Showing papers by "University of Texas Southwestern Medical Center published in 2010"
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TL;DR: Methods to monitor autophagy and to modulate autophagic activity are discussed, with a primary focus on mammalian macroautophagy.
3,998 citations
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Broad Institute1, Harvard University2, Novartis3, Brigham and Women's Hospital4, Jikei University School of Medicine5, Boston Children's Hospital6, University of North Carolina at Chapel Hill7, University of Texas Southwestern Medical Center8, Nagoya City University9, Autonomous University of Barcelona10, University Health Network11, Cornell University12, Beth Israel Deaconess Medical Center13, Memorial Sloan Kettering Cancer Center14, University of Pennsylvania15, University of Michigan16, University of Washington Medical Center17, Howard Hughes Medical Institute18, Massachusetts Institute of Technology19
TL;DR: It is demonstrated that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival, and a large majority of SCNAs identified in individual cancer types are present in several cancer types.
Abstract: A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.
3,375 citations
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TL;DR: Autophagy is a cell biological process that is a central component of the integrated stress response and can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli.
3,002 citations
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Emory University1, University of Iowa2, Wayne State University3, Brown University4, Case Western Reserve University5, University of Cincinnati6, University of Alabama at Birmingham7, University of Texas Health Science Center at Houston8, Indiana University9, University of California, San Diego10, Yale University11, University of Miami12, University of Texas Southwestern Medical Center13, Wake Forest University14, Duke University15, Stanford University16, University of Utah17, University of Rochester18, Tufts University19, University of New Mexico20, National Institutes of Health21
TL;DR: Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
Abstract: OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified. CONCLUSION: Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
2,277 citations
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University of Texas Southwestern Medical Center1, Radiation Therapy Oncology Group2, Thomas Jefferson University3, Washington University in St. Louis4, Indiana University5, Princess Margaret Cancer Centre6, Cleveland Clinic7, Dartmouth College8, University of Wisconsin-Madison9, Medical College of Wisconsin10
TL;DR: Patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.
Abstract: Context Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management. Objective To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer. Design, Setting, and Patients Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non–small cell tumors (measuring Main Outcome Measures The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival. Results A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported. Conclusion Patients with inoperable non–small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.
2,202 citations
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TL;DR: It is demonstrated that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
2,022 citations
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TL;DR: A hitherto underappreciated role of type I IFN-αβ signalling in the pathogenesis of TB is demonstrated, which has implications for vaccine and therapeutic development and a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic are provided.
Abstract: Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-gamma and type I IFN-alphabeta signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-alphabeta signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.
1,588 citations
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University of Virginia1, University of Chicago2, University of Texas MD Anderson Cancer Center3, Thomas Jefferson University4, Wake Forest University5, University of Colorado Denver6, Stanford University7, Memorial Sloan Kettering Cancer Center8, Orlando Regional Medical Center9, University of Texas Southwestern Medical Center10, University of Toronto11, University of Rochester12, University of Utah13, Johns Hopkins University14, University of Wisconsin-Madison15, Vrije Universiteit Brussel16, Fox Chase Cancer Center17, Duke University18
TL;DR: The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality.
Abstract: Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.
1,586 citations
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TL;DR: Advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes are reviewed and implications for rational therapeutics for these conditions are reviewed.
Abstract: Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.
1,538 citations
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Broad Institute1, University of Amsterdam2, University of California, Riverside3, University of Arizona4, Université Paris-Saclay5, University of Córdoba (Spain)6, Oregon State University7, Aix-Marseille University8, Pennsylvania State University9, Texas A&M University10, Purdue University11, University of California, Irvine12, Rothamsted Research13, Pacific Northwest National Laboratory14, University of Minnesota15, United States Department of Agriculture16, Centre national de la recherche scientifique17, University of Texas Southwestern Medical Center18, University of California, Los Angeles19, Commonwealth Scientific and Industrial Research Organisation20, Seoul National University21, University of Texas at Dallas22, University of Cambridge23, University of Wisconsin-Madison24, Cornell University25
TL;DR: Comparison of genomes of three phenotypically diverse Fusarium species revealed lineage-specific genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome, putting the evolution of fungal pathogenicity into a new perspective.
Abstract: Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective.
1,386 citations
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TL;DR: The analyses of systemic and tissue-specific knockout models of ATG genes in mice has led to an explosion of knowledge about the functions of autophagy in mammalian development and differentiation.
Abstract: It has been known for many decades that autophagy, a conserved lysosomal degradation pathway, is highly active during differentiation and development. However, until the discovery of the autophagy-related (ATG) genes in the 1990s, the functional significance of this activity was unknown. Initially, genetic knockout studies of ATG genes in lower eukaryotes revealed an essential role for the autophagy pathway in differentiation and development. In recent years, the analyses of systemic and tissue-specific knockout models of ATG genes in mice has led to an explosion of knowledge about the functions of autophagy in mammalian development and differentiation. Here we review the main advances in our understanding of these functions.
