Showing papers by "Icahn School of Medicine at Mount Sinai published in 2009"
TL;DR: Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
Abstract: Summary Background Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. Methods In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m 2 per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French–American–British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Findings Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21·1 months (IQR 15·1–26·9), median overall survival was 24·5 months (9·9–not reached) for the azacitidine group versus 15·0 months (5·6–24·1) for the conventional care group (hazard ratio 0·58; 95% CI 0·43–0·77; stratified log-rank p=0·0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50·8% (95% CI 42·1–58·8) of patients in the azacitidine group were alive compared with 26·2% (18·7–34·3) in the conventional care group (p Interpretation Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care. Funding Celgene Corporation.
2,282 citations
French Institute of Health and Medical Research1, Institut Gustave Roussy2, University of Paris-Sud3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, Boston Children's Hospital11, University of Gothenburg12, University of Freiburg13, University of California, San Francisco14, Buck Institute for Research on Aging15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Yale University25, Howard Hughes Medical Institute26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, University of Göttingen45, Stony Brook University46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells
2,218 citations
TL;DR: The efficacy of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy and there was a higher rate of adverse safety events in the intervention group than in the control group, which were mainly a result of periprocedural complications.
1,787 citations
TL;DR: It is the view of the AE-PCOS Society Task Force that PCOS should be defined by the presence of hyperandrogenism, ovarian dysfunction, and/or polycystic ovaries, and the exclusion of related disorders.
1,678 citations
TL;DR: More patients with hepatocellular carcinoma could be candidates for transplantation if the current dual approach to candidacy, based on the strict Milan criteria, were replaced with a more precise estimation of survival contouring individual tumour characteristics and use of the up-to-seven criteria.
Abstract: Summary Background Patients undergoing liver transplantation for hepatocellular carcinoma within the Milan criteria (single tumour ≤5 cm in size or ≤3 tumours each ≤3 cm in size, and no macrovascular invasion) have an excellent outcome. However, survival for patients with cancers that exceed these criteria remains unpredictable and access to transplantation is a balance of maximising patients' chances of cure and organ availability. The aim of this study was to explore the survival of patients with tumours that exceed the Milan criteria, to assess whether the criteria could be less restrictive, enabling more patients to qualify as transplant candidates, and to derive a prognostic model based on objective tumour characteristics, to see whether the Milan criteria could be expanded. Methods Data on patients who underwent transplantation for hepatocellular carcinoma despite exceeding Milan criteria at different centres were recorded via a web-based survey completed by specialists from each centre. The survival of these patients was correlated retrospectively with the size of the largest tumour nodule, number of nodules, and presence or absence of microvascular invasion detected at pathology. Contoured multivariable regression Cox models produced survival estimates by means of different combinations of the covariates. The primary aim of this study was to derive a prognostic model of overall survival based on tumour characteristics, according to the main parameters used in the Tumour Node Metastasis classification. The secondary aim was the identification of a subgroup of patients with hepatocellular carcinoma exceeding the Milan criteria, who achieved a 5-year overall survival of at least 70%—ie, similar to the outcome expected for patients who meet the Milan criteria. Findings Over a 10-month period, between June 25, 2006, and April 3, 2007, data for 1556 patients who underwent transplantation for hepatocellular carcinoma were entered on the database by 36 centres. 1112 patients had hepatocellular carcinoma exceeding Milan criteria and 444 patients had hepatocellular carcinoma shown not to exceed Milan criteria at post-transplant pathology review. In the group of patients with hepatocellular carcinomas exceeding the criteria, the median size of the largest nodule was 40 mm (range 4–200) and the median number of nodules was four (1–20). 454 of 1112 patients (41%) had microvascular invasion and, for those transplanted outside the Milan criteria, 5-year overall survival was 53·6% (95% CI 50·1–57·0), compared with 73·3% (68·2–77·7) for those that met the criteria. Hazard ratios (HR) associated with increasing values of size and number were 1·34 (1·25–1·44) and 1·51 (1·21–1·88), respectively. The effect was linear for size, whereas for number of tumours, the effect tended to plateau above three tumours. The effect of tumour size and number on survival was mediated by recurrence (b=0·08, SE=0·12, p=0·476). The presence of microvascular invasion doubled HRs in all scenarios. The 283 patients without microvascular invasion, but who fell within the Up-to-seven criteria (hepatocellular carcinomas with seven as the sum of the size of the largest tumour [in cm] and the number of tumours) achieved a 5-year overall survival of 71·2% (64·3–77·0). Interpretation More patients with hepatocellular carcinoma could be candidates for transplantation if the current dual (yes/no) approach to candidacy, based on the strict Milan criteria, were replaced with a more precise estimation of survival contouring individual tumour characteristics and use of the up-to-seven criteria. Funding Specific funding was not used to do this study.
