Showing papers by "Oregon Health & Science University published in 2013"
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John N. Weinstein1, John N. Weinstein2, Eric A. Collisson3, Gordon B. Mills1 +376 more•Institutions (31)
TL;DR: The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA with a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages.
Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.
5,294 citations
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Memorial Sloan Kettering Cancer Center1, Broad Institute2, Heidelberg University3, University of São Paulo4, University of California, Santa Cruz5, Harvard University6, Institute for Systems Biology7, University of Texas MD Anderson Cancer Center8, Case Western Reserve University9, Henry Ford Health System10, Duke University11, Emory University12, University of California, San Francisco13, Cedars-Sinai Medical Center14, St. Joseph's Hospital and Medical Center15, University of Florida16, Thomas Jefferson University17, University of Toronto18, Christiana Care Health System19, Mayo Clinic20, Penrose Hospital21, University of Southern California22, University of North Carolina at Chapel Hill23, Baylor College of Medicine24, University of British Columbia25, Oregon Health & Science University26, Washington University in St. Louis27
TL;DR: Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM.
3,593 citations
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TL;DR: A review of reported tissue optical properties summarizes the wavelength-dependent behavior of scattering and absorption in cells and tissues.
Abstract: A review of reported tissue optical properties summarizes the wavelength-dependent behavior of scattering and absorption. Formulae are presented for generating the optical properties of a generic tissue with variable amounts of absorbing chromophores (blood, water, melanin, fat, yellow pigments) and a variable balance between small-scale scatterers and large-scale scatterers in the ultrastructures of cells and tissues.
2,920 citations
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Chad J. Creighton1, Margaret Morgan1, Preethi H. Gunaratne1, Preethi H. Gunaratne2 +288 more•Institutions (27)
TL;DR: Remodelling cellular metabolism constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
Abstract: Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
2,548 citations
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TL;DR: Empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
2,058 citations
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University of Cincinnati1, Medical University of South Carolina2, Allen Institute for Brain Science3, University of Pittsburgh4, University of Melbourne5, University of Toronto6, Autonomous University of Barcelona7, Mayo Clinic8, Riverside Methodist Hospital9, Oregon Health & Science University10, Medical College of Wisconsin11, Utrecht University12, University of Paris13, University of Basel14, Royal Prince Alfred Hospital15, National Institutes of Health16
TL;DR: The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenoust-PA alone.
Abstract: BACKGROUND Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], −6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8–19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, −4.4 to 18.1) and those with a score of 19 or lower (−1.0 percentage point; 95% CI, −10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P = 0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P = 0.83). CONCLUSIONS The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.)
1,702 citations
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University of Texas MD Anderson Cancer Center1, Cornell University2, Rutgers University3, Barts Health NHS Trust4, University of Wisconsin-Madison5, Jagiellonian University6, Stanford University7, University of Virginia8, Hofstra University9, University of Manchester10, University of Ulm11, Ludwig Maximilian University of Munich12, Medical University of Warsaw13, University of Southampton14, Oregon Health & Science University15, Ohio State University16
TL;DR: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma and is enrolled into two groups: patients who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles.
Abstract: rolled into two groups: those who had previously received at least 2 cycles of bor - tezomib therapy and those who had received less than 2 complete cycles of bortezo - mib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression- free survival, overall survival, and safety. RESULTS The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytope - nia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treat - ment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval (CI), 15.8 to not reached), the estimated median progression- free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)
1,389 citations
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Duke University1, University of Melbourne2, Université de Montréal3, Royal College of Surgeons in Ireland4, University of Pennsylvania5, University of Washington6, Emory University7, Cincinnati Children's Hospital Medical Center8, Royal Children's Hospital9, Imperial College London10, New York University11, University of California, San Francisco12, University of Liverpool13, Royal Melbourne Hospital14, Columbia University15, Harvard University16, Vanderbilt University17, Cleveland Clinic18, Yeshiva University19, Mayo Clinic20, University of Pittsburgh21, University of Minnesota22, University of Virginia23, Saint Barnabas Medical Center24, University of Michigan25, Kaiser Permanente26, University of Chicago27, University of Texas Health Science Center at Houston28, Johns Hopkins University29, Children's Hospital Oakland Research Institute30, Boston Children's Hospital31, Oregon Health & Science University32, Cornell University33, United States Department of Veterans Affairs34, Washington University in St. Louis35
TL;DR: In this paper, a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms and Lennox-Gastaut syndrome (n = 115) was performed.
Abstract: Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.