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TL;DR: A role for the β-cell clock is demonstrated in coordinating insulin secretion with the sleep–wake cycle, and ablation of the pancreatic clock can trigger the onset of diabetes mellitus.
Abstract: During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis — a rhythmic process that is disturbed in people with diabetes. Experiments in mice now show that the pancreatic islets contain their own biological clock, which orchestrates insulin secretion during the sleep–wake cycle. The transcription factors CLOCK and BMAL1 are vital for this process, and mice with defective copies of the genes Clock and Bmal1 develop hypoinsulinaemia and diabetes. By demonstrating that a local tissue clock integrates circadian and metabolic signals in pancreatic β-cells, this work suggests that circadian analyses are crucial for deeper understanding of metabolic phenotypes, as well as for the treatment of metabolic diseases such as type 2 diabetes. Circadian rhythms control many physiological functions. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis — a rhythmic process that is disturbed in people with diabetes. These authors show that pancreatic islets contain their own clock: they have self-sustained circadian oscillations of CLOCK and BMAL1 genes and proteins, which are vital for the regulation of circadian rhythms. Without this clock, a cascade of cellular failure and pathology initiates the onset of diabetes mellitus. The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1,2,3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock5,6 and Bmal17 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus–secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep–wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.
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TL;DR: The unique adaptations of the intestinal immune system that maintain homeostatic interactions with a diverse resident microbiota are discussed.
Abstract: Humans harbour nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of co-evolution have moulded this human-microorganism interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment. Although intestinal microorganisms carry out essential functions for their hosts, they pose a constant threat of invasion owing to their sheer numbers and the large intestinal surface area. In this Review, we discuss the unique adaptations of the intestinal immune system that maintain homeostatic interactions with a diverse resident microbiota.
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TL;DR: The mechanism of jasmonate perception is unraveled, the ability of F-box proteins to evolve as multi-component signalling hubs is highlighted and inositol pentakisphosphate is identified, which interacts with both COI1 and JAZ adjacent to the ligand.
Abstract: Jasmonates are a family of plant hormones that regulate plant growth, development and responses to stress. The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of transcriptional repressor JAZ proteins. Despite its importance, the mechanism of jasmonate perception remains unclear. Here we present structural and pharmacological data to show that the true Arabidopsis jasmonate receptor is a complex of both COI1 and JAZ. COI1 contains an open pocket that recognizes the bioactive hormone (3R,7S)-jasmonoyl-l-isoleucine (JA-Ile) with high specificity. High-affinity hormone binding requires a bipartite JAZ degron sequence consisting of a conserved α-helix for COI1 docking and a loop region to trap the hormone in its binding pocket. In addition, we identify a third critical component of the jasmonate co-receptor complex, inositol pentakisphosphate, which interacts with both COI1 and JAZ adjacent to the ligand. Our results unravel the mechanism of jasmonate perception and highlight the ability of F-box proteins to evolve as multi-component signalling hubs.
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TL;DR: Despite the potential for residual axillary disease after SLND, SLND without ALND can offer excellent regional control and may be reasonable management for selected patients with early-stage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.
Abstract: Background and Objective:Sentinel lymph node dissection (SLND) has eliminated the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumor-free. However, completion ALND for patients with tumor-involved SNs remains the standard to achieve locoregional control. Few studies ha
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TL;DR: The protean roles of glutamine in cancer are reviewed, both in the direct support of tumor growth and in mediating some of the complex effects on whole-body metabolism that are characteristic of tumor progression.
Abstract: Several decades of research have sought to characterize tumor cell metabolism in the hope that tumor-specific activities can be exploited to treat cancer. Having originated from Warburg's seminal observation of aerobic glycolysis in tumor cells, most of this attention has focused on glucose metabolism. However, since the 1950s cancer biologists have also recognized the importance of glutamine (Q) as a tumor nutrient. Glutamine contributes to essentially every core metabolic task of proliferating tumor cells: it participates in bioenergetics, supports cell defenses against oxidative stress and complements glucose metabolism in the production of macromolecules. The interest in glutamine metabolism has been heightened further by the recent findings that c-myc controls glutamine uptake and degradation, and that glutamine itself exerts influence over a number of signaling pathways that contribute to tumor growth. These observations are stimulating a renewed effort to understand the regulation of glutamine metabolism in tumors and to develop strategies to target glutamine metabolism in cancer. In this study we review the protean roles of glutamine in cancer, both in the direct support of tumor growth and in mediating some of the complex effects on whole-body metabolism that are characteristic of tumor progression.
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TL;DR: Using massively parallel sequencing technology, a small-cell lung cancer cell line, NCI-H209, is sequenced to explore the mutational burden associated with tobacco smoking and identifies a tandem duplication that duplicates exons 3–8 of CHD7 in frame, and another two lines carrying PVT1–CHD7 fusion genes, indicating that ChD7 may be recurrently rearranged in this disease.
Abstract: Cancer is driven by mutation. Worldwide, tobacco smoking is the principal lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in frame, and another two lines carrying PVT1-CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.