1,547 citations
TL;DR: A series of routines that can be interfaced with the most popular classical molecular dynamics codes through a simple patching procedure, which leaves the possibility for the user to exploit many different MD engines depending on the system simulated and on the computational resources available.
1,423 citations
Dartmouth College1, Cedars-Sinai Medical Center2, HealthPartners3, University of Missouri4, Icahn School of Medicine at Mount Sinai5, Georgia Regents University6, Arizona State University7, Baylor College of Medicine8, University of Massachusetts Medical School9, University of California, San Francisco10, University of Pennsylvania11, University of Minnesota12
TL;DR: The USPSTF concludes that the current evidence is insufficient to assess additional benefits and harms of either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer.
Abstract: Description: Update of the 2002 U. S. Preventive Services Task Force (USPSTF) recommendation statement on screening for breast cancer in the general population. Methods: The USPSTF examined the evidence on the efficacy of 5 screening modalities in reducing mortality from breast cancer: film mammography, clinical breast examination, breast self-examination, digital mammography, and magnetic resonance imaging in order to update the 2002 recommendation. To accomplish this update, the USPSTF commissioned 2 studies: 1) a targeted systematic evidence review of 6 selected questions relating to benefits and harms of screening, and 2) a decision analysis that used population modeling techniques to compare the expected health outcomes and resource requirements of starting and ending mammography screening at different ages and using annual versus biennial screening intervals. Recommendations: The USPSTF recommends against routine screening mammography in women aged 40 to 49 years. The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient's values regarding specific benefits and harms. (Grade C recommendation) The USPSTF recommends biennial screening mammography for women between the ages of 50 and 74 years. (Grade B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of clinical breast examination beyond screening mammography in women 40 years or older. (I statement) The USPSTF recommends against clinicians teaching women how to perform breast self-examination. (Grade D recommendation) The USPSTF concludes that the current evidence is insufficient to assess additional benefits and harms of either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer. (I statement)
1,405 citations
University of Louisville1, University of Pittsburgh2, Royal Brisbane and Women's Hospital3, Carolinas Medical Center4, Beaumont Hospital5, University of Cincinnati6, Seoul National University7, Iwate Medical University8, Toho University9, Kaohsiung Medical University10, University of Paris11, University of Texas MD Anderson Cancer Center12, McGill University13, University of California, Los Angeles14, Memorial Sloan Kettering Cancer Center15, Mayo Clinic16, University of Chicago17, Icahn School of Medicine at Mount Sinai18, University of Hong Kong19, Duke University20, Vanderbilt University21, Roger Williams Medical Center22, Northwestern University23, University of Duisburg-Essen24, Washington University in St. Louis25
TL;DR: Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery, and national and international societies should become involved in the goal of establishing training standards and credentialing.
Abstract: Objective:To summarize the current world position on laparoscopic liver surgery.Summary Background Data:Multiple series have reported on the safety and efficacy of laparoscopic liver surgery. Small and medium sized procedures have become commonplace in many centers, while major laparoscopic liver re
1,366 citations
TL;DR: Several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls, and duplications 55 kilobases upstream of complementary DNA AK123120 indicate that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.
1,331 citations
TL;DR: It is concluded that butyrate enhances the intestinal barrier by regulating the assembly of tight junctions and this dynamic process is mediated by the activation of AMPK.
Abstract: Butyrate, one of the SCFA, promotes the development of the intestinal barrier. However, the molecular mechanisms underlying the butyrate regulation of the intestinal barrier are unknown. To test the hypothesis that the effect of butyrate on the intestinal barrier is mediated by the regulation of the assembly of tight junctions involving the activation of the AMP-activated protein kinase (AMPK), we determined the effect of butyrate on the intestinal barrier by measuring the transepithelial electrical resistance (TER) and inulin permeability in a Caco-2 cell monolayer model. We further used a calcium switch assay to study the assembly of epithelial tight junctions and determined the effect of butyrate on the assembly of epithelial tight junctions and AMPK activity. We demonstrated that the butyrate treatment increased AMPK activity and accelerated the assembly of tight junctions as shown by the reorganization of tight junction proteins, as well as the development of TER. AMPK activity was also upregulated by butyrate during calcium switch-induced tight junction assembly. Compound C, a specific AMPK inhibitor, inhibited the butyrate-induced activation of AMPK. The facilitating effect of butyrate on the increases in TER in standard culture media, as well as after calcium switch, was abolished by compound C. We conclude that butyrate enhances the intestinal barrier by regulating the assembly of tight junctions. This dynamic process is mediated by the activation of AMPK. These results suggest an intriguing link between SCFA and the intracellular energy sensor for the development of the intestinal barrier.
