New York City, NY, United States
New York City, NY, United States

The Icahn School of Medicine at Mount Sinai , formerly the Mount Sinai School of Medicine , is an American medical school in the New York City borough of Manhattan in the state of New York. Chartered by Mount Sinai Hospital in 1963, the ISMMS is one of the foremost medical schools in the United States, ranking 19th in research according to U.S. News & World Report, 18th in NIH funding among U.S Medical Schools , and 3rd in NIH funding per primary investigator.ISMMS and the Mount Sinai Hospital occupy a four-block area adjacent to Central Park on the Upper East Side of Manhattan, with architecture designed by I. M. Pei. ISMMS and Mount Sinai Hospital comprise the Mount Sinai Medical Center, of which Kenneth L. Davis, MD, is the president and CEO.In 2012–13, The Mount Sinai Medical Center was recognized on the U.S. News & World Report "Best Hospitals Honor Roll," ranking 14th among the approximately 5000 hospitals in the US with 11 nationally ranked specialties including cancer, geriatrics, gastroenterology, cardiology & heart surgery, otolaryngology, rehabilitation, diabetes & endocrinology, neurology & neurosurgery, gynecology, urology, and kidney disorders. Wikipedia.

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The present disclosure relates to methods for the treatment of sarcoidosis. In certain aspects and embodiments, the disclosure provides compositions containing 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and/or the use of such compositions for the treatment of Sarcoidosis. In another aspect, the disclosure relates to compositions containing 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof plus a second active agent. In yet another aspect, the disclosure relates to kits containing agents useful for the treatment of sarcoidosis.

Mount Sinai School of Medicine | Date: 2016-11-21

The present invention provides methods for treating pulmonary hypertension in a subject by delivering a therapeutic adeno-associated virus (AAV)-SERCA2 composition to a subject in need thereof.

Mount Sinai School of Medicine | Date: 2016-11-03

Modified nucleic acid adapters are provided that collectively provide a mixture of nucleotides at the 3 end of 5 adapters and at the 5 end of 3 adapters such that at least one adapter in each set has any given nucleotide at position 1, i.e., the nucleotide position available for ligation to a small RNA, and has any given nucleotide at position 2 adjacent to position 1 for use in overcoming bias during nucleic acid manipulation, such as small RNA characterization and/or profiling by, e.g., deep sequencing, along with methods for use of the modified adapters in small RNA characterization. The modified adapters have at least two mixed nucleotides at the adapter terminus to be ligated to a nucleic acid such as a small RNA.

Mount Sinai School of Medicine | Date: 2016-03-03

The present invention provides chimeric negative-stand RNA viruses that allow a subject, e.g., an avian, to be immunized against two infectious agents by using a single chimeric virus of the invention. In particular, the present invention provides chimeric influenza viruses engineered to express and incorporate into their virions a fusion protein comprising an ectodomain of a protein of an infectious agent and the transmembrane and cytoplasmic domain of an influenza virus protein. Such chimeric viruses induce an immune response against influenza virus and the infectious agent. The present invention also provides chimeric Newcastle Disease viruses (NDV) engineered to express and incorporate into their virions a fusion protein comprising the ectodomain of a protein of an infectious agent and the transmembrane and cytoplasmic domain of an NDV protein. Such chimeric viruses induce an immune response against NDV and the infectious agent.

Abbott Laboratories and Mount Sinai School of Medicine | Date: 2016-06-22

The present disclosure provides detection methods employing HCV core lipid binding domain and DNA binding domain monoclonal antibodies or antibody fragments. In certain embodiments, the lipid binding domain monoclonal antibody or antibody fragment recognizes an epitope in amino acids 141 to 161 of HCV core protein and the DNA binding domain antibody or antibody fragment recognizes an epitope in amino acids 95-123 (e.g., in amino acids 99-117) of HCV core protein.

Mount Sinai School of Medicine | Date: 2017-04-12

The present invention relates to novel Prothymosin Alpha (ProT) variants that are capable of inducing cell-mediated immune responses. These variants lack a nuclear localization signal and the proliferative oncogenic activity previously attributed to ProT. The variants of the invention are used in methods of treating, for example, viral infections, bacterial infections, fungal infections, cancer, ischemia and myeloproliferative blood disorders. Administration of a ProT variant to a subject in a therapeutically effective amount treats the infection or disease.

Gorog D.A.,Imperial College London | Fuster V.,Mount Sinai School of Medicine
Journal of the American College of Cardiology | Year: 2013

This review is a critical evaluation of publications in the past decade on the usefulness of platelet function tests (PFTs) in clinical cardiology, in aiding diagnosis, predicting risk, and monitoring therapy. The ideal PFT should: 1) detect baseline platelet hyperreactivity; 2) allow individualization of antiplatelet medication; 3) predict thrombotic risk; and 4) predict bleeding risk. The practicalities of clinical cardiology demand rapid, accurate, and reliable tests that are simple to operate at the bedside and available 24 h a day, 7 days a week. Point-of-care PFTs most widely evaluated clinically include PFA-100 and VerifyNow. None of these tests can reliably detect platelet hyperreactivity and thus identify a prothrombotic state. Identification of antiplatelet nonresponsiveness or hyporesponsiveness is highly test specific, and does not allow individualization of therapy. The power of PFTs in predicting thrombotic events for a given individual is variable and often modest, and alteration of antithrombotic treatment on the basis of the results of PFTs has not been shown to alter clinical outcome. PFTs in current mainstream use cannot reliably assess bleeding risk. These tests have been in use for over a decade, but the hopes raised by PFTs in clinical practice remain unfulfilled. Although physiologically relevant measurement of platelet function now is more important than ever, a critical reappraisal of available techniques in light of clinical requirements is needed. The use of native blood, global stimulus instead of individual agonists, contribution of thrombin generation by activated platelets to the test results, and establishment of a PFT therapeutic range for each antiplatelet drug should be considered and is discussed. © 2013 American College of Cardiology Foundation.

Patel G.,Mount Sinai School of Medicine | Bonomo R.A.,Research Service | Bonomo R.A.,University Hospitals Case Medical Center | Bonomo R.A.,Case Western Reserve University
Frontiers in Microbiology | Year: 2013

Carbapenems, once considered the last line of defense against of serious infections with Enterobacteriaceae, are threatened with extinction. The increasing isolation of carbapenem-resistant Gram-negative pathogens is forcing practitioners to rely on uncertain alternatives. As little as 5 years ago, reports of carbapenem resistance in Enterobacteriaceae, common causes of both community and healthcare-associated infections, were sporadic and primarily limited to case reports, tertiary care centers, intensive care units, and outbreak settings. Carbapenem resistance mediated by β-lactamases, or carbapenemases, has become widespread and with the paucity of reliable antimicrobials available or in development, international focus has shifted to early detection and infection control. However, as reports of Klebsiella pneumoniae carbapenemases, New Delhi metallo-β-lactamase-1, and more recently OXA-48 (oxacillinase-48) become more common and with the conveniences of travel, the assumption that infections with highly resistant Gram-negative pathogens are limited to the infirmed and the heavily antibiotic and healthcare exposed are quickly being dispelled. Herein, we provide a status report describing the increasing challenges clinicians are facing and forecast the "stormy waters" ahead. © 2013 Patel and Bonomo.

Suzuki A.,Mount Sinai School of Medicine | Stern S.A.,Mount Sinai School of Medicine | Bozdagi O.,Mount Sinai School of Medicine | Huntley G.W.,Mount Sinai School of Medicine | And 4 more authors.
Cell | Year: 2011

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation. © 2011 Elsevier Inc.

Calvo M.S.,U.S. Food and Drug Administration | Calvo M.S.,Mount Sinai School of Medicine | Uribarri J.,U.S. Food and Drug Administration | Uribarri J.,Mount Sinai School of Medicine
American Journal of Clinical Nutrition | Year: 2013

This review explores the potential adverse impact of the increasing phosphorus content in the American diet on renal, cardiovascular, and bone health of the general population. Increasingly, studies show that phosphorus intakes in excess of the nutrient needs of a healthy population may significantly disrupt the hormonal regulation of phosphate, calcium, and vitamin D, which contributes to disordered mineral metabolism, vascular calcification, impaired kidney function, and bone loss. Moreover, large epidemiologic studies suggest that mild elevations of serum phosphate within the normal range are associated with cardiovascular disease (CVD) risk in healthy populations without evidence of kidney disease. However, few studies linked high dietary phosphorus intake to mild changes in serum phosphate because of the nature of the study design and inaccuracies in the nutrient composition databases. Although phosphorus is an essential nutrient, in excess it could be linked to tissue damage by a variety of mechanisms involved in the endocrine regulation of extracellular phosphate, specifically the secretion and action of fibroblast growth factor 23 and parathyroid hormone. Disordered regulation of these hormones by high dietary phosphorus may be key factors contributing to renal failure, CVD, and osteoporosis. Although systematically underestimated in national surveys, phosphorus intake seemingly continues to increase as a result of the growing consumption of highly processed foods, especially restaurant meals, fast foods, and convenience foods. The increased cumulative use of ingredients containing phosphorus in food processing merits further study given what is nowbeing shown about the potential toxicity of phosphorus intake when it exceeds nutrient needs. Copyright © 2013 American Society for Nutrition.

Sanyal A.J.,Virginia Commonwealth University | Friedman S.L.,Mount Sinai School of Medicine | Mccullough A.J.,Cleveland Clinic | Dimick-Santos L.,U.S. Food and Drug Administration
Hepatology | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) in North America. It is a growing contributor to the burden of CDL requiring liver transplantation. Cirrhosis is also associated with an increased risk of hepatocellular cancer, which may occur even in the absence of cirrhosis in subjects with nonalcoholic steatohepatitis (NASH), the histological form of NAFLD associated with increased liver-related mortality. The diagnosis of NASH currently requires a liver biopsy. There are also no U.S. Food and Drug Administration (FDA)-approved therapies for NASH. Therefore, there is a need to develop better diagnostic and therapeutic strategies for patients with NASH, targeting both those with early-stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. The long relatively asymptomatic time interval in the progression of NAFLD and NASH to cirrhosis and ultimately liver failure, along with gaps in knowledge regarding disease modifiers, combine to present significant challenges in trial design. Therefore, there is an urgent need to develop methods to identify the populations at particular risk of disease progression and validate endpoints that reflect meaningful changes in health status in this population. This article summarizes the discussion at a joint workshop held September 5 and 6, 2013 in Silver Spring, Maryland, sponsored by the FDA and the American Association for the Study of Liver Diseases to develop guidance on diagnostic and therapeutic modalities for NASH. (Hepatology 2015;61:1392-1405) © 2015 by the American Association for the Study of Liver Diseases.

Montgomery G.H.,Mount Sinai School of Medicine | Schnur J.B.,Mount Sinai School of Medicine
CA Cancer Journal for Clinicians | Year: 2013

Answer questions and earn CME/CNE Hypnosis has been used to provide psychological and physical comfort to individuals diagnosed with cancer for nearly 200 years. The goals of this review are: 1) to describe hypnosis and its components and to dispel misconceptions; 2) to provide an overview of hypnosis as a cancer prevention and control technique (covering its use in weight management, smoking cessation, as an adjunct to diagnostic and treatment procedures, survivorship, and metastatic disease); and 3) to discuss future research directions. Overall, the literature supports the benefits of hypnosis for improving quality of life during the course of cancer and its treatment. However, a great deal more work needs to be done to explore the use of hypnosis in survivorship, to understand the mediators and moderators of hypnosis interventions, and to develop effective dissemination strategies. © 2012 American Cancer Society. Copyright © 2012 American Cancer Society, Inc.

Salem F.,Mount Sinai School of Medicine | Wyatt C.M.,Mount Sinai School of Medicine
Kidney International | Year: 2014

The epidemiology of kidney disease in HIV-infected individuals has changed significantly since the introduction of combination antiretroviral therapy (cART) in the mid 1990s. HIV-associated nephropathy (HIVAN), an aggressive form of collapsing focal segmental glomerulosclerosis (FSGS) caused by direct HIV infection of the kidney in a genetically susceptible host, emerged early in the HIV epidemic as a leading cause of end-stage renal disease. With the widespread use of cART, HIVAN is increasingly rare in populations with access to care, and the spectrum of HIV-related chronic kidney disease now reflects the growing burden of comorbid disease in the aging HIV population. Nonetheless, available data suggest that both HIV infection and cART nephrotoxicity continue to contribute to the increased risk of chronic kidney disease in HIV-infected individuals in the United States and Europe. Despite the genetic susceptibility to HIVAN in individuals of West African descent, limited data are available to define the prevalence and spectrum of HIV-related kidney disease in sub-Saharan Africa, which is home to two-thirds of the world's HIV population. In this mini-review, we characterize the changing epidemiology of HIV-related chronic kidney disease in Western nations and in sub-Saharan Africa. © 2014 International Society of Nephrology.

Messaoudi I.,University of California at Riverside | Basler C.F.,Mount Sinai School of Medicine
Current Opinion in Immunology | Year: 2015

Several enveloped RNA viruses of the arenavirus, bunyavirus, filovirus and flavivirus families are associated with a syndrome known as viral hemorrhagic fever (VHF). VHF is characterized by fever, vascular leakage, coagulation defects and multi organ system failure. VHF is currently viewed as a disease precipitated by viral suppression of innate immunity, which promotes systemic virus replication and excessive proinflammatory cytokine responses that trigger the manifestations of severe disease. However, the mechanisms by which immune dysregulation contributes to disease remain poorly understood. Infection of nonhuman primates closely recapitulates human VHF, notably Ebola and yellow fever, thereby providing excellent models to better define the immunological basis for this syndrome. Here we review the current state of our knowledge and suggest future directions that will better define the immunological mechanisms underlying VHF. © 2015 Elsevier Ltd.

Meier D.E.,Mount Sinai School of Medicine
CA Cancer Journal for Clinicians | Year: 2013

Answer questions and earn CME/CNE Scientific advances in novel cancer therapeutics have led to remarkable changes in oncology practice and longer lives for patients diagnosed with incurable malignancies. However, the myriad options for treatment have established a culture of cancer care that has not been matched with a similar availability of efficacious supportive care interventions aimed at relieving debilitating symptoms due to progressive disease and treatment side effects. Accumulating data show that the introduction of palliative care services at the time of diagnosis of advanced cancer leads to meaningful improvement in the experiences of patients and family caregivers by emphasizing symptom management, quality of life, and treatment planning. In this review article, the rationale and evidence base for this model of early palliative care services integrated into standard oncology care are presented. In addition, the implications and limitations of the existing data to 1) elucidate the mechanisms by which early palliative care benefits patients and families; 2) guide the dissemination and application of this model in outpatient settings; and 3) inform health care policy regarding the delivery of high-quality, cost-effective, and comprehensive cancer care are discussed. CA Cancer J Clin 2013. © 2013 American Cancer Society, Inc.

Mulder W.J.M.,Mount Sinai School of Medicine | Jaffer F.A.,Harvard University | Fayad Z.A.,Mount Sinai School of Medicine | Nahrendorf M.,Harvard University
Science Translational Medicine | Year: 2014

Bioengineering provides unique opportunities to better understand and manage atherosclerotic disease. The field is entering a new era that merges the latest biological insights into inflammatory disease processes with targeted imaging and nanomedicine. Preclinical cardiovascular molecular imaging allows the in vivo study of targeted nanotherapeutics specifically directed toward immune system components that drive atherosclerotic plaque development and complication. The firstmulticenter trials highlight the potential contribution of multimodality imaging to more efficient drug development. This review describes how the integration of engineering, nanotechnology, and cardiovascular immunology may yield precision diagnostics and efficient therapeutics for atherosclerosis and its ischemic complications.

Rosenson R.S.,Mount Sinai School of Medicine | Brewer H.B.,MedStar Research Institute | Rader D.J.,University of Pennsylvania
Circulation Research | Year: 2014

The period following an acute coronary syndrome (ACS) represents a critical time frame with a high risk for recurrent events and death. The pathogenesis of this increase in clinical cardiovascular disease events after ACS is complex, with molecular mechanisms including increased thrombosis and inflammation. Dyslipoproteinemia is common in patients with ACS and predictive of recurrent cardiovascular disease events after presentation with an ACS event. Although randomized clinical trials have provided fairly convincing evidence that high-dose statins reduce the risk of recurrent cardiovascular events after ACS, there remain questions about how aggressively to reduce low-density lipoprotein cholesterol levels in ACS. Furthermore, no other lipid-related interventions have yet been proven to be effective in reducing major cardiovascular events after ACS. Here, we review the relationship of lipoproteins as biomarkers to cardiovascular risk after ACS, the evidence for lipid-targeted interventions, and the potential for novel therapeutic approaches in this arena. © 2014 American Heart Association, Inc.

Culligan P.J.,Mount Sinai School of Medicine
Obstetrics and Gynecology | Year: 2012

Although surgical management of symptomatic pelvic organ prolapse (POP) is common and often necessary, conservative treatments such as pessaries, pelvic floor muscle training, or both can usually result in symptomatic improvement. When treating patients with POP, health care practitioners should focus primarily on identification and alleviation of POP-related symptoms. It is appropriate to offer nonsurgical management to most people with POP. This article reviews the objective and subjective evaluation and nonsurgical management of POP, emphasizing a simple, practical approach to pessary fitting and management. © 2012 The American College of Obstetricians and Gynecologists.

Ayllon J.,Mount Sinai School of Medicine
Current Topics in Microbiology and Immunology | Year: 2015

The non-structural protein 1 of influenza virus (NS1) is a relatively small polypeptide with an outstanding number of ascribed functions. NS1 is the main viral antagonist of the innate immune response during influenza virus infection, chiefly by inhibiting the type I interferon system at multiple steps. As such, its role is critical to overcome the first barrier the host presents to halt the viral infection. However, the pro-viral activities of this well-studied protein go far beyond and include regulation of viral RNA and protein synthesis, and disruption of the host cell homeostasis by dramatically affecting general gene expression while tweaking the PI3K signaling network. Because of all of this, NS1 is a key virulence factor that impacts influenza pathogenesis, and adaptation to new hosts, making it an attractive target for control strategies. Here, we will overview the many roles that have been ascribed to the NS1 protein, and give insights into the sequence features and structural properties that make them possible, highlighting the need to understand how NS1 can actually perform all of these functions during viral infection. © Springer International Publishing Switzerland 2014.

Wu J.,Mount Sinai School of Medicine | Roman A.-C.,Instituto Cajal | Carvajal-Gonzalez J.M.,Mount Sinai School of Medicine | Mlodzik M.,Mount Sinai School of Medicine
Nature Cell Biology | Year: 2013

Planar cell polarity (PCP) is cellular polarity within the plane of an epithelial tissue or organ. PCP is established through interactions of the core Frizzled (Fz)/PCP factors and, although their molecular interactions are beginning to be understood, the upstream input providing the directional bias and polarity axis remains unknown. Among core PCP genes, Fz is unique as it regulates PCP both cell-autonomously and non-autonomously, with its extracellular domain acting as a ligand for Van Gogh (Vang). We demonstrate in Drosophila melanogaster wings that Wg (Wingless) and dWnt4 (Drosophila Wnt homologue) provide instructive regulatory input for PCP axis determination, establishing polarity axes along their graded distribution and perpendicular to their expression domain borders. Loss-of-function studies reveal that Wg and dWnt4 act redundantly in PCP determination. They affect PCP by modulating the intercellular interaction between Fz and Vang, which is thought to be a key step in setting up initial polarity, thus providing directionality to the PCP process. © 2013 Macmillan Publishers Limited. All rights reserved.

Guo J.,Shanghai University | Friedman S.L.,Mount Sinai School of Medicine
Fibrogenesis and Tissue Repair | Year: 2010

Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies. © 2010 Guo and Friedman; licensee BioMed Central Ltd.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.2.1-2 | Award Amount: 8.13M | Year: 2013

Mental disorders are leading causes of disability, absence from work and premature retirement in Europe. While magnetic resonance imaging (MRI) facilities are broadly available and a vast research literature exists, few neuroimaging applications have reached clinical practice in psychiatry. A major problem is that mental illnesses are currently diagnosed as discrete entities defined clinically. Instead, recent results show that mental disorders are best understood as quantitative alterations in neural systems relevant across traditional diagnostic boundaries that reflect individual, genetic and environmental risk factors. In the IMAGEMEND consortium, we aim to discover these systems to identify the patient characteristics most relevant for treatment, derive biomarkers and decision rules from this systems-level dimensional account, and systematically validate biomarker panels in patient, high-risk and epidemiological samples to produce automated imaging-based diagnostic and predictive tests tailored for wide distribution throughout Europe in standard clinical settings. Focusing on schizophrenia, bipolar disorder and attention deficit-hyperactivity disorder, we have assembled Europes largest dataset combining neuroimaging, genetic, environmental, cognitive and clinical information on approximately 13000 participants, and have recruited international replication datasets of more than 30000 people. This unique resource will be processed using a new generation of multivariate statistical analysis to optimize existing imaging technology for the benefit of patients. We will also develop new imaging technology to enable the direct imaging-based therapeutic modification of neural circuits through rapid real-time MRI. Our deliverables will promote personalized treatment through more accurate patient stratification, allow diagnoses at the pre-symptomatic stage for early intervention and prevention, and improve prediction of treatment response and disease progression.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.3.2-1 | Award Amount: 3.62M | Year: 2012

Integrated delivery systems of care, e.g. networks of health organizations and professionals who work together to coordinate services to meet their patients needs, are an important way of linking fragmented services and maximizing system efficiency and seamlessness of patient transition. Research increasingly shows that patients with advanced cancer and advanced chronic disease are treated well by integrated palliative care pathways, with comparable quality of care at lower costs. Palliative care involves the multidisciplinary care for patients in the last phase of life-threatening disease and is expected to largely grow due to the ageing of the European population. However, palliative care in Europe is still mostly organized across institutional lines: hospital, home care, hospice. This project aims at the identification of best practices in integrated palliative care with regard to quality of life and quality of care. Mixed methods will be used to identify models for integrated palliative care in Europe and to assess patient/caregiver experiences and perceptions within these pathways at the one hand and organizational, managerial, financial and regulatory aspects of these integrated pathways at the other hand. The project will evaluate existing initiatives for patients with cancer, COPD and CHF, and will deliver recommendations on (requirements for) best practices in integrated palliative care. This will also include recommendations on (changes in) skill mix of health professionals. Results will be disseminated via conferences, articles, and an interactive website including an e-learning module. This project will contribute vastly to the improvement of the (organization of) care for patients with advanced cancer and chronic disease and can be extrapolated to other patients with complex care needs.

Fuster V.,Mount Sinai School of Medicine
Nature Reviews Cardiology | Year: 2013

The effect of a fixed-dose combination drug strategy ('polypill') on patients' adherence to medication was analysed in a series of 2,004 individuals with, or at high risk of, cardiovascular disease in the UMPIRE study. The polypill improved adherence by >20%, but the reduction in blood-pressure and cholesterol levels was modest. © 2013 Macmillan Publishers Limited.

Agency: Cordis | Branch: FP7 | Program: CSA-CA | Phase: HEALTH.2013.4.1-5 | Award Amount: 2.34M | Year: 2013

The overall goal of InterConnect is to establish a global network that will facilitate the co-ordination of population research on the interaction between genetic and environmental factors in the aetiology of obesity and diabetes. We aim to establish mechanisms for identification and classification of studies and the data that they hold and create a forum for harmonization of methods as a foundation for optimizing the use of existing data for the study of gene-environment interaction. We aim to establish a funders forum and a forum for stakeholders and bring these groups together with subject-specific researchers and methodologists to create an appropriately governed framework for sharing existing data, harmonizing the addition of new data and planning new studies. With the involvement of strong funders and stakeholders fora in InterConnect from the outset, the project will provide a network to link, co-ordinate and eventually integrate EU funded research activities with those in other continents. InterConnect will provide a forum for exchange of information and best practice between projects. This will be relevant both to the research community and also the funders. The engagement of stakeholders and our dissemination programme will ensure that the knowledge that is ultimately gained through collaborative work in this network will be translated into policy, social and economic benefits. Through its work on an ethical and legal framework, InterConnect will create a sustainable framework that will facilitate data sharing that is transparent and dynamic.

TARRYTOWN, N.Y., Nov. 4, 2016 (GLOBE NEWSWIRE) -- ENT and Allergy Associates, LLP (ENTA) is extremely proud and delighted to announce that Dr. Eric Smouha, currently Director of Otology and Neurology at Mount Sinai School of Medicine and Clinical Professor of Otolaryngology at that academic institution, has agreed to join the Practice's Fifth Avenue office, where he will be seeing adult and pediatric patients in need, beginning April 1, 2017. Dr. Smouha will retain privileges at Mt. Sinai Hospital. Eric Smouha, MD, FACS is board-certified in both Otolaryngology and Neuro-Otology. With nearly thirty years of experience, his clinical and academic interests span all aspects of otology and neurotology. Dr. Smouha has performed several hundred operations for cholesteatoma and has given instructional courses on cholesteatoma and complications of otitis media at the American Academy of Otolaryngology-Head and Neck Surgery and in the School of Graduate Education at Mount Sinai. With expertise on hearing preservation, he has performed hundreds of successful stapedectomy operations for the treatment of otosclerosis, cochlear implants for deafness, and newer surgically-implanted hearing devices. His publications include a textbook entitled Cholesteatoma, and articles on the management of cholesteatoma in the normal hearing ear, the treatment of CSF leaks of the skull base, and the surgical treatment of Meniere's disease. He has also conducted basic research on matrix metallo-proteinase enzymes in cholesteatoma, and on three-dimensional imaging of the temporal bone. Additionally, Dr. Smouha has done pivotal basic research in hearing preservation surgery of the inner ear. As a neurotologic surgeon, Dr. Smouha has expertise in the treatment of acoustic neuromas and diseases of the skull base. His meta-analysis on the conservative management of acoustic neuromas was presented at the North American Skull Base Society and published in the journal Laryngoscope, and is widely cited. He is a fellow of the American Academy of Otolaryngology-Head and Neck Surgery and the American College of Surgeons; and a member of the American Otological Society, the American Neurotological Society, the Triological Society, the North American Skull Base Society; and, a recipient of the Certificate of Honor of the American Academy of Otolaryngology-Head and Neck Surgery. He has been listed as a top doctor in New York Magazine, the New York Times Super Doctors, Castle-Connolly, and the Top Doctors of America. Voted Teacher of the Year in 2009 and 2014 by the resident staff, his devotion to training physicians has further established excellence in the otology teaching programs. His contributions to the field of Neuro-otology have established him as a leader in his field and an outstanding clinician.   Robert Glazer, CEO of ENTA, noted "Our vision, and goal, is to offer the communities we serve a superbly-trained and credentialed multidisciplinary team, so our patients are able to avail themselves of a comprehensive roster of services in a single location." He continued, "And that is exactly what we accomplish by adding a fellowship-trained physician like Dr. Smouha to our Fifth Avenue office in April." At the ENTA Fifth Avenue office, he joins Otolaryngologists Jay N. Dolitsky, M.D., F.A.A.P., David A. Godin, M.D., F.A.C.S., Roheen Raithatha, M.D., Ofer Jacobowitz, M.D., P.h.D., F.A.A.S.M., F.A.A.O.A. and Allergist/Immunologist Robert Sporter, M.D. "We are extremely pleased to welcome an accomplished colleague like Eric Smouha to our ranks," noted otolaryngologist David Godin, MD, "and I believe the patients of Fifth Avenue will be just as pleased."    Added Dr. Robert Green, President of ENTA, "As we continue to grow throughout the five boroughs of New York City, our need to attract the best and the brightest otolaryngologists and related sub-specialists grows in concert. Dr. Smouha represents the highest standards and offers a superb combination of credentials, expertise, and experience. We are confident his benefit to the community will be immediate, and palpable."   To learn more please visit or call 1-855-ENTA-DOC.   About ENT and Allergy Associates, LLP: ENT and Allergy has over 180 physicians practicing in 40+ office locations in Westchester, Putnam, Orange, Dutchess, Rockland, Nassau and Suffolk counties, New York City and northern/central New Jersey. The practice sees over 80,000 patients per month. Each ENT and Allergy Associates clinical location provides access to a full complement of services, including General Adult and Pediatric ENT and Allergy, Voice and Swallowing, Advanced Sinus and Skull Base Surgery, Facial Plastics and Reconstructive Surgery, Disorders of the Inner Ear and Dizziness, Asthma, Clinical Immunology, Diagnostic Audiology, Hearing Aid dispensing, Sleep and CT Services. ENTA has a clinical alliance with The Mount Sinai Hospital for the treatment of diseases of the head and neck and esophageal cancer, a clinical alliance with the Montefiore Medical Center for the tertiary treatment of pediatric patients in New York City and the Hudson Valley, a clinical alliance with the Northwell Health for the tertiary treatment of pediatric patients in Queens, Nassau and Suffolk Counties and a partnership with the American Cancer Society to educate and treat patients with smoking disorders and cancer. The Practice has also expanded its clinical capabilities to include advanced Immunodeficiency trials. ENT and Allergy Associates Management and Marketing teams have been recognized numerous times with awards and accolades including Health Leaders Media 2011 Top Leadership Team in Healthcare, Top Doctor Awards, ACS recognition award, AHAA Audiologist awards, The Westchester County Association Big W Awards and the Healthcare Marketing Report Healthcare Advertising Awards. Visit for more information. A photo accompanying this release is available at:

News Article | November 17, 2016

Mobile health technology leader, Irody, today announced the results of a study that showed electronic diaries or journal apps can be useful in clinical settings for enhanced patient and medication management. The study also highlights advantages of electronic tracking over traditional assessment methods of adherence. The study, “Medication adherence in women with epilepsy who are planning pregnancy,” which was published recently in the peer-reviewed journal, Epilepsia, was designed to evaluate the utility of electronic diary apps for tracking of medication adherence for women who have epilepsy and are trying to achieve pregnancy. This is important because in managing epilepsy it is important for the doctor to know how patients are actually using their medications. The controlled, multi-center observational study was conducted by New York University Langone Epilepsy Center, Mount Sinai School of Medicine, and Brigham and Women's Hospital, over the course of three-and-a-half years. “This strong collaboration of key stakeholders shows that there is significant potential for using digital technology for improving clinical efficiencies related to tracking patient compliance, and, as a result, for improving patient outcomes,” said Eyal Bartfeld, DMD, PhD, CEO of Irody and one of the authors of the study. “The results of this study illustrate how we can use technology to transform clinical care, the patient experience and — ultimately, patient outcomes — in the new value-based health care environment.” According to the article, participants in the study used the EpiDiary, an electronic diary mobile app, to record medication use, seizure activity, the use of other non-epileptic medications, menstrual cycles and sexual activity, as well as ongoing self-management and support activities. The study followed 86 women with epilepsy from their date of enrollment in the study until their date of delivery, or up to 12 months, if pregnancy was not achieved. “Monitoring of medication adherence presents a tremendous challenge to clinicians and to clinical researchers” said Jacqueline French MD, professor, New York University Comprehensive Epilepsy Center, and senior author on the study. “Poor adherence has been shown to negatively impact health care spending by resulting in more emergency room visits and hospitalizations, and may result in incomplete seizure control and increased risk of sudden death. Many times, patients do not report to their doctor about missed medication doses. This information could be used to discuss and improve compliance.” Highlights from the study include the following data points: The increased compliance seen by patients who used the electronic diary suggests that it may be useful to track medication adherence in future studies and in clinical settings. Study authors suggest that outcomes may be driven in part by the daily reminders and real-time feedback that is provided by the electronic diary, which facilitates compliance and long-term engagement. About Irody Based in Boston, Mass., Irody was founded by a group of scientists, technology leaders and entrepreneurs with expertise in computer vision and signal processing, medicine, epidemiology and medical informatics. The company’s proprietary pill recognition technology is the basis for solutions like mobile patient diaries such as EpiDiary. Irody’s cloud and mobile apps are currently in use in several clinical trials and by more than 30 academic institutions in the United States, Canada, Europe and Australia. Data from EpiDiary has been used for multiple peer-reviewed publications.