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TL;DR: The focus of the present study was to define the human plasma lipidome and to establish novel analytical methodologies to quantify the large spectrum of plasma lipids and to quantitatively assessed the levels of over 500 distinct molecular species distributed among the main lipid categories.
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TL;DR: Examples of when heterogeneity cannot be ignored are discussed and practical strategies for analyzing and interpreting cellular heterogeneity are described.
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University of California, San Diego1, University of Alabama at Birmingham2, Case Western Reserve University3, Brown University4, University of Utah5, University of Cincinnati6, Tufts University7, Emory University8, University of Texas Southwestern Medical Center9, University of Texas Health Science Center at Houston10, University of Rochester11, Indiana University12, Duke University13, Stanford University14, University of Miami15, Wayne State University16, Wake Forest University17, University of Iowa18, Yale University19, University of New Mexico20, National Institutes of Health21
TL;DR: The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants.
Abstract: BACKGROUND There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)
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TL;DR: It is demonstrated that, in mouse DCs, TLR agonists stimulate a profound metabolic transition to aerobic glycolysis, similar to the Warburg metabolism displayed by cancer cells.
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TL;DR: It is shown that LT-HSCs utilize glycolysis instead of mitochondrial oxidative phosphorylation to meet their energy demands and that Meis1 regulates HSC metabolism through transcriptional activation of Hif-1alpha.
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TL;DR: The three-dimensional dose, volume, and outcome data for lung are reviewed in detail and it is confirmed that there is no evident threshold "tolerance dose-volume" levels and there are strong volume and fractionation effects.
Abstract: The three-dimensional dose, volume, and outcome data for lung are reviewed in detail. The rate of symptomatic pneumonitis is related to many dosimetric parameters, and there are no evident threshold "tolerance dose-volume" levels. There are strong volume and fractionation effects.
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TL;DR: The strongest direct evidence that chronic neuroinflammation may have a more important role to play in PD versus other neurodegenerative diseases is reviewed and genetic deficiency is not the only way to reduce protective factors in the brain which may function to keep microglial responses in check or regulate the sensitivity of DA neurons are proposed.
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TL;DR: The discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors induces the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics stimulated research to better understand the actin–MRTF–SRF circuit.
Abstract: Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actin-MRTF-SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity.
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TL;DR: Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread, and within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density.
Abstract: A sensitive immunohistochemical method for phosphorylated α-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson’s disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer’s disease with Lewy bodies (ADLB) and 17 with Alzheimer’s disease with no Lewy bodies (ADNLB). The relative densities and frequencies of occurrence of phosphorylated α-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest.
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University of Alabama at Birmingham1, University of California, San Diego2, Case Western Reserve University3, Brown University4, University of Utah5, University of Cincinnati6, Tufts University7, Emory University8, University of Texas Southwestern Medical Center9, University of Texas Health Science Center at Houston10, University of Rochester11, Indiana University12, Duke University13, Stanford University14, University of Miami15, Wayne State University16, Wake Forest University17, University of Iowa18, Yale University19, University of New Mexico20, National Institutes of Health21
TL;DR: In this article, the authors performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation.
Abstract: BACKGROUND Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. METHODS We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. RESULTS The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. CONCLUSIONS A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)
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TL;DR: P predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans are generated.
Abstract: Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.
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University of Michigan1, University of Texas Southwestern Medical Center2, Harvard University3, National Institutes of Health4, University of Pennsylvania5, Children's Hospital of Wisconsin6, Duke University7, East Carolina University8, Wake Forest University9, University of Southern California10, University of Toronto11, Boston Children's Hospital12, Medical University of South Carolina13, University of Utah14, Alfred I. duPont Hospital for Children15, Emory University16, Cardinal Glennon Children's Hospital17
TL;DR: In children undergoing the Norwood procedure, transplantation-free survival at 12 months was better with the RVPA shunt than with the MBT shunt, and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups.
Abstract: Background The Norwood procedure with a modified Blalock–Taussig (MBT) shunt, the first palliative stage for single-ventricle lesions with systemic outflow obstruction, is associated with high mortality. The right ventricle–pulmonary artery (RVPA) shunt may improve coronary flow but requires a ventriculotomy. We compared the two shunts in infants with hypoplastic heart syndrome or related anomalies. Methods Infants undergoing the Norwood procedure were randomly assigned to the MBT shunt (275 infants) or the RVPA shunt (274 infants) at 15 North American centers. The primary outcome was death or cardiac transplantation 12 months after randomization. Secondary outcomes included unintended cardiovascular interventions and right ventricular size and function at 14 months and transplantation-free survival until the last subject reached 14 months of age. Results Transplantation-free survival 12 months after randomization was higher with the RVPA shunt than with the MBT shunt (74% vs. 64%, P=0.01). However, the R...
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TL;DR: It is reported that the RIG-I-like receptor (RLR) adaptor protein MAVS is located on peroxisomes and mitochondria and it is found thatperoxisomal and mitochondrial MAVS act sequentially to create an antiviral cellular state.