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Opal S.M.,Brown University | Dellinger R.P.,Robert Wood Johnson Medical School | Vincent J.-L.,Erasme University Hospital | Masur H.,U.S. National Institutes of Health | Angus D.C.,University of Pittsburgh
Critical Care Medicine

OBJECTIVE:: The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. DATA SOURCES:: We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. STUDY SELECTION:: Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. DATA EXTRACTION:: Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. DATA SYNTHESIS:: After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. CONCLUSIONS:: We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis. © 2014 by the Society of Critical Care Medicine. Source

Spector R.,Robert Wood Johnson Medical School | Johanson C.E.,Brown University
Molecular Brain

The purpose of this review is to discuss the implications of the 2009 discovery of the sixth deoxyribonucleoside (dN) [5-hydroxymethyldeoxycytidine (hmdC)] in DNA which is the most abundant in neurons. The concurrent discovery of the three ten-eleven translocation enzymes (TET) which not only synthesize but also oxidize hmdC in DNA, prior to glycosylase removal and base excision repair, helps explain many heretofore unexplained phenomena in brain including: 1) the high concentration of ascorbic acid (AA) in neurons since AA is a cofactor for the TET enzymes, 2) the requirement for reduced folates and the dN synthetic enzymes in brain, 3) continued DNA synthesis in non-dividing neurons to repair the dynamic formation/removal of hmdC, and 4) the heretofore unexplained mechanism to remove 5-methyldeoxycytidine, the fifth nucleoside, from DNA. In these processes, we also describe the important role of choroid plexus and CSF in supporting vitamin homeostasis in brain: especially for AA and folates, for hmdC synthesis and removal, and methylated deoxycytidine (mdC) removal from DNA in brain. The nexus linking AA and folates to methylation, hydroxymethylation, and demethylation of DNA is pivotal to understanding not only brain development but also the subsequent function. © 2014 Spector and Johanson; licensee BioMed Central Ltd. Source

Cold-shock response is elicited by the transfer of exponentially growing cells from their optimum temperature to a significantly lower growth temperature and is characterized by the induction of several cold-shock proteins. These proteins, which presumably possess a variety of different activities, are critical for survival and continued growth at low temperature. One of the main consequences of cold shock is stabilization of the secondary structures in nucleic acids leading to hindrance of RNA degradation. Cold-shock proteins, such as RNA helicase CsdA, and 3′-5′ processing exoribonucleases, such as PNPase and RNase R, are presumably involved in facilitating the RNA metabolism at low temperature. As a step toward elucidating the individual contributions of these proteins to low-temperature RNA metabolism, the global transcript profiles of cells lacking CsdA, RNase R and PNPase proteins as well as cells individually over-expressing these proteins as compared to the wild-type cells were analyzed at 15 °C. The analysis showed distinct sets of genes, which are possible targets of each of these proteins. This analysis will help further our understanding of the low-temperature RNA metabolism. © 2012 by the Molecular Biology Society of Japan/Wiley Publishing Ltd. Source

Hohenester E.,Imperial College London | Yurchenco P.D.,Robert Wood Johnson Medical School
Cell Adhesion and Migration

The heterotrimeric laminins are a defining component of all basement membranes and self-assemble into a cell-associated network. The three short arms of the cross-shaped laminin molecule form the network nodes, with a strict requirement for one α, one β and one γ arm. The globular domain at the end of the long arm binds to cellular receptors, including integrins, α-dystroglycan, heparan sulfates and sulfated glycolipids. Collateral anchorage of the laminin network is provided by the proteoglycans perlecan and agrin. A second network is then formed by type IV collagen, which interacts with the laminin network through the heparan sulfate chains of perlecan and agrin and additional linkage by nidogen. This maturation of basement membranes becomes essential at later stages of embryo development. © 2013 Landes Bioscience. Source

Fondell J.D.,Robert Wood Johnson Medical School
Biochimica et Biophysica Acta - General Subjects

Background: Mediator is an evolutionarily conserved multisubunit complex that plays an essential regulatory role in eukaryotic transcription of protein-encoding genes. The human complex was first isolated as a transcriptional coactivator bound to the thyroid hormone receptor (TR) and has since been shown to play a key coregulatory role for a broad range of nuclear hormone receptors (NRs) as well as other signal-activated transcription factors. Scope of review: We provide a general overview of Mediator structure and function, summarize the mechanisms by which Mediator is targeted to NRs, and outline recent evidence revealing Mediator as a regulatory axis for other distinct coregulatory factors, chromatin modifying enzymes and cellular signal transduction pathways. Major conclusions: Besides serving as a functional interface with the RNA polymerase II basal transcription machinery, Mediator plays a more versatile role in regulating transcription including the ability to: a) facilitate gene-specific chromatin looping events; b) coordinate chromatin modification events with preinitiation complex assembly; and c) regulate critical steps that occur during transcriptional elongation. The variably associated MED1 subunit continues to emerge as a pivotal player in Mediator function, not only as the primary interaction site for NRs, but also as a crucial interaction hub for other coregulatory factors, and as an important regulatory target for signal-activated kinases. General significance: Mediator plays an integral coregulatory role at NR target genes by functionally interacting with the basal transcription apparatus and by coordinating the action of chromatin modifying enzymes and transcription elongation factors. This article is part of a Special Issue entitled Thyroid hormone signalling. © 2012 Elsevier B.V. All rights reserved. Source

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