1,254 citations
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University of British Columbia1, Simon Fraser University2, Johns Hopkins University3, Centers for Disease Control and Prevention4, University of Calgary5, Yale University6, McGill University7, Oregon Health & Science University8, University of California, San Francisco9, University of North Carolina at Chapel Hill10, Vanderbilt University11, Kaiser Permanente12, Harvard University13, University of Washington14, National Institutes of Health15
TL;DR: A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population.
Abstract: Background: Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000–2007 in the U.S. and Canada.
1,182 citations
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TL;DR: Findings indicate that previous observations concerning Lgr5+ stem cells in actively self-renewing tissues can also be extended to damage-induced stem Cells in a tissue with a low rate of spontaneous proliferation.
Abstract: The Wnt target gene Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) marks actively dividing stem cells in Wnt-driven, self-renewing tissues such as small intestine and colon, stomach and hair follicles. A three-dimensional culture system allows long-term clonal expansion of single Lgr5(+) stem cells into transplantable organoids (budding cysts) that retain many characteristics of the original epithelial architecture. A crucial component of the culture medium is the Wnt agonist RSPO1, the recently discovered ligand of LGR5. Here we show that Lgr5-lacZ is not expressed in healthy adult liver, however, small Lgr5-LacZ(+) cells appear near bile ducts upon damage, coinciding with robust activation of Wnt signalling. As shown by mouse lineage tracing using a new Lgr5-IRES-creERT2 knock-in allele, damage-induced Lgr5(+) cells generate hepatocytes and bile ducts in vivo. Single Lgr5(+) cells from damaged mouse liver can be clonally expanded as organoids in Rspo1-based culture medium over several months. Such clonal organoids can be induced to differentiate in vitro and to generate functional hepatocytes upon transplantation into Fah(-/-) mice. These findings indicate that previous observations concerning Lgr5(+) stem cells in actively self-renewing tissues can also be extended to damage-induced stem cells in a tissue with a low rate of spontaneous proliferation.
1,179 citations
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TL;DR: Clinical and experimental studies delineating protumorigenic roles for immune cell subsets that are players in cancer-associated inflammation are discussed, leading to resolution, or at least neutralization, of cancer-promoting chronic inflammation, thereby facilitating cancer rejection.
Abstract: There have been substantial advances in cancer diagnostics and therapies in the past decade. Besides chemotherapeutic agents and radiation therapy, approaches now include targeting cancer cell–intrinsic mediators linked to genetic aberrations in cancer cells, in addition to cancer cell–extrinsic pathways, especially those regulating vascular programming of solid tumors. More recently, immunotherapeutics have entered the clinic largely on the basis of the recognition that several immune cell subsets, when chronically activated, foster tumor development. Here, we discuss clinical and experimental studies delineating protumorigenic roles for immune cell subsets that are players in cancer-associated inflammation. Some of these cells can be targeted to reprogram their function, leading to resolution, or at least neutralization, of cancer-promoting chronic inflammation, thereby facilitating cancer rejection.
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University of Pittsburgh1, Veterans Health Administration2, Loyola University Chicago3, Boston University4, University of New Mexico5, Arizona State University6, University of Arizona7, University of Texas Southwestern Medical Center8, University of Maryland, Baltimore9, Oregon Health & Science University10, Yale University11
TL;DR: Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy and safety outcomes included mortality, hyperkalemia, and acute kidney injury.
Abstract: Background Combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m 2 of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥30 ml per minute per 1.73 m 2 if the initial estimated GFR was ≥60 ml per minute per 1.73 m 2 or a decline of ≥50% if the initial estimated GFR was <60 ml per minute per 1.73 m 2 ), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary endpoint events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P = 0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = 0.10) decreased with time (P = 0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P = 0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.)
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Vanderbilt University1, McMaster University2, University of Ottawa3, University Medical Center Freiburg4, Cochrane Collaboration5, Beth Israel Deaconess Medical Center6, Mayo Clinic7, Oregon Health & Science University8, King Saud University9, Peninsula College of Medicine and Dentistry10, Canadian Agency for Drugs and Technologies in Health11, University of South Florida12
TL;DR: This article addresses GRADE's approach to determining the direction and strength of a recommendation, which describes the balance of desirable and undesirable outcomes of interest among alternative management strategies depending on four domains, namely estimates of effect for desirable and desirable outcomes ofinterest, confidence in the estimates ofEffect, estimates of values and preferences, and resource use.
