Showing papers by "University of Pennsylvania published in 2009"
TL;DR: The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use.
Abstract: The Modification of Diet in Renal Disease (MDRD) Study equation underestimates glomerular filtration rate (GFR) in patients with mild kidney disease. Levey and associates therefore developed and va...
18,691 citations
TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
12,380 citations
University of Colorado Boulder1, Harvard University2, Mayo Clinic3, Boston University4, University of Pennsylvania5, University of Pittsburgh6, University of Siena7, University Health Network8, Institut Gustave Roussy9, Oregon Health & Science University10, University of Texas MD Anderson Cancer Center11, Duke University12, University of Cincinnati13, Memorial Sloan Kettering Cancer Center14, MedStar Washington Hospital Center15
TL;DR: Evidence-based recommendations are developed to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer and represent, in the authors' opinion, contemporary optimal care for patients with these disorders.
Abstract: Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Gr...
10,501 citations
Johns Hopkins University1, University of Michigan2, University of Colorado Denver3, Ohio State University4, Boston University5, University of Pennsylvania6, University of Florida7, Mayo Clinic8, University of Siena9, Institut Gustave Roussy10, University of Cincinnati11, Memorial Sloan Kettering Cancer Center12
TL;DR: Evidence-based recommendations in response to the appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer represent, in the authors' opinion, contemporary optimal care for patients with these disorders.
Abstract: Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, a...
7,525 citations
Kevork N. Abazajian1, Jennifer K. Adelman-McCarthy2, Marcel A. Agüeros3, S. Allam2 +220 more•Institutions (77)
TL;DR: A series of improvements to the spectroscopic reductions are described, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.
Abstract: This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11,663 deg^2 of imaging data, with most of the ~2000 deg^2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry on a 120° long, 2°.5 wide stripe along the celestial equator in the Southern Galactic Cap, with some regions covered by as many as 90 individual imaging runs. We include a co-addition of the best of these data, going roughly 2 mag fainter than the main survey over 250 deg^2. The survey has completed spectroscopy over 9380 deg^2; the spectroscopy is now complete over a large contiguous area of the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog, reducing the rms statistical errors at the bright end to 45 milliarcseconds per coordinate. We further quantify a systematic error in bright galaxy photometry due to poor sky determination; this problem is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.
5,665 citations
TL;DR: It is shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), and that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
Abstract: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
3,508 citations
TL;DR: The authors argue that the use of a common conceptual framework would elevate the quality of professional development studies and subsequently the general understanding of how best to shape and implement teacher learning opportunities for the maximum benefit of both teachers and students.
Abstract: The author suggests that we apply recent research knowledge to improve our conceptualization, measures, and methodology for studying the effects of teachers’ professional development on teachers and students. She makes the case that there is a research consensus to support the use of a set of core features and a common conceptual framework in professional development impact studies. She urges us to move away from automatic biases either for or against observation, interviews, or surveys in such studies. She argues that the use of a common conceptual framework would elevate the quality of professional development studies and subsequently the general understanding of how best to shape and implement teacher learning opportunities for the maximum benefit of both teachers and students.
3,464 citations
TL;DR: Reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence, and data show how collagenCrosslinking can modulate tissue fibrosis and stiffness to force focal adhesion, growth factor signaling and breast malignancies.
3,396 citations
Book•
12 Jun 2009TL;DR: This book offers a highly accessible introduction to natural language processing, the field that supports a variety of language technologies, from predictive text and email filtering to automatic summarization and translation.
Abstract: This book offers a highly accessible introduction to natural language processing, the field that supports a variety of language technologies, from predictive text and email filtering to automatic summarization and translation. With it, you'll learn how to write Python programs that work with large collections of unstructured text. You'll access richly annotated datasets using a comprehensive range of linguistic data structures, and you'll understand the main algorithms for analyzing the content and structure of written communication. Packed with examples and exercises, Natural Language Processing with Python will help you: Extract information from unstructured text, either to guess the topic or identify "named entities" Analyze linguistic structure in text, including parsing and semantic analysis Access popular linguistic databases, including WordNet and treebanks Integrate techniques drawn from fields as diverse as linguistics and artificial intelligence This book will help you gain practical skills in natural language processing using the Python programming language and the Natural Language Toolkit (NLTK) open source library. If you're interested in developing web applications, analyzing multilingual news sources, or documenting endangered languages -- or if you're simply curious to have a programmer's perspective on how human language works -- you'll find Natural Language Processing with Python both fascinating and immensely useful.
3,361 citations
TL;DR: The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention and there is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake.
