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Hepatic decompensation/serious adverse events in post-liver transplantation recipients on sofosbuvir for recurrent hepatitis C virus

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World Journal of Gastroenterology 2016年第9期22卷 2844-2854页

作者： Neal Patel Kian Bichoupan Lawrence Ku Rachana Yalamanchili Alyson Harty Donald Gardenier Michel Ng David Motamed Viktoriya Khaitova Nancy Bach Charissa Chang Priya Grewal Meena Bansal Ritu Agarwal Lawrence Liu Gene Im Jennifer Leong Leona Kim-Schluger Joseph Odin Jawad Ahmad Scott Friedman Douglas Dieterich Thomas Schiano Ponni Perumalswami Andrea Branch Division of Liver Diseases Icahn School of Medicine at Mount Sinai Recanati Miller Transplant Institute Icahn School of Medicine at Mount Sinai

AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV ***: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite ***: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P 2, 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for ***: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.

关键词： Hepatitis C virus Sofosbuvir Ribavirin Anemia Hepatic decompensation Serious adverse event Liver transplant

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Re-re-treatment of hepatitis C virus: Eight patients who relapsed twice after direct-acting-antiviral drugs

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World Journal of Gastroenterology 2015年第43期21卷 12430-12438页

作者： Joshua Hartman Kian Bichoupan Neal Patel Sweta Chekuri Alyson Harty Douglas Dieterich Ponni Perumalswami Andrea D Branch Department of Medicine Icahn School of Medicine at the Mount Sinai Medical Center Division of Liver Disease Icahn School of Medicine at the Mount Sinai Medical Center

AIM: To determine risk factors associated with hepatitis C virus(HCV) treatment failure after direct acting antivirals in patients with complex treatment ***: All HCV mono-infected patients who received treatment at our institution were *** was restricted to patients who previously failed treatment with boceprevir(BOC) or telaprevir(TVR) and started simeprevir(SMV) and sofosbuvir(SOF) ± ribavirin(RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus(HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December,31 st 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics,HCV infection,and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/***: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon(PEG) and RBV who failed this triple therapy were subsequently retreated with an off-label all-oral regimen of SMV and SOF for 12 wk,with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response,but later relapsed. Eight(100%) patients were male. Mean age was 56(range,49-64). Eight(100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6(mean 3.8). Eight(100%) patients were male had liver cirrhosis as determi

关键词： Hepatitis C Protease inhibitor Relapse Simeprevir

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Characterizing functional consequences of DNA copy number alterations in breast and ovarian tumors by spaceMap

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Journal of Genetics and Genomics 2018年第7期45卷 361-371页

作者： Christopher J.Conley Umut Ozbek Pei Wang Jie Peng Department of Statistics University of California Davis Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai

We propose a novel conditional graphical model -- spaceMap -- to construct gene regulatory networks from multiple types of high dimensional omic profiles. A motivating application is to characterize the perturbation of DNA copy number alterations （CNAs） on downstream protein levels in tumors. Through a penalized multivariate regression framework, spaceMap jointly models high dimensional protein levels as responses and high dimensional CNAs as predictors. In this setup, spaceMap infers an undirected network among proteins together with a directed network encoding how CNAs perturb the protein network, spaceMap can be applied to learn other types of regulatory relationships from high dimensional molecular profiles, especially those exhibiting hub structures. Simulation studies show spaceMap has greater power in detecting regulatory relationships over competing methods. Additionally, spaceMap includes a network analysis toolkit for biological interpretation of inferred networks. We applies spaceMap to the CNAs, gene expression and proteomics data sets from CPTAC-TCGA breast （n = 77） and ovarian （n = 174） cancer studies. Each cancer exhibits disruption of＇ion transmembrane transport＇ and ＇regulation from RNA polymerase lI promoter＇ by CNA events unique to each cancer. Moreover, using protein levels as a response yields a more functionally-enriched network than using RNA expressions in both cancer types. The network results also help to pinpoint crucial cancer genes and provide insights on the functional consequences of important CNA in breast and ovarian cancers.

