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News Article | May 2, 2017
Site: www.eurekalert.org

A new study has found brain abnormalities in people with bipolar disorder. In the largest MRI study to date on patients with bipolar disorder, a global consortium published new research showing that people with the condition have differences in the brain regions that control inhibition and emotion. By revealing clear and consistent alterations in key brain regions, the findings published in Molecular Psychiatry on May 2 offer insight to the underlying mechanisms of bipolar disorder. "We created the first global map of bipolar disorder and how it affects the brain, resolving years of uncertainty on how people's brains differ when they have this severe illness," said Ole A. Andreassen, senior author of the study and a professor at the Norwegian Centre for Mental Disorders Research at the University of Oslo. Bipolar disorder affects about 60 million people worldwide, according to the World Health Organization. It is a debilitating psychiatric disorder with serious implications for those affected and their families. However, scientists have struggled to pinpoint neurobiological mechanisms of the disorder, partly due to the lack of sufficient brain scans. The study was part of an international consortium led by the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC: ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) spans 76 centers and includes 26 different research groups around the world. The researchers measured the MRI scans of 6,503 individuals, including 2,447 adults with bipolar disorder and 4,056 healthy controls. They also examined the effects of commonly used prescription medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. The study showed thinning of gray matter in the brains of patients with bipolar disorder when compared with healthy controls. The greatest deficits were found in parts of the brain that control inhibition and motivation -- the frontal and temporal regions. Some of the bipolar disorder patients with a history of psychosis showed greater deficits in the brain's gray matter. The findings also showed different brain signatures in patients who took lithium, anti-psychotics and anti-epileptic treatments. Lithium treatment was associated with less thinning of gray matter, which suggests a protective effect of this medication on the brain. "These are important clues as to where to look in the brain for therapeutic effects of these drugs," said Derrek Hibar, first author of the paper and a professor at the USC Stevens Neuroimaging and Informatics Institute when the study was conducted. He was a former visiting researcher at the University of Oslo and is now a senior scientist at Janssen Research and Development, LLC. Future research will test how well different medications and treatments can shift or modify these brain measures as well as improve symptoms and clinical outcomes for patients. Mapping the affected brain regions is also important for early detection and prevention, said Paul Thompson, director of the ENIGMA consortium and co-author of the study. "This new map of the bipolar brain gives us a roadmap of where to look for treatment effects," said Thompson, an associate director of the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine. "By bringing together psychiatrists worldwide, we now have a new source of power to discover treatments that improve patients' lives." Founded in 1885, the Keck School of Medicine of USC is among the nation's leaders in innovative patient care, scientific discovery, education, and community service. It is part of Keck Medicine of USC, the University of Southern California's medical enterprise, one of only two university-owned academic medical centers in the Los Angeles area. This includes the Keck Medical Center of USC, composed of the Keck Hospital of USC and the USC Norris Cancer Hospital. The two world-class, USC-owned hospitals are staffed by more than 500 physicians who are faculty at the Keck School. The school today has approximately 1,650 full-time faculty members and voluntary faculty of more than 2,400 physicians. These faculty direct the education of approximately 700 medical students and 1,000 students pursuing graduate and post-graduate degrees. The school trains more than 900 resident physicians in more than 50 specialty or subspecialty programs and is the largest educator of physicians practicing in Southern California. Together, the school's faculty and residents serve more than 1.5 million patients each year at Keck Hospital of USC and USC Norris Cancer Hospital, as well as USC-affiliated hospitals Children's Hospital Los Angeles and Los Angeles County + USC Medical Center. Keck School faculty also conduct research and teach at several research centers and institutes, including the USC Norris Comprehensive Cancer Center, the Zilkha Neurogenetic Institute, the Eli and Edythe Broad Center for Stem Cell Research and Regenerative Medicine at USC, the USC Cardiovascular Thoracic Institute, the USC Roski Eye Institute and the USC Institute of Urology. In 2016, U.S. News & World Report ranked Keck School of Medicine among the Top 40 medical schools in the country. For more information, go to keck.usc.edu.


