop them. In this view, multicentric CD can be seen as a common endpoint that can be expressed by traversing different paths. In some cases it is due to infection with the HHV-8 virus. This particular pathogen happens to express its own Il-6 type protein that, despite having just 40% sequence homology with our own Il-6, still manages to cause havoc. HHV-8 causes about half of the multicentric form of CD and provides one of many important clues. Other cases, which are called "idiopathic multicentric CD", may be due as yet unknown viral infection, purely autoimmune mechanisms, or even germ-line disturbances in innate immune regulation. One thing that could be a complication involved in the latter is the increasingly common finding of individuals possessing mosaic and chimeric germ lines. Genetic sequencing and subsequent functional proteomics will be one valuable source of new information here. Once suspect genes are identified they can potentially be expressed in different cells to see what effects different mutants may have on function. These days, it is perhaps just as likely that advanced simulation tools based on molecular dynamics will give the first functional clues about changes in protein folding or function in the cell. David mentioned that 15 patients, himself included are now getting whole genome sequencing done. This is much more useful than the commonly done 'exome sequencing' which can miss many important details including polymorphism in the promoter and other regulatory regions that get spliced out before the exomes are generated. Other critical aberrants like gene duplications will generally be missed in exome sequencing as well. A recent series of papers in Cell takes a functional genomics approach to understand variation in human cytokine production. After challenging cells from hundreds of different people with various bacterial, fungal, viral, and non-microbial stimuli, researchers comprehensively identified the cytokine 'quantitative trait loci' that influence the major cytokines (Il-6 included) in whole blood, in blood mononuclear cells, and in macrophages. These studies also looked at other different host and environmental factors, like for example, the influence of the gut microbiome. If reformulated more directly to CD patients important information at the individual scale may be obtained. Among other things, this could include better ways to take critical measurements. For example, developing a more uniform sampling protocol that takes into account the known daily, seasonal, and other natural rhythms of the body's many organ and systems. David is just one of many researchers at Penn, and elsewhere, who are now taking matters into their own hands. I am reminded of Scott Mackler, a former Penn researcher I consulted for some time ago. When diagnosed with ALS, Scott repurposed his labs efforts to focus on his this devastating disease. In checking now, Scott passed back in 2013 after a 15 year battle, but his legacy lives on. Today, several other home grown efforts are achieving incredible results. In one notable case, a mother with no previous medical background, and no initial funding, was able to found a company called Lysogene that in just a few years developed an FDA approved genetic therapy for the Sanfilippo disease that affected her newborn. Another instance is the case of Shirley Pepke, a genomics researcher who developed machine learning tools to tailor treatments for combating her ovarian cancer. In remission now, Shirley took what seemed like a big chance in going against her oncologist's recommendation of standard chemotherapy to try a new (an non-FDA approved) immuntherapy drug. Although it may not be possible to fully disambiguate exactly which of the Shirleys many different treatments 'worked', the important thing for her is that she is in fact now in remission. This general philosophy is in stark contrast to the 'drug trial centric' approach where the study is the goal rather than the individual. Perhaps an even more high profile case is that of Tom Marsilje, a research at Novartis who codeveloped an anti-cancer ALK inhibitor now marketed as Zykadia. Tom needed to get into a trial to treat his own colon cancer but was triaged out of it because he happened to have a pre-existing melanoma. A somewhat fortuitous but perhaps inevitable circumstance brought Tom together with Craig Venter who was promptly able to whole genome sequence Tom's cells. Using the data rendered they are now developing a personalized neoantigen vaccine, an immunotherapy, that may be able to stimulate his own immune cells to attack tumor. In another fortunate turn of events, the Castlemen network is pleased to be partnering with Janssen Research and Development, and Penn, to create the first global patient registry for CD. Fajgenbaum is serving as principle investigator on this new initiative to help defeat Castlemen disease once and for all. Explore further: Immune system B cells play a role in tackling liver cancer and provide a marker for patient prognosis More information: Yang Li et al. A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans, Cell (2016). DOI: 10.1016/j.cell.2016.10.017 Abstract As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases.

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