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Swiss Institute of Bioinformatics1, Cornell University2, Harvard University3, École Polytechnique Fédérale de Lausanne4, University Hospital of Lausanne5, University of California, San Francisco6, Charité7, French Institute of Health and Medical Research8, University of Lausanne9, Oregon Health & Science University10
TL;DR: Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease.
Abstract: �Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor–targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of ‘stemness’ and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI 1 in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease. Previous studies have identified molecular subtypes of various human cancers by gene expression profiling 2–8 , including CRC subtypes 9,10 . However, these subtypes have not been associated with outcomes in patients treated with specific therapeutic interventions. Therefore, we sought to refine the approach of molecular classification of CRC by associating gene expression profiles of CRC tumors with corresponding clinical response to cetuximab. We first used consensusbased non-negative matrix factorization (NMF) 11 to cluster two published gene expression data sets (GSE13294 (ref. 12) and GSE14333 (ref. 13)) derived from resected primary CRCs (core data sets, n = 445). These data were corrected for batch effects and merged using the distance-weighted discrimination method 5,14 before clustering. This analysis defined five distinct high-consensus molecular subtypes of CRC (Supplementary Fig. 1a–e and Supplementary Results and
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University of Texas Health Science Center at Houston1, University of California, San Francisco2, Oregon Health & Science University3, University of Pittsburgh4, Medical College of Wisconsin5, University of Washington6, University of Cincinnati7, University of Texas Health Science Center at San Antonio8, University of Texas Southwestern Medical Center9, San Antonio Military Medical Center10
TL;DR: Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission, and among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or Platelet ratios.
Abstract: Objective To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios. Design Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models. Setting Ten US level I trauma centers. Patients Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group). Main Outcome Measure In-hospital mortality. Results Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P Conclusions Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.
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TL;DR: It is shown that CyPD binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 423 (Bz-423), which sensitizes the PTP to Ca2+.
Abstract: Here we define the molecular nature of the mitochondrial permeability transition pore (PTP), a key effector of cell death. The PTP is regulated by matrix cyclophilin D (CyPD), which also binds the lateral stalk of the FOF1 ATP synthase. We show that CyPD binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 423 (Bz-423), that Bz-423 sensitizes the PTP to Ca2+ like CyPD itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca2+. Purified dimers of the ATP synthase, which did not contain voltage-dependent anion channel or adenine nucleotide translocator, were reconstituted into lipid bilayers. In the presence of Ca2+, addition of Bz-423 triggered opening of a channel with currents that were typical of the mitochondrial megachannel, which is the PTP electrophysiological equivalent. Channel openings were inhibited by the ATP synthase inhibitor AMP-PNP (γ-imino ATP, a nonhydrolyzable ATP analog) and Mg2+/ADP. These results indicate that the PTP forms from dimers of the ATP synthase.
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TL;DR: It is demonstrated that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggested that changes in arterials pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.
Abstract: CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid β, in a pathway that we have termed the “glymphatic” system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ∼50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ∼60%. When paravascular CSF–ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF–ISF exchange, while dobutamine increased the rate of paravascular CSF–ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.
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TL;DR: In this article, the authors evaluated correlations between spinopelvic parameters and health-related quality of life (HRQOL) scores in patients with spinal deformity and found that spinopels can provide a more complete assessment of the sagittal plane.
Abstract: Study design Prospective multicenter study evaluating operative (OP) versus nonoperative (NONOP) treatment for adult spinal deformity (ASD). Objective Evaluate correlations between spinopelvic parameters and health-related quality of life (HRQOL) scores in patients with ASD. Summary of background data Sagittal spinal deformity is commonly defined by an increased sagittal vertical axis (SVA); however, SVA alone may underestimate the severity of the deformity. Spinopelvic parameters provide a more complete assessment of the sagittal plane but only limited data are available that correlate spinopelvic parameters with disability. METHODS.: Baseline demographic, radiographical, and HRQOL data were obtained for all patients enrolled in a multicenter consecutive database. Inclusion criteria were: age more than 18 years and radiographical diagnosis of ASD. Radiographical evaluation was conducted on the frontal and lateral planes and HRQOL questionnaires (Oswestry Disability Index [ODI], Scoliosis Research Society-22r and Short Form [SF]-12) were completed. Radiographical parameters demonstrating highest correlation with HRQOL values were evaluated to determine thresholds predictive of ODI more than 40. Results Four hundred ninety-two consecutive patients with ASD (mean age, 51.9 yr) were enrolled. Patients from the OP group (n = 178) were older (55 vs. 50.1 yr, P Conclusion ASD is a disabling condition. Prospective analysis of consecutively enrolled patients with ASD demonstrated that PT and PI-LL combined with SVA can predict patient disability and provide a guide for patient assessment for appropriate therapeutic decision making. Threshold values for severe disability (ODI > 40) included: PT 22° or more, SVA 47 mm or more, and PI - LL 11° or more.