News Article | May 3, 2017
Site: www.biosciencetechnology.com

A new study has found brain abnormalities in people with bipolar disorder. In the largest MRI study to date on patients with bipolar disorder, a global consortium published new research showing that people with the condition have differences in the brain regions that control inhibition and emotion. By revealing clear and consistent alterations in key brain regions, the findings published in Molecular Psychiatry on May 2 offer insight to the underlying mechanisms of bipolar disorder. "We created the first global map of bipolar disorder and how it affects the brain, resolving years of uncertainty on how people's brains differ when they have this severe illness," said Ole A. Andreassen, senior author of the study and a professor at the Norwegian Centre for Mental Disorders Research at the University of Oslo. Bipolar disorder affects about 60 million people worldwide, according to the World Health Organization. It is a debilitating psychiatric disorder with serious implications for those affected and their families. However, scientists have struggled to pinpoint neurobiological mechanisms of the disorder, partly due to the lack of sufficient brain scans. The study was part of an international consortium led by the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC: ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) spans 76 centers and includes 26 different research groups around the world. The researchers measured the MRI scans of 6,503 individuals, including 2,447 adults with bipolar disorder and 4,056 healthy controls. They also examined the effects of commonly used prescription medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. The study showed thinning of gray matter in the brains of patients with bipolar disorder when compared with healthy controls. The greatest deficits were found in parts of the brain that control inhibition and motivation -- the frontal and temporal regions. Some of the bipolar disorder patients with a history of psychosis showed greater deficits in the brain's gray matter. The findings also showed different brain signatures in patients who took lithium, anti-psychotics and anti-epileptic treatments. Lithium treatment was associated with less thinning of gray matter, which suggests a protective effect of this medication on the brain. "These are important clues as to where to look in the brain for therapeutic effects of these drugs," said Derrek Hibar, first author of the paper and a professor at the USC Stevens Neuroimaging and Informatics Institute when the study was conducted. He was a former visiting researcher at the University of Oslo and is now a senior scientist at Janssen Research and Development, LLC. Future research will test how well different medications and treatments can shift or modify these brain measures as well as improve symptoms and clinical outcomes for patients. Mapping the affected brain regions is also important for early detection and prevention, said Paul Thompson, director of the ENIGMA consortium and co-author of the study. "This new map of the bipolar brain gives us a roadmap of where to look for treatment effects," said Thompson, an associate director of the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine. "By bringing together psychiatrists worldwide, we now have a new source of power to discover treatments that improve patients' lives."


Zhang X.,Janssen Research and Development LLC | Sui Z.,Janssen Research and Development LLC
Expert Opinion on Drug Discovery | Year: 2013

Introduction: The development and potential clinical use of tissue-selective androgen receptor modulators (SARMs) have advanced tremendously over the past few years. A key aspect of SARMs is the ability to clearly differentiate between the anabolic and androgenic activities. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, end-stage renal disease, osteoporosis, frailty and hypogonadism. Areas covered: The aim of the present paper is to summarize the current standing of research and development of SARMs and plausible molecular mechanisms underlying the potential for selective modulation of androgen receptor (AR) by different ligands. This paper also provides an update on SARM discovery paradigms for preclinical evaluations. Expert opinion: Promising results have been obtained in preclinical investigations and initial clinical trials, but long-term safety, tolerability and efficacy studies in patients are still necessary. Preclinically, improving knowledge of tissue selectivity at the molecular level, developing AR selectivity transcription profile, exploring in vitro/in vivo correlation, along with expanding selectivity evaluation among more androgen responsive tissues would accelerate the discovery of a new generation of more selective and safer clinical candidates, minimize false leads and hasten development of effective approaches for an expanded range of clinical conditions. © 2013 Informa UK, Ltd.


Caldwell G.W.,Janssen Research and Development LLC
Expert Opinion on Drug Discovery | Year: 2015

Introduction: The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. Areas covered: This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. Expert opinion: There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity. © 2015 Informa UK, Ltd.