Abstract: This document represents the first collaboration between 2 organizations-the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine-to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric critically ill patient (>1 month and 2-3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline. We used the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluation) to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary.
2,947 citations
TL;DR: Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, it is found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.
Abstract: Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
TL;DR: "Digital fluency" should mean designing, creating, and remixing, not just browsing, chatting, and interacting.
Abstract: "Digital fluency" should mean designing, creating, and remixing, not just browsing, chatting, and interacting.
TL;DR: It is shown that SCFA–GPR43 interactions profoundly affect inflammatory responses, and GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.
Abstract: The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.
TL;DR: A strategy for whole-body rehabilitation-consisting of interruption of sedation and physical and occupational therapy in the earliest days of critical illness-was safe and well tolerated, and resulted in better functional outcomes at hospital discharge, a shorter duration of delirium, and more ventilator-free days compared with standard care.
TL;DR: Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.
Abstract: Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.
TL;DR: It is suggested that TGF-beta within the tumor microenvironment induces a population of TAN with a protumor phenotype, and depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8(+) T cell activation.
University of Paris-Sud1, Institut Gustave Roussy2, French Institute of Health and Medical Research3, 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, University of Gothenburg11, Boston Children's Hospital12, University of Freiburg13, Buck Institute for Research on Aging14, University of California, San Francisco15, 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, Howard Hughes Medical Institute25, Yale University26, 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
Columbia University1, University of Oxford2, New York University3, Nathan Kline Institute for Psychiatric Research4, University College London5, University of Pennsylvania6, University of California, Los Angeles7, University of Iowa8, McGill University9, French Institute of Health and Medical Research10, French Institute for Research in Computer Science and Automation11, John Radcliffe Hospital12, Imperial College London13, Mauna Kea Technologies14
TL;DR: This study is the largest evaluation of nonlinear deformation algorithms applied to brain image registration ever conducted and suggests that the findings are generalizable to new subject populations that are labeled or evaluated using different labeling protocols.
University of Washington1, University of Paris2, Queen Mary University of London3, McMaster University4, Cornell University5, University of Pennsylvania6, University of New South Wales7, Medical University of Vienna8, Sapienza University of Rome9, Scripps Research Institute10, Boston Children's Hospital11, University of Toronto12, University of Oklahoma Health Sciences Center13
TL;DR: An International Working Group of recognized expert clinicians convened a 2-day structured meeting to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response.
TL;DR: In patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical outcomes are similar whether lower or higher PEEP levels are used.
Abstract: The members of the Writing Committee background Most patients requiring mechanical ventilation for acute lung injury and the acute res- piratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ven- tilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention. We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients. methods We randomly assigned 549 patients with acute lung injury and ARDS to receive me- chanical ventilation with either lower or higher PEEP levels, which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen. results Mean (±SD) PEEP values on days 1 through 4 were 8.3±3.2 cm of water in the lower- PEEP group and 13.2±3.5 cm of water in the higher-PEEP group (P<0.001). The rates of death before hospital discharge were 24.9 percent and 27.5 percent, respectively (P=0.48; 95 percent confidence interval for the difference between groups, -10.0 to 4.7 percent). From day 1 to day 28, breathing was unassisted for a mean of 14.5±10.4 days in the lower-PEEP group and 13.8±10.6 days in the higher-PEEP group (P = 0.50). conclusions These results suggest that in patients with acute lung injury and ARDS who receive me- chanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical out- comes are similar whether lower or higher PEEP levels are used.
TL;DR: Brief self-report and informant-report versions of the Grit Scale are introduced, which measures trait-level perseverance and passion for long-term goals, and evidence is presented for its internal consistency, test–retest stability, consensual validity with informant- report versions, and predictive validity.
Abstract: In this article, we introduce brief self-report and informant-report versions of the Grit Scale, which measures trait-level perseverance and passion for long-term goals. The Short Grit Scale (Grit-S) retains the 2-factor structure of the original Grit Scale (Duckworth, Peterson, Matthews, & Kelly, 2007) with 4 fewer items and improved psychometric properties. We present evidence for the Grit-S's internal consistency, test-retest stability, consensual validity with informant-report versions, and predictive validity. Among adults, the Grit-S was associated with educational attainment and fewer career changes. Among adolescents, the Grit-S longitudinally predicted GPA and, inversely, hours watching television. Among cadets at the United States Military Academy, West Point, the Grit-S predicted retention. Among Scripps National Spelling Bee competitors, the Grit-S predicted final round attained, a relationship mediated by lifetime spelling practice.