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Tulane University1, University of Pittsburgh2, Aarhus University3, University of Alberta4, University of Leicester5, Princeton University6, Oregon Health & Science University7, Korea Institute of Science and Technology8, Nazarbayev University9, Troy University10, Universidade Federal do Rio Grande do Sul11, University of Toronto12, University of Southern Mississippi13, University of Zurich14, DePauw University15
TL;DR: A detailed catalog of zebrafish behaviors that covers both larval and adult models is developed, representing a beginning of creating a more comprehensive ethogram ofZebrafish behavior, which will improve interpretation of published findings, foster cross-species behavioral modeling, and encourage new groups to apply zebra fish neurobehavioral paradigms in their research.
Abstract: Zebrafish (Danio rerio) are rapidly gaining popularity in translational neuroscience and behavioral research. Physiological similarity to mammals, ease of genetic manipulations, sensitivity to pharmacological and genetic factors, robust behavior, low cost, and potential for high-throughput screening contribute to the growing utility of zebrafish models in this field. Understanding zebrafish behavioral phenotypes provides important insights into neural pathways, physiological biomarkers, and genetic underpinnings of normal and pathological brain function. Novel zebrafish paradigms continue to appear with an encouraging pace, thus necessitating a consistent terminology and improved understanding of the behavioral repertoire. What can zebrafish 'do', and how does their altered brain function translate into behavioral actions? To help address these questions, we have developed a detailed catalog of zebrafish behaviors (Zebrafish Behavior Catalog, ZBC) that covers both larval and adult models. Representing a beginning of creating a more comprehensive ethogram of zebrafish behavior, this effort will improve interpretation of published findings, foster cross-species behavioral modeling, and encourage new groups to apply zebrafish neurobehavioral paradigms in their research. In addition, this glossary creates a framework for developing a zebrafish neurobehavioral ontology, ultimately to become part of a unified animal neurobehavioral ontology, which collectively will contribute to better integration of biological data within and across species.
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TL;DR: A collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry, identifies 19 loci associated at P < 5 × 10−8, which show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis.
Abstract: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry We identified 19 loci associated at P < 5 × 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined Our findings provide new directions for biological, genetic and therapeutic studies of AMD
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TL;DR: It is concluded that actigraphy is overall a useful and valid means for estimating total sleep time and wakefulness after sleep onset in field and workplace studies, with some limitations in specificity.
Abstract: OBJECTIVES We validated actigraphy for detecting sleep and wakefulness versus polysomnography (PSG). DESIGN Actigraphy and polysomnography were simultaneously collected during sleep laboratory admissions. All studies involved 8.5 h time in bed, except for sleep restriction studies. Epochs (30-sec; n = 232,849) were characterized for sensitivity (actigraphy = sleep when PSG = sleep), specificity (actigraphy = wake when PSG = wake), and accuracy (total proportion correct); the amount of wakefulness after sleep onset (WASO) was also assessed. A generalized estimating equation (GEE) model included age, gender, insomnia diagnosis, and daytime/nighttime sleep timing factors. SETTING Controlled sleep laboratory conditions. PARTICIPANTS Young and older adults, healthy or chronic primary insomniac (PI) patients, and daytime sleep of 23 night-workers (n = 77, age 35.0 ± 12.5, 30F, mean nights = 3.2). INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Overall, sensitivity (0.965) and accuracy (0.863) were high, whereas specificity (0.329) was low; each was only slightly modified by gender, insomnia, day/night sleep timing (magnitude of change 30 min/night. CONCLUSIONS This validation quantifies strengths and weaknesses of actigraphy as a tool measuring sleep in clinical and population studies. Overall, the participant-specific accuracy is relatively high, and for most participants, above 80%. We validate this finding across multiple nights and a variety of adults across much of the young to midlife years, in both men and women, in those with and without insomnia, and in 77 participants. We conclude that actigraphy is overall a useful and valid means for estimating total sleep time and wakefulness after sleep onset in field and workplace studies, with some limitations in specificity.