关键词： Integrative genomics Proteogenomics Conditional graphical models Network analysis

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Expanding the donor pool: Hepatitis C, hepatitis B and human immunodeficiency virus-positive donors in liver transplantation

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World Journal of Gastroenterology 2019年第47期25卷 6799-6812页

作者： James F Crismale Jawad Ahmad Division of Liver Diseases Icahn School of Medicine at Mount Sinai

Liver transplantation(LT)remains the best option for patients with end-stage liver disease but the demand for organs from deceased donors continues to outweigh the available *** advent of highly effective anti-viral treatments has reduced the number of patients undergoing LT for hepatitis C(HCV)and hepatitis B(HBV)related liver disease and yet the number of patients waiting for LT continues to increase,driven by an increase in the patients listed with a diagnosis of cirrhosis due to non-alcoholic steatohepatitis and alcoholrelated liver *** addition,human immunodeficiency virus(HIV)infection,which was previously a contra-indication for LT,is no longer a fatal disease due to the effectiveness of HIV therapy and patients with HIV and liver disease are now developing indications for *** rising demand for LT is projected to increase further in the future,thus driving the need to investigate potential means of expanding the pool of potential *** mechanism for doing so is utilizing organs from donors that previously would have been discarded or used only in exceptional circumstances such as HCV-positive,HBV-positive,and HIVpositive *** advent of highly effective anti-viral therapy has meant that these organs can now be used with excellent outcomes in HCV,HBV or HIV infected recipients and in some cases uninfected recipients.

关键词： Hepatitis C Hepatitis B Human immunodeficiency virus Liver transplantation

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Severe liver injury due to herbal and dietary supplements and the role of liver transplantation

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World Journal of Gastroenterology 2019年第46期25卷 6704-6712页

作者： Priya Grewal Jawad Ahmad Division of Liver Diseases Icahn School of Medicine at Mount Sinai

Herbal and dietary supplements(HDS)are increasingly used worldwide for numerous,mainly unproven health *** HDS industry is poorly regulated compared to prescription medicines and most products are easily *** induced liver injury(DILI)is a well-recognized entity associated with prescription and over the counter medications and many reports have emerged of potential HDS-related *** is considerable geographic variability in the risk and severity of DILI associated with HDS but the presentation of severe liver injury is similar with a hepatocellular pattern accompanied by *** type of injury can lead to acute liver failure and the need for liver *** will often fail to mention their use of HDS,considering it natural and therefore *** physicians should understand that these products can be associated with DILI and explicitly ask about HDS use in any patient with otherwise unexplained acute liver injury.

关键词： Herbal and dietary supplements Drug induced liver injury Liver transplantation Acute liver failure Geographic variability

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Necrolytic acral erythema in a human immunodeficiency virus/hepatitis C virus coinfected patient:A case report

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World Journal of Hepatology 2019年第2期11卷 226-233页

作者： Katerina G Oikonomou Dost Sarpel Alexandra Abrams-Downey Adnan Mubasher Douglas T Dieterich Division of Infectious Diseases Icahn School of Medicine at Mount Sinai Department of Pathology Icahn School of Medicine at Mount Sinai Division of Liver Diseases Icahn School of Medicine at Mount Sinai

BACKGROUND Necrolytic acral erythema(NAE) is a rare dermatological disorder,which is associated with hepatitis C virus(HCV) infection or zinc *** is characterized by erythematous or violaceous lesions occurring primarily in the lower *** treatment includes systemic steroids and oral zinc *** report a case of NAE in a 66-year-old human immunodeficiency virus(HIV)/HCV co-infected woman with *** is rarely reported in co-infected patients and the exact mechanisms of pathogenesis are still *** SUMMARY A 66-year-old HIV/HCV co-infected female patient presented with painless,nonpruritic rash of extremities for one week and underwent extensive work-up for possible rheumatologic disorders including vasculitis and *** skin biopsies of right and left thigh revealed thickened parakeratotic stratum corneum most consistent with *** was started on prednisone and zinc supplementation with resolution of the lesions and improvement of *** Clinicians should maintain high clinical suspicion for early recognition of NAE in patients with rash and HCV.