15 Jun 2009-Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
TL;DR: The Adult OSA Task Force of the American Academy of Sleep Medicine (AASM) was assembled to produce a clinical guideline from a review of existing practice parameters and available literature as discussed by the authors.
Abstract: Background Obstructive sleep apnea (OSA) is a common chronic disorder that often requires lifelong care. Available practice parameters provide evidence-based recommendations for addressing aspects of care. Objective This guideline is designed to assist primary care providers as well as sleep medicine specialists, surgeons, and dentists who care for patients with OSA by providing a comprehensive strategy for the evaluation, management and long-term care of adult patients with OSA. Methods The Adult OSA Task Force of the American Academy of Sleep Medicine (AASM) was assembled to produce a clinical guideline from a review of existing practice parameters and available literature. All existing evidence-based AASM practice parameters relevant to the evaluation and management of OSA in adults were incorporated into this guideline. For areas not covered by the practice parameters, the task force performed a literature review and made consensus recommendations using a modified nominal group technique. Recommendations Questions regarding OSA should be incorporated into routine health evaluations. Suspicion of OSA should trigger a comprehensive sleep evaluation. The diagnostic strategy includes a sleep-oriented history and physical examination, objective testing, and education of the patient. The presence or absence and severity of OSA must be determined before initiating treatment in order to identify those patients at risk of developing the complications of sleep apnea, guide selection of appropriate treatment, and to provide a baseline to establish the effectiveness of subsequent treatment. Once the diagnosis is established, the patient should be included in deciding an appropriate treatment strategy that may include positive airway pressure devices, oral appliances, behavioral treatments, surgery, and/or adjunctive treatments. OSA should be approached as a chronic disease requiring long-term, multidisciplinary management. For each treatment option, appropriate outcome measures and long-term follow-up are described.
TL;DR: Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects.
Abstract: If the clinical diagnosis of probable AD is imprecise with accuracy rates of approximately 90% or lower using established consensus criteria for probable AD, but definite AD requires autopsy confirmation, it is not surprising that diagnostic accuracy is lower at early and presymptomatic stages of AD.1–4 It is believed that the development of full-blown AD takes place over an approximately 20-year prodromal period, but this is difficult to determine in the absence of biomarkers that reliably signal the onset of nascent disease before the emergence of measurable cognitive impairments. Because intervention with disease-modifying therapies for AD is likely to be most efficacious before significant neurodegeneration has occurred, there is an urgent need for biomarker-based tests that enable a more accurate and early diagnosis of AD.5–7 Moreover, such tests could also improve monitoring AD progression, evaluation of new AD therapies, and enrichment of AD cohorts with specific subsets of AD subjects in clinical trials.
The defining lesions of AD are neurofibrillary tangles and senile plaques formed, respectively, by neuronal accumulations of abnormal hyperphosphorylated tau filaments and extracellular deposits of amyloid β (Aβ) fibrils, mostly the 1 to 42 peptide (Aβ1-42), the least soluble of the known Aβ peptides produced from Aβ precursor protein by the action of various peptidases.1–3 Hence, for these and other reasons summarized in consensus reports on AD biomarkers, cerebrospinal fluid (CSF), total tau (t-tau), and Aβ were identified as being among the most promising and informative AD biomarkers.5,6 Increased levels of tau in CSF are thought to occur after its release from damaged and dying neurons that harbor dystrophic tau neurites and tangles, whereas reduced CSF levels of Aβ1-42 are believed to result from large-scale accumulation of this least soluble of Aβ peptides into insoluble plaques in the AD brain. The combination of increased CSF concentrations of t-tau and phosphotau (p-tau) species and decreased concentrations of Aβ1-42 are considered to be a pathological CSF biomarker signature that is diagnostic for AD.5,6,8,9 Notably, recent studies have provided compelling preliminary data to suggest that this combination of CSF tau and Aβ biomarker changes may predict the conversion to AD in mild cognitive impairment (MCI) subjects.10 Thus, an increase in levels of CSF tau associated with a decline in levels of CSF Aβ1-42 may herald the onset of AD before it becomes clinically manifest.