Raju T.S.,Janssen Research and Development L.L.C. | Lang S.E.,Janssen Research and Development L.L.C.
Current Opinion in Biotechnology | Year: 2014

Terminal sialic acid residues of glycoconjugates exhibit remarkable functional and structural diversity. They affect biological activity, serum half-life and structural stability of glycoproteins. Alternatively, they act as mediators for pathogens to invade host systems. These surface exposed N-glycans are easily accessible for interactions with receptors, enzymes, etc. In contrast, Fc N-glycans of IgGs are sequestered within the two CH2 domains and exhibit high degree of heterogeneity. They are required for antibody effector functions including binding to C1q protein. Biological significance of Fc glycans has been extensively studied and importance of terminal galactose, bisecting GlcNAc and core fucose has been realized. This review focuses on the recent advances in structure and functions of terminal sialic acid residues of Fc glycans. © 2014 Elsevier Ltd.


Raju T.S.,Janssen Research and Development LLC
Methods in Molecular Biology | Year: 2013

Recombinant monoclonal antibodies (rMAbs) are becoming major human therapeutics to treat lifethreatening diseases such as cancer. These rMAbs are produced using either in vitro cell culture processes or transgenic technology in animals or plants. Glycans present in the Fc region can affect functions of rMAbs. These Fc glycans are heterogeneous and impact binding of rMAbs to Fc gamma receptors (FcγRs) and C1q protein. As a result Fc glycans affect antibody-dependent cellular cytotoxicity and complementdependent cytotoxicity of rMAbs. Thus understanding the glycan heterogeneity is necessary during the development of these rMAbs as human therapeutics. Because of their biological significance, understanding the glycan structure and their impact on the function of antibody molecules is also a regulatory requirement. Glycan mapping by NP-HPLC with fluorescence detection is a sensitive and reproducible method. Labeling of released glycans with anthranilic acid (AA) using reductive amination procedure improves sensitivity of detection. The NP-HPLC method resolves both neutral and sialylated glycans, thus enabling the user to obtain a broad heterogeneity profile of Fc glycans in a single run. Added advantage of the method is that the labeled glycans can be characterized using mass spectrometry and the method is also amenable for LC-MS analysis. © Springer Science+Business Media New York 2013.


Swiecki M.,University of Washington | Swiecki M.,Janssen Research AndDevelopment LLC | Colonna M.,University of Washington
Nature Reviews Immunology | Year: 2015

Plasmacytoid dendritic cells (pDCs) are a unique DC subset that specializes in the production of type I interferons (IFNs). pDCs promote antiviral immune responses and have been implicated in the pathogenesis of autoimmune diseases that are characterized by a type I IFN signature. However, pDCs can also induce tolerogenic immune responses. In this Review, we summarize recent progress in the field of pDC biology, focusing on the molecular mechanisms that regulate the development and functions of pDCs, the pathways involved in their sensing of pathogens and endogenous nucleic acids, their functions at mucosal sites, and their roles in infection, autoimmunity and cancer. © 2015 Macmillan Publishers Limited. All rights reserved.


Fung-Leung W.-P.,Janssen Research and Development L.L.C.
Annals of the New York Academy of Sciences | Year: 2013

Phosphoinositide 3-kinase gamma (PI3Kγ) kinase activity is important for its signaling functions in T cell development, activation, differentiation, and trafficking. Protection of PI3Kγ knockout mice from disease in multiple autoimmune models suggests that targeting PI3Kγ alone, or in combination with PI3Kδ, could be a promising approach to disease therapy. © 2013 New York Academy of Sciences.


Thurmond R.L.,Janssen Research and Development LLC
Frontiers in Pharmacology | Year: 2015

The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into clinical efficacy in humans. © 2015 Thurmond.


Hu C.,Janssen Research and Development LLC
CPT: Pharmacometrics and Systems Pharmacology | Year: 2014

Exposure-response modeling facilitates effective dosing regimen selection in clinical drug development, where the end points are often disease scores and not physiological variables. Appropriate models need to be consistent with pharmacology and identifiable from the time courses of available data. This article describes a general framework of applying mechanism-based models to various types of clinical end points. Placebo and drug model parameterization, interpretation, and assessment are discussed with a focus on the indirect response models. © 2014 ASCPT All rights reserved 2163-8306/14.

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