The International Association of HealthCare Professionals is pleased to welcome Jacqueline Dauhajre, MD, Ophthalmologist, to their prestigious organization with her upcoming publication in The Leading Physicians of the World. Dr. Jacqueline Dauhajre is a highly trained and qualified ophthalmologist with an extensive expertise in all facets of her work. Dr. Dauhajre has been in practice for more than 29 years and is currently serving patients within her own private practice located on the Upper East Side of New York. She is also affiliated with Mount Sinai Medical Center and St. Vincent’s Hospital. Dr. Dauhajre attended Mount Sinai School of Medicine, graduating with her Medical Degree in 1987. She subsequently completed her internship at Mount Sinai Medical Center, before undertaking her residency at SUNY Downstate Medical Center. She then returned to Mount Sinai Medical Center to complete her fellowship training. Dr. Dauhajre is certified by the American Board of Ophthalmology, and keeps up to date with the latest advances and developments in her field by maintaining a professional membership with the American Academy of Ophthalmology. Dr. Dauhajre is dedicated to providing the highest level of quality and compassionate care to her patients suffering with eye trouble or disease. She attributes her success to hard work, her desire to learn, and her unwavering motivation. When she is not assisting patients, Dr. Dauhajre enjoys dining out, reading, and traveling. Learn more about Dr. Dauhajre by reading her upcoming publication in The Leading Physicians of the World. is a hub for all things medicine, featuring detailed descriptions of medical professionals across all areas of expertise, and information on thousands of healthcare topics.  Each month, millions of patients use FindaTopDoc to find a doctor nearby and instantly book an appointment online or create a review. features each doctor’s full professional biography highlighting their achievements, experience, patient reviews and areas of expertise.  A leading provider of valuable health information that helps empower patient and doctor alike, FindaTopDoc enables readers to live a happier and healthier life.  For more information about FindaTopDoc, visit

News Article | November 8, 2016

Women’s reproductive years can bring about changes on both the body and the complexion, including stubborn brown, tan or grayish skin patches known as melasma, according to Romeo Morales, MD, of Advanced Dermatology P.C. Characterized by increased pigmentation on the nose, cheeks or jawline, melasma is almost entirely a women’s affliction, with 90% of those affected being females between the ages of 20 and 50. Triggered by factors such as hormones, genetic susceptibility and sun exposure, melasma impacts an estimated 6 million women in the United States, according to the American Academy of Dermatology. The condition is often called the “mask of pregnancy” because its resulting dark areas on the face are even more commonplace while women are expecting. Those with darker skin, such as people of Latin, African, Asian, Indian, Middle Eastern or Mediterranean descent, are also disproportionately affected. “Most of those coping with melasma have a history of daily or regular sun exposure, which is perhaps the biggest contributing factor,” says Dr. Morales, who is also a Clinical Instructor and Dermatology Attending at Mount Sinai School of Medicine. “Fortunately, several treatments can lighten both the skin and the emotional weight of dealing with this condition.” Tips: How can melasma be effectively treated? Diagnosing melasma is usually pretty straightforward, with a dermatologist able to tell what it is just by looking at the skin. If there’s any question as to how deeply the melasma pigment may penetrate the skin, a dermatologist may look at patches under a device known as a Wood’s lamp. Sometimes melasma can disappear on its own, particularly when the trigger – excessive sun exposure, pregnancy or oral contraceptive use – ends. But those who want to take a more active role in reducing the spots’ prominence can try these treatments: Hydroquinone: Often tried before other treatments, hydroquinone comes in cream, lotion, gel or liquid form and works by lightening the skin. Higher-strength hydroquinone, available only by prescription, tends to be more effective than lower-strength versions available over the counter, Dr. Morales says. Tretinoin and corticosteroids: To enhance the effects of hydroquinone, a second medication containing these ingredients may be prescribed. Some versions contain three compounds – hydroquinone, tretinoin and a corticosteroid – which are called a “triple cream.” Other topical medications: Also applied to the skin, these may include the skin-lighteners azelaic acid or kojic acid. In-office procedures: Chemical peels, microdermabrasion, or dermabrasion procedures may be used if topical treatments don’t get rid of melasma. These treatments, which are done in a dermatologist’s office, slough off the top layers of the skin to lighten it. Preventing melasma requires vigilance Unfortunately, treating melasma isn’t a “once-and-done” proposition, where the problem is permanently solved. That’s why it’s imperative to keep up efforts to prevent melasma from recurring, Dr. Morales says. “This requires sensible vigilance,” he adds, “since melasma will simply come back if you don’t pay attention to sun protection and other prevention measures.” Melasma prevention tactics include: Daily sunscreen use: Since sun exposure is the main risk factor for developing melasma, daily sunscreen use is a must. Choose a sunscreen with broad-spectrum protection with an SPF of 30 or higher. Don’t forget to wear it even on cloudy days and re-apply after swimming or sweating. Wide-brimmed hats: Since research indicates sunscreen alone doesn’t provide all the protection needed to keep melasma at bay, wear a broad-brimmed hat when outdoors. These hats keep rays off vulnerable areas of the face. “Stay in the shade whenever possible,” Dr. Morales advises. Gentle skin care products: Cleansers that sting, burn or irritate the skin can worsen melasma, so use gentle products. Skipping waxing: Hair-removal efforts on the face need to veer away from waxing, since this can inflame the skin and exacerbate melasma. “Given the stubborn nature of melasma it’s important to follow your dermatologist’s advice regarding treatment and prevention,” Dr. Morales says. “The good news is that with proper treatment and prevention, most people see terrific results in keeping their skin clear of melasma.” Romeo Morales, M.D., F.A.A.D., specializes in many areas of medical and surgical dermatology with a particular interest in skin cancer screening and prevention. Advanced Dermatology P.C. and the Center for Laser and Cosmetic Surgery (New York & New Jersey) is one of the leading dermatology centers in the nation with 18 locations in New York and New Jersey, offering highly experienced physicians in the fields of cosmetic and laser dermatology as well as plastic surgery and state-of-the-art medical technologies.

WESTWOOD, NJ, March 03, 2017-- Dr. Phyllis G. Supino has been included in Marquis Who's Who. As in all Marquis Who's Who biographical volumes, individuals profiled are selected on the basis of current reference value. Factors such as position, noteworthy accomplishments, visibility, and prominence in a field are all taken into account during the selection process.Recognized for more than four decades of invaluable contributions to her field, Dr. Supino parlays her knowledge into her role as professor of medicine and public health and director of clinical epidemiology and clinical research for the division of cardiovascular medicine at the State University of New York Downstate College of Medicine, where she has worked since 2008. Prior to entering the field, she earned a Bachelor of Science in biological sciences from the City College of New York. Dr. Supino became an instructor of psychology and research associate in cognitive psychology at Princeton University in 1975, and the following year, she earned an Ed.D. in science education from Rutgers University, and was the recipient of the Phi Delta Kappa Award for Excellence in Dissertation Research. Upon graduating, she started with The Educational Improvement Center through the New Jersey Department of Education, where she worked as director of research and evaluation for two years. Subsequently, she took on a variety of other roles in higher institutions, including Robert Wood Johnson Medical School, Cornell University Medical College, Mount Sinai School of Medicine, where she served as the director of research in emergency medicine, and Weill Cornell Medical College, where she worked before obtaining her current role. Over the years, her primary research focus has been cardiovascular medicine.In order to remain abreast of changes in the field, Dr. Supino affiliates herself with the New York Academy of Medicine, where she is a fellow, as well as the International Academy of Cardiology, where she serves as a member of its scientific advisory board, the American Statistical Association, and the American Heart Association. Throughout her career, she has parlayed her extensive knowledge to articles in professional journals and to her textbook, "Principles of Research Methodology: Guide for Clinical Investigators," which helps medical professionals to understand the scientific process. Dr. Supino is also credited with developing the first comprehensive approved course on clinical research methodology for physicians at Weill Medical College, Mount Sinai School of Medicine, and the State University of New York Downstate College of Medicine, and is proud to have served as a research mentor to more than 100 medical students, residents, fellows, and junior faculty and as a member of the editorial board and reviewer for a number of medical journals. Further, she was honored with her appointment as chair of the Institutional Review Board at SUNY Downstate, as well as with The Howard Gilman Award for Excellence in Research and Teaching in Cardiovascular Diseases, the Best Mentor of the Year Award from the Mount Sinai School of Medicine Emergency Department, and the Best National Science Abstract Award, which was given to her by the American Society of Nuclear Cardiology and International Affiliates. As a testament to her success, Dr. Supino was featured in Who's Who of American Women, Who's Who in the World, and Who's Who in the East.About Marquis Who's Who :Since 1899, when A. N. Marquis printed the First Edition of Who's Who in America , Marquis Who's Who has chronicled the lives of the most accomplished individuals and innovators from every significant field of endeavor, including politics, business, medicine, law, education, art, religion and entertainment. Today, Who's Who in America remains an essential biographical source for thousands of researchers, journalists, librarians and executive search firms around the world. Marquis publications may be visited at the official Marquis Who's Who website at

News Article | December 20, 2016

WALTHAM, Mass., Dec. 20, 2016 (GLOBE NEWSWIRE) -- Minerva Neurosciences, Inc. (NASDAQ:NERV), a clinical-stage biopharmaceutical company focused on the development of therapies to treat central nervous system (CNS) disorders, today announced the appointment of Michael Davidson, M.D., as chief medical officer effective December 19, 2016.  His responsibilities will include the strategic development and clinical advancement of the Company’s products, which target schizophrenia (MIN-101), insomnia (MIN-202), major depressive disorder (MIN-117) and Parkinson’s disease (MIN-301). Dr. Davidson brings to Minerva significant experience in the research and development of drugs to treat diseases of the central nervous system.  He is currently professor of psychiatry at the Sackler School of Medicine, Tel Aviv University.  Dr. Davidson trained in psychiatry at the Mount Sinai School of Medicine in New York, where he served as professor of psychiatry and director of research. “Dr. Davidson’s deep expertise in CNS disorders, his insights into the development strategy and regulatory review of new agents to treat these conditions and his broad knowledge of clinical operations are expected to help us realize the potential of Minerva’s portfolio of products to treat unmet medical needs,” said Dr. Remy Luthringer, president and chief executive officer of Minerva.  “During the past year, we have benefitted from his capabilities as a consultant, and we are looking forward to his increased involvement as we interact with regulatory agencies in the U.S. and Europe and as we embark upon pivotal clinical testing with our lead product, MIN-101 for schizophrenia.” Dr. Davidson has been a consultant for a number of pharmaceutical and biotechnology companies, including Pfizer, Johnson and Johnson, Teva, Roche, Novartis, Lilly, Forest, BioLineRx, Sanofi-Aventis, Takeda, Orion and Servier.  He is a board member and reviewer for several professional organizations and neuroscience and psychiatry publications.  Dr. Davidson has served as chief editor of European Neuropsychopharmacology, fellow of the American College of Neuropsychopharmacology and board member of the International Psychogeriatric Association.  He received the Neuroscience Award from the European College of Neuropsychopharmacology in 1999 and from the International College of Neuropsychopharmacology in 2006.  Dr. Davidson is the recipient of over 50 research grants and has published over 300 articles primarily in peer reviewed journals in the areas of schizophrenia and Alzheimer’s disease. In schizophrenia he has generated and published data focused on the underlying biology of the disease and on investigational treatments. Minerva Neurosciences, Inc. is a clinical-stage biopharmaceutical company focused on the development and commercialization of a portfolio of products to treat CNS diseases.  Minerva’s proprietary compounds include: MIN-101, which has completed a Phase IIb clinical trial for schizophrenia; MIN-117, which has completed a Phase IIa clinical trial development for MDD;  MIN-202 (JNJ-42847922), which has completed Phase IIa and Phase Ib clinical trials for insomnia and MDD, respectively; and MIN-301, in pre-clinical development for Parkinson’s disease.  Minerva’s common stock is listed on the NASDAQ Global Market under the symbol “NERV.”  For more information, please visit This press release contains forward-looking statements which are subject to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended.  Forward-looking statements are statements that are not historical facts, reflect management’s expectations as of the date of this press release, and involve certain risks and uncertainties.  Forward-looking statements include statements herein with respect to the timing and results of future clinical milestones with MIN-101, MIN-117, MIN-202 and MIN-301; the clinical and therapeutic potential of MIN-101, MIN-117, MIN-202 and MIN-301; our ability to successfully develop and commercialize MIN-101, MIN-117, MIN-202 and MIN-301; and management’s ability to successfully achieve its goals.  These forward-looking statements are based on our current expectations and may differ materially from actual results due to a variety of factors including, without limitation, whether MIN-101, MIN-117, MIN-202 and MIN-301 will advance further in the clinical trials process and whether and when, if at all, they will receive final approval from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies and for which indications; whether the results of future clinical trials of MIN-101, MIN-117, MIN-202 and MIN-301, if any, will be consistent with the results of past clinical trials; whether MIN-101, MIN-117, MIN-202 and MIN-301 will be successfully marketed if approved; whether our therapeutic product discovery and development efforts with MIN-101, MIN-117, MIN-202 and MIN-301 will be successful; our ability to achieve the results contemplated by our co-development agreements; management’s ability to successfully achieve its goals; our ability to raise additional capital to fund our operations on terms acceptable to us; and general economic conditions.  These and other potential risks and uncertainties that could cause actual results to differ from the results predicted are more fully detailed under the caption “Risk Factors” in our filings with the Securities and Exchange Commission, including our Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, filed with the Securities and Exchange Commission on November 3, 2016.  Copies of reports filed with the SEC are posted on our website at The forward-looking statements in this press release are based on information available to us as of the date hereof, and we disclaim any obligation to update any forward-looking statements, except as required by law.

SHAPE, the Society for Heart Attack Prevention and Eradication (, a nonprofit grassroots organization dedicated to the mission of eradicating heart attacks, today announced the agenda of its first focus group meeting on prediction of near-future heart attacks using artificial intelligence. The meeting is led by Dr. Morteza Naghavi the founder and executive director of SHAPE and features leading cardiovascular researchers from around the world.. This will be the 20th scientific meeting held by SHAPE since 2001. Detailed agenda of the meeting is shown below. The First Machine Learning Vulnerable Patient Symposium A Focus Group Meeting on Developing an Artificial Intelligence-based Forecast System A Satellite Event in Conjunction with 2016 Annual Scientific Sessions of American Heart Association This event is open to public. Participation via GoToMeeting can be requested. Dinner will be served 7:30 PM. This is the 20th Vulnerable Plaque & Vulnerable Patient Symposium held by SHAPE since 2001. Welcome: Morteza Naghavi, M.D. Founder of SHAPE and Executive Chairman of the SHAPE Task Force Opening Remarks: Valentin Fuster, M.D., Ph.D. Professor of Medicine and Physician-in-Chief, Mount Sinai Hospital and Icahn School of Medicine Jagat Narula M.D., Ph.D. Chief of Cardiology, Mount Sinai West & St. Luke’s Hospitals Associate, Dean, Arnhold Institute for Global Health at Mount Sinai Icahn School of Medicine Ioannis Kakadiaris, Ph.D. Professor of Computer Science and Biomedical Engineering, Director of Machine Learning Laboratory University of Houston Topic: What is Machine Learning and How Can It Shape the Future of Healthcare? Invited Online Presentations: Two Examples of Machine Learning Studies in CVD Risk Assessment (10 minutes each) CVD prediction using support vector machine in a large Australian cohort. Dinesh Kumar, Ph.D. and Sridhar Arjunan, Ph.D. Biosignals Lab, School of Electrical and Computer Engineering, RMIT University, Melbourne, Australia (2) Prediction of revascularization after myocardial perfusion SPECT by machine learning in a large clinical population Piotr Slomka, Ph.D. Chief Scientist, Artificial Intelligence in Medicine Program, Department of Imaging Cedars-Sinai Medical Center, Professor, UCLA School of Medicine, Los Angeles, CA Moderated Discussions on the Vulnerable Patient Project Machine Learning for Prediction of Near-Term CHD Events All investigators will be asked to give a very brief introduction of their study and how it can fit in Background: Imagine instead of the existing daily weather forecasts and hurricane alerts we were told the probability of a storm within the next 10 years! This is how heart attacks are predicted today. We teach our physicians to calculate the 10-year probability of a heart attack and sudden cardiac death based on their patients’ risk factors. Long term predictions do not trigger immediate preventive actions. Although some people develop warning symptoms, half of men and two-thirds of women who die suddenly of coronary heart disease (CHD) have no previous symptoms. Imagine if we could alert people months, weeks, or even days before a heart attack and trigger immediate preventive actions. The Idea: Use machine learning to create new algorithms to detect who will experience a CHD event within a year (The Vulnerable Patient). Algorithms will be based on banked biospecimen and information collected days up to 12 months prior to the event. We will utilize existing cohorts such as MESA, Heinz Nixdorf Recall Study, Framingham Heart Study, BioImage Study and the Dallas Heart Study. External validation to test for discrimination and calibration will be conducted using other longitudinal observational studies that provide adjudicated cardiovascular event information such as the MiHeart, JHS, DANRISK and ROBINSCA. Additionally, we will use machine learning to characterize individuals who, despite high conventional risk, have lived over 80 years with no CHD events (The Invulnerable ). We expect to discover new targets for drug and possibly vaccine development. We will make the algorithms available as an open source tool to collect additional data over time and increase its predictive value. Organizers: SHAPE as the originating and organizing center for the entire project, recruiting new studies and biobanks, conducting workshops with researchers from each study, fundraising, creating an open source platform community for future enhancement and collaborations. Stanford as the coordinating center for collecting data and samples, and basic science labs. Mount Sinai as the data review and publication center. Machine Learning Lab to be decided, either Google, Apple, IBM, Facebook, Amazon or wherever we find a strong industry partner or sponsor. Director, Cardiac Computed Tomography, Associate Professor of Medicine, Johns Hopkins University Division of Cardiology, The Johns Hopkins Hospital Imagine the new machine learning Vulnerable Patient detection algorithm (heart attack forecaster) is created and validated. If studies confirm the algorithm is able to detect the Vulnerable Patient with 50% or more certainty. In other words, 1 out of 2 patients classified as Vulnerable Patient goes to have an ASCVD event in the following 12 months. Now the questions are: A)    What preventive actions would you take if your asymptomatic patient tested positive as a Vulnerable Patient? B)    What preventive actions would you take if the patient was you?! (This question is meant to circumvent regulatory and financial limitations that may apply to your patients but may not hold you back). Moderators will invite comments from all participants in the meeting. Invited Key Opinion Leaders (Alphabetic Order) Arthur Agatston, M.D. Founder of South Beach Diet, Director of Wellness at Baptist Hospital and Professor of Medicine at University of Miami, FL Daniel Berman, M.D. Professor of Medicine at UCLA, Director of Cardiac Imaging and Nuclear Cardiology at Cedars-Sinai, Los Angeles, CA Michael Blaha, M.D., M.P.H., Director of Clinical Research, Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University, Baltimore, MD Mathew Budoff, M.D. Professor of Medicine and Director of Preventive Cardiology, UCLA Harbor, Los Angeles, CA Adolfo Correa, M.D., Ph.D. Chief Science Officer, Jackson Heart Study, Professor of Medicine and Pediatrics, University of Mississippi, Jackson, MS Rahul Deo, M.D., Ph.D. Assistant Professor of Medicine, Division of Cardiology, University of California, San Francisco, CA Raimund Erbel, M.D. Professor of Medicine, Chief of Cardiology and Director of West German Heart Centre, University Essen, Germany Sergio Fazio, M.D., Ph.D. Chair of Preventive Cardiology and Professor of Medicine, Oregon Health and Science University, Portland, OR Zahi Fayad, M.D. Professor of Radiology and Medicine (Cardiology), Director of the Translational and Molecular Imaging Institute, Mount Sinai Hospital, New York, NY Philip Greenland, M.D., Professor of Cardiology, Director, Institute for Public Health and Medicine, Center for Population Health Sciences, Chicago, IL Robert Harrington, M.D. Chair of the Department of Medicine, Professor of Medicine, Stanford University School of Medicine, Stanford, CA Harvey Hecht, M.D., Director of Cardiac CT Imaging Laboratory, Mount Sinai School of Medicine, New York, NY Karl-Heinz Jöckel, Ph.D. Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Germany Ioannis Kakadiaris, Ph.D. Professor of Computer Science and Biomedical Engineering, University of Houston, Houston, TX Stanley Kleis, Ph.D. Professor of Mechanical Engineering and Biomedical Engineering, University of Houston, Houston, TX Tatiana Kuznetsova, M.D. Professor and Director, Hypertension and Cardiovascular Epidemiology, University of Leuven, Leuven, Belgium Daniel Levy, M.D. Director of Framingham Heart Study, and Intramural Investigator, National Institute of Health, Bethesda, MD Roxana Mehran, M.D. Professor of Medicine and Director of Interventional Clinical Trials, Mount Sinai School of Medicine, New York, NY Ralph Metcalfe, Ph.D. Professor of Mechanical and Biomedical Engineering, University of Houston, Houston, TX Susanne Moebus, Ph.D., M.P.H. Biologist & Epidemiologist, Head of the Centre for Urban Epidemiology, University Essen, Germany Morteza Naghavi, M.D. Founder and Executive Chairman of the SHAPE Task Force, President of MEDITEX, Houston, TX Tasneem Z. Naqvi, M.D. Professor of Medicine and Director of Echocardiography, College of Medicine, May Clinic, Scottsdale, AZ Jagat Narula, M.D., Ph.D. Associate Dean for Global Affairs, Professor of Medicine (Cardiology), Mount Sinai Hospital and School of Medicine, New York, NY Ulla Roggenbuck, Ph.D. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Germany Henrik Sillesen, M.D. Professor and Head of Dept. of Vascular Surgery, Rigs Hospitalet, University of Copenhagen, Copenhagen, Denmark Robert Superko, M.D. Professor of Medicine and President at Cholesterol, Genetics, and Heart Disease Institute, Carmel, CA Pierre-Jean Touboul, M.D. Professor of Neurology, Department of Neurology and Stroke Center, AP-HP Bichat University Hospital, Neurology and Stroke Center, Paris, France Nathan Wong, M.P.H., Ph.D. Professor of Epidemiology and Director, Heart Disease Prevention Program, University of California, Irvine, CA Symposium Registration About SHAPE The Society for Heart Attack Prevention and Eradication (SHAPE) is a non-profit organization that promotes education and research related to prevention, detection, and treatment of heart attacks. SHAPE is committed to raising public awareness about revolutionary discoveries that are opening exciting avenues that can lead to the eradication of heart attacks. SHAPE's mission is to eradicate heart attacks in the 21st century. SHAPE has recently embarked on “Machine Learning Heart Attack Forecast System (Vulnerable Patient Project)” Project which is a collaborative effort between world’s leading cardiovascular researchers to develop a new Heart Attack Forecast System empowered by artificial intelligence. Additional information on this innovative project will be announced soon. To learn more about SHAPE visit Contact information: 1-877-SHAPE11 and info(at)shapesociety(dot)org. Learn more about the Vulnerable Patient About SHAPE Task Force The SHAPE Task Force, an international group of leading cardiovascular physicians and researchers, has created the SHAPE Guidelines, which educates physicians on how to identify asymptomatic atherosclerosis (hidden plaques) and implement proper therapies to prevent a future heart attack. According to the SHAPE Guidelines, men 45-75 and women 55-75 need to be tested for hidden plaques in coronary or carotid arteries. Individuals with high risk atherosclerosis (high plaque score) should be treated even if their cholesterol level is within statistical “normal range.” If they have plaques, the so-called normal is not normal for them. The higher the amount of plaque burden in the arteries the higher the risk and the more vulnerable to heart attack. SHAPE Guideline aims to identify the asymptomatic “Vulnerable Patient” and offer them intensive preventive therapy to prevent a future heart attack. Knowing one's plaque score can be a matter of life and death. The SHAPE Task Force includes the following: Click below to learn about SHAPE Centers of Excellence Drs Naghavi, PK Shah, Daniel Berman, and Mathew Budoff members of the SHAPE Task Force explain how hospitals and community clinics can become a SHAPE Center of Excellence and establish themselves a leader in preventive health.

Palucka K.,Baylor Research Institute | Palucka K.,Baylor University | Palucka K.,Mount Sinai School of Medicine | Banchereau J.,Baylor Research Institute | And 2 more authors.
Immunity | Year: 2010

The effective vaccines developed against a variety of infectious agents, including polio, measles, and hepatitis B, represent major achievements in medicine. These vaccines, usually composed of microbial antigens, are often associated with an adjuvant that activates dendritic cells (DCs). Many infectious diseases are still in need of an effective vaccine including HIV, malaria, hepatitis C, and tuberculosis. In some cases, the induction of cellular rather than humoral responses may be more important because the goal is to control and eliminate the existing infection rather than to prevent it. Our increased understanding of the mechanisms of antigen presentation, particularly with the description of DC subsets with distinct functions, as well as their plasticity in responding to extrinsic signals, represent opportunities to develop novel vaccines. In addition, we foresee that this increased knowledge will permit us to design vaccines that will reprogram the immune system to intervene therapeutically in cancer, allergy, and autoimmunity. © 2010 Elsevier Inc.

Schadt E.E.,Mount Sinai School of Medicine | Woo S.,University of Washington | Woo S.,Fred Hutchinson Cancer Research Center | Hao K.,Mount Sinai School of Medicine | Hao K.,Seattle Genetics
Nature Genetics | Year: 2012

RNA profiling can be used to capture the expression patterns of many genes that are associated with expression quantitative trait loci (eQTLs). Employing published putative cis eQTLs, we developed a Bayesian approach to predict SNP genotypes that is based only on RNA expression data. We show that predicted genotypes can accurately and uniquely identify individuals in large populations. When inferring genotypes from an expression data set using eQTLs of the same tissue type (but from an independent cohort), we were able to resolve 99% of the identities of individuals in the cohort at P adjusted ĝ‰Currency sign 1 × 10 -5. When eQTLs derived from one tissue were used to predict genotypes using expression data from a different tissue, the identities of 90% of the study subjects could be resolved at P adjusted ≤ 1 × 10 -5. We discuss the implications of deriving genotypic information from RNA data deposited in the public domain. © 2012 Nature America, Inc. All rights reserved.

Sandin S.,Karolinska Institutet | Sandin S.,King's College London | Lichtenstein P.,Karolinska Institutet | Kuja-Halkola R.,Karolinska Institutet | And 3 more authors.
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved. OBJECTIVE: To provide estimates of familial aggregation and heritability of ASD. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort including 2 049 973 Swedish children born 1982 through 2006. We identified 37 570 twin pairs, 2 642 064 full sibling pairs, 432 281 maternal and 445 531 paternal half sibling pairs, and 5 799 875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained. MAIN OUTCOMES AND MEASURES: The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors. RESULTS: In the sample, 14 516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100 000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude. We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64). CONCLUSIONS AND RELEVANCE: Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children. Copyright 2014 American Medical Association. All rights reserved.

Olson L.,Mount Sinai School of Medicine | Olson L.,Oklahoma Medical Research Foundation | Soriano P.,Mount Sinai School of Medicine
Developmental Cell | Year: 2011

Mural cells (pericytes and vascular smooth muscle cells) provide trophic and structural support to blood vessels. Vascular smooth muscle cells alternate between a synthetic/proliferative state and a differentiated/contractile state, but the dynamic states of pericytes are poorly understood. To explore the cues that regulate mural cell differentiation and homeostasis, we have generated conditional knockin mice with activating mutations at the PDGFRβ locus. We show that increased PDGFRβ signaling drives cell proliferation and downregulates differentiation genes in aortic vascular smooth muscle. Increased PDGFRβ signaling also induces a battery of immune response genes in pericytes and mesenchymal cells and inhibits differentiation of white adipocytes. Mural cells are emerging as multipotent progenitors of pathophysiological importance, and we identify PDGFRβ signaling as an important in vivo regulator of their progenitor potential. © 2011 Elsevier Inc.

Alcami A.,Autonomous University of Madrid | Lira S.A.,Mount Sinai School of Medicine
Current Opinion in Immunology | Year: 2010

Viruses encode a variety of mechanisms to evade host immune pathways. Large DNA viruses (herpesviruses and poxviruses) encode proteins that mimic chemokines and chemokine receptors. Also, some viruses encode secreted proteins that bind chemokines and have structure unrelated to host proteins. Recent research in this area has led to the identification of new viral proteins that modulate the chemokine system, has provided information on the molecular mechanisms leading to interference of chemokine signaling, and has shed light into the function of these proteins in the context of infection. The therapeutic value of these viral proteins to inhibit immune responses that cause pathology has been explored further. Finally, a new family of chemokine binding proteins identified in ticks expands this strategy of immune modulation beyond the virus world. © 2010 Elsevier Ltd.

Schadt E.E.,Mount Sinai School of Medicine | Bjorkegren J.L.M.,Cardiovascular Genomics | Bjorkegren J.L.M.,University of Tartu | Bjorkegren J.L.M.,Clinical Gene Networks AB
Science Translational Medicine | Year: 2012

Complete repertoires of molecular activity in and between tissues provided by new high-dimensional "omics"technologies hold great promise for characterizing human physiology at all levels of biological hierarchies. The combined effects of genetic and environmental perturbations at any level of these hierarchies can lead to vicious cycles of pathology and complex systemic diseases. The challenge lies in extracting all relevant information from the rapidly increasing volumes of omics data and translating this information first into knowledge and ultimately into wisdom that can yield clinically actionable results. Here, we discuss how molecular networks are central to the implementation of this new biology in medicine and translation to preventive and personalized health care.