However, before the utility of CSF Aβ1-42 and tau concentrations for diagnosis of AD can be established, it is critical to standardize the methodology for their measurement.5–8,10 For example, among the published studies of CSF tau and Aβ, there is considerable variability in the observed levels of these analytes, as well as their diagnostic sensitivity and specificity. This is attributable to variability in analytical methodology standardization and other factors that differ between studies of the same CSF analytes in similar but not identical cohorts.5–7
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) was launched in 2004 to address these and other limitations in AD biomarkers (see reviews in Shaw and colleagues7 and Mueller and coauthors,11 and the ADNI Web site [http://www.adni-info.org/index] where the ADNI grant and all ADNI data are posted for public access). To this end, the Biomarker Core of ADNI conducts studies on ADNI-derived CSF samples to measure CSF Aβ1-42, t-tau, and p-tau (tau phosphorylated at threonine181 [p-tau181p]) in standardized assays. Evaluation of CSF obtained at baseline evaluation of 416 of the 819 ADNI subjects is now complete, and we report here our findings on the performance of these tests using a standardized multiplex immunoassay system that measures the biomarkers simultaneously in the same sample aliquot in ADNI subjects and in an independent cohort of autopsy-confirmed AD cases.
TL;DR: It is shown that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors, and regulation of T cell exhaustion by various inhibitory pathways was nonredundant.
Abstract: T cell exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.
TL;DR: In this paper, the authors provide a conceptual framework that reflects the joint activities of risk assessment and risk mitigation that are fundamental to disruption risk management in supply chains, and consider empirical results from a rich data set covering the period 1995-2000 on accidents in the U. S. Chemical Industry.
Abstract: There are two broad categories of risk affecting supply chain design and management: (1) risks arising from the problems of coordinating supply and demand, and (2) risks arising from disruptions to normal activities. This paper is concerned with the second category of risks, which may arise from natural disasters, from strikes and economic disruptions, and from acts of purposeful agents, including terrorists. The paper provides a conceptual framework that reflects the joint activities of risk assessment and risk mitigation that are fundamental to disruption risk management in supply chains. We then consider empirical results from a rich data set covering the period 1995–2000 on accidents in the U. S. Chemical Industry. Based on these results and other literature, we discuss the implications for the design of management systems intended to cope with supply chain disruption risks.
TL;DR: Some of the physical processes by which cues from the ECM can influence stem cell fate are reviewed, with particular relevance to the use of stem cells in tissue engineering and regenerative medicine.
[...]
TL;DR: This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR), with a description of the current state of the understanding of TCR signaling and a summary of recent findings.
Abstract: This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR). In celebration of this anniversary, we begin with a brief introduction outlining the chronology of the earliest studies that established the basic paradigm for how the engaged TCR transduces its signals. This review continues with a description of the current state of our understanding of TCR signaling, as well as a summary of recent findings examining other key aspects of T cell activation, including cross talk between the TCR and integrins, the role of costimulatory molecules, and how signals may negatively regulate T cell function.
TL;DR: It is found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect hist one acetylations in an ACL-dependent manner.
Abstract: Histone acetylation in single cell eukaryotes relies on acetyl-CoA synthetase enzymes that utilize acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure to only low concentrations of extracellular acetate. We show that histone acetylation in mammalian cells is dependent on ATP-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We find that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can impact histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth-factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.
TL;DR: It is proposed that the effectiveness of vertical integration as a strategy to manage ecosystem interdependence increases over the course of the technology life cycle.
Abstract: The success of an innovating firm often depends on the efforts of other innovators in its environment. How do the challenges faced by external innovators affect the focal firm's outcomes? To address this question we first characterize the external environment according to the structure of interdependence. We follow the flow of inputs and outputs in the ecosystem to distinguish between upstream components that are bundled by the focal firm, and downstream complements that are bundled by the firm's customers. We argue that the effect of external innovation challenges depends not only on their magnitude, but also on their location in the ecosystem relative to the focal firm - whereas greater innovation challenges in components enhances the benefits that accrue to technology leaders, greater innovation challenges in complements erodes these benefits. We further argue that the effectiveness of vertical integration as a strategy to manage ecosystem interdependence increases over the course of the technology life cycle. We explore these arguments in the context of the global semiconductor lithography industry from its emergence in 1962 to 2005 across nine distinct technology generations. We find strong support for our arguments.
TL;DR: It was evident that multiple mechanistic steps lead to the stable heritance of the epigenetic phenotype.
Abstract: A recent meeting (December 2008) regarding chromatin-based epigenetics was hosted by the Banbury Conference Center and Cold Spring Harbor Laboratory. The intent was to discuss aspects of epigenetic control of genomic function, and to arrive at a consensus definition of "epigenetics" to be considered by the broader community. It was evident that multiple mechanistic steps lead to the stable heritance of the epigenetic phenotype. Below we provide our view and interpretation of the proceedings at the meeting.