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University of Pittsburgh1, Columbia University Medical Center2, University of Washington3, University of North Dakota4, National Institutes of Health5, Legacy Good Samaritan Medical Center6, East Carolina University7, Cornell University8, Virginia Mason Medical Center9, Oregon Health & Science University10
TL;DR: There was substantial weight loss 3 years after bariatric surgery, with the majority experiencing maximum weight change during the first year, however, there was variability in the amount and trajectories of weight loss and in diabetes, blood pressure, and lipid outcomes.
Abstract: Importance Severe obesity (body mass index [BMI] =35) is associated with a broad range of health risks. Bariatric surgery induces weight loss and short-term health improvements, but little is known about long-term outcomes of these operations.
Objective To report 3-year change in weight and select health parameters after common bariatric surgical procedures.
Design and Setting The Longitudinal Assessment of Bariatric Surgery (LABS) Consortium is a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers.
Participants and Exposure Adults undergoing first-time bariatric surgical procedures as part of routine clinical care by participating surgeons were recruited between 2006 and 2009 and followed up until September 2012. Participants completed research assessments prior to surgery and 6 months, 12 months, and then annually after surgery.
Main Outcomes and Measures Three years after Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB), we assessed percent weight change from baseline and the percentage of participants with diabetes achieving hemoglobin A1c levels less than 6.5% or fasting plasma glucose values less than 126 mg/dL without pharmacologic therapy. Dyslipidemia and hypertension resolution at 3 years was also assessed.
Results At baseline, participants (N?=?2458) were 18 to 78 years old, 79% were women, median BMI was 45.9 (IQR, 41.7-51.5), and median weight was 129 kg (IQR, 115-147). For their first bariatric surgical procedure, 1738 participants underwent RYGB, 610 LAGB, and 110 other procedures. At baseline, 774 (33%) had diabetes, 1252 (63%) dyslipidemia, and 1601 (68%) hypertension. Three years after surgery, median actual weight loss for RYGB participants was 41 kg (IQR, 31-52), corresponding to a percentage of baseline weight lost of 31.5% (IQR, 24.6%-38.4%). For LAGB participants, actual weight loss was 20 kg (IQR, 10-29), corresponding to 15.9% (IQR, 7.9%-23.0%). The majority of weight loss was evident 1 year after surgery for both procedures. Five distinct weight change trajectory groups were identified for each procedure. Among participants who had diabetes at baseline, 216 RYGB participants (67.5%) and 28 LAGB participants (28.6%) experienced partial remission at 3 years. The incidence of diabetes was 0.9% after RYGB and 3.2% after LAGB. Dyslipidemia resolved in 237 RYGB participants (61.9%) and 39 LAGB participants (27.1%); remission of hypertension occurred in 269 RYGB participants (38.2%) and 43 LAGB participants (17.4%).
Conclusions and Relevance Among participants with severe obesity, there was substantial weight loss 3 years after bariatric surgery, with the majority experiencing maximum weight change during the first year. However, there was variability in the amount and trajectories of weight loss and in diabetes, blood pressure, and lipid outcomes.
Trial Registration clinicaltrials.gov Identifier: NCT00465829
Bariatric surgery results in large, sustained weight loss in severely obese populations. Although generally accepted as the most effective means for inducing weight loss in very heavy patients, few studies exist reporting outcomes longer than 2 years after the surgery was performed. Long-term outcome studies that do exist are mostly case series, are from limited geographical areas, or report surgical procedures no longer performed.1- 5 For example, high-quality long-term outcomes from the Swedish Obesity Study are well described, but most of the participants underwent a vertical banded gastroplasty procedure, an operation no longer used.6- 8 Six-year follow-up after Roux-en-Y gastric bypass (RYGB) was reported, but these data may not be generalizable because all the participants were from 1 surgical practice in Utah.9 Even though surgically induced weight loss is much more effective than nonsurgical treatments for seriously obese patients, surgery is still not universally accepted because of incomplete knowledge of long-term outcomes from the procedures.
The Longitudinal Assessment of Bariatric Surgery (LABS) Consortium was formed to acquire long-term data on the safety, effectiveness, and durability of bariatric surgical procedures currently performed in the United States using standardized data collection practices. LABS is a multicenter, observational cohort study with standardized and detailed data collection protocols. LABS has 3 phases; LABS-1, LABS-2, and LABS-3.10 The 30-day safety of bariatric surgery was reported in LABS-1.11 LABS-2 focused on longer-term safety, outcomes, and durability of health changes. The major priorities for LABS-2 were to determine weight, medical, surgical, and behavioral outcomes, including incidence and remission of comorbid conditions, and to evaluate patient, procedure, and other characteristics that were associated with these outcomes. LABS-3 included 2 substudies that examined mechanisms of diabetes change and psychosocial aspects in more detail.
We now report the major clinical outcomes from LABS-2, including 3-year weight change from baseline and diabetes, lipid, and hypertension outcomes after RYGB and laparoscopic adjustable gastric band (LAGB) procedures.
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TL;DR: There are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids, and further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance.
Abstract: Morphine and related µ-opioid receptor (MOR) agonists remain among the most effective drugs known for acute relief of severe pain. A major problem in treating painful conditions is that tolerance limits the long-term utility of opioid agonists. Considerable effort has been expended on developing an understanding of the molecular and cellular processes that underlie acute MOR signaling, short-term receptor regulation, and the progression of events that lead to tolerance for different MOR agonists. Although great progress has been made in the past decade, many points of contention and controversy cloud the realization of this progress. This review attempts to clarify some confusion by clearly defining terms, such as desensitization and tolerance, and addressing optimal pharmacological analyses for discerning relative importance of these cellular mechanisms. Cellular and molecular mechanisms regulating MOR function by phosphorylation relative to receptor desensitization and endocytosis are comprehensively reviewed, with an emphasis on agonist-biased regulation and areas where knowledge is lacking or controversial. The implications of these mechanisms for understanding the substantial contribution of MOR signaling to opioid tolerance are then considered in detail. While some functional MOR regulatory mechanisms contributing to tolerance are clearly understood, there are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids. Further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance.
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TL;DR: Gene expression and differentiation profiles in human NT-ESCs were similar to embryo-derived ESCs, suggesting efficient reprogramming of somatic cells to a pluripotent state.
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TL;DR: This survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive.
Abstract: Infections caused by antibiotic-resistant bacteria, especially the “ESKAPE” pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's “10 × '20 Initiative.”
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Paris Descartes University1, Autonomous University of Madrid2, University of Leeds3, National Health Service4, Charité5, Cairo University6, Tokyo Medical and Dental University7, Chang Gung University8, University of the Republic9, University of Pavia10, University of Glasgow11, Medical University of Vienna12, Seoul National University13, University of Twente14, Oregon Health & Science University15, University of Massachusetts Medical School16
TL;DR: In this multinational sample of rheumatoid arthritis patients, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities.
Abstract: Background Patients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions. Objectives To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide. Methods Study design: international, cross-sectional. Patients: consecutive RA patients. Data collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and
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TL;DR: Assessment of general surgery graduate trainees entering accredited surgical subspecialty fellowships in North America revealed deficits in domains of operative autonomy, progressive responsibility, longitudinal follow-up, and scholarly focus after general surgery education.
Abstract: Objective:To assess readiness of general surgery graduate trainees entering accredited surgical subspecialty fellowships in North America.Methods:A multidomain, global assessment survey designed by the Fellowship Council research committee was electronically sent to all subspecialty program director
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Radboud University Nijmegen1, University of Picardie Jules Verne2, Karolinska Institutet3, French Institute of Health and Medical Research4, Instituto Adolfo Lutz5, Complutense University of Madrid6, Autonomous University of Madrid7, University of Colorado Denver8, Health Protection Agency9, Statens Serum Institut10, Trinity College, Dublin11, National Taiwan University12, University of Warsaw13, Ontario Ministry of the Environment14, University of Zagreb15, University of the Witwatersrand16, Sungkyunkwan University17, University of Freiburg18, Federal University of São Paulo19, Norwegian Institute of Public Health20, University of Toronto21, University of Bordeaux22, Guy's and St Thomas' NHS Foundation Trust23, United Hospitals24, Pasteur Institute25, National Health Laboratory Service26, Greenslopes Private Hospital27, Autonomous University of Barcelona28, University of Calgary29, National Institute for Health and Welfare30, Medical University of Warsaw31, Oregon Health & Science University32
TL;DR: A snapshot of NTM species distribution demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents.
Abstract: A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location.
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McMaster University1, Norwegian Institute of Public Health2, University of Florida3, University of Oxford4, United States Department of Veterans Affairs5, University of Basel6, Mayo Clinic7, University Hospital of Basel8, Harvard University9, University at Buffalo10, University of Freiburg11, Agency for Healthcare Research and Quality12, Oregon Health & Science University13, Case Western Reserve University14
TL;DR: Although this rating system represents discrete steps on an ordinal scale, it is helpful to view confidence in estimates as a continuum, and the final rating of confidence may differ from that suggested by separate consideration of each domain.