Gaspar-Maia A.,University of California at San Francisco | Gaspar-Maia A.,Mount Sinai School of Medicine | Alajem A.,Hebrew University of Jerusalem | Meshorer E.,Hebrew University of Jerusalem | Ramalho-Santos M.,University of California at San Francisco
Nature Reviews Molecular Cell Biology | Year: 2011

Pluripotent stem cells can be derived from embryos or induced from adult cells by reprogramming. They are unique among stem cells in that they can give rise to all cell types of the body. Recent findings indicate that a particularly 'open' chromatin state contributes to maintenance of pluripotency. Two principles are emerging: specific factors maintain a globally open chromatin state that is accessible for transcriptional activation; and other chromatin regulators contribute locally to the silencing of lineage-specific genes until differentiation is triggered. These same principles may apply during reacquisition of an open chromatin state upon reprogramming to pluripotency, and during de-differentiation in cancer. © 2011 Macmillan Publishers Limited. All rights reserved.

Lim J.K.,Mount Sinai School of Medicine | Murphy P.M.,National Institute of Allergy and Infectious Diseases
Experimental Cell Research | Year: 2011

West Nile virus (WNV) is a re-emerging pathogen responsible for fatal outbreaks of meningoencephalitis in humans. Recent research using a mouse model of infection has indicated that specific chemokines and chemokine receptors help mediate the host response to WNV acting by at least three mechanisms: control of early neutrophil recruitment to the infection site (Cxcr2), control of monocytosis in blood (Ccr2) and control of leukocyte movement from blood to brain (Cxcr4, Cxcr3, Cxcl10 and possibly Ccr5). CCR5 also appears to be important in human infection, since individuals genetically deficient in this receptor have increased risk of symptomatic disease once infected. These findings provide detailed insight into non-redundant chemokine roles in organ-specific leukocyte recruitment during infection, and emphasize the importance of the balance between pathogen control and immunopathology in determining overall clinical outcome. © 2011.

Margolis E.B.,University of California at San Francisco | Hjelmstad G.O.,University of California at San Francisco | Fujita W.,Mount Sinai School of Medicine | Fields H.L.,University of California at San Francisco
Journal of Neuroscience | Year: 2014

The ventral tegmental area (VTA) is required for the rewarding and motivational actions of opioids and activation of dopamine neurons has been implicated in these effects. The canonical model posits that opioid activation of VTA dopamine neurons is indirect, through inhibition of GABAergic inputs. However, VTA dopamine neurons also express postsynaptic ÷-opioid peptide (MOP) receptors. We report here that in Sprague Dawley rat, the MOP receptor-selective agonist DAMGO (0.5-3 ÷M) depolarized or increased the firing rate of 87 of 451 VTA neurons (including 22 of 110 dopamine neurons). This DAMGO excitation occurs in the presence of GABAA receptor blockade and its EC50 value is two orders of magnitude lower than for presynaptic inhibition of GABA release on to VTA neurons. Consistent with a postsynaptic channel opening, excitations were accompanied by a decrease in input resistance. Excitations were blocked by CdCl2 (100 ÷M, n 5) and -agatoxin-IVA (100 nM, n = 3), nonselective and Cav2.1 Ca2+ channel blockers, respectively. DAMGO also produced a postsynaptic inhibition in 233 of 451 VTA neurons, including 45 of 110 dopamine neurons. The mean reversal potential of the inhibitory current was -78 ±7 mV and inhibitions were blocked by the K+ channel blocker BaCl2 (100 ÷M, n 7). Blockade of either excitation or inhibition unmasked the opposite effect, suggesting that MOP receptors activate concurrent postsynaptic excitatory and inhibitory processes in most VTA neurons. These results provide a novel direct mechanism for MOP receptor control of VTA dopamine neurons. © 2014 the authors.

Heeger P.S.,Mount Sinai School of Medicine | Kemper C.,King's College London
Immunobiology | Year: 2012

Our understanding of the complement system has markedly evolved from its early beginnings as a protein system merely detecting and tagging a pathogen for further clearance. For example, the repertoire of danger that complement recognizes covers currently a wide range of distinct self and non-self danger signals. Further, complement is now firmly established as instructor of adaptive B and T cell immunity. This review focuses on two the recent emerging paradigms in the field. Firstly, that complement is not only vitally required for the induction of Th1 immunity but also for the timely contraction of this protective response and therefore for prevention of autoimmunity and immune homeostasis. Secondly, that local rather than systemic complement is impacting on immunemodulation during a T cell response. © 2011 Elsevier GmbH.

Friedman S.L.,Mount Sinai School of Medicine | Sheppard D.,University of California at San Francisco | Duffield J.S.,University of Washington | Violette S.,Biogen Idec
Science Translational Medicine | Year: 2013

Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common feature of chronic tissue injury. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the more common fibrotic diseases, which in aggregate represent a huge unmet clinical need. New appreciation of the common features of fibrosis that are conserved among tissues has led to a clearer understanding of how epithelial injury provokes dysregulation of cell differentiation, signaling, and protein secretion. At the same time, discovery of tissue-specific features of fibrogenesis, combined with insights about genetic regulation of fibrosis, has laid the groundwork for biomarker discovery and validation, and the rational identification of mechanism-based antifibrotic drugs. Together, these advances herald an era of sustained focus on translating the biology of fibrosis into meaningful improvements in quality and length of life in patients with chronic fibrosing diseases.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-01-2014 | Award Amount: 6.22M | Year: 2015

A large body of evidence supports associations between exposure to anthropogenic chemicals and endocrine disruptive effects, leading to disorders in humans and wildlife. Based on the scientific documentation it is beyond doubt that endocrine disrupting chemicals (EDCs) are of concern and need to be handled according to the risks they pose, as single chemicals or as mixtures. To develop chemical risk assessment to respond to these concerns, there is an urgent need to improve our understanding of the mechanisms and health effects of EDCs, in particular in mixtures. This will require selection, refinement and development of tools for assessment of EDC mixtures to bring current risk assessment procedures to a level where they can support risk management. This project is designed to promote the use of safe chemicals for the next generation. EDC-MixRisk aims to meet the societal need for improved decision-making regarding human exposure risks to mixtures of EDCs. EDC-MixRisk will determine risks for multiple adverse health outcomes based on molecular mechanisms involved after early life exposure to EDC mixtures. The task is approached through interdisciplinary cooperation between experts in epidemiology, experimental toxicology and molecular biology, and risk assessment. The value of this combined research effort is: i) Identification of EDC mixtures that are associated with multiple adverse health outcomes in three health domains (growth and metabolism, neurodevelopment and sexual development) in epidemiology; ii) Identification of molecular mechanisms and pathways underlying the associations between exposure and adverse health outcomes by the use and development of state-of-the-art experimental models and iii) Development of a transparent and systematic framework in risk assessment for integrating epidemiological and experimental research to facilitate the assessment of risk and societal impact, thus promoting better risk management for EDCs and their mixtures.

News Article | December 27, 2016

NEW YORK, Dec. 27, 2016 (GLOBE NEWSWIRE) -- AXIM® Biotechnologies, Inc. (AXIM® Biotech) (OTC:AXIM), a world leader in cannabinoid research and development, is proud to announce the addition of world-renowned surgeon and eye expert to the Company’s Advisory Board; Professor Robert Ritch. Prof. Ritch is the Surgeon Director Emeritus and Chief of Glaucoma Services at New York Eye and Ear Infirmary of Mount Sinai School of Medicine in New York (NYEE). A photo accompanying this release is available at “We are very excited to welcome this distinguished specialist to join our Advisory Board,” said George E. Anastassov, MD, DDS, MBA and Chief Executive Officer of AXIM® Biotech. “At AXIM, we focus on proprietary delivery mechanisms for cannabinoids and finding solutions for conditions for which there is currently no effective treatment and Glaucoma is one of the fields of study we are planning to enter based on our proprietary IP. Prof. Ritch will be helping us with our glaucoma and xerophthalmia (dry eye) products development.” Prof. Robert Ritch holds the Shelley and Steven Einhorn Distinguished Chair in Ophthalmology and is Surgeon Director Emeritus and Chief of Glaucoma Services at New York Eye and Ear Infirmary of Mount Sinai (NYEE). He has devoted his career to broadening the understanding of the underlying etiologies and mechanisms of glaucoma and innovation in its medical, laser, and surgical treatment. Prof. Ritch received his B.A. cum laude from Harvard College and an M.A. in cell biology from Harvard University. He received his M.D. from Albert Einstein College of Medicine and, after a residency in Ophthalmology at Mount Sinai School of Medicine, received fellowships in glaucoma from the Heed Foundation and the National Institutes of Health. A Diplomat of the American Board of Ophthalmology, Prof. Ritch is a Fellow of the American Academy of Ophthalmology, the American College of Surgeons, the International College of Surgeons, the Royal College of Ophthalmology, the Association for Research in Vision and Ophthalmology, and the New York Academy of Medicine, and is a member of more than 35 scientific and medical societies around the world. About AXIM® AXIM® Biotechnologies, Inc. (OTC:AXIM) is an innovative biotechnology Company focusing on research, development and production of pharmaceutical, nutraceutical and cosmetic products where we prioritize the well-being of our customers while embracing a solid fiscal strategy. For more information, visit the Company website at FORWARD-LOOKING DISCLAIMER This press release may contain certain forward-looking statements and information, as defined within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, and is subject to the Safe Harbor created by those sections. This material contains statements about expected future events and/or financial results that are forward-looking in nature and subject to risks and uncertainties. Such forward-looking statements by definition involve risks, uncertainties and other factors, which may cause the actual results, performance or achievements of Axim Biotechnologies, Inc. to be materially different from the statements made herein. LEGAL DISCLOSURE AXIM® Biotechnologies does not sell or distribute any products that are in violation of the United States Controlled Substances Act (US.CSA).

Henschke C.I.,Mount Sinai School of Medicine | Yip R.,Mount Sinai Medical Center | Yankelevitz D.F.,Mount Sinai School of Medicine | Smith J.P.,New York Medical College
Annals of Internal Medicine | Year: 2013

Background: Low-dose computed tomography screening for lung cancer can reduce mortality among high-risk persons, but "false-positive" findings may result in unnecessary evaluations with attendant risks. The effect of alternative thresholds for defining a positive result on the rates of positive results and cancer diagnoses is unknown. Objective: To assess the frequency of positive results and potential delays in diagnosis in the baseline round of screening by using more restrictive thresholds. Design: Prospective cohort study. Setting: Multi-institutional International Early Lung Cancer Action Program. Patients: 21 136 participants with baseline computed tomography performed between 2006 and 2010. Measurements: The frequency of solid and part-solid pulmonary nodules and the rate of lung cancer diagnosis by using current (5 mm) and more restrictive thresholds of nodule diameter. Results: The frequency of positive results in the baseline round by using the current definition of positive result (any parenchymal, solid or part-solid, noncalcified nodule ≥5.0 mm) was 16% (3396/21136). When alternative threshold values of 6.0, 7.0, 8.0 and 9.0 mm were used, the frequencies of positive results were 10.2% (95% CI, 9.8% to 10.6%), 7.1% (CI, 6.7% to 7.4%), 5.1% (CI, 4.8% to 5.4%), and 4.0% (CI, 3.7% to 4.2%), respectively. Use of these alternative definitions would have reduced the work-up by 36%, 56%, 68%, and 75%, respectively. Concomitantly, lung cancer diagnostics would have been delayed by at most 9 months for 0%, 5.0% (CI, 1.1% to 9.0%), 5.9% (CI, 1.7 to 10.1%), and 6.7% (CI, 2.2% to 11.2%) of the cases of cancer, respectively. Limitation: This was a retrospective analysis and thus whether delays in diagnosis would have altered outcomes cannot be determined. Conclusion: These findings suggest that using a threshold of 7 or 8 mm to define positive results in the baseline round of computed tomography screening for lung cancer should be prospectively evaluated to determine whether the benefits of decreasing further work-up outweigh the consequent delay in diagnosis in some patients. Primary Funding Source: The Flight Attendant Medical Research Institute and the American Legacy Foundation. © 2013 American College of Physicians.

Imperiale T.F.,Indiana University | Imperiale T.F.,Center for Innovation | Ransohoff D.F.,University of North Carolina at Chapel Hill | Itzkowitz S.H.,Mount Sinai School of Medicine | And 5 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening. METHODS: We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings. RESULTS: Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P = 0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P = 0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT. CONCLUSIONS: In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. Copyright © 2014 Massachusetts Medical Society.

Haraldsson B.S.,Sahlgrenska University Hospital | Haraldsson B.S.,Mount Sinai School of Medicine
Kidney International | Year: 2014

A new study by Xu et al. presents compelling evidence for an important role of the glomerular endothelium in acute kidney injury. They show that lipopolysaccharide reduces the endothelial surface layer, resulting in mild albuminuria, reduced glomerular filtration rate, and fewer endothelial fenestrae. Tumor necrosis factor- (TNF-) is identified as instrumental in these lipopolysaccharide effects through the TNF- type 1 receptor. The study highlights that the glomerular endothelium has a key role in the maintenance of the glomerular filtration barrier © 2013 International Society of Nephrology.

La Merrill M.,Mount Sinai School of Medicine | Birnbaum L.S.,U.S. National Cancer Institute
Mount Sinai Journal of Medicine | Year: 2011

Childhood and adolescent rates of obesity and overweight are continuing to increase in much of the world. Risk factors such as diet composition, excess caloric intake, decreased exercise, genetics, and the built environment are active areas of etiologic research. The obesogen hypothesis, which postulates that prenatal and perinatal chemical exposure can contribute to risk of childhood and adolescent obesity, remains relatively underexamined. This review surveys numerous classes of chemicals for which this hypothesis has been explored. We focus on human data where they exist and also discuss the findings of rodent and cell culture studies. Organochlorine chemicals as well as several classes of chemicals that are peroxisome proliferator-activated receptor agonists are identified as possible risk factors for obesity. Recommendations for future epidemiologic and experimental research on the chemical origins of obesity are also given. © 2011 Mount Sinai School of Medicine.

Lebwohl M.,Mount Sinai School of Medicine | Swanson N.,Oregon Health And Science University | Anderson L.L.,Dermatology Associates of Tyler | Melgaard A.,Data Management | And 2 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Actinic keratosis is a common precursor to sun-related squamous-cell carcinoma. Treating actinic keratoses and the surrounding skin area (i.e., field therapy) can eradicate clinical and subclinical actinic keratoses. Topical field therapy currently requires weeks or months of treatment. We investigated the efficacy and safety of a new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities). METHODS: In four multicenter, randomized, double-blind studies, we randomly assigned patients with actinic keratoses on the face or scalp or on the trunk or extremities to receive ingenol mebutate or placebo (vehicle), self-applied to a 25-cm 2 contiguous field once daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities. Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured. RESULTS: In a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P<0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P<0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae. CONCLUSIONS: Ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses. (Funded by LEO Pharma; numbers, NCT00742391, NCT00916006, NCT00915551, and NCT00942604.) Copyright © 2012 Massachusetts Medical Society.

Cullen B.R.,Duke University | Cherry S.,University of Pennsylvania | Tenoever B.R.,Mount Sinai School of Medicine
Cell Host and Microbe | Year: 2013

While RNA interference (RNAi) functions as an antiviral response in plants, nematodes, and arthropods, a similar antiviral role in mammals has remained controversial. Three recent papers provide evidence that either favors or challenges this hypothesis. Here, we discuss these new findings in the context of previous research. © 2013 Elsevier Inc.

Ciociola A.A.,Alcon | Cohen L.B.,Mount Sinai School of Medicine | Kulkarni P.,University of South Florida
American Journal of Gastroenterology | Year: 2014

Objectives: This article provides an overview of FDA's regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future. Methods: A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry R&D productivity and drug development cost estimates. Results: While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from $868M to $1,241M USD. Several new laws have been enacted, including the FDA Safety and Innovation Act (FDASIA) of 2013, which is designed to improve the drug approval process and enhance access to new medicines. Conclusions: The FDA's improved processes for drug approval and post-market surveillance have achieved the goal of providing patients with timely access to effective drugs while minimizing the risk of drug-related harm. The FDA drug approval process is not without controversy, as a number of well-known gastroenterology drugs have been withdrawn from the US market over the past few years. With the approval of the new FDASIA law, the FDA will continue to improve their processes and, working together with the ACG through the FDA-Related Matters Committee, continue to develop safe and effective drugs for our patients. © 2014 by the American College of Gastroenterology.

Schreck C.,Mount Sinai School of Medicine | O'Connor P.M.,Medical College of Wisconsin
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011

Schreck C, O'Connor PM. NAD(P)H oxidase and renal epithelial ion transport. Am J Physiol Regul Integr Comp Physiol 300: R1023-R1029, 2011. First published January 26, 2011; doi:10.1152/ajpregu.00618.2010.-A fundamental requirement for cellular vitality is the maintenance of plasma ion concentration within strict ranges. It is the function of the kidney to match urinary excretion of ions with daily ion intake and nonrenal losses to maintain a stable ionic milieu. NADPH oxidase is a source of reactive oxygen species (ROS) within many cell types, including the transporting renal epithelia. The focus of this review is to describe the role of NADPH oxidase-derived ROS toward local renal tubular ion transport in each nephron segment and to discuss how NADPH oxidase-derived ROS signaling within the nephron may mediate ion homeostasis. In each case, we will attempt to identify the various subunits of NADPH oxidase and reactive oxygen species involved and the ion transporters, which these affect. We will first review the role of NADPH oxidase on renal Na+ and K+ transport. Finally, we will review the relationship between tubular H+ efflux and NADPH oxidase activity. © 2011 the American Physiological Society.

Purpose To compare the benefits of fluocinolone acetonide implant therapy versus systemic corticosteroid therapy supplemented (when indicated) with immunosuppression for intermediate uveitis, posterior uveitis, and panuveitis. Design Additional follow-up of a randomized comparative effectiveness trial cohort. Participants Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis randomized to implant or systemic therapy. Main Outcome Measures Best-corrected visual acuity (BCVA), visual field mean deviation (MD), activity of uveitis, and presence of macular edema (per reading center grading) ascertained prospectively. Methods Trial participants were followed-up for 54 months from original randomization. Results The visual function trajectory in uveitic eyes demonstrated a similar (P = 0.73) degree of modest (not statistically significant) improvement from baseline to 54 months in both groups (mean improvement in BCVA at 54 months, 2.4 and 3.1 letters in the implant and systemic groups, respectively). Many had excellent initial visual acuity, limiting the potential for improvement. The mean automated perimetry MD score remained similar to baseline throughout 48 months of follow-up in both groups. Overall control of inflammation was superior in the implant group at every time point assessed (P < 0.016), although most eyes in the systemic therapy arm also showed substantial improvement, achieving complete control or low levels of inflammation. Although macular edema improved significantly more often with implant treatment within the first 6 months, the systemic group gradually improved over time such that the proportions with macular edema converged in the 2 groups by 36 months and overlapped thereafter (P = 0.41 at 48 months). Conclusions Visual outcomes of fluocinolone acetonide implant and systemic treatment for intermediate uveitis, posterior uveitis, and panuveitis were similarly favorable through 54 months. The implant maintained a clear advantage in controlling inflammation through 54 months. Nevertheless, with systemic therapy, most patients also experienced greatly improved inflammatory status. Macular edema improved equally with longer follow-up. Based on cost effectiveness and side-effect considerations, systemic therapy may be indicated as the initial treatment for many bilateral uveitis cases. However, implant therapy is a reasonable alternative, especially for unilateral cases and when systemic therapy is not feasible or is not successful. © 2015 American Academy of Ophthalmology.

Purpose To evaluate the risks and quality-of-life (QoL) outcomes of fluocinolone acetonide implant versus systemic therapy with corticosteroid and immunosuppression when indicated for intermediate uveitis, posterior uveitis, and panuveitis. Design Additional follow-up of a randomized trial cohort. Participants Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis, randomized to implant or systemic therapy. Methods Randomized subjects with intermediate uveitis, posterior uveitis, or panuveitis (479 eyes) were followed up over 54 months, with 79.2% completing the 54-month visit. Main Outcome Measures Local and systemic potential complications of the therapies and self-reported health utility and vision-related and generic health-related QoL were studied prospectively. Results Among initially phakic eyes, cataract and cataract surgery occurred significantly more often in the implant group (hazard ratio [HR], 3.0; P = 0.0001; and HR, 3.8; P < 0.0001, respectively). In the implant group, most cataract surgery occurred within the first 2 years. Intraocular pressure elevation measures occurred more frequently in the implant group (HR range, 3.7-5.6; all P < 0.0001), and glaucoma (assessed annually) also occurred more frequently (26.3% vs. 10.2% by 48 months; HR, 3.0; P = 0.0002). In contrast, potential complications of systemic therapy, including measures of hypertension, hyperlipidemia, diabetes, bone disease, and hematologic and serum chemistry indicators of immunosuppression toxicity, did not differ between groups through 54 months. Indices of QoL initially favored implant therapy by a modest margin. However, all summary measures of health utility and vision-related or generic health-related QoL were minimally and nonsignificantly different by 54 months, with the exception of the 36-item Short-Form Health Survey physical component summary score, which favored implant by a small margin at 54 months (3.17 on a scale of 100; P = 0.01, not adjusted for multiple comparisons). Mean QoL results were favorable in both groups. Conclusions These results suggest that fluocinolone acetonide implant therapy is associated with a clinically important increased risk of glaucoma and cataract with respect to systemic therapy, suggesting that careful monitoring and early intervention to prevent glaucoma is warranted with implant therapy. Systemic therapy subjects avoided a significant excess of toxicities of systemic corticosteroid and immunosuppressive therapies in the trial. Self-reported QoL measures initially favored implant therapy, but over time the measures converged, with generally favorable QoL in both groups. © 2015 American Academy of Ophthalmology.

Gupta V.,University of Toronto | Hari P.,Medical College of Wisconsin | Hoffman R.,Mount Sinai School of Medicine
Blood | Year: 2012

The discovery of JAK2617F mutation paved the way for the development of small molecule inhibitors of JAK1/2 resulting in first approved JAK1/2 inhibitor, ruxolitinib, for the treatment of patients with myelofibrosis (MF). Although JAK1/2 inhibitor therapy is effective in decreasing the burden of symptoms associated with splenomegaly and MF-related constitutional symptoms, it is neither curative nor effective in reducing the risk of leukemic transformation. Presently, allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for MF. Asignificant risk of regimen-related toxicities, graft failure, and GVHD are major barriers to the success of HCT in MF. Because of significant HCT-associated morbidity and mortality, divergent opinions regarding its appropriate role in this clinical situation have emerged. In this review, the risk-benefit ratios of modern drug therapy compared with HCT in MF patients are analyzed. A risk-adapted approach individualized to each patient's biologic characteristics and comorbidities is described, which is currently warranted in determining optimal treatment strategies for patients with MF. Inclusion of JAK1/2 inhibitor therapy in future transplant conditioning regimens may provide an opportunity to overcome some of these barriers, resulting in greater success with HCT for MF patients. © 2012 by The American Society of Hematology.

Sarkar A.X.,Mount Sinai School of Medicine | Christini D.J.,New York Medical College | Sobie E.A.,Mount Sinai School of Medicine
Journal of Physiology | Year: 2012

Across individuals within a population, several levels of variability are observed, from the differential expression of ion channels at the molecular level, to the various action potential morphologies observed at the cellular level, to divergent responses to drugs at the organismal level. However, the limited ability of experiments to probe complex interactions between components has hitherto hindered our understanding of the factors that cause a range of behaviours within a population. Variability is a challenging issue that is encountered in all physiological disciplines, but recent work suggests that novel methods for analysing mathematical models can assist in illuminating its causes. In this review, we discuss mathematical modelling studies in cardiac electrophysiology and neuroscience that have enhanced our understanding of variability in a number of key areas. Specifically, we discuss parameter sensitivity analysis techniques that may be applied to generate quantitative predictions based on considering behaviours within a population of models, thereby providing novel insight into variability. Our discussion focuses on four issues that have benefited from the utilization of these methods: (1) the comparison of different electrophysiological models of cardiac myocytes, (2) the determination of the individual contributions of different molecular changes in complex disease phenotypes, (3) the identification of the factors responsible for the variable response to drugs, and (4) the constraining of free parameters in electrophysiological models of heart cells. Together, the studies that we discuss suggest that rigorous analyses of mathematical models can generate quantitative predictions regarding how molecular-level variations contribute to functional differences between experimental samples. These strategies may be applicable not just in cardiac electrophysiology, but in a wide range of disciplines. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.

Cormode D.P.,University of Pennsylvania | Naha P.C.,University of Pennsylvania | Fayad Z.A.,Mount Sinai School of Medicine
Contrast Media and Molecular Imaging | Year: 2014

Computed tomography (CT) is an X-ray-based whole-body imaging technique that is widely used in medicine. Clinically approved contrast agents for CT are iodinated small molecules or barium suspensions. Over the past seven years there has been a great increase in the development of nanoparticles as CT contrast agents. Nanoparticles have several advantages over small molecule CT contrast agents, such as long blood-pool residence times and the potential for cell tracking and targeted imaging applications. Furthermore, there is a need for novel CT contrast agents, owing to the growing population of renally impaired patients and patients hypersensitive to iodinated contrast. Micelles and lipoproteins, a micelle-related class of nanoparticle, have notably been adapted as CT contrast agents. In this review we discuss the principles of CT image formation and the generation of CT contrast. We discuss the progress in developing nontargeted, targeted and cell tracking nanoparticle CT contrast agents. We feature agents based on micelles and used in conjunction with spectral CT. The large contrast agent doses needed will necessitate careful toxicology studies prior to clinical translation. However, the field has seen tremendous advances in the past decade and we expect many more advances to come in the next decade. Copyright © 2014 John Wiley & Sons, Ltd.

Ramirez F.,Mount Sinai School of Medicine | Sakai L.Y.,Oregon Health And Science University
Cell and Tissue Research | Year: 2010

Fibrillin-1 and fibrillin-2 are large cysteine-rich glycoproteins that serve two key physiological functions: as supporting structures that impart tissue integrity and as regulators of signaling events that instruct cell performance. The structural role of fibrillins is exerted through the temporal and hierarchical assembly of microfibrils and elastic fibers, whereas the instructive role reflects the ability of fibrillins to sequester transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) complexes in the extracellular matrix. Characterization of fibrillin mutations in human patients and in genetically engineered mice has demonstrated that perturbation of either function manifests in disease. More generally, these studies have indicated that fibrillins are integral components of a broader biological network of extracellular, cell surface, and signaling molecules that orchestrate morphogenetic and homeostatic programs in multiple organ systems. They have also suggested that the relative composition of fibrillin-rich microfibrils imparts contextual specificity to TGFβ and BMP signaling by concentrating the ligands locally so as to regulate cell differentiation within a spatial context during organ formation (positive regulation) and by restricting their bioavailability so as to modulate cell performance in a timely fashion during tissue remodeling/repair (negative regulation). Correlative evidence suggests functional coupling of the cell-directed assembly of microfibrils and targeting of TGFβ and BMP complexes to fibrillins. Hence, the emerging view is that fibrillin-rich microfibrils are molecular integrators of structural and instructive signals, with TGFβ and BMPs as the nodal points that convert extracellular inputs into discrete and context-dependent cellular responses. © 2009 Springer-Verlag.

Papa L.,Mount Sinai School of Medicine | Manfredi G.,New York Medical College | Germain D.,Mount Sinai School of Medicine
Genes and Cancer | Year: 2015

Cancer cells have elevated levels of reactive oxygen species (ROS), which are generated in majority by the mitochondria. In the mitochondrial matrix, the manganese dismutase SOD2 acts as a major anti-oxidant enzyme. The deacetylase SIRT3 regulates the activity of SOD2. Recently, SIRT3 was reported to be decreased in 87% of breast cancers, resulting therefore in a decrease in the activity of SOD2 and an elevation in ROS. In addition to SIRT3, we recently reported that SOD2 itself is down-regulated in breast cancer cell lines upon activation of oncogenes, such as Ras. Since in absence of SOD2, superoxide levels are elevated and may cause irreversible damage, mechanisms must exist to retain superoxide below a critical threshold and maintain viability of cancer cells. The copper/zinc dismutase SOD1 localizes in the cytoplasm, the inter-membrane space of the mitochondria and the nucleus. Emerging evidences from several groups now indicate that SOD1 is overexpressed in cancers and that the activity of SOD1 may be essential to maintain cellular ROS under this critical threshold. This review summarizes the studies reporting important roles of SOD1 in cancer and addresses the potential cross-talk between the overexpression of SOD1 and the regulation of the mitochondrial unfolded protein response (UPRmt). While mutations in SOD1 is the cause of 20% of cases of familial amyotrophic lateral sclerosis (fALS), a devastating neurodegenerative disease, these new studies expand the role of SOD1 to cancer. © 2015, Impact Journals LLC. All rights reserved.

Vashi A.,Mount Sinai School of Medicine | Rhodes K.V.,University of Pennsylvania
Annals of Emergency Medicine | Year: 2011

Study objective: The goal of this study is to quantitatively and qualitatively assess the quality and content of verbal discharge instructions at 2 emergency departments (EDs). Methods: This was a secondary data analysis of 844 ED audiotapes collected during a study of patient-emergency provider communication at 1 urban and 1 suburban ED. ED visits of nonemergency adult female patients were recorded with a digital audiotape. Of 844 recorded ED visits, 477 (57%) audiotapes captured audible discharge instructions suitable for analysis. Audiotapes were double coded for the following discharge content: (1) explanation of illness, (2) expected course, (3) self-care, (4) medication instructions, (5) symptoms prompting return to the ED, (6) time-specified for follow-up visit, (7) follow-up care instructions, (8) opportunities for questions, and (9) patient confirmation of understanding. Analysis included descriptive statistics, χ2 tests, 2-sample t tests, and logistic regression models. Results: Four hundred seventy-seven of 871 (55%) patient tapes contained audible discharge instructions. The majority of discharges were conducted by the primary provider (emergency physician or nurse practitioner). Ninety-one percent of discharges included some opportunity to ask questions, although most of these were minimal. Only 22% of providers confirmed patients' understanding of instructions. Conclusion: Verbal ED discharge instructions are often incomplete, and most patients are given only minimal opportunities to ask questions or confirm understanding. Please see page 316 for the Editor's Capsule Summary of this article. © 2010 American College of Emergency Physicians.

Pan P.-Y.,New York Medical College | Yue Z.,Mount Sinai School of Medicine
Parkinsonism and Related Disorders | Year: 2014

Genetic studies over the past 15 years have revolutionized our understanding towards the etiology of Parkinson's disease (PD). These studies have discovered many disease-linked genetic loci (PARK 1 to 18), which are now being interrogated for cellular pathways contributing to PD. Various pathogenic pathways were proposed but validation of each pathway awaits rigorous experimental testing. Here we review recent progress in understanding the influence of disease risk genes on cellular functions, specifically, autophagy pathways. Autophagy is a cell self-eating, lysosomal degradation system that plays an important role in cell homeostasis and survival. Neurons are post-mitotic cells and particularly vulnerable to the impairment of autophagic degradation due to their inability to redistribute damaged proteins and organelles to daughter cells. Emerging evidence has implicated dysfunctional autophagy in a growing number of neurodegenerative diseases including PD. We will also discuss the prospect of intervening autophagy pathways as a potential strategy to treat PD. © 2013 Elsevier Ltd.

Palucka K.,Baylor Research Institute | Palucka K.,Mount Sinai School of Medicine | Banchereau J.,Hoffmann-La Roche
Nature Reviews Cancer | Year: 2012

Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer. © 2012 Macmillan Publishers Limited. All rights reserved.

Garrido M.M.,Geriatric Research Education and Clinical Center | Garrido M.M.,Mount Sinai School of Medicine | Prigerson H.G.,Dana-Farber Cancer Institute
Cancer | Year: 2014

BACKGROUND The objective of the current study was to determine the best set of predictors of psychological disorders, regrets, health-related quality of life, and mental health function among bereaved caregivers of patients with cancer, thereby identifying promising targets for interventions to improve bereavement adjustment. METHODS Coping with Cancer is a longitudinal study of patients with advanced cancer and their informal caregivers who were enrolled from 2002 to 2008. The main outcome measure was bereavement adjustment of 245 caregivers (eg, depression, anxiety, and regrets) 6 months after the loss of the patient. The Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders determined whether caregivers met the criteria for major depressive disorder or an anxiety disorder. Changes in health-related quality of life and mental health function from baseline to after the patient's death were assessed with the Medical Outcomes Study Short Form (SF-36). RESULTS Greater than 50% of the caregivers reported regret about the cancer patient's end-of-life care; better patient quality of death (adjusted odds ratio, 0.77; 95% confidence interval, 0.67-0.88) reduced the risk of bereavement regret. The incidence of major depressive disorder or anxiety among the bereaved caregivers was 12.6% and was less likely for caregivers with better mental health before the loss of the patient (adjusted odds ratio, 0.03; 95% confidence interval, 0.004-0.25). Better patient quality of death also predicted improved caregiver health-related quality of life (adjusted standardized beta,.28; P <.001). The completion of a do-not-resuscitate order was found to be predictive of improved mental health from before the death of the patient to after the death (adjusted standardized beta,.29; P <.001). CONCLUSIONS Reducing caregiver distress, encouraging advance care planning by patients, and improving patients' quality of death appear to be promising targets of interventions to improve caregiver bereavement adjustment. Cancer 2014;120:918-925. © 2013 American Cancer Society. Using prospective data from patients with advanced cancer and their primary informal caregivers, the results of the current study demonstrate that reducing caregiver distress, encouraging advance care planning by patients, and improving patients' quality of death appear to be promising targets of interventions to improve caregiver bereavement adjustment. © 2013 American Cancer Society.

Zsebo K.,Celladon | Yaroshinsky A.,AY Statistical Consulting | Rudy J.J.,Celladon | Wagner K.,Celladon | And 3 more authors.
Circulation Research | Year: 2014

Rationale: The Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) study was a phase 1/phase 2 first-in-human clinical gene therapy trial using an adeno-associated virus serotype 1 (AAV1) vector carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a) in patients with advanced heart failure. The study explored potential benefits of the therapy at 12 months, and results were previously reported. Objective: To report long-term (3-year) clinical effects and transgene expression in the patients in CUPID 1. Methods and results: A total of 39 patients with advanced heart failure who were on stable, optimal heart failure therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a in 1 of 3 doses (low-dose, 6×1011 DNase-resistant particles; mid-dose, 3×10 12 DNase-resistant particles; and high-dose, 1×1013 DNase-resistant particles) versus placebo. The following recurrent cardiovascular and terminal events were tracked for 3 years in all groups: myocardial infarction, worsening heart failure, heart failure-related hospitalization, ventricular assist device placement, cardiac transplantation, and death. The number of cardiovascular events, including death, was highest in the placebo group, high but delayed in the low-and mid-dose groups, and lowest in the high-dose group. Evidence of long-term transgene presence was also observed in high-dose patients. The risk of prespecified recurrent cardiovascular events was reduced by 82% in the high-dose versus placebo group (P=0.048). No safety concerns were noted during the 3-year follow-up. Conclusions: After a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure, positive signals of cardiovascular events persist for years. © 2013 American Heart Association, Inc.

Genzyme and Mount Sinai School of Medicine | Date: 2012-11-16

The invention relates to dose escalation enzyme replacement therapy using acid sphingomyelinase (ASM) for the treatment of human subjects having acid sphingomyelinase deficiency (ASMD), and, in particular, patients with non-neurological manifestations of Niemann-Pick Disease (NPD), and in certain embodiments, NPD type B.

Genzyme and Mount Sinai School of Medicine | Date: 2012-11-16

The invention relates to dose escalation enzyme replacement therapy using acid sphingomyelinase (ASM) for the treatment of human subjects having acid sphingomyelinase deficiency (ASMD), and, in particular, patients with non-neurological manifestations of Niemann-Pick Disease (NPD), and in certain embodiments, NPD type B.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.1-3 | Award Amount: 7.82M | Year: 2013

Long-term side-effects of radiotherapy impact on the quality-of-life (QoL) of cancer survivors. These side-effects could be reduced if predicted in advance. Previous work identified clinical and biological predictors but a major, coordinated approach is needed to validate them so they can be used clinically. The EU has ~17.8 million people living with a prior diagnosis of cancer of whom ~7 million received radiotherapy. In the long-term, potentially 20% of those suffering with mild to severe side-effects (~1.4 million) might benefit from alleviation of symptoms, with resulting reductions in the cost of care in the EU. REQUITE aims to develop validated clinical models and incorporate biomarkers to identify before treatment cancer patients at risk of side-effects and use the models to design interventional trials aimed at reducing side-effects and improving QoL in cancer survivors who underwent radiotherapy. REQUITE will: 1. carry out a multi-centre, longitudinal, observational study to collect standardised data and samples in breast, prostate and lung cancer patients; 2. validate biomarkers with published evidence of predictive value; 3. replicate published clinical models and incorporate replicated biomarkers to create validated predictive algorithms; 4. use the prospectively validated models and biomarkers to design interventional trial protocols aiming to reduce side-effects and improve QoL in high-risk patients. REQUITE builds on collaborations with a proven history of data sharing, enlarged to a consortium with expertise in patient recruitment, knowledge management, biomarker testing and predictive model development. SME involvement for biomarker assays will facilitate future clinical implementation and commercial exploitation. The outcome of this project will be validated predictive models for three common cancers and trial protocols using the models to investigate interventions aimed at reducing long-term side-effects and improving the QoL of cancer survivors.

Genzyme and Mount Sinai School of Medicine | Date: 2015-07-08

The invention relates to dose escalation enzyme replacement therapy using acid sphingomyelinase (ASM) for the treatment of human subjects having acid sphingomyelinase deficiency (ASMD), and, in particular, patients with non-neurological manifestations of Niemann-Pick Disease (NPD), and in certain embodiments, NPD type B.

Genzyme and Mount Sinai School of Medicine | Date: 2014-01-16

The invention relates to dose escalation enzyme replacement therapy using acid sphingomyelinase (ASM) for the treatment of human subjects having acid sphingomyelinase deficiency (ASMD), and, in particular, patients with non-neurological manifestations of Niemann-Pick Disease (NPD), and in certain embodiments, NPD type B.

News Article | March 4, 2016

Daniela Kaufer has a personal interest in the effects of stress. “My mum's family had a very traumatic experience when their mother died in childbirth,” she explains. The three children grew up motherless, in 1950s war-torn Israel, but there was a marked difference in how well the siblings coped. “My mum had an extremely difficult early life,” she says. “Yet she is extremely resilient.” Kaufer, who is a neuroscientist at the University of California, Berkeley, says that why her mother in particular coped so well has fascinated her. Research into how people react to early trauma began in earnest after the Second World War. Distressing events such as the death of a parent have been found to increase children's short-term risk of major depression, anxiety disorders and post-traumatic stress disorder (PTSD). With advances in techniques to study genes and to explore the brain, the neurobiological study of stress is undergoing a revolution — and our view of the stress response is changing. Until about 20 years ago, the absence of a severe negative reaction such as PTSD was thought to be a lack of response. Instead, “resilience is now viewed as a reactive response”, says Kaufer. What resilience means in terms of gene expression, numbers of cells and brain networks is now the focus of research. “Years ago, most would have thought that resilient individuals escape some of the bad things that stress induces in the brains of more susceptible individuals,” explains neurobiologist Eric Nestler at Mount Sinai School of Medicine, New York. “Now we believe susceptible individuals lack some of the more adaptive changes that occur in the resilient brain.” Stress is an unavoidable component of life, and the stress response is a crucial survival mechanism. “The brain is a detector of threatening information,” says neuropsychologist Sonia Lupien at the University of Montreal, Canada. “This is its most important job if you want to survive.” Acute stress readies us for action, but chronic stress wears us down, altering the brain genetically and neurologically and priming us for mental health problems. Whether a person is resilient to stress depends heavily on their life history. Understanding the effects of early-life difficulties could provide new ways to treat or prevent mental illnesses such as severe depression or PTSD in susceptible individuals. Confronted with a life-threatening situation, hormones and neurotransmitters prep us for action. Specific stress hormones — cortisol in primates, corticosterone in most rodents — are released, some of which surge across the blood–brain barrier. Stress gets everywhere: all our cells host receptors for the hormone. “Every brain area has something happen to it,” says Kaufer. The human brain has two types of receptor for cortisol. One has a six to tenfold higher affinity for the molecule than the other, and so is activated earlier, by smaller amounts of cortisol. The hippocampus (which is pivotal for memory) and the amygdala (the centre for emotions) contain lots of the high-affinity receptors, and are, therefore, activated by slight rises in the hormone. The frontal lobe, which is involved in executive planning and control, has only the low-affinity receptor, and is activated later, after the tide has risen. And, as Lupien and colleagues found, both memory formation and recall in adults can be influenced by cortisol1. The existence of two receptor types means that response to stress is not linear. “The relationship between circulating stress hormone and memory is an inverted U-shape function,” Lupien explains. “Up to a certain level, stress hormones are good for your memory” — when the cortisol binds only to the high-affinity receptors, the ability to lay down and retrieve memory is enhanced. When the low-affinity receptors are activated, the relationship enters the right-hand side of the U-shape and the response shifts, she adds. The duration of stress is also important. A transient bout of stress causes a proliferation of neural stem cells and a spike in numbers of new neurons, which take at least two weeks to mature. The brain seems to be preparing itself in case a second stressor comes calling. Chronic stress is not so beneficial. It slashes investment in new neurons, prunes the tree-like shape of existing ones, and suppresses new connections. If stress hormones remain elevated for months or years, they can stimulate physiological changes: the hippocampus shrinks and the amygdala grows, for example. Eventually, the complex feedback system that suppresses the excess secretion of cortisol is disturbed. Once this happens, the capacity to discriminate between threat levels falls away. Either everything seems threatening (anxiety) or else nothing does (depression or burnout). Old ideas that certain individuals have an inherent 'hardiness' or an innate ability to bounce back from severe stress have fallen by the wayside. Instead, resilience and our response to trauma are recognized as being more dynamic, changing throughout life. It's a complicated milieu, but one of the main ways that stress marks the brain is through epigenetics. This does not change genes, but it can change their expression by attaching methyl groups to DNA or associated proteins. At McGill University in Montreal, neuroscientist Michael Meaney's group has been exploring the stress response in rats. It found that high-licking and low-licking grooming strategies in mother rats gave rise to different offspring2. The lesser-grooming mums produced pups with high anxiety, poor stress-recovery and low cognitive performance. The pups' brain circuits that switch off stress were sluggish, owing to higher DNA methylation and lower expression of the 'off' receptors in the hippocampus. Well-groomed pups showed the opposite. People might be tempted to label high-groomers as better mothers, says Kaufer. “But it is not 'good mums' or 'bad mums', just a different parenting style.” Parenting style can reflect the environment and prepare the offspring, she explains. Being a cautious, worried rat — the offspring of a less-thorough groomer — makes sense if you live in an alley full of cats. “The stress response is one of the most conserved things in evolution,” Kaufer says. This means that animal findings tend to be applicable to humans. However, what is good for avoiding predators may not be a healthy adaptation to the continued stress of modern life. Kieran O'Donnell, a neuroscientist in Meaney's lab, says that the epigenetic changes in the anxious rat brains seem to have human analogies. “We see the same sorts of changes in DNA methylation of the hormone receptor in people who suffered child maltreatment,” he says. “The question is, can we intervene and do anything about this?” O'Donnell is currently investigating whether the children of vulnerable young mums who received regular nurse visits after they had given birth show changes in DNA methylation 27 years later. Chronic stress in early life stamps an especially long-lasting mark on the brain. Some people carry an epigenetic signature of stress from exposure as a baby — or even as an embryo. Emotional stress in pregnant women, for example, can alter their children's epigenetics and the neural connections in their babies' amygdalas. Later exposure to severe trauma can activate this signature, explains neurobiologist Alon Chen, of the Weizmann Institute of Science in Rehovot, Israel. He was involved in a study that reported that chronic stress can reduce the number of hormone receptors in the hippocampus needed to shut off the stress response3. This means that individuals exposed to chronic stress early in life may be more susceptible to a stress-related disorder as an adult, owing to a disrupted feedback loop. “It is not healthy to stay in a stress situation for a long time,” says Chen. “Returning to a normal level is an important part of the stress-response machinery.” Stress affects our relationships with others (and socializing is itself an agent in cognitive health; see page S14). Nestler has devised a 'bully mouse' scenario (pictured) in which, for 5 to 10 minutes a day over 10 days, a normal mouse is placed in a cage that is already occupied by a larger, more aggressive strain of mouse that intimidates the incomer. At all other times, the mice are kept close enough to see and smell one another, but they are separated by mesh. Nestler's team found that afterwards, some of the bullied mice avoid all social contact, even with smaller, non-aggressive mice. As with memory, the way that sociability changes with stress is not linear. Kaufer's lab found that rats exposed to moderate stress — in this case, being immobilized in a bag — displayed more positive social behaviour, such as huddling, resource sharing and reduced aggression4. The researchers also saw an increase in the prosocial hormone oxytocin. But if the immobilized rats were exposed to fox odour, the addition of this high-level-stress inducer caused them to lose all pro-social behaviours. Oxytocin plummeted, as did its receptors. “This is really interesting because it can start to explain the social withdrawal that you can see in some psychopathologies like PTSD and depression,” Kaufer says. Yet even in these scenarios, some rodents did better than others. Nestler and his colleagues found that some of their mice were resilient to the bullying, and that these mice showed a greater number of gene-expression changes5. So resilience was a reaction, endowing the individuals with greater adaptability. “We don't know the underlying cause,” says Nestler, adding that the search is on for genes with altered expression in the brains of resilient individuals. His lab is now planning to look at the role of individual messenger RNAs and proteins in mediating resilience to try and tease out what is different in the cells and neural circuits of resistant mice. This research could deliver benefits for treating stress-related disorders such as depression. Most antidepressant drug-discovery efforts have focused on ways to undo the bad effects of stress. “Understanding resilience offers an additional approach,” says Nestler, “to look for ways to induce mechanisms of natural resilience in those individuals who are inherently more susceptible.” Research into stress is changing how we view mental-health conditions. Epigenetic and brain-chemistry changes caused by life stresses can be reversed by activities such as exercise, yoga, meditation and mental stimulation. And soon these types of behavioural intervention might be complemented by pharmaceuticals. “We may learn the molecular mechanisms important for resilience,” says O'Donnell. “And then use that to help those susceptible to stress or who have suffered ill treatment or trauma.”

News Article | February 21, 2017

In both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a blood cancer were associated with B-NHL. Each group had unique risk factors too. Non-Hodgkin lymphomas (NHL), tumors which may originate from B or T lymphocytes, account for approximately 3% of the worldwide cancer burden. Most epidemiological studies of NHL have been carried out in North American and European populations, with a few focusing on East Asian populations. Very few epidemiological studies have been conducted on B-cell non-Hodgkin lymphoma (B-NHL) in Middle Eastern populations. Since Israelis and Palestinians represent genetically and culturally diverse populations living in geographic proximity, research analyzing their risk factors can enrich our understanding of genes and environment in the causation of lymphoma. Despite sharing the same ecosystem, the populations differ in terms of lifestyle, health behaviors and medical systems. Yet both populations report high incidences of NHL, which represents the fifth most common malignancy in Israel and the eighth most common malignancy among West Bank Palestinians. (As of 2012, Israel also ranked first in the world in NHL incidence rates.) Now, Israeli and Palestinian researchers have conducted a large scale epidemiological study examining risk factors for B-NHL and its subtypes in these two populations. The team was led by Prof. Ora Paltiel, Director of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, in the Hebrew University's Faculty of Medicine, and a Senior Physician in Hadassah's Hematology Department. Recruiting from both the Palestinian Arab and Israeli Jewish populations, the researchers looked at medical history, environmental and lifestyle factors among 823 people with B-cell non-Hodgkin lymphoma (B-NHL) and 808 healthy controls. Using data from questionnaires, pathology review, serology and genotyping, they uncovered some risk factors common to both populations and other factors unique to each population. The data, reported in the peer-reviewed journal PLOS ONE, showed that in both populations, overall B-NHL was associated with recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a blood cancer. An inverse association was noted with alcohol use. Some exposures, including smoking and greater-than-monthly indoor pesticide use, were associated with specific subtypes of B-NHL. The data also pointed to differences between the populations. Among Palestinian Arabs only, risk factors included gardening and a history of herpes, mononucleosis, rubella, or blood transfusion, while these factors were not identified in the Israeli Jewish population. In contrast, risk factors that applied to Israeli Jews only included growing fruits and vegetables, and self-reported autoimmune diseases. The researchers concluded that differences in the observed risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by lymphoma subtypes infer specific causal factors for different types of the disease. These findings require further investigation as to their mechanisms. The fact that risk factors operate differently in different ethnic groups raises the possibility of gene-environment interactions, that is, that environmental exposures act differently in individuals of different genetic backgrounds. But this divergence may reflect differences in diet, cultural habits, socioeconomic, environmental and housing conditions, medical services, exposure to infections in early life or other factors. This study reflects a unique joint scientific effort involving Israeli and Palestinian investigators, and demonstrates the importance of cooperative research even in politically uncertain climates. Cancer epidemiology will be enriched through the broadening of analytic research to include under-studied populations from a variety of ethnicities and geographic regions. "Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions. The study provided opportunities for training Palestinian and Israeli researchers, and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations," said Prof. Ora Paltiel, Director of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, and a Senior Physician in Hadassah's Hematology Department. Participating institutions in this research included: Braun School of Public Health and Community Medicine, and Depts. of Hematology and Pathology, Hadassah-Hebrew University Medical Center; Dept. of Medical Laboratory Sciences and Dept. of Community Medicine, Faculty of Medicine, Al Quds University; Cancer Care Center, Augusta Victoria Hospital; Beit Jalla Hospital; Department of Statistics, Hebrew University; Department of Primary Health Care, Palestinian Ministry of Health; Tisch Cancer Institute and Institute for Translational Epidemiology, Mount Sinai School of Medicine; Rambam Medical Center and Rappaport Faculty of Medicine, Technion; Chaim Sheba Medical Center and Meir Medical Center and Tel Aviv University.

News Article | December 6, 2016

SALT LAKE CITY--(BUSINESS WIRE)--Central Logic, which recently launched the first web-based technology to operationalize care coordination using real-time data – Central Logic Patient Connect - announced today the appointment of Abraham Warshaw, MD, Senior Vice President of Mount Sinai Health System and Associate Professor of Population Health Science and Policy at Icahn School of Medicine at Mount Sinai, to its recently formed Executive Advisory Board. Central Logic is the healthcare industry’s leading provider of innovative transfer center, on-call scheduling technology and innovative data solutions. Warshaw also is Chief and Medical Director for Access Services which oversees the health system’s transfer services at the Mount Sinai Health System in New York City. “We are thrilled that Dr. Warshaw has joined Central Logic’s executive advisory board,” said Dr. Barry Chaiken, MD, chairman of the executive advisory board. “Dr. Warshaw’s expertise and insight will be invaluable to Central Logic as it looks to deploy its offerings across the entire spectrum of patient care. His background in transfer service complements Central Logic’s mission of revolutionizing care and I believe he will help push our innovation to even greater heights.” Warshaw is board certified in emergency medicine and, in his role at Mount Sinai, has served as a consultant and committee member relating to a number of topics including hospital operations, physician relations and emergency management. “Our goal in creating the executive advisory board is to bring together industry leaders who are committed to helping me guide the company into the future,” said Central Logic board chair and CEO, Jennifer Holmes. “This group of healthcare leaders will ensure Central Logic continues to launch innovative solutions like our newly-released Central Logic Patient Connect which improves population health management and helps providers operationalize their care coordination efforts.” “Dr. Warshaw has dedicated his career to serving patients and the industry,” Holmes continued. “I’m confident his clinical expertise and knowledge of the challenges healthcare providers face today will play a significant role on our executive advisory board.” Warshaw completed his residency in emergency medicine at Long Island Jewish Hospital, received his Doctor of Medicine degree from SUNY-Downstate, and holds a faculty appointment as associate professor in the department of Population Health Sciences and Policy at the Mount Sinai School of Medicine. About Central Logic: As the healthcare industry’s leading provider of innovative web-based data technology, Central Logic’s team works collaboratively with more than 500 hospitals and thousands of healthcare professionals – including physicians, administrators and healthcare staff – to operationalize transfer center, on-call scheduling, care coordination and population health management with comprehensive patient analytics and real-time reporting solutions. Its flagship solution, Central Logic Patient Connect, was launched in 2016 and uniquely gives visibility to real-time patient data from inside and outside a hospital’s four walls. Founded in 2005, the company helps hospitals and systems standardize processes, centralize actionable data and operationalize care coordination.

« C'est une avancée importante pour le traitement de l'APLV en pédiatrie. Cette maladie touche des millions de personnes dans le monde entier, et qui s'exposent chaque jour au risque d'une réaction potentiellement mortelle en cas de consommation d'un produit contenant des traces infimes de protéines de lait de vache, » a déclaré la Docteur Anna Nowak-Wegrzyn, Professeure Adjointe spécialiste en Pédiatrie, Allergie et Immunologie. Dr. Nowak-Wegrzyn officie au Jaffe Food Allergy Institute du Mount Sinai School of Medicine, à New York, et est l'investigatrice principale de l'étude MILES, conduite au Mount Sinai Medical Center. « Aujourd'hui, l'APLV est l'une des allergies alimentaires la plus fréquente chez les enfants. Nous sommes impatients d'obtenir les résultats de cette étude sans précédent. Si les essais cliniques confirment l'innocuité et l'efficacité de Viaskin Milk, et que son utilisation est approuvée par les autorités réglementaires, il pourrait s'agir du premier produit candidat à proposer une solution thérapeutique aux patients souffrant de cette allergie ». L'étude MILES est une étude de phase I/II multicentrique, randomisée contre placebo, réalisée en double aveugle, évaluant l'innocuité et l'efficacité du produit Viaskin® Milk chez une population pédiatrique (âgée de 2 à 17 ans) souffrant d'allergie aux protéines du lait de vache - ou APLV IgE-médiée, et présentant des taux d'IgE élevés aux protéines du lait de vache. L'étude est menée dans des centres cliniques sélectionnés aux États-Unis et au Canada. La partie A de l'étude est terminée. Le protocole de l'étude MILES prévoit le recrutement d'environ 176 patients dans 18 centres cliniques. Les patients éligibles chez lesquels une allergie aux protéines du lait de vache IgE-médiée est confirmée passeront un premier test de provocation oral lors de la phase de sélection, au cours de laquelle des doses croissantes de protéines de lait de vache leur seront administrées. Les patients présentant un niveau élevé d'IgE spécifiques du lait ainsi que des symptômes objectifs de réaction allergique à une dose déclenchante de protéines de lait de vache <=300 mg (environ 9,4 ml de lait de vache) seront randomisés dans le cadre de l'étude. Le critère d'efficacité principal sera le pourcentage de patients répondant au traitement après 12 mois, définis comme les patients qui remplissant au moins l'un des critères suivants : (1) augmentation d'un facteur 10 de la dose cumulée réactive (DCR) de protéines de lait de vache au test de provocation oral du 12e mois, par rapport à la valeur à l'inclusion, et atteignant au moins 144 mg de protéines de lait de vache (environ 4,5 ml de lait) ou (2) une DCR de protéines de lait de vache supérieur ou égale à 1 444 mg (environ 45 ml de lait) lors du test de provocation oral du 12e mois. Les critères secondaires d'évaluation de l'efficacité comprennent, parmi d'autres éléments, le pourcentage de sujets répondant au traitement au 24e mois, les DCR moyenne et médiane de protéines de lait de vache aux 12e et 24e mois et le changement par rapport au début de l'étude, et le changement dans les évaluations de la qualité de vie aux 12e et 24e mois par rapport au début de l'étude. L'allergie aux protéines de lait de vache (APLV) est l'allergie alimentaire la plus fréquente chez le nourrisson et le jeune enfant et affecte de 2 à 3 % de la population générale. Les symptômes peuvent comprendre des troubles gastro-intestinaux, notamment des vomissements et la diarrhée, une éruption cutanée, un angio-oedème (gonflement rapide de la peau) et une anaphylaxie. La seule option disponible pour la prise en charge de l'APLV est l'éviction du lait de vache, qui peut entraîner un déséquilibre nutritionnel, un retard staturo-pondéral et une mauvaise qualité de vie. DBV Technologies a créé le patch Viaskin®, une plateforme technologique totalement brevetée avec de nombreuses applications potentielles en immunothérapie. L'immunothérapie par voie épicutanée, ou EPIT®, utilise le Viaskin® pour administrer des composés biologiquement actifs au système immunitaire sur une peau intacte. Viaskin est non-invasif, auto-administré et pourrait permettre une prise en charge en toute sécurité des patients souffrant d'allergie alimentaire, pour lesquelles il n'existe pas de traitements approuvés. Le programme de développement comprend des essais cliniques sur Viaskin Peanut et Viaskin Milk, une étude expérimentale sur le Viaskin Egg et un essai clinique preuve de concept dans l'oesophagite à éosinophiles. DBV a également développé sa plateforme technologique dans le domaine des vaccins et de certaines maladies auto-immunes pour lesquelles les besoins médicaux sont insatisfaits. Le siège social de DBV Technologies est à Montrouge, France et la Société a également des bureaux à New York, États-Unis. Les actions sont négociées sur le segment B d'Euronext Paris (mnémonique : DBV, code ISIN : FR0010417345), intégrée à l'indice SBF120. DBV est également cotée sur le Nasdaq Global Select Market sous la forme d'American Depositary Shares, chaque ADS représentant la moitié d'une action ordinaire (mnémonique : DBVT). Pour plus d'informations, visitez notre site Web : Ce communiqué de presse contient des déclarations prospectives. Ce dernier événement ne change pas les normes d'approbation et ne constitue pas une garantie de succès. Ces déclarations prospectives ne constituent ni des promesses ni des garanties et comportent des risques et des aléas substantiels. Les produits de la Société n'ont, à ce jour, été autorisés à la vente dans aucun pays. Les aléas liés de manière générale avec les activités de recherche et développement, les essais cliniques, ainsi que les examens et autorisations réglementaires y associés, le risque dû au fait que l'historique des résultats précliniques puisse ne pas refléter les résultats des futurs essais cliniques et que l'historique des résultats des essais cliniques puisse ne pas refléter les résultats des futurs essais, constituent autant de facteurs qui pourraient donner lieu à des résultats substantiellement différents de ceux décrits ou anticipés dans les présentes. Une liste détaillée et une description de ces risques, aléas et autres risques figurent dans les documents déposés par la société auprès de l'Autorité des Marchés Financiers au titre de ses obligations réglementaires, dans les documents et rapports de la société déposés auprès de la Security and Echange Commission aux Etats-Unis, et dans le rapport annuel de la société relatif à l'exercice social clôturé le 31 décembre 2015, ainsi que les enregistrements et rapports qui seront effectués par la société. Les investisseurs existants et potentiels sont avertis qu'ils ne doivent pas se fier indûment à ces déclarations prospectives qui ne valent qu'à la date des présentes.

--Updated Median Duration of Complete Response of 8 Months in All Responding Patients-- NEWTOWN, Pa., Dec. 05, 2016 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, today announced the presentation of data from a Phase 2 clinical trial of oral rigosertib and azacitidine in higher-risk myelodysplastic syndromes (HR-MDS) at the 58th American Society of Hematology (ASH) Annual Meeting in San Diego, California. “The complete remission rate amongst HMA-naïve HR-MDS patients is higher and responses occur more rapidly and durably with the oral rigosertib combination compared to historic single-agent azacitidine,” commented Lewis R. Silverman, M.D., lead investigator in the trial and Associate Professor of Medicine, Hematology and Medical Oncology, at the Icahn School of Medicine at Mount Sinai.  “Furthermore, the addition of oral rigosertib to azacitidine does not substantially change the adverse event profile of single-agent azacitidine, and thus may overcome the limitations identified in other HMA-based combinations.” The current standard of care for higher-risk MDS patients is one of two approved hypomethylating agents (azacitidine and decitabine, approved by the FDA in 2004 and 2006). Although these drugs are currently the standard of care in HR-MDS therapy, their overall response rate and duration of benefit is limited to a subset of eligible patients and all responding patients ultimately progress. Thus, there is an urgent need for improving therapeutic options for newly diagnosed HR-MDS patients. The 09-08 trial tested oral rigosertib in combination with injectable azacitidine in a dose ranging study (Phase 1), followed by an expansion cohort (Phase 2) to evaluate the efficacy and safety of the combination. Both 1st-line and 2nd-line HR-MDS patients were included in the study. Summary of Presented Data from the 09-08 Combination Therapy Trial The poster entitled, “Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study,” was presented by Dr. Shyamala Navada of Mount Sinai School of Medicine at the Myelodysplastic Syndromes Session on Sunday, December 4, 2016 at the ASH Annual Meeting in San Diego, California.  A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website. “We are pleased by the positive efficacy signal observed over extended periods of treatment, and the acceptable tolerability of oral rigosertib and azacitidine in 1st-line HR-MDS,” stated Ramesh Kumar, Ph.D., President and CEO of Onconova.  “We presented Phase 2 data to the FDA as part of our End-of-Phase 2 meeting in September 2016, and based on these discussions, we are designing a randomized, placebo controlled Phase 3 clinical trial comparing the combination of oral rigosertib plus azacitidine to azacitidine plus placebo in 1st-line HR-MDS patients with the primary composite endpoint of CR and PR rate per 2006 IWG criteria. Based on our discussions with the FDA the primary efficacy endpoint of this trial will be composite response and not survival, permitting accelerated evaluation of outcomes.” In a second poster at the conference a safety review of 557 MDS/AML patients treated with rigosertib in clinical studies, including the randomized Phase 3 ONTIME trial was presented.  The poster entitled, “Comprehensive Analysis of Safety: Rigosertib in 557 Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML),” can be accessed by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website. Onconova Therapeutics is a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova's clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. The Company’s most advanced product candidate, rigosertib, is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf and PI3 kinases. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.  In addition to rigosertib, two other candidates are in the clinical stage, and several candidates are in pre-clinical stages.  For more information, please visit The oral form of rigosertib provides a more convenient dosing for use where the duration of treatment may extend to multiple years. To date, more than 350 patients have been treated with the oral formulation of rigosertib, either as a single agent or in combination with other drugs.  Phase 1 studies with oral rigosertib were conducted in hematological malignancies, lower-risk MDS and solid tumors. Combination therapy of oral rigosertib with azacitidine and chemoradiotherapy has also been explored. The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trial involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 global INSPIRE trial as 2nd-line treatment for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is suited for patients with advanced disease and provides long duration of exposure and ensures adequate dosing under a controlled setting. 1Fenaux et al for the international Vidaza High risk MDS survival study group, Lancet Oncology 2009, 10:223-232. Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. These statements relate to future events or Onconova Therapeutics, Inc.'s future operations, clinical development of Onconova's product candidates and presentation of data with respect thereto, regulatory approvals, expectations regarding the sufficiency of Onconova's cash and other resources to fund operating expenses and capital expenditures, Onconova's anticipated milestones and future expectations and plans and prospects. Although Onconova believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Onconova has attempted to identify forward-looking statements by terminology including “believes,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “should,” “approximately” or other words that convey uncertainty of future events or outcomes. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Onconova’s need for additional financing and current plans and future needs to scale back operations if adequate financing is not obtained, the success and timing of Onconova’s clinical trials and regulatory approval of protocols, and those discussed under the heading “Risk Factors” in Onconova’s most recent Annual Report on Form 10-K and quarterly reports on Form 10-Q. Any forward-looking statements contained in this release speak only as of its date. Onconova undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.