1,297 citations
Stanford University1, NorthShore University HealthSystem2, Columbia University3, Medical Research Council4, Cardiff University5, Centre for Mental Health6, University of Colorado Denver7, Emory University8, Washington University in St. Louis9, Icahn School of Medicine at Mount Sinai10, LSU Health Sciences Center New Orleans11, University of California, San Francisco12, Roy J. and Lucille A. Carver College of Medicine13, Massachusetts Institute of Technology14, Virginia Commonwealth University15
TL;DR: It is demonstrated that common schizophrenia susceptibility alleles can be detected and the characterization of these signals will suggest important directions for research on susceptibility mechanisms.
Abstract: Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
TL;DR: Research has shown that resilience is mediated by adaptive changes in several neural circuits involving numerous neurotransmitter and molecular pathways, which shape the functioning of the neural circuits that regulate reward, fear, emotion reactivity and social behaviour.
Abstract: Every individual experiences stressful life events. In some cases acute or chronic stress leads to depression and other psychiatric disorders, but most people are resilient to such effects. Recent research has begun to identify the environmental, genetic, epigenetic and neural mechanisms that underlie resilience, and has shown that resilience is mediated by adaptive changes in several neural circuits involving numerous neurotransmitter and molecular pathways. These changes shape the functioning of the neural circuits that regulate reward, fear, emotion reactivity and social behaviour, which together are thought to mediate successful coping with stress.
Colorado Department of Public Health and Environment1, Agency for Healthcare Research and Quality2, Arizona State University3, Cincinnati Children's Hospital Medical Center4, Dartmouth College5, Cedars-Sinai Medical Center6, Group Health Cooperative7, Regions Hospital8, University of Missouri9, Icahn School of Medicine at Mount Sinai10, Georgia Regents University11, Baylor College of Medicine12, University of Massachusetts Medical School13, University of California, San Francisco14, University of Pennsylvania15, University of Minnesota16
TL;DR: These results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.
Abstract: Interleukin 17-producing T helper cells (T(H)-17 cells) are important in experimental autoimmune encephalomyelitis, but their route of entry into the central nervous system (CNS) and their contribution relative to that of other effector T cells remain to be determined. Here we found that mice lacking CCR6, a chemokine receptor characteristic of T(H)-17 cells, developed T(H)-17 responses but were highly resistant to the induction of experimental autoimmune encephalomyelitis. Disease susceptibility was reconstituted by transfer of wild-type T cells that entered into the CNS before disease onset and triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of choroid plexus in mice and humans. Our results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.
TL;DR: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes, and suggests that glucose-lowering regimens should be tailored to the individual.
Abstract: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84–0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76–0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90–1.20) and 1.10 for cardiovascular death (95% CI 0.84–1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91–3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89–1.13, vs HR 0.84, 95% CI 0.74–0.94, respectively; interaction p = 0.04). Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.
TL;DR: A growing body of data suggests that ED crowding is associated both with objective clinical endpoints, such as mortality, as well as clinically important processes of care,such as time to treatment for patients with time-sensitive conditions such as pneumonia.
Abstract: Background: An Institute of Medicine (IOM) report defines six domains of quality of care: safety, patient-centeredness, timeliness, efficiency, effectiveness, and equity. The effect of emergency department (ED) crowding on these domains of quality has not been comprehensively evaluated.
Objectives: The objective was to review the medical literature addressing the effects of ED crowding on clinically oriented outcomes (COOs).
Methods: We reviewed the English-language literature for the years 1989–2007 for case series, cohort studies, and clinical trials addressing crowding’s effects on COOs. Keywords searched included “ED crowding,”“ED overcrowding,”“mortality,”“time to treatment,”“patient satisfaction,”“quality of care,” and others.
Results: A total of 369 articles were identified, of which 41 were kept for inclusion. Study quality was modest; most articles reflected observational work performed at a single institution. There were no randomized controlled trials. ED crowding is associated with an increased risk of in-hospital mortality, longer times to treatment for patients with pneumonia or acute pain, and a higher probability of leaving the ED against medical advice or without being seen. Crowding is not associated with delays in reperfusion for patients with ST-elevation myocardial infarction. Insufficient data were available to draw conclusions on crowding’s effects on patient satisfaction and other quality endpoints.