关键词： Necrolytic acral erythema Human immunodeficiency virus Hepatitis C virus Zinc deficiency Case report

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Lipogenic metabolism： a viable target for prostate cancer treatment？

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Asian Journal of Andrology 2014年第5期16卷 661-663页

作者： Mengmeng Liang David J Mulholland icahn school of Medicine at mount sinai New York NY USA I

Cancer cells often depend on altered metabolism compared with their normal counterparts.1-4 As observed in 1924 by Otto Warburg, cancer cells show preferential glucose consumption by way of aerobic glycolysis while normal cells generally assume mitochondrial oxidative phosphorylation.4 Another metabolic hallmark of carcinogenesis is altered lipid metabolism, whereby cancer cells may adopt enhanced de novo lipid production （lipogenesis）.l-3 Enhanced lipid metabolism is also observed in individuals with metabolic syndromes potentially a consequence of increasing popularity of the Standard American Diet, composed of high levels of saturated fats and carbohydrates.5 A growing body of epidemiological data indicates a positive correlation between the occurrence of metabolic syndromes, such as cardiovascular disease, obesity, type-2 diabetes and associated hyperinsulemia, with the aggressiveness of cancer.6-9 Remarkably, it is estimated that for every 1% reduction in saturated fats, replaced by polyunsaturated, there would be a 2%-3% reduction in cardiovascular disease.10 Thus, it is conceivable that an equally remarkable attenuation in cancer progression might be achieved with such a reduction in lipid accumulation.

关键词： Lipogenic metabolism a viable target

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Intersectional gene inactivation: there is more to conditional mutagenesis than Cre

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Science China(Life Sciences) 2018年第9期61卷 1115-1117页

作者： Philippe Soriano Department of Cell Developmental and Regenerative Biology Icahn School of Medicine at Mount Sinai

The efforts of many laboratories worldwide and large scale international mutagenesis consortia have resulted in mutagenesis of nearly all mouse genes, and present efforts are devoted to large scale phenotyping of germline null mutant mice (Ayadi et al., 2012). Although early lethality associated with loss of function of a given gene may prevent elucidating its function at a later stage or in a given tissue, conditional alleles in which a critical part of the gene is flanked by recombinase target sites provide an opportunity for addressing gene function at later stages (Branda and Dymecki,2004). Fortunately, many of the mutant alleles generated by the consortia allow for conditional mutagenesis using site directed recombinases.

关键词： there is more to conditional mutagenesis than Cre

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Molecular mechanism of noradrenaline during the stress-induced major depressive disorder

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Neural Regeneration Research 2018年第7期13卷 1159-1169页

作者： Kenjiro Seki Satomi Yoshida Manoj Kumar Jaiswal Department of Pharmacology School of Pharmaceutical ScienceOhu University Department of Psychiatry Icahn School of Medicine at Mount Sinai

Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity ***-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of *** of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder（MDD） and several antidepressants functions by increasing the monoamine level at the synapses in the ***,it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of *** to noradrenergic receptor stimulation,it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of *** addition,enhanced noradrenaline（NA） release is central response to stress and thought to be a risk factor for the development of ***,fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus（LC）.However,it is unclear how they alter the firing activity of LC *** inconsistent reports about antidepressant effect of NA-reuptake inhibitors（NRIs） and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of *** this review,we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in *** will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons,hypothalamic-pituitary-adrenal axis（HPA-axis） and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.

关键词： major depression stress noradrenaline noradrenaline-reuptake inhibitors serotonin receptors hypothalamic-pituitary-adrenal axis locus coeruleus selective serotonin reuptake inhibitors serotonin noradrenaline-reuptake inhibitors

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Nociceptors and Macrophages in Bacterial Meningitis:Partners in Crime?

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Neuroscience Bulletin 2024年第3期40卷 418-420页

作者： Fang Gao Hongzhen Hu The Kimberly and Eric J.Waldman Department of Dermatology Icahn School of Medicine at Mount SinaiNew York NY10029USA The Nash Family Department of Neuroscience Icahn School of Medicine at Mount SinaiNew York NY10029USA The Mark Lebwohl Center for Neuroinfammation and Sensation Icahn School of Medicine at Mount SinaiNew York NY10029USA Friedman Brain Institute Icahn School of Medicine at Mount SinaiNew York NY10029USA

Bacterial meningitis is a serious and potentially life-threatening infection that affects the protective layers surrounding the brain and spinal cord,known as the *** types of bacteria,including Streptococcus pneumoniae,Neisseria meningitidis,and Haemophilus influenzae,can cause this *** populations,such as infants,children,immunocompromised adults,and the elderly,are particularly vulnerable to these *** of bacterial meningitis can manifest suddenly and may include high fever,severe and persistent headache,stiff neck,vomiting,sensitivity to light,and confusion or changes in mental state[1,2].Identifying these symptoms in infants can be more challenging and may lead to long-term disability or death[3].Despite the effectiveness of vaccines,it is crucial to understand how bacteria invade the brain and how our innate immune system responds to infection(Fig.1).

关键词： protective infection suddenly

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