DBV Technologies Completes Enrollment of Phase II Study of Viaskin Milk for the Treatment of Milk Allergic Patients Most advanced product candidate for the treatment of IgE-mediated cow's milk allergy in development today FDA Fast Track designation for Viaskin Milk was granted in September 2016 DBV Technologies (Euronext: DBV - ISIN: FR0010417345 - Nasdaq Stock Market: DBVT), today announced that enrollment for Part B, or Phase II, of the Phase I/II study of Viaskin Milk for the treatment of patients with IgE-mediated cow's milk protein allergy (CMPA) has been completed. The MILES trial is evaluating the efficacy and safety of Viaskin Milk in desensitizing children two to 17 years of age suffering from CMPA. The Viaskin Milk patch is based on DBV's epicutaneous immunotherapy (EPIT), a proprietary technology platform that can deliver biologically active compounds to the immune system through the skin. The blinded part of the MILES study is expected to complete in the second half of 2017. No safety concerns were observed during Part A of the MILES Study (Phase I), for which study results were presented at the 2016 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting in Los Angeles, CA, on March 6, by Karine Rutault, Director, Clinical Projects, DBV Technologies. In Phase II, or Part B of the MILES study, a total of 283 patients were screened. The Company expects approximately 176 children with IgE-mediated CMPA will be randomized 1:1:1:1 to receive one of the three doses of Viaskin Milk (150 µg, 300 µg, 500 µg) or placebo for 12 months. "This is an important milestone for the treatment of pediatric CMPA, a disease affecting millions of patients worldwide, who are often times at risk of experiencing life-threatening reactions to undetectable traces of cow's milk protein in their everyday lives," said Dr. Anna Nowak-Wegrzyn, Associate Professor, Pediatrics, Allergy and Immunology at Jaffe Food Allergy Institute, Mount Sinai School of Medicine in New York and the Principal Investigator of the MILES trial at Mount Sinai Medical Center. "CMPA is one of the most common food allergies in children today and we look forward to seeing the results from this groundbreaking trial. Viaskin Milk, if proven safe and effective in clinical trials, could be the first product candidate to offer a potential treatment option for these patients, if approved." About the MILES Study The Viaskin Milk Efficacy and Safety (MILES) trial is a multi-center, double-blind, placebo-controlled, randomized Phase I/II trial to study the safety and efficacy of Viaskin Milk in pediatric patient populations (age two to 17) suffering from IgE-mediated cow's milk protein allergy, or CMPA, with elevated IgE levels related to cow's milk protein. The trial is being conducted in select U.S. and Canadian clinical centers. Part A of the MILES trial has been completed with no safety concerns. Approximately 194 subjects are expected to be randomized for treatment at 17 sites, including 18 subjects from Part A and 176 subjects from Part B, under the proposed amended MILES Part B protocol. Eligible subjects with confirmed IgE-mediated CMPA will perform an initial food challenge at screening with escalating doses of cow's milk proteins. Subjects who display objective symptoms of an allergic response to an eliciting dose of 300 mg cow's milk proteins (approximately 9.4 mL of cow's milk) or below will be randomized in the trial. The primary efficacy endpoint will be the percentage of subjects who are treatment responders after 12 months, defined as subjects who meet at least one of the following criteria: (1) a 10-fold or greater increase in the cumulative reactive dose, or CRD, of cow's milk proteins at month 12 of the food challenge as compared to baseline value in addition to reaching tolerance to at least 144 mg of cow's milk protein (approximately 4.5 mL of milk) or (2) a CRD of cow's milk protein greater than or equal to 1,444 mg (approximately 45 mL of milk) at month 12 of the food challenge. Secondary efficacy endpoints include, among others, the percentage of subjects who are treatment responders at month 24, the mean and median CRD of cow's milk proteins at months 12 and 24 as well as the change in CRD from baseline, the change from baseline in the severity of symptoms elicited during the food challenge from baseline to months 12 and 24, and the change from baseline in quality of life assessments at months 12 and 24. About Viaskin Milk Viaskin Milk is an investigational therapy in development for the treatment of pediatric cow's milk protein allergy (CMPA) and Eosinophilic Esophagitis (EoE). The Viaskin Milk patch is based on epicutaneous immunotherapy (EPIT), a proprietary technology platform that can deliver biologically active compounds to the immune system through intact skin without allowing compound passage into the blood. About Cow's Milk Protein Allergy Cow's milk protein allergy (CMPA) is the most common food allergy in infants and young children, affecting 2% to 3% of the general population. Symptoms can include gastrointestinal problems such as vomiting and diarrhea, skin rash, angioedema or rapid swelling of the skin, and anaphylaxis. The only option available for CMPA management is the avoidance of cow's milk, which can lead to issues of dietary imbalance, failure to thrive and poor quality of life. About DBV Technologies  DBV Technologies is developing Viaskin®, a proprietary technology platform with broad potential applications in immunotherapy. Viaskin is based on epicutaneous immunotherapy, or EPIT®, DBV's method of delivering biologically active compounds to the immune system through intact skin. With this new class of self-administered and non-invasive product candidates, the company is dedicated to safely transforming the care of food allergic patients, for whom there are no approved treatments. DBV's food allergies programs include ongoing clinical trials of Viaskin Peanut and Viaskin Milk, and preclinical development of Viaskin Egg. DBV is also pursuing a human proof-of-concept clinical study of Viaskin Milk for the treatment of Eosinophilic Esophagitis, and exploring potential applications of its platform in vaccines and other immune diseases. DBV Technologies has global headquarters in Montrouge, France and New York, NY. Company shares are traded on segment B of Euronext Paris (Ticker: DBV, ISIN code: FR0010417345), part of the SBF120 index, and traded on the Nasdaq Global Select Market in the form of American Depositary Shares (each representing one-half of one ordinary share) (Ticker: DBVT). For more information on DBV Technologies, please visit our website: Forward Looking Statements This press release contains forward-looking statements, including statements regarding the potential safety and efficacy of Viaskin Milk and statements reflecting management's expectations for clinical development of Viaskin Milk and the commercial potential of Viaskin Milk. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. Among the factors that could cause actual results to differ materially from those described or projected herein include uncertainties associated generally with research and development, clinical trials and related regulatory reviews and approvals, the risk that historical preclinical results may not be predictive of future clinical trial results, and the risk that historical clinical trial results may not be predictive of future trial results. A further list and description of these risks, uncertainties and other risks can be found in the Company's regulatory filings with the French Autorité des Marchés Financiers, the Company's Securities and Exchange Commission filings and reports, including in the Company's Annual Report on Form 20-F for the year ended December 31, 2015 and future filings and reports by the Company. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. DBV Technologies undertakes no obligation to update or revise the information contained in this Press Release, whether as a result of new information, future events or circumstances or otherwise.

Funk A.J.,University of Alabama at Birmingham | McCullumsmith R.E.,University of Alabama at Birmingham | Haroutunian V.,Mount Sinai School of Medicine | Meador-Woodruff J.H.,University of Alabama at Birmingham
Neuropsychopharmacology | Year: 2012

Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3′-5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK- and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC=36, DLPFC=35) and a comparison (ACC=33, DLPFC=31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK- and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK- and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK- and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Nowak-Wegrzyn A.,Mount Sinai School of Medicine | Katz Y.,Tel Aviv University | Mehr S.S.,Childrens Hospital at Westmead | Koletzko S.,Ludwig Maximilians University of Munich
Journal of Allergy and Clinical Immunology | Year: 2015

Non-IgE-mediated gastrointestinal food-induced allergic disorders (non-IgE-GI-FAs) account for an unknown proportion of food allergies and include food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). Non-IgE-GI-FAs are separate clinical entities but have many overlapping clinical and histologic features among themselves and with eosinophilic gastroenteropathies. Over the past decade, FPIES has emerged as the most actively studied non-IgE-GI-FA, potentially because of acute and distinct clinical features. FPIAP remains among the common causes of rectal bleeding in infants, while classic infantile FPE is rarely diagnosed. The overall most common allergens are cow's milk and soy; in patients with FPIES, rice and oat are also common. The most prominent clinical features of FPIES are repetitive emesis, pallor, and lethargy; chronic FPIES can lead to failure to thrive. FPIAP manifests with bloody stools in well-appearing young breast-fed or formula-fed infants. Features of FPE are nonbloody diarrhea, malabsorption, protein-losing enteropathy, hypoalbuminemia, and failure to thrive. Non-IgE-GI-FAs have a favorable prognosis; the majority resolve by 1 year in patients with FPIAP, 1 to 3 years in patients with FPE, and 1 to 5 years in patients with FPIES, with significant differences regarding specific foods. There is an urgent need to better define the natural history of FPIES and the pathophysiology of non-IgE-GI-FAs to develop biomarkers and novel therapies. © 2015 American Academy of Allergy, Asthma & Immunology.

Bowers M.E.,Mount Sinai School of Medicine | Yehuda R.,Mount Sinai School of Medicine | Yehuda R.,Mental Health Care Center
Neuropsychopharmacology | Year: 2016

The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically by data from Holocaust survivor offspring cohorts and other populations. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly have an impact on offspring, a concept we refer to here as 'intergenerational transmission', via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in affecting offsprings' long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress- or trauma-exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine the extent of parental stress effects. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, and limitations in our knowledge, we summarize current information and conclude by presenting hypotheses that have been prompted by recent studies in the field. © 2016 American College of Neuropsychopharmacology. All rights reserved.

Jarvinen K.M.,Albany Medical College | Nowak-Wegrzyn A.,Mount Sinai School of Medicine
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, often with diarrhea, leading to acute dehydration and lethargy or weight loss and failure to thrive if chronic. FPIES is elicited most commonly by milk and soy proteins; however, rice, oat, and other solid foods may also elicit FPIES. Certain FPIES features overlap with food protein-induced enteropathy and proctocolitis, whereas others overlap with anaphylaxis. FPIES is not well recognized among pediatricians and emergency department physicians; the affected children are often mismanaged as having acute viral gastrointestinal illness, sepsis, or surgical disease, delaying diagnosis of FPIES for many months. The aim of this review is to provide case-driven presentation of the features of FPIES. Although randomized clinical trials on management options are missing, the relevant current literature and authors' experience are reviewed in detail. © 2013 American Academy of Allergy, Asthma & Immunology.

Mueller T.M.,University of Alabama at Birmingham | Haroutunian V.,Mount Sinai School of Medicine | Meador-Woodruff J.H.,University of Alabama at Birmingham
Neuropsychopharmacology | Year: 2014

The molecular mechanisms of schizophrenia have been under investigation for decades; however, the exact causes of this debilitating neuropsychiatric disorder are still unknown. Previous studies have identified multiple affected neurotransmitter systems, brain regions, and cell types, each making a unique contribution to symptom presentation and pathophysiology. Numerous studies have identified gene and protein expression changes in schizophrenia, but the role of post-translational modifications, specifically N-glycosylation, has only recently become a target of investigation. N-glycosylation of molecules associated with glutamatergic neurotransmission is disrupted in schizophrenia, but it was unknown if these alterations are exclusive to the glutamatergic system or due to a more generalized deficit.In normal human cortex, we found evidence for N-glycosylation of the α1, β1, and β2 γ-aminobutyric type A receptor (GABAA R) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the α1, α4, and β1-3 GABAA R subunits. Examining GABAA R subunit N-glycosylation in matched pairs of schizophrenia (N=14) and comparison (N=14) of superior temporal gyrus revealed a smaller molecular mass of immature N-glycans on the α1 subunit, more immature N-glycosylation of the 49-kDa β1 subunit isoform, and altered total N-glycosylation of the β2 GABAA R subunit in schizophrenia. Measures of altered N-glycosylation of the β1 and β2 subunits were confounded by an increased apparent molecular mass of all β1 and β2 subunit isoforms in schizophrenia. Although N-glycosylation of α1, β1, and β2 were all changed in schizophrenia, the concentrations of GABAA R subunits themselves were unchanged. These findings suggest that disruptions of N-glycosylation in schizophrenia are not exclusive to glutamate and may indicate a potential disruption of a central cell signaling process in this disorder. © 2014 American College of Neuropsychopharmacology.

Dubinsky M.,Mount Sinai School of Medicine | Braun J.,University of California at Los Angeles
Gastroenterology | Year: 2015

The microbiome plays multifaceted roles in the pathogenesis of inflammatory bowel diseases (IBD). Accordingly, the clinical challenge of patient heterogeneity in disease phenotype and response to treatment should in part be addressed by biomarkers that detect the host response to microbiota, and the levels of microbial taxa and products eliciting the host response in susceptible individuals. Molecular analysis has revealed much evidence for microbial taxonomic membership and microbial products in association with IBD, but their utility as clinical biomarkers is still in its infancy. A rich area of progress has been the development and validation of host serologic microbial biomarkers, which have achieved a distinctive position in the diagnosis and prognosis in IBD, and as a template for defining other categories of microbial biomarkers in disease state and phenotype. © 2015 AGA Institute.

Llovet J.M.,Mount Sinai School of Medicine | Villanueva A.,Mount Sinai School of Medicine | Lachenmayer A.,University of Bern | Finn R.S.,University of California at Los Angeles
Nature Reviews Clinical Oncology | Year: 2015

Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents. © 2015 Macmillan Publishers Limited.

Bauman A.E.,University of Sydney | Reis R.S.,Pontifical Catholic University of Parana | Reis R.S.,Federal University of Paraná | Sallis J.F.,University of California at San Diego | And 4 more authors.
The Lancet | Year: 2012

Physical inactivity is an important contributor to non-communicable diseases in countries of high income, and increasingly so in those of low and middle income. Understanding why people are physically active or inactive contributes to evidence-based planning of public health interventions, because effective programmes will target factors known to cause inactivity. Research into correlates (factors associated with activity) or determinants (those with a causal relationship) has burgeoned in the past two decades, but has mostly focused on individual-level factors in high-income countries. It has shown that age, sex, health status, self-efficacy, and motivation are associated with physical activity. Ecological models take a broad view of health behaviour causation, with the social and physical environment included as contributors to physical inactivity, particularly those outside the health sector, such as urban planning, transportation systems, and parks and trails. New areas of determinants research have identified genetic factors contributing to the propensity to be physically active, and evolutionary factors and obesity that might predispose to inactivity, and have explored the longitudinal tracking of physical activity throughout life. An understanding of correlates and determinants, especially in countries of low and middle income, could reduce the effect of future epidemics of inactivity and contribute to effective global prevention of non-communicable diseases.

Rubio M.D.,University of Alabama at Birmingham | Wood K.,University of Alabama at Birmingham | Haroutunian V.,Mount Sinai School of Medicine | Meador-Woodruff J.H.,University of Alabama at Birmingham
Neuropsychopharmacology | Year: 2013

Protein expression abnormalities have been implicated in the pathophysiology of schizophrenia, but the underlying cause of these changes is not known. We sought to investigate ubiquitin and ubiquitin-like (UBL) systems (SUMOylation, NEDD8ylation, and Ufmylation) as putative mechanisms underlying protein expression abnormalities seen in schizophrenia. For this, we performed western blot analysis of total ubiquitination, free ubiquitin, K48- and K63-linked ubiquitination, and E1 activases, E2 conjugases, and E3 ligases involved in ubiquitination and UBL post-translational modifications in postmortem brain tissue samples from persons with schizophrenia (n=13) and comparison subjects (n=13). We studied the superior temporal gyrus (STG) of subjects from the Mount Sinai Medical Center brain collection that were matched for age, tissue pH, and sex. We found an overall reduction of protein ubiquitination, free ubiquitin, K48-linked ubiquitination, and increased K63 polyubiquitination in schizophrenia. Ubiquitin E1 activase UBA (ubiquitin activating enzyme)-6 and E3 ligase Nedd (neural precursor cell-expressed developmentally downregulated)-4 were decreased in this illness, as were E3 ligases involved in Ufmylation (UFL1) and SUMOylation (protein inhibitor of activated STAT 3, PIAS3). NEDD8ylation was also dysregulated in schizophrenia, with decreased levels of the E1 activase UBA3 and the E3 ligase Rnf7. This study of ubiquitin and UBL systems in schizophrenia found abnormalities of ubiquitination, Ufmylation, SUMOylation, and NEDD8ylation in the STG in this disorder. These results suggest a novel approach to the understanding of schizophrenia pathophysiology, where a disruption in homeostatic adaptation of the cell underlies discreet changes seen at the protein level in this illness.

Rackovsky S.,Mount Sinai School of Medicine | Rackovsky S.,Cornell University
Physical Review Letters | Year: 2011

The existence of conformational switching in proteins, induced by single amino acid mutations, presents an important challenge to our understanding of the physics of protein folding. Sequence-local methods, commonly used to detect structural homology, are incapable of accounting for this phenomenon. We examine a set of proteins, derived from the GA and GB domains of Streptococcus protein G, which are known to show a dramatic conformational change as a result of single-residue replacement. It is shown that these sequences, which are almost identical locally, can have very different global patterns of physical properties. These differences are consistent with the observed complete change in conformation. These results suggest that sequence-local methods for identifying structural homology can be misleading. They point to the importance of global sequence analysis in understanding sequence-structure relationships. © 2011 American Physical Society.

Olanow C.W.,Mount Sinai School of Medicine | Kieburtz K.,University of Rochester
Movement Disorders | Year: 2010

A disease-modifying therapy that slows or stops disease progression is one of the major unmet needs in the management of Parkinson's disease. To date, no therapy has been approved for disease modification despite promising laboratory data and positive results in clinical trials. This is because confounding symptomatic or pharmacologic effects cannot be excluded. The delayed start study provides an opportunity to define therapies that provide benefit that cannot be explained by an early symptomatic effect alone. However, this trial design does not necessarily provide a meaningful measure of the effect of the intervention on cumulative disability. In contrast, the long-term simple study provides a measure of the effect of the drug on cumulative disability but does not address mechanism of action. Together these two trials provide a road map for defining a disease modifying drug and determining the long term cumulative effect of the drug on the disease. © 2010 Movement Disorder Society.

Gandy S.,Mount Sinai School of Medicine | DeKosky S.T.,University of Virginia
Annual Review of Medicine | Year: 2013

Alzheimer's disease (AD) is the major cause of late-life brain failure. In the past 25 years, autosomal dominant forms of AD were found to be primariy attributable to mutations in one of two presenilins, polytopic proteins that contain the catalytic site of the ?-secretase protease that releases the amyloid beta (Aβ) peptide. Some familial AD is also due to mutations in the amyloid precursor protein (APP), but recently a mutation in APP was discovered that reduces Aβ generation and is protective against AD, further implicating amyloid metabolism. Prion-like seeding of amyloid fibrils and neurofibrillary tangles has been invoked to explain the stereotypical spread of AD within the brain. Treatment trials with anti-Aβ antibodies have shown target engagement, if not significant treatment effects. Attention is increasingly focused on presymptomatic intervention, because Aβ mismetabolism begins up to 25 years before symptoms begin. AD trials deriving from new biological information involve extraordinary international collaboration and may hold the best hope for success in the fight against AD. Copyright © 2013 by Annual Reviews.

Lencioni R.,University of Pisa | Llovet J.M.,Hospital Clinic | Llovet J.M.,Mount Sinai School of Medicine
Seminars in Liver Disease | Year: 2010

The endpoint in cancer research is overall survival. Nonetheless, other potential surrogate endpoints, such as response rate and time to progression, are currently used. Measurement of response rate in hepatocellular carcinoma (HCC) has become a controversial issue. The World Health Organization (WHO) criteria underestimate the actual response rate; thus, they were amended in 2000 by a panel of experts convened by the European Association for the Study of the Liver (EASL) to take into account treatment-induced tumor necrosis. Applying these guidelines, there was an association between response rate and outcome prediction. More recently, the Response Evaluation Criteria in Solid Tumors (RECIST) guideline was proposed as a method for measuring treatment response based on tumor shrinkage, which is a valuable measure of antitumor activity of cytotoxic drugs. This method was initially adopted by regulatory agencies, such as the U.S. Food and Drug Administration (FDA), for drug approval. However, anatomic tumor response metrics can be misleading when applied to molecular-targeted therapies or locoregional therapies in HCC. In 2008, a group of experts convened by the American Association for the Study of Liver Diseases (AASLD) developed a set of guidelines aimed at providing a common framework for the design of clinical trials in HCC and adapted the concept of viable tumortumoral tissue showing uptake in arterial phase of contrast-enhanced radiologic imaging techniquesto formally amend RECIST. These amendments conformed the AASLD-JNCI (Journal of the National Cancer Institute) guidelines and are summarized and clarified in the current article. They are referred to herein as the modified RECIST assessment (mRECIST). Further studies are needed to confirm the accuracy of this measurement compared with conventional gold standards such as pathologic studies of explanted livers. © 2010 by Thieme Medical Publishers, Inc.

Jarvinen K.M.,Albany Medical College | Nowak-Wegrzyn A.,Mount Sinai School of Medicine
The journal of allergy and clinical immunology. In practice | Year: 2013

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, often with diarrhea, leading to acute dehydration and lethargy or weight loss and failure to thrive if chronic. FPIES is elicited most commonly by milk and soy proteins; however, rice, oat, and other solid foods may also elicit FPIES. Certain FPIES features overlap with food protein-induced enteropathy and proctocolitis, whereas others overlap with anaphylaxis. FPIES is not well recognized among pediatricians and emergency department physicians; the affected children are often mismanaged as having acute viral gastrointestinal illness, sepsis, or surgical disease, delaying diagnosis of FPIES for many months. The aim of this review is to provide case-driven presentation of the features of FPIES. Although randomized clinical trials on management options are missing, the relevant current literature and authors' experience are reviewed in detail. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Bernstein D.L.,North Shore Long Island Jewish Health System | Hulkova H.,Charles University | Bialer M.G.,North Shore Long Island Jewish Health System | Desnick R.J.,Mount Sinai School of Medicine
Journal of Hepatology | Year: 2013

Cholesteryl ester storage disease (CESD) is caused by deficient lysosomal acid lipase (LAL) activity, predominantly resulting in cholesteryl ester (CE) accumulation, particularly in the liver, spleen, and macrophages throughout the body. The disease is characterized by microvesicular steatosis leading to liver failure, accelerated atherosclerosis and premature demise. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed. Here, the findings in 135 CESD patients described in the literature are reviewed. Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene (LIPA) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased. All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure. Pathognomonic birefringent CE crystals or their remnant clefts were observed in hepatic cells. Extrahepatic manifestations included portal hypertension, esophageal varices, and accelerated atherosclerosis. Liver failure in 17 reported patients resulted in liver transplantation and/or death. Genotyping identified 31 LIPA mutations in 55 patients; 61% of mutations were the common exon 8 splice-junction mutation (E8SJM-1G>A), for which 18 patients were homozygous. Genotype/phenotype correlations were limited; however, E8SJM-1G>A homozygotes typically had early-onset, slowly progressive disease. Supportive treatment included cholestyramine, statins, and, ultimately, liver transplantation. Recombinant LAL replacement was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Dekosky S.T.,University of Virginia | Blennow K.,Gothenburg University | Ikonomovic M.D.,University of Pittsburgh | Gandy S.,Mount Sinai School of Medicine
Nature Reviews Neurology | Year: 2013

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE) - which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression - has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE. © 2013 Macmillan Publishers Limited. All rights reserved.

Sudol M.,Weis Center for Research | Sudol M.,Mount Sinai School of Medicine
Oncogene | Year: 2011

Plasminogen activator (PLAU) is a serine protease that converts plasminogen to plasmin, a general protease, which promotes fibrinolysis and degradation of extracellular matrix. PLAU was reported in 1970s as one of the robustly induced enzymatic activities in Rous sarcoma virus (RSV)-transformed chicken cells. More than three decades later, with the completion of the sequencing of the chicken genome and the subsequent availability of Affymetrix GeneChip genome arrays, several laboratories have surveyed the transcriptional program affected by the RSV transformation. Interestingly, the PLAU gene was shown to be the most highly upregulated transcript. The induction of PLAU was a transformation-dependent process because viruses with deleted Src gene did not induce the transcription of the PLAU gene. Both Src and PLAU genes are associated with and contribute to the complex phenotype of human cancer. Although the activity and structures of these two enzymes are well characterized, the precise molecular function of these gene products in signaling networks is still not fully understood. Yet, the knowledge of their association with cancer is already translated into the clinical setting. Src kinase inhibitors are being tested in clinical trials of cancer therapy, and PLAU gene and its inhibitor have been included as biomarkers with strong prognostic and therapeutic predictive values. This vignette reviews the history of PLAU and Src discovery, and illuminates the complexity of their relationship, but also points to their emerging impact on public health. © 2011 Macmillan Publishers Limited All rights reserved.

Weingart S.D.,Mount Sinai School of Medicine | Levitan R.M.,Thomas Jefferson University
Annals of Emergency Medicine | Year: 2012

Patients requiring emergency airway management are at great risk of hypoxemic hypoxia because of primary lung pathology, high metabolic demands, anemia, insufficient respiratory drive, and inability to protect their airway against aspiration. Tracheal intubation is often required before the complete information needed to assess the risk of periprocedural hypoxia is acquired, such as an arterial blood gas level, hemoglobin value, or even a chest radiograph. This article reviews preoxygenation and peri-intubation oxygenation techniques to minimize the risk of critical hypoxia and introduces a risk-stratification approach to emergency tracheal intubation. Techniques reviewed include positioning, preoxygenation and denitrogenation, positive end expiratory pressure devices, and passive apneic oxygenation. © 2011 American College of Emergency Physicians.

Zhong J.,Burke Medical Research Institute | Zhong J.,Cornell University | Zou H.,Mount Sinai School of Medicine
Current Opinion in Neurobiology | Year: 2014

Neuronal competence to re-extend axons and a permissive environment that allows growth cone navigation are two major determinants for successful axon regeneration. Here, we review the roles of bone morphogenetic protein (BMP) signaling in mediating both neuronal and glial injury responses after CNS injury. BMPs can activate a pro-regenerative transcription program in neurons through Smad-mediated canonical pathway, or act locally on cytoskeleton assembly at distal axons via non-canonical pathways. Emerging evidence implicates retrograde BMP signalosomes in connecting the cytoskeletal and nuclear responses. In addition, BMP/Smad signaling modulates neurotrophin-mediated axonal outgrowth, and interacts with the epigenetic machinery to initiate epigenetic reprogramming for axon regeneration. Besides their influences on neurons, BMPs also regulate astrogliosis, inflammatory processes, and neural progenitor cell differentiation at the injury site, all of which can either positively or negatively modify the injury microenvironment. Lastly, an increasing number of BMP signaling partners, sensitizers, and downstream effectors collectively fine-tune the signaling intensity and spatiotemporal dynamics of BMP activity in an integrated signaling network during axon regeneration. © 2014 Elsevier Ltd.

Wang C.,Cornell University | Pan Y.,Cornell University | Pan Y.,Mount Sinai School of Medicine | Wang B.,Cornell University
Development | Year: 2010

Gli2 and Gli3 are primary transcriptional regulators that mediate hedgehog (Hh) signaling. Mechanisms that stabilize and destabilize Gli2 and Gli3 are essential for the proteins to promptly respond to Hh signaling or to be inactivated following the activation. In this study, we show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them. By contrast, RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins, but not those of their repressors, whereas introducing Sufu into the MEFs stabilizes Gli2 and Gli3 full-length proteins and rescues Gli3 processing. Consistent with these findings, forced Spop expression promotes Gli2 and Gli3 degradation and Gli3 processing. The functions of Sufu and Spop oppose each other through their competitive binding to the N- and C-terminal regions of Gli3 or the C-terminal region of Gli2. More importantly, the Gli3 repressor expressed by a Gli3 mutant allele (Gli3Δ699) can mostly rescue the ventralized neural tube phenotypes of Sufu mutant embryos, indicating that the Gli3 repressor can function independently of Sufu. Our study provides a new insight into the regulation of Gli2 and Gli3 stability and processing by Sufu and Spop, and reveals the unexpected Sufu-independent Gli3 repressor function.

Olguin P.,Mount Sinai School of Medicine | Glavic A.,University of Chile | Mlodzik M.,Mount Sinai School of Medicine
Current Biology | Year: 2011

Frizzled/planar cell polarity (Fz/PCP) signaling controls the orientation of sensory bristles and cellular hairs (trichomes) along the anteroposterior axis of the Drosophila thorax (notum) [1-4]. A subset of the trichome-producing notum cells differentiate as "tendon cells," serving as attachment sites for the indirect flight muscles (IFMs) to the exoskeleton [5]. Through the analysis of chascon (chas), a gene identified by its ability to disrupt Fz/PCP signaling under overexpression conditions, and jitterbug (jbug)/filamin [6], we show that maintenance of anteroposterior planar polarization requires the notum epithelia to balance mechanical stress generated by the attachment of the IFMs. chas is expressed in notum tendon cells, and its loss of function disturbs cellular orientation at and near the regions where IFMs attach to the epidermis. This effect is independent of the Fz/PCP and fat/dachsous systems [7]. The chas phenotype arises during normal shortening of the IFMs [8] and is suppressed by genetic ablation of the IFMs. chas acts through jbug/filamin and cooperates with MyosinII to modulate the mechanoresponse of notum tendon cells. These observations support the notion that the ability of epithelia to respond to mechanical stress generated by one or more interactions with other tissues during development and organogenesis influences the maintenance of its shape and PCP features. © 2011 Elsevier Ltd.