Conclusions: A growing body of data suggests that ED crowding is associated both with objective clinical endpoints, such as mortality, as well as clinically important processes of care, such as time to treatment for patients with time-sensitive conditions such as pneumonia. At least two domains of quality of care, safety and timeliness, are compromised by ED crowding.
University of Pennsylvania1, University of Miami2, University of California, Los Angeles3, Icahn School of Medicine at Mount Sinai4, University of Southern California5, University of Washington6, University of North Carolina at Chapel Hill7, University of California, Davis8, Yale University9, University of Illinois at Chicago10, University of Utah11, University of Iowa12, Indiana University13, Vanderbilt University14, University of Pittsburgh15
TL;DR: The results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to the authors' knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.
TL;DR: It is shown that human occludin (OCLN) is an essential HCV cell entry factor that is able to render murine cells infectable with HCVpp and the identification of OCLN as a new HCV entry factor further highlights the importance of the tight junction complex in the viral entry process.
Abstract: Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of much needed specific antiviral therapies and an effective vaccine has been hampered by the lack of a convenient small animal model. The determinants restricting HCV tropism to human and chimpanzee hosts are unknown. Replication of the viral RNA has been demonstrated in mouse cells, but these cells are not infectable with either lentiviral particles bearing HCV glycoproteins (HCVpp) or HCV produced in cell culture (HCVcc) (A.P., M.E. and C.M.R., unpublished observations), suggesting that there is a block at the level of entry. Here we show, using an iterative complementary DNA library screening approach, that human occludin (OCLN) is an essential HCV cell entry factor that is able to render murine cells infectable with HCVpp. Similarly, OCLN is required for the HCV-susceptibility of human cells, because its overexpression in uninfectable cells specifically enhanced HCVpp uptake, whereas its silencing in permissive cells impaired both HCVpp and HCVcc infection. In addition to OCLN, HCVpp infection of murine cells required expression of the previously identified HCV entry factors CD81 (ref. 4), scavenger receptor class B type I (SR-BI, also known as SCARB1) and claudin-1 (CLDN1). Although the mouse versions of SR-BI and CLDN1 function at least as well as the human proteins in promoting HCV entry, both OCLN and CD81 must be of human origin to allow efficient infection. The species-specific determinants of OCLN were mapped to its second extracellular loop. The identification of OCLN as a new HCV entry factor further highlights the importance of the tight junction complex in the viral entry process, and provides an important advance towards efforts to develop small animal models for HCV.
TL;DR: It is shown that DC development progresses from the macrophage and DC precursor to common DC precursors that give rise to pDCs and classical spleen DCs, but not monocytes, and finally to committed precursor of cDCs (pre-cDCs).
Abstract: Dendritic cells (DCs) in lymphoid tissue arise from precursors that also produce monocytes and plasmacytoid DCs (pDCs). Where DC and monocyte lineage commitment occurs and the nature of the DC precursor that migrates from the bone marrow to peripheral lymphoid organs are unknown. We show that DC development progresses from the macrophage and DC precursor to common DC precursors that give rise to pDCs and classical spleen DCs (cDCs), but not monocytes, and finally to committed precursors of cDCs (pre-cDCs). Pre-cDCs enter lymph nodes through and migrate along high endothelial venules and later disperse and integrate into the DC network. Further cDC development involves cell division, which is controlled in part by regulatory T cells and fms-like tyrosine kinase receptor-3.
TL;DR: Three robust HCC subclasses are observed, each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels, and it is indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation.
Abstract: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum α-fetoprotein levels An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of β-catenin mutation but rather was the result of transforming growth factor-β activation, thus representing a new mechanism of WNT pathway activation in HCC These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease [Cancer Res 2009;69(18):7385–92]
TL;DR: Multiple studies have demonstrated the effectiveness of simulation in the teaching of basic science and clinical knowledge, procedural skills, teamwork, and communication as well as assessment at the undergraduate and graduate medical education levels.