Long E.F.,University of California at Los Angeles | Swain G.W.,Mount Sinai School of Medicine | Mangi A.A.,Yale University
Circulation: Heart Failure | Year: 2014

Background: Treatment options for end-stage heart failure include inotrope-dependent medical therapy, orthotopic heart transplantation (OHT), left ventricular assist device (LVAD) as destination therapy or bridge to transplant. Methods and Results: We developed a state-transition model to simulate 4 treatment options and associated morbidity and mortality. Transition probabilities, costs, and utilities were estimated from published sources. Calculated outcomes included survival, quality-adjusted life-years, and incremental cost-effectiveness. Sensitivity analyses were performed on model parameters to test robustness. Average life expectancy for OHT-eligible patients is estimated at 1.1 years, with 39% surviving to 1 year. OHT with a median wait time of 5.6 months is estimated to increase life expectancy to 8.5 years, and costs <$100 000/quality-adjusted life-year gained, relative to inotrope-dependent medical therapy. Bridge to transplant- LVAD followed by OHT further is estimated to increase life expectancy to 12.3 years, for $226 000/quality-adjusted life-year gained versus OHT. Among OHT-ineligible patients, mean life expectancy with inotrope-dependent medical therapy is estimated at 9.4 months, with 26% surviving to 1 year. Patients who instead received destination therapy-LVAD are estimated to live 4.4 years on average from extrapolation of recent constant hazard rates beyond the first year. This strategy costs $202 000/quality-adjusted life-year gained, relative to inotrope-dependent medical therapy. Patient's age, time on wait list, and costs associated with care influence outcomes. Conclusions: Under most scenarios, OHT prolongs life and is cost effective in eligible patients. Bridge to transplant-LVAD is estimated to offer >3.8 additional life-years for patients waiting ≥6 months, but does not meet conventional costeffectiveness thresholds. Destination therapy-LVAD significantly improves life expectancy in OHT-ineligible patients. However, further reductions in adverse events or improved quality of life are needed for destination therapy-LVAD to be cost effective. © 2014 American Heart Association, Inc.

Sudol M.,Weis Center for Research | Sudol M.,Mount Sinai School of Medicine | Harvey K.F.,Peter MacCallum Cancer Center | Harvey K.F.,University of Melbourne
Trends in Biochemical Sciences | Year: 2010

Metazoans have evolved several pathways to regulate the size of organs and ultimately that of organisms. One such pathway is known as Salvador-Warts-Hippo, or simply Hippo. Research on the Hippo pathway has grown exponentially during the past 8 years, revealing a complex signaling network. Intriguingly, within this complexity, there are levels of modularity. One level of modularity is represented by the unusually wide occurrence of the WW module in the Hippo core kinase cassette, the upstream regulatory components and the downstream nuclear proteins. We suggest that the prevalence of WW domain-mediated complexes in the Hippo pathway should facilitate its molecular analysis and aid prediction of new pathway components. © 2010 Elsevier Ltd.

Trasande L.,Mount Sinai School of Medicine | Liu Y.,Northern New Jersey Center
Health Affairs | Year: 2011

A 2002 analysis documented $54.9 billion in annual costs of environmentally mediated diseases in US children. However, few important changes in federal policy have been implemented to prevent exposures to toxic chemicals. We therefore updated and expanded the previous analysis and found that the costs of lead poisoning, prenatal methylmercury exposure, childhood cancer, asthma, intellectual disability, autism, and attention deficit hyperactivity disorder were $76.6 billion in 2008. To prevent further increases in these costs, efforts are needed to institute premarket testing of new chemicals; conduct toxicity testing on chemicals already in use; reduce lead-based paint hazards; and curb mercury emissions from coal-fired power plants. © 2011 Project HOPE-The People-to-People Health Foundation, Inc.

Sosa M.S.,Tisch Cancer Institute | Sosa M.S.,Mount Sinai School of Medicine | Bragado P.,Tisch Cancer Institute | Bragado P.,Mount Sinai School of Medicine | And 3 more authors.
Nature Reviews Cancer | Year: 2014

Metastases arise from residual disseminated tumour cells (DTCs). This can happen years after primary tumour treatment because residual tumour cells can enter dormancy and evade therapies. As the biology of minimal residual disease seems to diverge from that of proliferative lesions, understanding the underpinnings of this new cancer biology is key to prevent metastasis. Analysis of approximately 7 years of literature reveals a growing focus on tumour and normal stem cell quiescence, extracellular and stromal microenvironments, autophagy and epigenetics as mechanisms that dictate tumour cell dormancy. In this Review, we attempt to integrate this information and highlight both the weaknesses and the strengths in the field to provide a framework to understand and target this crucial step in cancer progression. © 2014 Macmillan Publishers Limited.

News Article | October 28, 2016

BOSTON, MA--(Marketwired - October 28, 2016) - National Parents Organization recognizes the goals of the National Domestic Violence Awareness Month year-round by raising awareness of the tragic impact domestic violence has on many families throughout the nation. As President Obama has said, domestic violence impacts "women, men, and children of every age, background, and belief." National Parents Organization will continue to support shared parenting (50/50 custody) when parents divorce or separate only in cases where domestic violence is not an issue. The organization's leadership urges others to also join in the fight against domestic violence by supporting shared parenting. International experts have concluded that shared parenting can help reduce domestic violence. At the 2015 International Conference on Shared Parenting, which included about 120 research scientists and other experts from more than 20 countries, participants concluded that "…shared parenting [after parental separation or divorce] is recognized as the most effective means for both reducing high parental conflict and preventing first-time family violence." This is in stark contrast to the practices of most family courts in the Unites States, which have assumed that shared parenting between high conflict parents after separation or divorce is dangerous and should not be tried. National Parents Organization is pleased that a handful of states -- including Missouri, Arizona, Nevada, Utah, Minnesota, and South Dakota -- have implemented laws that encourage shared parenting. More than 20 states have considered similar proposals in the last year. National Parents Organization's Founder and Board Chairman Ned Holstein, MD, was a featured speaker during the International Conference on Shared Parenting. Of the conference's conclusions, he said, "Remember when we were told not to eat butter until the experts found that it is actually preferable to margarine? Well, we now have the startling reversal that shared parenting after parental separation or divorce is the most effective means for reducing high parental conflict, and that it decreases the subsequent onset of first-time family violence. It is wonderful to know that we have a way to help the children of high-conflict couples who separate or divorce." According to federal statistics from sources including the U.S. Centers for Disease Control, the U.S. Department of Justice and the U.S. Census Bureau, children raised by single parents account for: A regular contributor to local and national media, Dr. Holstein is Founder and Chair of the Board of National Parents Organization. Dr. Holstein was appointed by the Governor of Massachusetts to the Massachusetts Working Group on Child-Centered Family Law, and he was previously appointed by a Massachusetts Chief Justice to a task force charged with reviewing and revising the state's child support guidelines. A graduate of Harvard College, Holstein also earned a Master's degree in psychology from the Massachusetts Institute of Technology. His medical degree is from Mount Sinai School of Medicine, where he later served on the faculty as a teacher and researcher. National Parents Organization, a charitable and educational 501 (c)(3) organization, seeks better lives for children through family law reform that establishes equal rights and responsibilities for fathers and mothers after divorce or separation. The organization is focused on promoting shared parenting and preserving a child's strong bond with both parents, which is critically important to their emotional, mental, and physical health. In 2014, National Parents Organization released the Shared Parenting Report Card, the first study to rank the states on child custody laws. Visit the National Parents Organization website at

News Article | November 18, 2016

Marvell Scott, M.D., Discusses Treatment of Professional Athletes Using Injections That Do Not Have the Risks Associated with Steroids, Opioids, or NSAIDs. Marvell Scott, M.D., conducted a webinar about alternative pain relief treatments on October 12, 2016, which was watched by doctors from coast to coast. The event is now available to watch online HERE In the webinar, Dr. Scott discusses how he treats several musculoskeletal conditions including orthopedic surgery recovery, tennis elbow, tendonitis, tendinopathy, partial tears, post-surgical and post-traumatic arthrofibrosis, sports injuries, musculoskeletal pain, and osteoarthritis. Dr. Scott’s practice includes a wide range of patients, from some of the greatest athletes in the world to older patients dealing with high levels of disability due to intractable pain. Dr. Scott began his practice exclusively using a wide range of conventional drugs like glucocorticoid injections, but has since broadened his range of medications to include the use of natural medications, where they have proven to be effective. Today MediNatura™ injections and topical medicines are a mainstay of the alternative side of Dr. Scott’s practice. “In my practice, we have seen that the risks with Traumeel®, Zeel®, and other MediNatura™ injections are minimal in comparison with traditional glucocorticoid injections, but the benefits for pain relief are comparable,” said Dr. Scott. Many of his patients have endured exhaustive attempts to alleviate their pain through conventional treatment options, including multiple cortisone injections. “Cortisone is your synthetic version of cortisol, which is your aging hormone, so there are a lot of limitations with frequency and dosage,” said Dr. Scott. “With MediNatura™ products like Traumeel®, Zeel®, Neuralgo-Rheum®, and other injections I am able to inject a much broader spectrum of areas without weakening the tendon or suppressing the immune system.” “I treat well over 100 patients a week. Twenty to thirty injections a day, sometimes seven days a week. This may be tens of thousands of injections, and I haven’t had any real adverse reactions,” said Dr. Scott. In the webinar, Dr. Scott mentions that his professional athlete clients needed reassurance that Traumeel® and Zeel® contain no performance-enhancing drugs (PEDs). To address this concern, Dr. Scott independently hired a prestigious U.S. laboratory to conduct testing, which confirmed that the treatments are free of banned substances, including PEDs. Additionally, Traumeel® and Zeel® have never caused an issue with the random drug screening tests conducted on professional athletes. Dr. Scott completed his internal medicine residency at Mount Sinai School of Medicine’s sister hospital Cabrini Medical Center. He did his sports medicine specialty fellowship at UMDNJ-Robert Wood Johnson Medical School, where he worked with Rutgers and Princeton’s 30 varsity sports teams. Almost eight years ago, while working in northern Italy with the EuroLeague (a professional basketball league) and with the international soccer team A.C. Milan, he was introduced to the MediNatura™ products. He also learned that the doctors who treat the German Olympic team, German national soccer team, and multiple professional soccer teams such as Real Madrid and Bayern Munich, were successfully using Traumeel®. MediNatura™ Inc., a Delaware Corporation headquartered in greater Philadelphia, specializes in prescription and over the counter pharmaceuticals made from natural medicines. You can reach MediNatura™ toll-free at 1-844-633-4628 Monday through Friday from 8 a.m. to 5 p.m. MST or visit MediNatura™ imports Traumeel®, Zeel®, and other injections from Germany, where they are manufactured in FDA-audited factories according to strict U.S. pharmaceutical standards for purity and sterility. Full prescribing information for Traumeel® is available at CLICK HERE and for Zeel® at CLICK HERE.

News Article | November 28, 2016

BOSTON, MA--(Marketwired - November 28, 2016) - During Military Family Appreciation Month, National Parents Organization joins the rest of the nation to express gratitude to our military families for their service and sacrifice. While deployment is certainly challenging enough on its own, that stress can increase drastically when military parents are also dealing with child custody battles following a divorce or separation. National Parents Organization believes an additional way to provide support and appreciation for military families is not to make child custody decisions while a parent is deployed. "The child development research is now crystal clear that children do best when their loving bonds with each parent are protected after parents separate or divorce," says Ned Holstein, MD, founder of National Parents Organization. "Unfortunately, some active duty service members have found that the custody of their children has been changed in important ways while they were serving their country overseas and unable to be present in family court. Sometimes when they return from overseas duty, they cannot even find their children." To ensure child custody decisions are not made while one parent is deployed, National Parents Organization supports laws passed in states such as Michigan, California, and Nevada that provide protections for military parents. National Parents Organization believes these laws have set a good example of how things should be, and encourages more states to follow in this example to help ensure greater peace of mind for military families. "The recent law change in Michigan is a step in the right direction -- it is good for children, who will be enabled to resume their loving relations with a parent who returns from overseas military duty, and any need for a change in the parenting time arrangements can be considered then, with both parties present," Dr. Holstein said. According to federal statistics from sources including the U.S. Centers for Disease Control, the U.S. Department of Justice and the U.S. Census Bureau, children raised by single parents account for: A regular contributor to local and national media, Dr. Holstein is Founder and Chair of the Board of National Parents Organization. Dr. Holstein was appointed by the Governor of Massachusetts to the Massachusetts Working Group on Child-Centered Family Law, and he was previously appointed by a Massachusetts Chief Justice to a task force charged with reviewing and revising the state's child support guidelines. A graduate of Harvard College, Holstein also earned a Master's degree in psychology from the Massachusetts Institute of Technology. His medical degree is from Mount Sinai School of Medicine, where he later served on the faculty as a teacher and researcher. National Parents Organization, a charitable and educational 501 (c)(3) organization, seeks better lives for children through family law reform that establishes equal rights and responsibilities for fathers and mothers after divorce or separation. The organization is focused on promoting shared parenting and preserving a child's strong bond with both parents, which is critically important to their emotional, mental, and physical health. In 2014, National Parents Organization released the Shared Parenting Report Card, the first study to rank the states on child custody laws. Visit the National Parents Organization website at

News Article | December 5, 2016

TORONTO, ON--(Marketwired - December 05, 2016) - Dr. Evdokia Anagnostou, MD, has been appointed as the inaugural Dr. Stuart D. Sims Chair in Autism, an honour bestowed to an individual who demonstrates extraordinary academic leadership towards improving the quality of life for kids with autism spectrum disorders (ASD) and their families through research and teaching. Anagnostou is a senior clinician scientist and co-lead of the Autism Research Centre at Holland Bloorview Kids Rehabilitation Hospital. She is also an associate professor in the Department of Pediatrics at the University of Toronto. "I am honoured to receive this recognition and excited that it will support further research to expand our knowledge of ASD to help kids and their families thrive," says Anagnostou. "When researchers, families, and health professionals work together, we can be transformative in our efforts to translate findings from the basic sciences into effective treatments for kids with ASD and their families. This chair will help further that vision." Anagnostou first joined Holland Bloorview in 2008 as a child neurologist and clinician scientist. Her research is centred on how genes affect the brain, body and behaviour with the goal of translating that understanding into new ways and effective treatments to help individuals with autism and associated neurodevelopmental disorders. She is the lead of the Province of Ontario Neurodevelopmental Disorders (POND) network and the Canada Research Chair (Tier II) in Translational Therapeutics in Autism. Anagnostou is also a co-lead of the Autism Treatment Network (Toronto site) focused on providing the best quality care to children with ASD and their families. She received her undergraduate degree from McGill University, completed her neurology training at McGill University in 2003 and postdoctoral fellowship in Autism/Developmental Disabilities at Mount Sinai School of Medicine in 2005. "This chair appointment recognizes Dr. Anagnostou as a trail-blazing scientific leader in the field of autism," says Tom Chau, vice president of research at Holland Bloorview. "She has galvanized an international community around better treatments for young people with autism, uniting basic, clinical and health service scientists in an expansive, transdisciplinary, client and family-centred program of research. As the inaugural incumbent, I have no doubt that she will further illuminate a path to discovery, innovation and eventually enhanced quality of life." "As a family, we are delighted to have been involved with establishing the Autism Chair. Having met Dr. Anagnostou many times, we are impressed with her dedication and commitment to advance her research to benefit children with ASD. We also have been positively impacted by the work done at Holland Bloorview," said Charles Sims. The Chair is named after Dr. Stuart Sims (1929-2001) who graduated from the University of Toronto and practiced in Toronto as an Obstetrician-Gynecologist. He contributed greatly to medicine and the advancement of care for his patients. The Dr. Stuart D. Sims Chair in Autism is supported by Holland Bloorview and the University of Toronto. To donate to the Dr. Stuart D. Sims Chair in Autism and help fund advances in autism research, please click here. Holland Bloorview Kids Rehabilitation Hospital is Canada's largest children's rehabilitation hospital, fully affiliated with the University of Toronto. We pioneer treatments, technologies, therapies and real-world programs that give children with disabilities the tools to participate fully in life. The Autism Research Centre conducts research aimed at improving outcomes and quality of life for children with autism spectrum disorders and their families. Visit to learn more.

Roberts A.E.,Boston Childrens Hospital | Allanson J.E.,Childrens Hospital of Eastern | Tartaglia M.,Instituto Superiore Of Sanita | Gelb B.D.,Mount Sinai School of Medicine
The Lancet | Year: 2013

Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning diffi culties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding diffi culties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.

Lieberman J.A.,University of Memphis | Chehade M.,Mount Sinai School of Medicine
Current Allergy and Asthma Reports | Year: 2013

Omalizumab is a humanized monoclonal anti-IgE antibody that is currently FDA-approved for allergic asthma. Given its mechanism of action, recent reports have suggested its possible clinical use for food allergy and some forms of anaphylaxis. Omalizumab exerts its action by binding to circulating IgE, reducing IgE receptor expression, and decreasing mediator release from mast cells and basophils. Clinical trials using omalizumab in patients with food allergy resulted in achieving tolerance to higher amounts of the allergen in some patients. When used as an adjunct therapy during immunotherapy trials in patients with food allergy and anaphylaxis, omalizumab allowed more rapid and higher doses of immunotherapy to be given. Omalizumab has also been reported to be effective in a few patients with idiopathic anaphylaxis and mast cell disorders. Large multi-center trials are needed to confirm the above findings, and to identify subsets of patients that would benefit the most from omalizumab. © 2012 Springer Science+Business Media New York.

Steenland K.,Emory University | Fletcher T.,London School of Hygiene and Tropical Medicine | Savitz D.A.,Mount Sinai School of Medicine
Environmental Health Perspectives | Year: 2010

Objective and sources: We reviewed the epidemiologic literature for PFOA. Data synthesis: Perfluorooctanoic acid (PFOA) does not occur naturally but is present in the serum of most residents of industrialized countries (U.S. median, 4 ng/mL). Drinking water is the primary route of exposure in some populations, but exposure sources are not well understood. PFOA has been used to manufacture such products as Gore-Tex and Teflon. PFOA does not break down in the environment; the human half-life is estimated at about 3 years. PFOA is not metabolized in the body; it is not lipophilic. PFOA is not directly genotoxic; animal data indicate that it can cause several types of tumors and neonatal death and may have toxic effects on the immune, liver, and endocrine systems. Data on the human health effects of PFOA are sparse. There is relatively consistent evidence of modest positive associations with cholesterol and uric acid, although the magnitude of the cholesterol effect is inconsistent across different exposure levels. There is some but much less consistent evidence of a modest positive correlation with liver enzymes. Most findings come from cross-sectional studies, limiting conclusions. Two occupational cohort studies do not provide consistent evidence for chronic disease; both are limited by sample size and reliance on mortality data. Reproductive data have increased recently but are inconsistent, and any observed adverse effects are modest. Conclusions: Epidemiologic evidence remains limited, and to date data are insufficient to draw firm conclusions regarding the role of PFOA for any of the diseases of concern.

Kutty S.,Creighton University | Sengupta P.P.,Mount Sinai School of Medicine | Khandheria B.K.,University of Wisconsin - Milwaukee
Journal of the American College of Cardiology | Year: 2012

The patent foramen ovale (PFO) is a normal interatrial communication during fetal life that persists after birth in approximately 1 of every 4 adults. PFO is a potential route for embolic transit from the systemic venous circulation to the brain. Though there is compelling circumstantial evidence implicating PFO, the precise role of PFO in the pathogenesis of cryptogenic stroke is not yet established. Several randomized trials of transcatheter PFO closure versus medical management are ongoing. Results of these trials may improve our ability to select the best treatment for individual patients. Further well-designed studies are necessary to address several unresolved issues related to PFO stroke and PFO migraine pathophysiology, and to identify the patients who would most likely benefit from PFO closure. The purpose of this review is to summarize contemporary understanding, discuss current treatments, and explore some of the knowledge gaps pertaining to the clinical significance of PFO. © 2012 American College of Cardiology Foundation.

Colvin A.C.,Mount Sinai School of Medicine | Harrast J.,930 North York Road | Harner C.,University of Pittsburgh
Journal of Bone and Joint Surgery - Series A | Year: 2012

Background: Recent advances in diagnosis and instrumentation have facilitated the arthroscopic treatment of hip pathology. However, little has been reported on trends in the utilization of hip arthroscopy. The purpose of this study was to examine changes in the use of hip arthroscopy as reflected in the American Board of Orthopaedic Surgery (ABOS) database. We also surveyed directors of both sports and joint reconstruction fellowships to determine attitudes toward hip arthroscopy training. Methods: The number of hip arthroscopy cases in the ABOS database during 1999 through 2009 was determined. A survey was devised to determine the type of hip arthroscopy training that was currently being offered at the fellowship level. Results: The number of hip arthroscopy procedures performed by ABOS candidates increased significantly from 0.02 cases per candidate in 1999 to 0.36 cases per candidate in 2009 (p < 0.0001). From 2003 through 2009, a significantly greater percentage of ABOS candidates with sports fellowship training (10.4%) than candidates without such training (2.9%) performed hip arthroscopy (p < 0.0001). During this same time period, candidates in the Northeast and Northwest performed the most hip arthroscopy procedures as a percentage of total procedures (p < 0.0001). Nearly half of the sports and joint reconstruction fellowships that included hip arthroscopy as a component of the training in 2010 had added it within the past three years. Fellows performed fewer than twenty hip arthroscopy cases per year in the majority of training programs. Conclusions: The number of hip arthroscopy procedures performed by candidates taking Part II of the ABOS examination increased eighteenfold between 1999 and 2009. This increase is likely the result of several factors, including an increase in the number of programs offering training in hip arthroscopy. Copyright © 2012 by The Journal of Bone and Joint Surgery, Incorporated.

Xu S.-Y.,New England Biolabs | Gupta Y.K.,Mount Sinai School of Medicine
Nucleic Acids Research | Year: 2013

Many bacteriophage and prophage genomes encode an HNH endonuclease (HNHE) next to their cohesive end site and terminase genes. The HNH catalytic domain contains the conserved catalytic residues His-Asn-His and a zinc-binding site [CxxC]2. An additional zinc ribbon (ZR) domain with one to two zinc-binding sites ([CxxxxC], [CxxxxH], [CxxxC], [HxxxH], [CxxC] or [CxxH]) is frequently found at the N-terminus or C-terminus of the HNHE or a ZR domain protein (ZRP) located adjacent to the HNHE. We expressed and purified 10 such HNHEs and characterized their cleavage sites. These HNHEs are site-specific and strand-specific nicking endonucleases (NEase or nickase) with 3- to 7-bp specificities. A minimal HNH nicking domain of 76 amino acid residues was identified from Bacillus phage γ HNHE and subsequently fused to a zinc finger protein to generate a chimeric NEase with a new specificity (12-13 bp). The identification of a large pool of previously unknown natural NEases and engineered NEases provides more 'tools' for DNA manipulation and molecular diagnostics. The small modular HNH nicking domain can be used to generate rare NEases applicable to targeted genome editing. In addition, the engineered ZF nickase is useful for evaluation of off-target sites in vitro before performing cell-based gene modification. © 2012 The Author(s). Published by Oxford University Press.

Samatar A.A.,TheraMet Biosciences | Poulikakos P.I.,Mount Sinai School of Medicine
Nature Reviews Drug Discovery | Year: 2014

The RAS-RAF-MEK-ERK signalling pathway is hyperactivated in a high percentage of tumours, most frequently owing to activating mutations of the KRAS, NRAS and BRAF genes. Recently, the use of compounds targeting components of ERK signalling, such as RAF or MEK inhibitors, has led to substantial improvement in clinical outcome in metastatic melanoma and has shown promising clinical activity in additional tumour types. However, response rates are highly variable and the efficacy of these drugs is primarily limited by the development of resistance. Both intrinsic and acquired resistance to RAF and MEK inhibitors are frequently associated with the persistence of ERK signalling in the presence of the drug, implying the need for more innovative approaches to target the pathway. © 2014 Macmillan Publishers Limited. All rights reserved.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.1-6 | Award Amount: 3.94M | Year: 2010

Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. Its incidence is growing and with more than 700,000 annual cases worldwide -50,000 in Europe-, it is the 3rd cause of cancer-related mortality. Most patients are diagnosed at advanced stages with dismal survival rates lower than 1 year, even after sorafenib, the sole systemic therapy available. The main goal of the HEPTROMIC project is to produce breakthrough knowledge in two critical aspects of HCC research: prognostic prediction and identification of oncogenic drivers susceptible for intervention, leading towards more personalized treatment algorithms. The HEPTROMIC Consortium proposes a 3-year translational research study bringing together an outstanding team of researchers with clinical and genomic expertise along with cutting-edge technology. Eight partners -six academic and two SMEs- will address the following objectives by applying high-end transcriptome, methylome and deep sequencing technology in a large set of 1,140 human samples: Objective 1) Genomic characterization of poor prognosis subclass of hepatocellular carcinoma. Objective 2) Identification of driver oncogenic events as potential treatment targets. Findings obtained will be confirmed in sophisticated experimental models that closely mimics human liver cancer. Objective 3) Design of prognostic devices for clinical translation. This transfer of knowledge will be led by SMEs with entrepreneurial management skills with experience in creating new products increasing European competitiveness and boosting the innovative capacity of industries. Overall, the Consortium foresees impacts on improved patient survival by refining prognosis and decision-making, identifying targets amenable for selective therapies and by improving the allocation of resources. In summary, HEPTROMIC will strength links between the academic and industry spheres, ultimately contributing to reduce liver cancer mortality.

Mount Sinai School of Medicine and The University Of Texas System | Date: 2013-05-30

Provided herein are compositions and methods useful for increasing a pro-inflammatory immune response, treating an autoimmune disorder, inflammation, or transplant rejection in a mammal by activating a leukocyte immunoglobulin-like receptor (LILR) protein. Also provided are compositions and methods useful for increasing a pro-inflammatory immune response, treating cancer, and treating infectious disease in a mammal by blocking the activation of a LILR protein.

Mount Sinai School of Medicine and Lehigh University | Date: 2010-09-16

The present invention concerns conjugate compounds comprising a bisphosphonate covalently bonded to a prostatic acid phosphatase inhibitor and compositions comprising such conjugates. Methods for treating and inhibiting prostate cancer bone metastases, and determining whether a conjugate is useful for such treatment are also provided. In some instances, the bisphosphonate is alendronate, and it is covalently bonded to either tartaric acid or glyceric acid.

Mount Sinai School of Medicine, Weizmann Institute of Science and University of Duisburg - Essen | Date: 2016-10-05

The present invention relates to a method for treating or preventing pathogenic infections in a subject having Cystic Fibrosis, COPD, and/or an open wound. This method involves selecting a subject having Cystic Fibrosis, COPD, and/or an open wound and administering to the selected subject a ceramidase under conditions effective to reduce ceramide and to treat or prevent the pathogenic infection. The method also involves the use of a ceramidase in combination with other drugs to reduce infection, reduce ceramide, or improve lung function in Cystic Fibrosis, COPD, and/or open wound patients.

Lehigh University and Mount Sinai School of Medicine | Date: 2013-10-16

The present invention concerns conjugate compounds comprising a bisphosphonate covalently bonded to a prostatic acid phosphatase inhibitor and compositions comprising such conjugates. Methods for treating and inhibiting prostate cancer bone metastases, and determining whether a conjugate is useful for such treatment are also provided. In some instances, the bisphosphonate is alendronate, and it is covalently bonded to either tartaric acid or glyceric acid.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 99.78K | Year: 2013

DESCRIPTION (provided by applicant): Type II restriction enzymes (REases) are indispensible tools of modern medical research. It has long been a goal of REase manufacturers to be able to offer programmable specificity enzymes, where the sequence recognizedand resulting cutting activity can be precisely directed to any desired point in a DNA, as this will offer opportunity for improvement in many applications, from DNA sequencing to gene therapy. We have identified a new family of Type II endonucleases thatare amenable for the first time to the rational engineering of new DNA binding and cleavage specificities. To commercialize potentially thousands of new enzymes, we propose a structure-based approach, using crystallographic information to identify specificity determinants, which can then be rationally mutated to generate new nucleases with programmable specificities. In phase I of this application, we will prepare large amounts of several MmeI family enzymes, with the goal of having in hand well-diffracting crystals for two MmeI-family enzymes. In preliminary studies we have obtained well-diffracting cocrystals of MmeI that are highly suitable for structure determination. In Phase II, we will first determine structures for two MmeI family enzymes bound to DNA and then, as part of aim 2, use that information together with structure-based amino acid sequence alignments to generate a code of position-specific amino acids for the engineering of nucleases with programmable specificities. In aim 3, we will generate the potentially thousands of new specificity enzymes using site-directed mutagenesis protocols and, in aim 4, refine our understanding of specificity within this novel family of enzymes through structures of select mutants. An important application of MmeI-like enzymes is in technologies such as Serial Analysis of Gene Expression (SAGE) and paired-end sequence reads in next-generation DNA sequencing methods. Thus, as part of aim 5, we will use the structural information to engineer enzymes with extended reach between the recognition and cleavage sites for improving the quality of SAGE data and for speeding the assembly of genomes in DNA sequencing methods. Engineered Mme-I-like enzymes also offer the potential for targeted therapeutic use with minimal offtarget cleavage and toxicity. In aim 6, we will use our structural information to generate rare cutting MmeI-like endonucleases for therapeutic use. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Type II restriction enzymes (REases) are indispensible tools of modern medical research. We propose to generate and commercialize thousands of new REases with programmable specificities for applications ranging from DNA sequencing to gene therapy.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 761.59K | Year: 2013

DESCRIPTION (provided by applicant): Type II restriction enzymes (REases) are indispensible tools of modern medical research. It has long been a goal of REase manufacturers to be able to offer programmable specificity enzymes, where the sequence recognizedand resulting cutting activity can be precisely directed to any desired point in a DNA, as this will offer opportunity for improvement in many applications, from DNA sequencing to gene therapy. We have identified a new family of Type II endonucleases thatare amenable for the first time to the rational engineering of new DNA binding and cleavage specificities. To commercialize potentially thousands of new enzymes, we propose a structure-based approach, using crystallographic information to identify specificity determinants, which can then be rationally mutated to generate new nucleases with programmable specificities. In phase I of this application, we will prepare large amounts of several MmeI family enzymes, with the goal of having in hand well-diffracting crystals for two MmeI-family enzymes. In preliminary studies we have obtained well-diffracting cocrystals of MmeI that are highly suitable for structure determination. In Phase II, we will first determine structures for two MmeI family enzymes bound to DNA and then, as part of aim 2, use that information together with structure-based amino acid sequence alignments to generate a code of position-specific amino acids for the engineering of nucleases with programmable specificities. In aim 3, we will generate the potentially thousands of new specificity enzymes using site-directed mutagenesis protocols and, in aim 4, refine our understanding of specificity within this novel family of enzymes through structures of select mutants. An important application of MmeI-like enzymes is in technologies such as Serial Analysis of Gene Expression (SAGE) and paired-end sequence reads in next-generation DNA sequencing methods. Thus, as part of aim 5, we will use the structural information to engineer enzymes with extended reach between the recognition and cleavage sites for improving the quality of SAGE data and for speeding the assembly of genomes in DNA sequencing methods. Engineered Mme-I-like enzymes also offer the potential for targeted therapeutic use with minimal offtarget cleavage and toxicity. In aim 6, we will use our structural information to generate rare cutting MmeI-like endonucleases for therapeutic use. PUBLIC HEALTH RELEVANCE Type II restriction enzymes (REases) are indispensible tools of modern medical research. We propose to generate and commercialize thousands of new REases with programmable specificities for applications ranging from DNA sequencing to gene therapy.

TEL AVIV, Israel, March 02, 2017 (GLOBE NEWSWIRE) -- Cellect Biotechnology Ltd. (Nasdaq:APOP) (TASE:APOP), a developer of stem cells isolation technology, today announced the appointment of Dr. Michael Berelowitz to the Company’s Board of Directors. Cellect’s Board now includes seven members, five of whom are independent. Dr. Berelowitz is a former Head of Clinical Development and Medical Affairs at Pfizer and brings over 40 years of clinical, development and academic research experience. Prior to Pfizer, he spent a number of years in academia and has held appointments at the University of Chicago, University of Cincinnati College of Medicine, SUNY at Stony Brook and most recently, Mount Sinai School of Medicine. Commenting on his appointment, Dr. Berelowitz, said: “Cellect is a unique company with strong potential to become a major influencer in the future of regenerative medicine. I have always supported front-runners and I am happy to be a part of Cellect’s team on this journey.” Cellect’s Chairman of the Board, Nuriel Chirich Kasbian, said: “It is key that we construct the strongest board possible to help Cellect rise above its challenges. Dr. Berelowitz is a true asset to our company and its future growth. I welcome him to our board of directors.” Among his many accomplishments, Dr. Berelowitz has chaired the Task Force on Research of the New York State Council on Diabetes. He has also served on several editorial boards including the Journal of Clinical Endocrinology and Metabolism; Endocrinology; Reviews in Endocrine and Metabolic Disorders and Clinical Diabetes. Dr. Berelowitz has authored and co-authored more than 100 peer-reviewed journal articles and book chapters. Cellect Biotechnology is traded on both the NASDAQ and Tel Aviv Stock Exchange (NASDAQ:APOP) (NASDAQ:APOPW) (TASE:APOP). The Company has developed a breakthrough technology for the isolation of stem cells from any given tissue that aims to improve a variety of stem cells applications. The Company’s technology is expected to provide pharma companies, medical research centers and hospitals with the tools to rapidly isolate stem cells in quantity and quality that will allow stems cell related treatments and procedures. Cellect’s technology is applicable to a wide variety of stem cells related treatments in regenerative medicine and that current clinical trials are aimed at the cancer treatment of bone marrow transplantations. Forward Looking Statements     This press release contains forward-looking statements about the Company’s expectations, beliefs and intentions. Forward-looking statements can be identified by the use of forward-looking words such as “believe”, “expect”, “intend”, “plan”, “may”, “should”, “could”, “might”, “seek”, “target”, “will”, “project”, “forecast”, “continue” or “anticipate” or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. For example, forward-looking statements are used in this press release when we discuss Cellect having a strong potential to become a major influencer in the future of regenerative medicine, that Cellect has developed a breakthrough technology for the isolation of stem cells from any given tissue and that Cellect’s technology is expected to provide pharma companies, medical research centers and hospitals with the tools to rapidly isolate stem cells in quantity and quality that will allow stems cell related treatments and procedures. These forward-looking statements and their implications are based on the current expectations of the management of the Company only, and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. In addition, historical results or conclusions from scientific research and clinical studies do not guarantee that future results would suggest similar conclusions or that historical results referred to herein would be interpreted similarly in light of additional research or otherwise. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; we may encounter delays or obstacles in launching and/or successfully completing our clinical trials; our products may not be approved by regulatory agencies, our technology may not be validated as we progress further and our methods may not be accepted by the scientific community; we may be unable to retain or attract key employees whose knowledge is essential to the development of our products; unforeseen scientific difficulties may develop with our process; our products may wind up being more expensive than we anticipate; results in the laboratory may not translate to equally good results in real clinical settings; results of preclinical studies may not correlate with the results of human clinical trials; our patents may not be sufficient; our products may harm recipients; changes in legislation; inability to timely develop and introduce new technologies, products and applications, which could cause the actual results or performance of the Company to differ materially from those contemplated in such forward-looking statements. Any forward-looking statement in this press release speaks only as of the date of this press release. The Company undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. More detailed information about the risks and uncertainties affecting the Company is contained under the heading “Risk Factors” in Cellect Biotechnology Ltd.'s final prospectus dated July 29, 2016 filed with the U.S. Securities and Exchange Commission, or SEC, which is available on the SEC's website, and in the Company’s period filings with the SEC and the Tel-Aviv Stock Exchange.

Chin M.-L.,Mount Sinai School of Medicine | Chin M.-L.,Academia Sinica, Taiwan | Mlodzik M.,Mount Sinai School of Medicine
Developmental Cell | Year: 2013

Establishment of planar cell polarity (PCP) in a tissue requires coordination of directional signals from cell to cell. It is thought that this is mediated by the core PCP factors, which include cell-adhesion molecules. Here, we demonstrate that furrowed, the Drosophila selectin, is required for PCP generation. Disruption of PCP in furrowed-deficient flies results from a primary defect in Fz levels and cell adhesion. Furrowed localizes at or near apical junctions, largely colocalizing with Frizzled and Flamingo (Fmi). It physically interacts with and stabilizes Frizzled, and it mediates intercellular Frizzled-Van Gogh (Vang)/Strabismus interactions, similarly to Fmi. Furrowed does so through a homophilic cell-adhesion role that is distinct from its known carbohydrate-binding function described during vertebrate blood-cell/endothelial cell interactions. Importantly, the carbohydrate function is dispensable for PCP establishment. Invivo studies suggest that Furrowed functions partially redundantly with Fmi, mediating intercellular Frizzled-Vang interactions between neighboring cells. © 2013 Elsevier Inc.

Trautwein C.,RWTH Aachen | Friedman S.L.,Mount Sinai School of Medicine | Schuppan D.,University Hospital Freiburg | Schuppan D.,Beth Israel Deaconess Medical Center | Pinzani M.,University College London
Journal of Hepatology | Year: 2015

Understanding the molecular mechanisms underlying liver fibrogenesis is fundamentally relevant to developing new treatments that are independent of the underlying etiology. The increasing success of antiviral treatments in blocking or reversing the fibrogenic progression of chronic liver disease has unearthed vital information about the natural history of fibrosis regression, and has established important principles and targets for antifibrotic drugs. Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models, none has been thoroughly validated in the clinic or commercialized as a therapy for fibrosis. In addition, it is likely that combination therapies that affect two or more key pathogenic targets and/or pathways will be needed. To accelerate the preclinical development of these combination therapies, reliable single target validation is necessary, followed by the rational selection and systematic testing of combination approaches. Improved noninvasive tools for the assessment of fibrosis content, fibrogenesis and fibrolysis must accompany in vivo validation in experimental fibrosis models, and especially in clinical trials. The rapidly changing landscape of clinical trial design for liver disease is recognized by regulatory agencies in the United States (FDA) and Western Europe (EMA), who are working together with the broad range of stakeholders to standardize approaches to testing antifibrotic drugs in cohorts of patients with chronic liver diseases.

Madan R.K.,Beth Israel Deaconess Medical Center | Madan R.K.,Mount Sinai School of Medicine | Levitt J.,Mount Sinai School of Medicine
Journal of the American Academy of Dermatology | Year: 2014

Topical salicylic acid is often used in dermatologic conditions because of its keratolytic, bacteriostatic, fungicidal, and photoprotective properties. The bioavailability of salicylic acid differs depending on the vehicle used and pH of transcellular fluids. Although rare, salicylic acid toxicity (salicylism) can occur from topical application. Physicians should be mindful of the potential for salicylism or even death from topically applied salicylic acid. © 2013 by the American Academy of Dermatology, Inc.

Schapira A.H.V.,University College London | Olanow C.W.,Mount Sinai School of Medicine | Greenamyre J.T.,University of Pittsburgh | Bezard E.,Institut Universitaire de France | Bezard E.,French National Center for Scientific Research
The Lancet | Year: 2014

Summary Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of α-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels. © 2014 Elsevier Ltd.

Sobie E.A.,Mount Sinai School of Medicine | Lederer W.J.,University of Maryland, Baltimore
Journal of Molecular and Cellular Cardiology | Year: 2012

Evidence obtained in recent years indicates that, in cardiac myocytes, release of Ca 2+ from the sarcoplasmic reticulum (SR) is regulated by changes in the concentration of Ca 2+ within the SR. In this review, we summarize recent advances in our understanding of this regulatory role, with a particular emphasis on dynamic and local changes in SR [Ca 2+]. We focus on five important questions that are to some extent unresolved and controversial. These questions concern: (1) the importance of SR [Ca 2+] depletion in the termination of Ca 2+ release; (2) the quantitative extent of depletion during local release events such as Ca 2+ sparks; (3) the influence of SR [Ca 2+] refilling on release refractoriness and the propensity for pathological Ca 2+ release; (4) dynamic changes in SR [Ca 2+] during propagating Ca 2+ waves; and (5) the speed of Ca 2+ diffusion within the SR. With each issue, we discuss data supporting alternative viewpoints, and we identify fundamental questions that are being actively investigated. We conclude with a discussion of experimental and computational advances that will help to resolve controversies. This article is part of a special issue entitled "Local Signaling in Myocytes.". © 2011 Elsevier Ltd.

Condon C.,University Pierre and Marie Curie | Bechhofer D.H.,Mount Sinai School of Medicine
Current Opinion in Microbiology | Year: 2011

Regulation of bacterial gene expression at the post-transcriptional level has emerged as a major control mechanism, although not yet as well recognized as the mechanisms of control at the transcriptional level. In this article, we focus on regulated RNA decay in the control of gene expression in Gram-positive organisms, with an emphasis on Bacillus subtilis. Discovery of new ribonuclease activities in B. subtilis and other Gram-positive species, especially the dual-functioning RNase J1, which specifies both an endonuclease activity and the long-sought bacterial 5'-to-3' exoribonuclease activity, has led to the recognition of intriguing mechanisms of gene regulation at the level of RNA decay. © 2011 Elsevier Ltd.

Silbiger J.J.,Mount Sinai School of Medicine | Silbiger J.J.,Mount Sinai Services at Elmhurst Hospital Center
Journal of the American Society of Echocardiography | Year: 2011

Ischemic mitral regurgitation is a common complication of the healing phase of myocardial infarction. A number of mechanisms have been invoked in its pathogenesis, including alterations of papillary muscle position, annular dynamics, and intraventricular synchrony. The echocardiographic hallmark of ischemic mitral regurgitation is systolic tethering of the mitral valve leaflets away from the annular plane. A number of leaflet tethering parameters have been described (tenting height and area, leaflet angles) that provide insight into the mechanism of tethering as well as prognostic information about the durability of mitral valve repair. Restrictive annuloplasty and coronary artery revascularization promote reverse remodeling and remain the most common surgical treatment. Innovative subannular therapies and a number of percutaneous interventions are under investigation. Copyright 2011 by the American Society of Echocardiography.

Pezic D.,California Institute of Technology | Manakov S.A.,California Institute of Technology | Sachidanandam R.,Mount Sinai School of Medicine | Aravin A.A.,California Institute of Technology
Genes and Development | Year: 2014

Transposable elements (TEs) occupy a large fraction of metazoan genomes and pose a constant threat to genomic integrity. This threat is particularly critical in germ cells, as changes in the genome that are induced by TEs will be transmitted to the next generation. Small noncoding piwi-interacting RNAs (piRNAs) recognize and silence a diverse set of TEs in germ cells. In mice, piRNA-guided transposon repression correlates with establishment of CpG DNA methylation on their sequences, yet the mechanism and the spectrum of genomic targets of piRNA silencing are unknown. Here we show that in addition to DNA methylation, the piRNA pathway is required to maintain a high level of the repressive H3K9me3 histone modification on long interspersed nuclear elements (LINEs) in germ cells. piRNA-dependent chromatin repression targets exclusively full-length elements of actively transposing LINE families, demonstrating the remarkable ability of the piRNA pathway to recognize active elements among the large number of genomic transposon fragments. © 2014 Pezic et al.

Bjorkegren J.L.M.,Mount Sinai School of Medicine | Bjorkegren J.L.M.,Karolinska Institutet | Bjorkegren J.L.M.,University of Tartu | Kovacic J.C.,Mount Sinai School of Medicine | And 2 more authors.
Journal of the American College of Cardiology | Year: 2015

Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key "drivers" of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities. © 2015 American College of Cardiology Foundation.

Arbab-Zadeh A.,Johns Hopkins University | Fuster V.,Mount Sinai School of Medicine
Journal of the American College of Cardiology | Year: 2015

The cardiovascular science community has pursued the quest to identify vulnerable atherosclerotic plaque in patients for decades, hoping to prevent acute coronary events. However, despite major advancements in imaging technology that allow visualization of rupture-prone plaques, clinical studies have not demonstrated improved risk prediction compared with traditional approaches. Considering the complex relationship between plaque rupture and acute coronary event risk suggested by pathology studies and confirmed by clinical investigations, these results are not surprising. This review summarizes the evidence supporting a multifaceted hypothesis of the natural history of atherosclerotic plaque rupture. Managing patients at risk of acute coronary events mandates a greater focus on the atherosclerotic disease burden rather than on features of individual plaques. © 2015 American College of Cardiology Foundation.

Sicherer S.H.,Mount Sinai School of Medicine | Wood R.A.,Johns Hopkins University
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Peanut allergy is often severe, potentially fatal, usually persistent, and appears to have increased in prevalence. An accurate diagnosis is essential because there is a significant burden on quality of life. The tools available for diagnosis include the medical history, skin prick test (SPT), determination of serum peanut-specific IgE antibodies (PN-IgE), and medically supervised oral food challenges. Numerous studies, almost exclusively in children, have correlated clinical outcomes against SPTs and PN-IgE with informative results. The diagnostic utility of SPT and PN-IgE is maximized by considering the degree of positive result and consideration of the medical history (a priori estimation of risk). Emerging tests that evaluate IgE binding to specific proteins in peanut (component testing) add important additional diagnostic information in specific settings. Studies are increasingly focused on how the results of tests considered in combination (or performed serially) may increase diagnostic accuracy. Here, we review the utility of currently available tests and provide suggestions on how to best use them to accurately predict peanut allergy. Still, the physician-supervised oral food challenge remains the most definitive test available. © 2013 American Academy of Allergy, Asthma & Immunology.

Sia G.M.,Howard Hughes Medical Institute | Sia G.M.,Johns Hopkins University | Clem R.L.,Mount Sinai School of Medicine | Huganir R.L.,Howard Hughes Medical Institute | Huganir R.L.,Johns Hopkins University
Science | Year: 2013

Synapse formation in the developing brain depends on the coordinated activity of synaptogenic proteins, some of which have been implicated in a number of neurodevelopmental disorders. Here, we show that the sushi repeat-containing protein X-linked 2 (SRPX2) gene encodes a protein that promotes synaptogenesis in the cerebral cortex. In humans, SRPX2 is an epilepsy- and language-associated gene that is a target of the foxhead box protein P2 (FoxP2) transcription factor. We also show that FoxP2 modulates synapse formation through regulating SRPX2 levels and that SRPX2 reduction impairs development of ultrasonic vocalization in mice. Our results suggest FoxP2 modulates the development of neural circuits through regulating synaptogenesis and that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders.

Sicherer S.H.,Elliot and Roslyn Jaffe Food Allergy Institute | Munoz-Furlong A.,Food Allergy and Anaphylaxis Network | Godbold J.H.,Mount Sinai School of Medicine | Sampson H.A.,Elliot and Roslyn Jaffe Food Allergy Institute
Journal of Allergy and Clinical Immunology | Year: 2010

Background: Allergy to peanuts and tree nuts (TNs) is the leading cause of fatal allergic reactions in the United States, and the prevalence appears to be increasing. Objectives: We sought to determine the US prevalence of self-reported peanut, TN, and sesame allergy in 2008 and compare results with comparable surveys conducted in 1997 and 2002. Methods: A nationwide, cross-sectional, random telephone survey for peanut and TN allergy was conducted with a previously used questionnaire, with additional questions about sesame. Results: A total of 5,300 households (13,534 subjects) were surveyed (participation rate, 42% vs 52% in 2002 and 67% in 1997). Peanut allergy, TN allergy, or both was reported by 1.4% of subjects (95% CI, 1.2% to 1.6%) compared with 1.2% in 2002 and 1.4% in 1997. For adults, the prevalence was 1.3% (95% CI, 1.1% to 1.6%), which was not significantly different from prior surveys. However, the prevalence of peanut or TN allergy for children younger than 18 years was 2.1% (95% CI, 1.6% to 2.7%) compared with 1.2% in 2002 (P = .007) and 0.6% in 1997 (P < .001). The prevalence of peanut allergy in children in 2008 was 1.4% (95% CI, 1.0% to 1.9%) compared with 0.8% in 2002 (P = not significant) and 0.4% in 1997 (P < .0001). The prevalence of childhood TN allergy increased significantly across the survey waves (1.1% in 2008, 0.5% in 2002, and 0.2% in 1997). Sesame allergy was reported by 0.1% (95% CI, 0.0% to 0.2%). Conclusions: Although caution is required in comparing surveys, peanut allergy, TN allergy, or both continue to be reported by more than 1% of the US population (eg, >3 million subjects) and appear to be increasingly reported among children over the past decade. Sesame allergy is reported much less commonly. © 2010 American Academy of Allergy, Asthma & Immunology.

Jabs D.A.,Mount Sinai School of Medicine | Jabs D.A.,Johns Hopkins University
American Journal of Ophthalmology | Year: 2011

Purpose To update information on cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) and to integrate information on its pathogenesis and clinical outcomes. Design Literature review. Methods Selected articles from the medical literature, particularly large epidemiologic studies, including the Johns Hopkins Cytomegalovirus Retinitis Cohort Study, the Longitudinal Study of the Ocular Complications of AIDS, and the Cytomegalovirus Retinitis and Viral Resistance Study, were reviewed. Clinical information is discussed in light of knowledge on CMV, its pathogenesis, and its interactions with human immunodeficiency virus (HIV). Results Cytomegalovirus uses several mechanisms to evade the immune system and establish latent infection in immunologically normal hosts. With immune deficiency, such as late-stage AIDS, CMV reactivates, is disseminated to the eye, and establishes a productive infection, resulting in retinal necrosis. HIV and CMV potentiate each other: CMV accelerates HIV disease, and CMV retinitis is associated with increased mortality. Randomized clinical trials have demonstrated the efficacy of treatments for CMV retinitis. Systemically administered treatment for CMV retinitis decreases AIDS mortality. Highly active antiretroviral therapy (HAART) effectively suppresses HIV replication, resulting in immune recovery, which, if sufficient, controls retinitis without anti-CMV therapy. Resistant CMV, detected in the blood, correlates with resistant virus in the eye and is associated with worse clinical outcomes, including mortality. Host factors, including host genetics and access to care, play a role in the development of CMV retinitis. Conclusions Clinical outcomes of CMV retinitis in patients with AIDS are dependent on characteristics of the virus and host and on HIV-CMV interactions. © 2011 Elsevier Inc.

Alnylam Pharmaceuticals and Mount Sinai School of Medicine | Date: 2015-07-31

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ALAS1 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of ALAS1.

Alnylam Pharmaceuticals and Mount Sinai School of Medicine | Date: 2014-10-03

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ALAS1 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of ALAS1.

Faith J.J.,Immunology Institute and Institute for Genomics and Multiscale Biology | Colombel J.-F.,Mount Sinai School of Medicine | Gordon J.I.,University of Washington
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

It has been 35 y since Carl Woese reported in PNAS how sequencing ribosomal RNA genes could be used to distinguish the three domains of life on Earth. During the past decade, 16S rDNA sequencing has enabled the now frequent enumeration of bacterial communities that populate the bodies of humans representing different ages, cultural traditions, and health states. A challenge going forward is to quantify the contributions of community members to wellness, disease risk, and disease pathogenesis. Here, we explore a theoretical framework for studies of the inheritance of bacterial strains and discuss the advantages and disadvantages of various study designs for assessing the contribution of strains to complex diseases.

Funderburk S.F.,Mount Sinai School of Medicine | Wang Q.J.,University of Kentucky | Yue Z.,Mount Sinai School of Medicine
Trends in Cell Biology | Year: 2010

An increasing body of research on autophagy provides overwhelming evidence for its connection to diverse biological functions and human diseases. Beclin 1, the first mammalian autophagy protein to be described, appears to act as a nexus point between autophagy, endosomal, and perhaps also cell death pathways. Beclin 1 performs these roles as part of a core complex that contains vacuolar sorting protein 34 (VPS34), a class III phosphatidylinositol-3 kinase. The precise mechanism of Beclin 1-mediated regulation of these cellular functions is unclear, but substantial progress has recently been made in identifying new players and their functions in Beclin 1-VSP34 complexes. Here we review emerging studies that are beginning to unveil the physiological functions of Beclin 1-VPS34 in the central control of autophagic activity and other trafficking events through the formation of distinct Beclin 1-VPS34 protein complexes. © 2010 Elsevier Ltd.

Martel-Laferriere V.,Center Hospitalier Of Luniversite Of Montreal | Dieterich D.T.,Mount Sinai School of Medicine
Liver International | Year: 2014

Treating hepatitis C virus (HCV) in HIV/HCV co-infected patients is a challenge. Even if the benefits of achieving a sustained virological response are clear, the rates achieved with the combination of pegylated-interferon and ribavirin are disappointing. The addition of direct acting antiviral agents (DAAs) to the treatment of hepatitis C is revolutionizing the treatment of HCV in mono-infected patients. Even if there have not been any agents approved for the treatment of co-infected patients, many studies specifically designed for this population are ongoing. This article reviews available data on the use of DAAs in co-infected patients and the challenges associated with these new drugs. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Reddy V.Y.,Mount Sinai School of Medicine | Mobius-Winkler S.,University of Leipzig | Miller M.A.,Mount Sinai School of Medicine | Neuzil P.,Homolka Hospital | And 4 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives The purpose of this study was to assess the safety and efficacy of left atrial appendage (LAA) closure in nonvalvular atrial fibrillation (AF) patients ineligible for warfarin therapy. Background The PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) trial demonstrated that LAA closure with the Watchman device (Boston Scientific, Natick, Massachusetts) was noninferior to warfarin therapy. However, the PROTECT AF trial only included patients who were candidates for warfarin, and even patients randomly assigned to the LAA closure arm received concomitant warfarin for 6 weeks after Watchman implantation. Methods A multicenter, prospective, nonrandomized study was conducted of LAA closure with the Watchman device in 150 patients with nonvalvular AF and CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score ≥1, who were considered ineligible for warfarin. The primary efficacy endpoint was the combined events of ischemic stroke, hemorrhagic stroke, systemic embolism, and cardiovascular/unexplained death. Results The mean CHADS2 score and CHA2DS2-VASc (CHADS2 score plus 2 points for age ≥75 years and 1 point for vascular disease, age 65 to 74 years, or female sex) score were 2.8 ± 1.2 and 4.4 ± 1.7, respectively. History of hemorrhagic/bleeding tendencies (93%) was the most common reason for warfarin ineligibility. Mean duration of follow-up was 14.4 ± 8.6 months. Serious procedure- or device-related safety events occurred in 8.7% of patients (13 of 150 patients). All-cause stroke or systemic embolism occurred in 4 patients (2.3% per year): ischemic stroke in 3 patients (1.7% per year) and hemorrhagic stroke in 1 patient (0.6% per year). This ischemic stroke rate was less than that expected (7.3% per year) based on the CHADS2 scores of the patient cohort. Conclusions LAA closure with the Watchman device can be safely performed without a warfarin transition, and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation. (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology [ASAP]; NCT00851578).© 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.

Montalescot G.,Group 47 | Brieger D.,University of Sydney | Dalby A.J.,Milpark Hospital | Park S.-J.,University of Ulsan | Mehran R.,Mount Sinai School of Medicine
Journal of the American College of Cardiology | Year: 2015

The duration of dual antiplatelet therapy (DAPT) after coronary stenting has been evaluated in randomized studies with apparently conflicting results. Although longer exposure associates with more bleeding complications, late stent thrombosis (ST) and myocardial infarction are reduced. In addition, as new drug-eluting stents carry a lower risk of ST compared with the first-generation drug-eluting stents and possibly even bare-metal stents, a shift toward better protection from ST may have an effect on the duration and intensity of DAPT. Whether the duration of DAPT should be shorter or longer than the currently recommended 6 to 12 months is analyzed in this review, drawing on lessons from the most recent studies. © 2015 American College of Cardiology Foundation.

Stein C.R.,Mount Sinai School of Medicine | Savitz D.A.,Brown University | Bellinger D.C.,Harvard University
Epidemiology | Year: 2013

BACKGROUND:: In animal studies, perfluorinated compounds affect fetal growth, development, viability, and postnatal growth. The limited epidemiologic findings on child neurobehavioral development are mixed. METHODS:: We recruited and evaluated 320 children who participated in the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community highly exposed to perfluorooctanoate (PFOA) through contaminated drinking water. We examined associations among estimated in utero PFOA exposure, measured childhood PFOA serum concentration, and subsequent performance on neuropsychological tests 3-4 years later at ages 6-12 years. We assessed Intelligence Quotient (IQ) reading and math skills, language, memory and learning, visual-spatial processing, and attention. All multivariable linear regression models were adjusted for age, sex, home environment, test examiner, and maternal IQ. Models with measured childhood PFOA were additionally adjusted for child body mass index. RESULTS:: Children in the highest as compared with lowest quartile of estimated in utero PFOA had increases in Full Scale IQ (β 4.6, 95% confidence interval [CI] = 0.7-8.5) and decreases in characteristics of attention deficit/hyperactivity disorder as measured by the Clinical Confidence Index of Connors' Continuous Performance Test-II (β -8.5, 95% CI = -16.1 to -0.8). There were negligible associations between PFOA and reading or math skills or neuropsychological functioning. CONCLUSION:: These results do not suggest an adverse association between the levels of PFOA exposure experienced by children in this cohort and their performance on neuropsychological tests. Copyright © 2013 by Lippincott Williams & Wilkins.

Frank M.J.,Brown University | Fossella J.A.,Mount Sinai School of Medicine
Neuropsychopharmacology | Year: 2011

Many of the individual differences in cognition, motivation, and learningFand the disruption of these processes in neurological conditionsFare influenced by genetic factors. We provide an integrative synthesis across human and animal studies, focusing on a recent spate of evidence implicating a role for genes controlling dopaminergic function in frontostriatal circuitry, including COMT, DARPP-32, DAT1, DRD2, and DRD4. These genetic effects are interpreted within theoretical frameworks developed in the context of the broader cognitive and computational neuroscience literature, constrained by data from pharmacological, neuroimaging, electrophysiological, and patient studies. In this framework, genes modulate the efficacy of particular neural computations, and effects of genetic variation are revealed by assays designed to be maximally sensitive to these computations. We discuss the merits and caveats of this approach and outline a number of novel candidate genes of interest for future study. © 2011 Nature Publishing Group All rights reserved.

Bichoupan K.,Mount Sinai School of Medicine | Dieterich D.T.,Mount Sinai School of Medicine | Martel-Laferriere V.,Center Hospitalier Of Luniversite Of Montreal
Current HIV/AIDS Reports | Year: 2014

Approximately one-third of patients infected with human immunodeficiency virus (HIV) are concomitantly infected with hepatitis C virus (HCV). As a result, liver disease remains a major source of morbidity and mortality in HIV patients. Prior to 2011, treatments of HCV lacked efficacy in clinical trials in HIV/HCV co-infected patients. Fortunately, several direct-acting antivirals (DAAs) have now entered clinical practice and others have reached advanced stages of clinical development. These therapies offer significant benefits such as improved rates of sustained virologic response (SVR), shortened durations of treatment, and compatibility with HIV antiretroviral therapies. Treatments such as sofosbuvir (SOF) have received approval for HIV/HCV co-infected patients. Moreover, interferon-free options exist for HIV/HCV co-infected patients who may be ineligible or intolerant of interferon. Despite these improvements, physicians must be aware of the differences between these DAAs, the patient characteristics that play a role on the effectiveness of these medications, and the drug-drug interactions these DAAs may have with existing HIV antiretroviral therapies. The aim of this review is to discuss the prevalence and incidence of HIV/HCV co-infection, critical factors related to patient evaluation, current treatment options, and new developments in the management of HIV/HCV co-infected patients. © 2014 Springer Science+Business Media.

Mount Sinai School of Medicine and University of Hong Kong | Date: 2014-10-17

Disclosed is a fully chemically defined, small molecule-mediated, directed differentiation system that promotes differentiation of stem cells, including embryonic stem cells, induced pluripotent stem cells, and adult stem cells, such as human forms of these stem cell types, to ventricular cardiomyocytes in a highly efficient, reproducible and scalable fashion. Also disclosed is a cost-effective and efficient protocol, or method, for generating cardiomyocytes and a cost-effective and efficient method of maturing cardiomyocytes. The disclosed differentiation system provides a platform to perform large-scale pharmacological screenings and to provide a valuable source of each of cardiac progenitor cells and cardiomyocytes for cell replacement therapies in cardiac repair.

Stein C.R.,Mount Sinai School of Medicine | Savitz D.A.,Brown University
Environmental Health Perspectives | Year: 2011

Background: Perfluorinated compounds (PFCs) are persistent environmental pollutants. Toxicology studies demonstrate the potential for perfluorooctanoic acid (PFOA) and other PFCs to affect human growth and development. Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder with suspected environmental and genetic etiology. Objectives: We examined the cross-sectional association between serum PFC concentration and parent or self-report of doctor-diagnosed ADHD with and without current ADHD medication. Methods: We used data from the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community highly exposed to PFOA through contaminated drinking water, to study non-Hispanic white children 5-18 years of age. Logistic regression models were adjusted for age and sex. Results: Of the 10,546 eligible children, 12.4% reported ADHD and 5.1% reported ADHD plus ADHD medication use. We observed an inverted J-shaped association between PFOA and ADHD, with a small increase in prevalence for the second quartile of exposure compared with the lowest, and a decrease for the highest versus lowest quartile. The prevalence of ADHD plus medication increased with perfluorohexane sulfonate (PFHxS) levels, with an adjusted odds ratio of 1.59 (95% confidence interval, 1.21-2.08) comparing the highest quartile of exposure to the lowest. We observed a modest association between perfluorooctane sulfonate and ADHD with medication. Conclusions: The most notable finding for PFOA and ADHD, a reduction in prevalence at the highest exposure level, is unlikely to be causal, perhaps reflecting a spurious finding related to the geographic determination of PFOA exposure in this population or to unmeasured behavioral or physiologic correlates of exposure and outcome. Possible positive associations between other PFCs and ADHD, particularly PFHxS, warrant continued investigation.

News Article | January 27, 2017

A paper on this discovery, led by Mount Sinai School of Medicine in New York, is published in the journal Nature Cell Biology. The researchers suggest that the work could lead to new drugs and therapies that transform the treatment of metastatic cancers, most of which cannot be cured with current approaches. Most deaths to cancer are due to metastasis - a disease stage that begins when cancer cells escape primary tumors, migrate through the blood or lymph system, and establish secondary tumors in other parts of the body. The secondary, or metastatic, tumor is the same form of cancer as the primary tumor. When metastatic cells are examined, they have features matching those of the primary cancer and not of the tissue that the secondary tumor has formed in. Finding ways to stop cancer cells acquiring the ability to migrate, or establish and grow secondary tumors, could save many lives. Hypoxia, a condition in which cells are starved of oxygen, is a known hallmark of solid tumors that triggers responses and induces resistance to chemotherapy and radiotherapy. Until now, however, it has not been clear how hypoxia in primary tumors influences what happens to cancer cells that migrate to new sites, and how this affects the prognosis of the disease. The new study suggests that hypoxic microenvironments in primary tumors give rise to dormant disseminated tumor cells (DTCs) that "hide" from therapy and may be a cause of disease relapse and poor outcomes. Senior author Julio A. Aguirre-Ghiso, Ph.D., a professor of medicine, hematology, and medical oncology at Mount Sinai, says: "This research highlights the signals in the primary tumor that instruct disseminated cancer cells to become dormant." "Dormant cells must be targeted to address the whole spectrum of the disease and attacking the cancer," he adds. With the help of biosensors, nanotechnology, and advanced imaging, the team implanted drugs that create hypoxic and non-hypoxic niches in breast tumors in mice and observed the effect on cells. The researchers were able to isolate the cancer cells one by one and find out how they behaved when they traveled from the primary tumor to the lungs. Genetically encoded biosensors allowed them to determine which cells were dormant, which ones were exposed to low oxygen, and their reactions to therapy. They discovered that hypoxic tumor microenvironments not only produce DTCs that rapidly grow and spread, but also send a large proportion of them into a dormant state that makes them better able to evade chemotherapy. The study suggests, therefore, that the poor prognoses associated with hypoxic tumors may arise not only because they produce more aggressive cancer cells, but also because they program many of them to enter a dormant state where they can hide from chemotherapy. Researchers also found genes in the primary tumor that correlated with the behavior of dormant, treatment-resistant cells in the secondary tumors. They suggest that these genes could form the basis of a biomarker to predict which patients are likely to have more of the dormant, resistant cells. Prof. Aguirre-Ghiso describes the study as "an important step to further explore the biology of these dormant cells and design therapies that specifically address this biology," and he concludes: Learn how cancer cells' ability to break free and spread arises from a 'broken switch'.

Ahmed R.,Northumbria University | Dunford J.,Northumbria University | Mehran R.,Mount Sinai School of Medicine | Robson S.,Northumbria University | And 2 more authors.
Journal of the American College of Cardiology | Year: 2014

Cardiovascular disease continues to be the leading cause of death in the western world. Due to advancements in diagnosis, prevention, and treatment, cardiovascular mortality has fallen in recent years. Previous studies have evaluated the impact of traditional risk factors such as hypercholesterolemia and smoking. However, limited studies have been conducted to evaluate sex discrepancies among patients with cardiovascular disease. Pre-eclampsia is a multisystem placentally mediated disease, which usually arises after 32 weeks of gestation and classically presents with hypertension and proteinuria. Pre-eclampsia affects 2% to 8% of all pregnancies worldwide and is often complicated by fetal growth restriction. Women with a history of pre-eclampsia are at increased risk of future cardiovascular complications. Therefore, this topic is of significance to the cardiovascular health of over 300 million women worldwide. The goal of this review is to determine the association of pre-eclampsia and future cardiovascular risk and to explore the potential management options for these high-risk women. © 2014 by the American College of Cardiology Foundation.

Chakrabarti L.A.,Institute Pasteur Paris | Simon V.,Mount Sinai School of Medicine
Current Opinion in Immunology | Year: 2010

HIV-1 can be contained by the immune system, as demonstrated by the existence of rare individuals who spontaneously control HIV-1 replication in the absence of antiretroviral therapy. Emerging evidence points to the importance of a very active cellular immune response in mediating HIV-1 control. The rapid induction of interferon-dependent HIV restriction factors, the presence of protective MHC class I alleles, and the development of a high avidity T-cell response may all cooperate in limiting HIV replication at an early stage. This review will focus on recent advances in understanding the immune mechanisms of HIV control, and on the lessons that may be drawn for the development of candidate HIV vaccines. © 2010 Elsevier Ltd.

Madias J.E.,Mount Sinai School of Medicine | Madias J.E.,Elmhurst Hospital Center
International Journal of Cardiology | Year: 2014

Diagnosis of Takotsubo syndrome (TTS), the reversible, acute heart failure pathological entity, precipitated by stress, is based on the fulfillment of sets of criteria, developed by careful characterization of the precipitants, symptoms, results of imaging testing, clinical course, and follow-up of many patients presented with this affliction. As understanding of TTS, increase in its awareness, and the diversion in its presentation have evolved, the various proposed diagnostic criteria, naturally have started to appear outmoded. The author argues that the initially proposed Mayo Clinic criteria, the subsequently revised Mayo Clinic criteria, the Japanese Circulation Society guidelines, the Johns Hopkins criteria, and the Gothenburg criteria for the diagnosis of TTS have been outpaced by the rapidly accumulating clinical experience, and thus need to be replaced by more realistic sets of diagnostic rules. To this effect the author proposes a set of diagnostic criteria for TTS, which include 2 plausible, albeit speculative, notions, that of the milder forms or formes frustes of TTS, and the existence of "TTS comorbidity" in patients with various other illnesses, which either precipitate TTS, or are being brought about by TTS. © 2014 Elsevier Ireland Ltd.

Olanow C.W.,Mount Sinai School of Medicine | Mcnaught K.,National Tourette Syndrome Association
Movement Disorders | Year: 2011

Parkinson's disease (PD) is characterized by protein accumulation in the form of Lewy bodies and neurites. It is thus reasonable to consider that alterations in protein handling in the form of increased production, impaired clearance, or both might be central to the etiopathogenesis of the disease. Increasing genetic, laboratory and pathologic evidence has accumulated over the past 25 years supporting this hypothesis. A vicious cycle could develop in which increased protein accumulation from any cause could lead to interference with lysosomal and proteasomal clearance mechanisms causing further protein accumulation. Eventually, protein accumulation could overwhelm the cell's defenses and lead to the formation of toxic oligomers and amyloid-based inclusions such as Lewy bodies, disruption of critical cell processes, and ultimately neurodegeneration. More recent findings of Lewy pathology in implanted embryonic dopamine neurons in PD patients raises the intriguing possibility that PD might be a prion disorder. These concepts suggests new targets and novel candidate therapies that might be neuroprotective for PD. © 2011 Movement Disorder Society.

Craddock N.,University of Cardiff | Sklar P.,Mount Sinai School of Medicine
The Lancet | Year: 2013

Studies of families and twins show the importance of genetic factors affecting susceptibility to bipolar disorder and suggest substantial genetic and phenotypic complexity. Robust and replicable genome-wide significant associations have recently been reported in genome-wide association studies at several common polymorphisms, including variants within the genes CACNA1C, ODZ4, and NCAN. Strong evidence exists for a polygenic contribution to risk (ie, many risk alleles of small effect). A notable finding is the overlap of susceptibility between bipolar disorder and schizophrenia for several individual risk alleles and for the polygenic risk. By contrast, genomic structural variation seems to play a smaller part in bipolar disorder than it does in schizophrenia. Together, these genetic findings suggest directions for future studies to delineate the aetiology and pathogenesis of bipolar disorder, indicate the need to re-evaluate our diagnostic classifications, and might eventually pave the way for major improvements in clinical management. © 2013 Elsevier Ltd.

Brennan P.,International Agency for Research on Cancer IARC | Hainaut P.,International Agency for Research on Cancer IARC | Boffetta P.,International Agency for Research on Cancer IARC | Boffetta P.,Mount Sinai School of Medicine
The Lancet Oncology | Year: 2011

Lung cancer is the most common form of cancer death worldwide. Although reduction of tobacco consumption remains the most appropriate strategy to reduce lung-cancer burden, identification of genes involved in the cause of disease could contribute to further understanding of the underlying mechanisms, and eventually lead to additional prevention strategies and targeted treatments. Common gene variants involved in lung cancer have been recently identified through large, collaborative, genome-wide association studies. These studies identified three separate loci that are associated with lung cancer (5p15, 6p21, and 15q25) and include genes that regulate acetylcholine nicotinic receptors and telomerase production. However, much about genetic risk remains to be discovered, and rarer gene variants, such as those of the CHEK2 gene, likely account for most of the remaining risk. There is also a need for studies that investigate how genetic susceptibility is associated with clinical outcome measures, including treatment response and tumour relapse. © 2011 Elsevier Ltd.

Landrigan P.J.,Mount Sinai School of Medicine | Goldman L.R.,George Washington University
Health Affairs | Year: 2011

A key policy breakthrough occurred nearly twenty years ago with the discovery that children are far more sensitive than adults to toxic chemicals in the environment. This finding led to the recognition that chemical exposures early in life are significant and preventable causes of disease in children and adults. We review this knowledge and recommend a new policy to regulate industrial and consumer chemicals that will protect the health of children and all Americans, prevent disease, and reduce health care costs. The linchpins of a new US chemical policy will be: first, a legally mandated requirement to test the toxicity of chemicals already in commerce, prioritizing chemicals in the widest use, and incorporating new assessment technologies; second, a tiered approach to premarket evaluation of new chemicals; and third, epidemiologic monitoring and focused health studies of exposed populations. © 2011 Project HOPE-The People-to-People Health Foundation, Inc.

Cecere G.,Columbia University | Hoersch S.,Massachusetts Institute of Technology | O'keeffe S.,Columbia University | Sachidanandam R.,Mount Sinai School of Medicine | Grishok A.,Columbia University
Nature Structural and Molecular Biology | Year: 2014

Argonaute proteins and their small RNA cofactors short interfering RNAs are known to inhibit gene expression at the transcriptional and post-transcriptional levels. In Caenorhabditis elegans, the Argonaute CSR-1 binds thousands of endogenous siRNAs (endo-siRNAs) that are antisense to germline transcripts. However, its role in gene expression regulation remains controversial. Here we used genome-wide profiling of nascent RNA transcripts and found that the CSR-1 RNA interference pathway promoted sense-oriented RNA polymerase II transcription. Moreover, a loss of CSR-1 function resulted in global increase in antisense transcription and ectopic transcription of silent chromatin domains, which led to reduced chromatin incorporation of centromere-specific histone H3. On the basis of these findings, we propose that the CSR-1 pathway helps maintain the directionality of active transcription, thereby propagating the distinction between transcriptionally active and silent genomic regions. © 2014 Nature America, Inc.

Holmes D.R.,Mayo Medical School | Kar S.,Cedars Sinai Medical Center | Price M.J.,Scripps Research Institute | Whisenant B.,Intermountain Medical Center | And 4 more authors.
Journal of the American College of Cardiology | Year: 2014

BACKGROUND: In the PROTECT AF (Watchman Left Atrial Appendage Closure Technology for Embolic Protection in Patients With Atrial Fibrillation) trial that evaluated patients with nonvalvular atrial fibrillation (NVAF), left atrial appendage (LAA) occlusion was noninferior to warfarin for stroke prevention, but a periprocedural safety hazard was identified. OBJECTIVES: The goal of this study was to assess the safety and efficacy of LAA occlusion for stroke prevention in patients with NVAF compared with long-term warfarin therapy. METHODS: This randomized trial further assessed the efficacy and safety of the Watchman device. Patients with NVAF who had a CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and previous stroke/transient ischemic attack) score ≥2 or 1 and another risk factor were eligible. Patients were randomly assigned (in a 2:1 ratio) to undergo LAA occlusion and subsequent discontinuation of warfarin (intervention group, n = 269) or receive chronic warfarin therapy (control group, n = 138). Two efficacy and 1 safety coprimary endpoints were assessed. RESULTS: At 18 months, the rate of the first coprimary efficacy endpoint (composite of stroke, systemic embolism [SE], and cardiovascular/unexplained death) was 0.064 in the device group versus 0.063 in the control group (rate ratio 1.07 [95% credible interval (CrI): 0.57 to 1.89]) and did not achieve the prespecified criteria noninferiority (upper boundary of 95% CrI ≥1.75). The rate for the second coprimary efficacy endpoint (stroke or SE >7 days' postrandomization) was 0.0253 versus 0.0200 (risk difference 0.0053 [95% CrI: -0.0190 to 0.0273]), achieving noninferiority. Early safety events occurred in 2.2% of the Watchman arm, significantly lower than in PROTECT AF, satisfying the pre-specified safety performance goal. Using a broader, more inclusive definition of adverse effects, these still were lower in PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial than in PROTECT AF (4.2% vs. 8.7%; p = 0.004). Pericardial effusions requiring surgical repair decreased from 1.6% to 0.4% (p = 0.027), and those requiring pericardiocentesis decreased from 2.9% to 1.5% (p = 0.36), although the number of events was small. CONCLUSIONS: In this trial, LAA occlusion was noninferior to warfarin for ischemic stroke prevention or SE >7 days' post-procedure. Although noninferiority was not achieved for overall efficacy, event rates were low and numerically comparable in both arms. Procedural safety has significantly improved. This trial provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have an absolute contraindication to short-term warfarin therapy. © 2014 by the American College of Cardiology Foundation.

Sanofi S.A., Scripps Research Institute, Mount Sinai School of Medicine, Whitehead Institute For Biomedical Research and Massachusetts Institute of Technology | Date: 2014-03-20

The present invention relates to methods of constructing an integrated artificial immune system that comprises appropriate in vitro cellular and tissue constructs or their equivalents to mimic the normal tissues that interact with vaccines in mammals. The artificial immune system can be used to test the efficacy of vaccine candidates in vitro and thus, is useful to accelerate vaccine development and testing drug and chemical interaction with the immune system.

Massachusetts Institute of Technology, Brigham, Women's Hospital, Mount Sinai School of Medicine and New York University | Date: 2013-06-19

Methods for making particles, such as nanoparticles, devices useful in the methods, and particles made by the method are described herein. The methods involves the use of a microfluidic device, such that upon mixing solutions of the materials to form the particles (or a solution of the material or materials to form the particles and a non-solvent for the material or materials), at least two symmetrical microvortices are formed simultaneously. The method can be used to prepare polymeric or non-polymeric particles and hybrid particles, such as lipid-polymer hybrid particles, as well as such particles containing one or more agents associated with the particles.

O'Carroll D.,Mouse Biology Unit | Schaefer A.,Mount Sinai School of Medicine
Neuropsychopharmacology | Year: 2013

MicroRNAs (miRNAs) are small, noncoding RNAs that mediate posttranscriptional gene suppression in a sequence-specific manner. The ability of a single miRNA species to target multiple messenger RNAs (mRNAs) makes miRNAs exceptionally important regulators of various cellular functions. The regulatory capacity of miRNAs is increased further by the miRNA ability to suppress gene expression using multiple mechanisms that range from translational inhibition to mRNA degradation. The high miRNA diversity multiplied by the large number of individual miRNA targets generates a vast regulatory RNA network than enables flexible control of mRNA expression. The gene-regulatory capacity and diversity of miRNAs is particularly valuable in the brain, where functional specialization of neurons and persistent flow of information requires constant neuronal adaptation to environmental cues. In this review we will summarize the current knowledge about miRNA biogenesis and miRNA expression regulation with a focus on the role of miRNAs in the mammalian nervous system. © 2013 American College of Neuropsychopharmacology. All rights reserved.

Siu A.L.,Mount Sinai School of Medicine | Siu A.L.,James ters Veterans Affairs Medical Center
JAMA - Journal of the American Medical Association | Year: 2016

DESCRIPTION New US Preventive Services Task Force (USPSTF) recommendation on screening for autism spectrum disorder (ASD) in young children. METHODS The USPSTF reviewed the evidence on the accuracy, benefits, and potential harms of brief, formal screening instruments for ASD administered during routine primary care visits and the benefits and potential harms of early behavioral treatment for young children identified with ASD through screening. POPULATION This recommendation applies to children aged 18 to 30 months who have not been diagnosed with ASD or developmental delay and for whom no concerns of ASD have been raised by parents, other caregivers, or health care professionals. RECOMMENDATION The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for ASD in young children for whom no concerns of ASD have been raised by their parents or a clinician. (I statement). © 2016 American Medical Association.

Rosenson R.S.,Mount Sinai School of Medicine | Stafforini D.M.,University of Utah
Journal of Lipid Research | Year: 2012

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH), is a unique member of the phospholipase A2superfamily. This enzyme is characterized by its ability to specifically hydrolyze PAF as well as glycerophospholipids containing short, truncated, and/or oxidized fatty acyl groups at the sn-2 position of the glycerol backbone. In humans, Lp-PLA 2 circulates in active form as a complex with low- and high-density lipoproteins. Clinical studies have reported that plasma Lp-PLA2 activity and mass are strongly associated with atherogenic lipids and vascular risk. These observations led to the hypothesis that Lp-PLA2 activity and/or mass levels could be used as biomarkers of cardiovascular disease and that inhibition of the activity could offer an attractive therapeutic strategy. Darapladib, a compound that inhibits Lp-PLA2 activity, is anti-atherogenic in mice and other animals, and it decreases atherosclerotic plaque expansion in humans. However, disagreement continues to exist regarding the validity of Lp-PLA2 as an independent marker of atherosclerosis and a scientifically justified target for intervention. Circulating Lp-PLA 2 mass and activity are associated with vascular risk, but the strength of the association is reduced after adjustment for basal concentrations of the lipoprotein carriers with which the enzyme associates. Genetic studies in humans harboring an inactivating mutation at this locus indicate that loss of Lp-PLA2function is a risk factor for inflammatory and vascular conditions in Japanese cohorts. Consistently, overexpression of Lp-PLA 2 has anti-inflammatory and anti-atherogenic properties in animal models. This thematic review critically discusses results from laboratory and animal studies, analyzes genetic evidence, reviews clinical work demonstrating associations between Lp-PLA2 and vascular disease, and summarizes results from animal and human clinical trials in which administration of darapladib was tested as a strategy for the management of atherosclerosis. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.

Siu A.L.,Mount Sinai School of Medicine | Siu A.L.,James ters Veterans Affairs Medical Center
Annals of Internal Medicine | Year: 2015

Description: Update of the 2009 U.S. Preventive Services Task Force (USPSTF) recommendation on counseling and interventions to prevent tobacco use and tobacco-related disease in adults, including pregnant women. Methods: The USPSTF reviewed the evidence on interventions for tobacco smoking cessation that are relevant to primary care (behavioral interventions, pharmacotherapy, and complementary or alternative therapy) in adults, including pregnant women. Population: This recommendation applies to adults aged 18 years or older, including pregnant women. Recommendations: The USPSTF recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and U.S. Food and Drug Administration-approved pharmacotherapy for cessation to adults who use tobacco. (A recommendation) The USPSTF recommends that clinicians ask all pregnant women about tobacco use, advise them to stop using tobacco, and provide behavioral interventions for cessation to pregnant women who use tobacco. (A recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of pharmacotherapy interventions for tobacco cessation in pregnant women. (I statement) The USPSTF concludes that the current evidence is insufficient to recommend electronic nicotine delivery systems for tobacco cessation in adults, including pregnant women. The USPSTF recommends that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety (previously stated). (I statement) © 2015 American College of Physicians.

Cerutti A.,Catalan Institution for Research and Advanced Studies | Cerutti A.,Hospital Del Mar | Cerutti A.,Mount Sinai School of Medicine | Chen K.,Mount Sinai School of Medicine | Chorny A.,Mount Sinai School of Medicine
Annual Review of Immunology | Year: 2011

Mucosal surfaces are colonized by large communities of commensal bacteria and represent the primary site of entry for pathogenic agents. To prevent microbial intrusion, mucosal B cells release large amounts of immunoglobulin (Ig) molecules through multiple follicular and extrafollicular pathways. IgA is the most abundant antibody isotype in mucosal secretions and owes its success in frontline immunity to its ability to undergo transcytosis across epithelial cells. In addition to translocating IgA onto the mucosal surface, epithelial cells educate the mucosal immune system as to the composition of the local microbiota and instruct B cells to initiate IgA responses that generate immune protection while preserving immune homeostasis. Here we review recent advances in our understanding of the cellular interactions and signaling pathways governing IgA production at mucosal surfaces and discuss new findings on the regulation and function of mucosal IgD, the most enigmatic isotype of our mucosal antibody repertoire. © 2011 by Annual Reviews. All rights reserved.

Gabor Miklos G.L.,Secure Genetics Pty Ltd | Maleszka R.,Mount Sinai School of Medicine
Hormones and Behavior | Year: 2011

A 2010 Nature editorial entitled ". Time for the Epigenome" trumpets the appearance of the International Human Epigenome Consortium and likens it to Biology's equivalent of the Large Hadron Collider. It strongly endorses the viewpoint that selective modifications of "marks" on DNA and histones constitute the crucial codes of life, a proposition which is hotly contested (Ptashne et al., in 2010). This proposition reflects the current mindset that DNA and histone modifications are the prime movers in gene regulation during evolution. This claim is perplexing, since the well characterized organisms, Drosophila melanogaster and Caenorhabditis elegans, lack methylated DNA "marks" and the DNA methytransferase enzymology. Despite their complete absence, D. melanogaster nevertheless has extensive gene regulatory networks which drive sophisticated development, gastrulation, migration of germ cells and yield a nervous system with significant neural attributes. In stark contrast, the honey bee Apis mellifera deploys its human-type DNA methyltransferase enzymology to "mark" its DNA and it too has sophisticated development. What roles therefore is DNA methylation playing in different animals? The honey bee brings a fresh perspective to this question. Its combinatorial chemistry of pheromones, tergal and cuticular exudates provide an exquisite communication system between thousands of individuals. The development of queen and worker is strictly controlled by differential feeding of royal jelly and their adult behaviors are accompanied by epigenomic changes. Their interfaces with different "environments" are extensive, allowing an evaluation of the roles of epigenomes in behavior in a natural environment, in the space of a few weeks, and at requisite levels of experimental rigor. © 2010 Elsevier Inc.

Sugar I.P.,Mount Sinai School of Medicine | Chong P.L.-G.,Temple University
Journal of the American Chemical Society | Year: 2012

Despite extensive studies for nearly three decades, lateral distribution of molecules in cholesterol/phospholipid bilayers remains elusive. Here we present a statistical mechanical model of cholesterol/phospholipid mixtures that is able to rationalize almost every critical mole fraction (X cr) value previously reported for sterol superlattice formation as well as the observed biphasic changes in membrane properties at X cr. This model is able to explain how cholesterol superlattices and cholesterol/phospholipid condensed complexes are interrelated. It gives a more detailed characterization of the LG Iregion (a broader region than the liquid disordered-liquid ordered mixed-phase region), which is considered to be a sludgelike mixture of fluid phase and aggregates of rigid clusters. A rigid cluster is formed by a cholesterol molecule and phospholipid molecules that are condensed to the cholesterol. Rigid clusters of similar size tend to form aggregates, in which cholesterol molecules are regularly distributed into superlattices. According to this model, the extent and type of sterol superlattices, thus the lateral distribution of the entire membrane, should vary with cholesterol mole fraction in a delicate, predictable, and nonmonotonic manner, which should have profound functional implications. © 2011 American Chemical Society.

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics. Copyright © by the American College of Chest Physicians 2013.

Levesque B.G.,University of California at San Diego | Sandborn W.J.,University of California at San Diego | Ruel J.,Mount Sinai School of Medicine | Feagan B.G.,Robarts Research Institute | And 2 more authors.
Gastroenterology | Year: 2015

It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn's disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn's Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration-sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of "treat-to-target" algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization. © 2015 AGA Institute.

Sudol M.,00 North Academy Avenue | Sudol M.,Mount Sinai School of Medicine
Structure | Year: 2012

WW domains are small modules that mediate protein/protein interactions. In this issue of Structure, Aragón and colleagues show that a WW domain of YAP can mediate complexes with either the canonical PY motif in an inhibitory Smad or engage in phosphorylation-dependent complexes with one of the activated Smads. The propensity of YAP WW to recognize a pSP motif is a surprising find with a number of far-reaching ramifications. © 2012 Elsevier Ltd.

Vachon M.-L.,Laval University | Dieterich D.T.,Mount Sinai School of Medicine
Seminars in Liver Disease | Year: 2011

The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drugdrug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development. Copyright © 2011 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Rappaport J.,Temple University | Volsky D.J.,Mount Sinai School of Medicine
Journal of NeuroVirology | Year: 2015

Combination antiretroviral therapy (ART) has altered the outcomes of HIV infection in treated populations by greatly reducing the incidence of opportunistic infections, cancer, and HIV-associated dementia. Despite these benefits, treated patients remain at high risk of chronic diseases affecting the peripheral organs and brain. Generally, these morbidities are attributed to persistence of latent HIV in resting T cells, chronic inflammation, and metabolic effects of ART. This review makes the case that monocytes/macrophages warrant attention as persistent reservoirs of HIV under ART, source of systemic and brain inflammation, and important targets for HIV eradication to control chronic HIV diseases. © 2015, Journal of NeuroVirology, Inc.

Adams D.H.,Mount Sinai School of Medicine | Rosenhek R.,Vienna University Hospital | Falk V.,University of Zürich
European Heart Journal | Year: 2010

Degenerative mitral valve disease often leads to leaflet prolapse due to chordal elongation or rupture, and resulting in mitral valve regurgitation. Guideline referral for surgical intervention centres primarily on symptoms and ventricular dysfunction. The recommended treatment for degenerative mitral valve disease is mitral valve reconstruction, as opposed to valve replacement with a bioprosthetic or mechanical valve, because valve repair is associated with improved event free survival. Recent studies have documented a significant number of patients are not referred in a timely fashion according to established guidelines, and when they are subjected to surgery, an alarming number of patients continue to undergo mitral valve replacement. The debate around appropriate timing of intervention for asymptomatic severe mitral valve regurgitation has put additional emphasis on targeted surgeon referral and the need to ensure a very high rate of mitral valve repair, particularly in the non-elderly population. Current clinical practice remains suboptimal for many patients, and this review explores the need for a 'best practice revolution' in the field of degenerative mitral valve regurgitation. © The Author 2010.

Piccolo R.,University of Bern | Giustino G.,Mount Sinai School of Medicine | Mehran R.,Mount Sinai School of Medicine | Windecker S.,University of Bern
The Lancet | Year: 2015

Summary Stable coronary artery disease is the most common clinical manifestation of ischaemic heart disease and a leading cause of mortality worldwide. Myocardial revascularisation is a mainstay in the treatment of symptomatic patients or those with ischaemia-producing coronary lesions, and reduces ischaemia to a greater extent than medical treatment. Documentation of ischaemia and plaque burden is fundamental in the risk stratification of patients with stable coronary artery disease, and several invasive and non-invasive techniques are available (eg, fractional flow reserve or intravascular ultrasound) or being validated (eg, instantaneous wave-free ratio and optical coherence tomography). The use of new-generation drug-eluting stents and arterial conduits greatly improve clinical outcome in patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). PCI is feasible, safe, and effective in many patients with stable coronary artery disease who remain symptomatic despite medical treatment. In patients with multivessel and left main coronary artery disease, the decision between PCI or CABG is guided by the local Heart Team (team of different cardiovascular specialists, including non-invasive and invasive cardiologists, and cardiac surgeons), who carefully judge the possible benefits and risks inherent to PCI and CABG. In specific subsets, such as patients with diabetes and advanced, multivessel coronary artery disease, CABG remains the standard of care in view of improved protection against recurrent ischaemic adverse events. © 2015 Elsevier Ltd.

Simonyan K.,Mount Sinai School of Medicine | Horwitz B.,U.S. National Institutes of Health
Neuroscientist | Year: 2011

Speech production is one of the most complex and rapid motor behaviors, and it involves a precise coordination of more than 100 laryngeal, orofacial, and respiratory muscles. Yet we lack a complete understanding of laryngeal motor cortical control during production of speech and other voluntary laryngeal behaviors. In recent years, a number of studies have confirmed the laryngeal motor cortical representation in humans and have provided some information about its interactions with other cortical and subcortical regions that are principally involved in vocal motor control of speech production. In this review, the authors discuss the organization of the peripheral and central laryngeal control based on neuroimaging and electrical stimulation studies in humans and neuroanatomical tracing studies in nonhuman primates. It is hypothesized that the location of the laryngeal motor cortex in the primary motor cortex and its direct connections with the brain stem laryngeal motoneurons in humans, as opposed to its location in the premotor cortex with only indirect connections to the laryngeal motoneurons in nonhuman primates, may represent one of the major evolutionary developments in humans toward the ability to speak and vocalize voluntarily. © 2011 The Author(s).

Mount Sinai School of Medicine, Yale University and U.S. National Institutes of Health | Date: 2014-06-17

Methods and compositions for the treatment of treatment-resistant depression are described. More specifically, the invention demonstrates that intranasal administration of ketamine is effective to ameliorate the symptoms of depression in a patient who has not responded to an adequate trial of one antidepressant in the current episode and has recurrent or chronic depressive symptoms (>2 years).

Mount Sinai School of Medicine, U.S. National Institutes of Health and Yale University | Date: 2014-03-05

Methods and compositions for the treatment of treatment-resistant depression are described. More specifically, the invention demonstrates that intranasal administration of ketamine is effective to ameliorate the symptoms of depression in a patient who has not responded to an adequate trial of one antidepressant in the current episode and has recurrent or chronic depressive symptoms (>2 years).

Gladstone and Mount Sinai School of Medicine | Date: 2013-03-13

The present disclosure provides compositions and methods for reactivating latent immunodeficiency vims. The methods generally involve contacting an HIV-infected cell in which HIV is latent with an agent that binds a bromodomain (BRD) in the cell. Latently infected cells contain replication-competent integrated HIV-1 genomes that are blocked at the transcriptional level, resulting in the absence of viral protein expression. The present disclosure provides methods for reducing the reservoir of latent immunodeficiency virus in an individual.

Mount Sinai School of Medicine and Temple University | Date: 2013-11-26

The present invention relates to compounds according to Formula I: and salts thereof, wherein R^(1), R^(2), R^(3), R^(4), Ar, and n are as defined herein. Methods for preparing compounds of Formula I are also provided. The present invention further includes methods of treating cellular proliferative disorders, such as cancer, with the compounds of Formula I.

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