Abstract: Medical schools and residencies are currently facing a shift in their teaching paradigm. The increasing amount of medical information and research makes it difficult for medical education to stay current in its curriculum. As patients become increasingly concerned that students and residents are "practicing" on them, clinical medicine is becoming focused more on patient safety and quality than on bedside teaching and education. Educators have faced these challenges by restructuring curricula, developing small-group sessions, and increasing self-directed learning and independent research. Nevertheless, a disconnect still exists between the classroom and the clinical environment. Many students feel that they are inadequately trained in history taking, physical examination, diagnosis, and management. Medical simulation has been proposed as a technique to bridge this educational gap. This article reviews the evidence for the utility of simulation in medical education. We conducted a MEDLINE search of original articles and review articles related to simulation in education with key words such as simulation, mannequin simulator, partial task simulator, graduate medical education, undergraduate medical education, and continuing medical education. Articles, related to undergraduate medical education, graduate medical education, and continuing medical education were used in the review. One hundred thirteen articles were included in this review. Simulation-based training was demonstrated to lead to clinical improvement in 2 areas of simulation research. Residents trained on laparoscopic surgery simulators showed improvement in procedural performance in the operating room. The other study showed that residents trained on simulators were more likely to adhere to the advanced cardiac life support protocol than those who received standard training for cardiac arrest patients. In other areas of medical training, simulation has been demonstrated to lead to improvements in medical knowledge, comfort in procedures, and improvements in performance during retesting in simulated scenarios. Simulation has also been shown to be a reliable tool for assessing learners and for teaching topics such as teamwork and communication. Only a few studies have shown direct improvements in clinical outcomes from the use of simulation for training. Multiple studies have demonstrated the effectiveness of simulation in the teaching of basic science and clinical knowledge, procedural skills, teamwork, and communication as well as assessment at the undergraduate and graduate medical education levels. As simulation becomes increasingly prevalent in medical school and resident education, more studies are needed to see if simulation training improves patient outcomes.
TL;DR: The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation.
Abstract: Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview ...
TL;DR: It is hypothesized that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.
Abstract: Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1-Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.
TL;DR: It is shown that monocytes gave rise exclusively to CD103(-)CX(3)CR1(+) lamina propria DCs under the control of macrophage-colony-stimulating factor receptor (M-CSFR) and Fms-like thyrosine kinase 3 (Flt3) ligands.
TL;DR: This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of theDifferent approaches.
Abstract: Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches.
TL;DR: Members of the International Expert Committee have recommended that diabetes should be diagnosed if A1C is ≤6.5%, without need to measure the plasma glucose concentration, but there are concerns that practical limitations will lead to false positives and negatives with this approach.
Abstract: Members of the International Expert Committee have recommended that diabetes should be diagnosed if A1C is ≤6.5%, without need to measure the plasma glucose concentration (1). We are concerned that practical limitations will lead to false positives and negatives with this approach.
A given A1C instrument may identify some but not other abnormal hemoglobins (http://www.ngsp.org/prog/index2.html). How, therefore, can we be sure whether a hemoglobinopathy is causing (or preventing) diagnosis? Before diagnosis, should we not also exclude iron deficiency anemia, which may increase A1C by 1–1.5%, as well as hemolytic anemia and renal failure or chronic infections, which also lower …
TL;DR: This work reports that the influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I CARD ubiquitination, thereby suppressing Rig-I signal transduction and revealing a mechanism by which influenza virus inhibits host IFN response.
TL;DR: In this article, the effects of albuminuria and reduced estimated GFR (eGFR) on the risk for cardiovascular and renal events among individuals with type 2 diabetes were investigated. But, there was no evidence of an interaction between the effect of higher eGFR and lower UACR.
Abstract: There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.
TL;DR: Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with the two doses were associated with different outcomes, the study results must be interpreted with caution.
Abstract: In this double-blind trial, we examined the possibility that rasagiline has diseasemodifying effects in Parkinson’s disease. A total of 1176 subjects with untreated Parkinson’s disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson’s Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed-start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72. Results Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (±SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09±0.02 points per week in the early-start group vs. 0.14±0.01 points per week in the placebo group, P = 0.01), less worsening in the score between baseline and week 72 (2.82±0.53 points in the early-start group vs. 4.52±0.56 points in the delayed-start group, P = 0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085±0.02 points per week in the early-start group vs. 0.085±0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47±0.50 points in the earlystart group and 3.11±0.50 points in the delayed-start group, P = 0.60). Conclusions Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials. gov number, NCT00256204.)
TL;DR: This work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis.
Abstract: Multiple members of the let-7 family of miRNAs are often repressed in human cancers, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins LIN28 and LIN28B block let-7 precursors from being processed to mature miRNAs, suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency approximately 15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. LIN28 and LIN28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis.