Showing papers by "Johns Hopkins University published in 2007"
TL;DR: The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneurs tumour of the fourth ventricle, Papillary tumourof the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis.
Abstract: The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO ‘Blue Book’, the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.
13,134 citations
McMaster University1, Northwestern University2, University of Texas Health Science Center at San Antonio3, Johns Hopkins University4, University of Mississippi5, University of Utah6, LDS Hospital7, Centers for Disease Control and Prevention8, Baylor College of Medicine9, United States Department of Veterans Affairs10, Winthrop-University Hospital11, Stony Brook University12, University of Barcelona13
TL;DR: This work presents a meta-analyses of the immune system’s response to chronic obstructive pulmonary disease and shows clear patterns of decline in the immune systems of elderly patients with compromised immune systems.
Abstract: Lionel A. Mandell, Richard G. Wunderink, Antonio Anzueto, John G. Bartlett, G. Douglas Campbell, Nathan C. Dean, Scott F. Dowell, Thomas M. File, Jr. Daniel M. Musher, Michael S. Niederman, Antonio Torres, and Cynthia G. Whitney McMaster University Medical School, Hamilton, Ontario, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, and Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi School of Medicine, Jackson; Division of Pulmonary and Critical Care Medicine, LDS Hospital, and University of Utah, Salt Lake City, Utah; Centers for Disease Control and Prevention, Atlanta, Georgia; Northeastern Ohio Universities College of Medicine, Rootstown, and Summa Health System, Akron, Ohio; State University of New York at Stony Brook, Stony Brook, and Department of Medicine, Winthrop University Hospital, Mineola, New York; and Cap de Servei de Pneumologia i Allergia Respiratoria, Institut Clinic del Torax, Hospital Clinic de Barcelona, Facultat de Medicina, Universitat de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, CIBER CB06/06/0028, Barcelona, Spain.
5,558 citations
TL;DR: The prevalence of CKD in the United States in 1999-2004 is higher than it was in 1988-1994 and this increase is partly explained by the increasing prevalence of diabetes and hypertension and raises concerns about future increased incidence of kidney failure and other complications.
Abstract: ContextThe prevalence and incidence of kidney failure treated by dialysis and transplantation in the United States have increased from 1988 to 2004. Whether there have been changes in the prevalence of earlier stages of chronic kidney disease (CKD) during this period is uncertain.ObjectiveTo update the estimated prevalence of CKD in the United States.Design, Setting, and ParticipantsCross-sectional analysis of the most recent National Health and Nutrition Examination Surveys (NHANES 1988-1994 and NHANES 1999-2004), a nationally representative sample of noninstitutionalized adults aged 20 years or older in 1988-1994 (n = 15 488) and 1999-2004 (n = 13 233).Main Outcome MeasuresChronic kidney disease prevalence was determined based on persistent albuminuria and decreased estimated glomerular filtration rate (GFR). Persistence of microalbuminuria (>30 mg/g) was estimated from repeat visit data in NHANES 1988-1994. The GFR was estimated using the abbreviated Modification of Diet in Renal Disease Study equation reexpressed to standard serum creatinine.ResultsThe prevalence of both albuminuria and decreased GFR increased from 1988-1994 to 1999-2004. The prevalence of CKD stages 1 to 4 increased from 10.0% (95% confidence interval [CI], 9.2%-10.9%) in 1988-1994 to 13.1% (95% CI, 12.0%-14.1%) in 1999-2004 with a prevalence ratio of 1.3 (95% CI, 1.2-1.4). The prevalence estimates of CKD stages in 1988-1994 and 1999-2004, respectively, were 1.7% (95% CI, 1.3%-2.2%) and 1.8% (95% CI, 1.4%-2.3%) for stage 1; 2.7% (95% CI, 2.2%-3.2%) and 3.2% (95% CI, 2.6%-3.9%) for stage 2; 5.4% (95% CI, 4.9%-6.0%) and 7.7% (95% CI, 7.0%-8.4%) for stage 3; and 0.21% (95% CI, 0.15%-0.27%) and 0.35% (0.25%-0.45%) for stage 4. A higher prevalence of diagnosed diabetes and hypertension and higher body mass index explained the entire increase in prevalence of albuminuria but only part of the increase in the prevalence of decreased GFR. Estimation of GFR from serum creatinine has limited precision and a change in mean serum creatinine accounted for some of the increased prevalence of CKD.ConclusionsThe prevalence of CKD in the United States in 1999-2004 is higher than it was in 1988-1994. This increase is partly explained by the increasing prevalence of diabetes and hypertension and raises concerns about future increased incidence of kidney failure and other complications of CKD.
4,567 citations
TL;DR: The Phase II HapMap is described, which characterizes over 3.1 million human single nucleotide polymorphisms genotyped in 270 individuals from four geographically diverse populations and includes 25–35% of common SNP variation in the populations surveyed, and increased differentiation at non-synonymous, compared to synonymous, SNPs is demonstrated.
Abstract: We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.
4,565 citations
TL;DR: Recent advances in understanding how epigenetic alterations participate in the earliest stages of neoplasia, including stem/precursor cell contributions, are reviewed and the growing implications of these advances for strategies to control cancer are discussed.
4,269 citations
TL;DR: Invasive MRSA infection affects certain populations disproportionately and is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.
Abstract: ContextAs the epidemiology of infections with methicillin-resistant Staphylococcus aureus (MRSA) changes, accurate information on the scope and magnitude of MRSA infections in the US population is needed.ObjectivesTo describe the incidence and distribution of invasive MRSA disease in 9 US communities and to estimate the burden of invasive MRSA infections in the United States in 2005.Design and SettingActive, population-based surveillance for invasive MRSA in 9 sites participating in the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network from July 2004 through December 2005. Reports of MRSA were investigated and classified as either health care–associated (either hospital-onset or community-onset) or community-associated (patients without established health care risk factors for MRSA).Main Outcome MeasuresIncidence rates and estimated number of invasive MRSA infections and in-hospital deaths among patients with MRSA in the United States in 2005; interval estimates of incidence excluding 1 site that appeared to be an outlier with the highest incidence; molecular characterization of infecting strains.ResultsThere were 8987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care–associated: 5250 (58.4%) were community-onset infections, 2389 (26.6%) were hospital-onset infections; 1234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100 000 (interval estimate, 24.4-35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100 000; interval estimate, 92.6-156.9), blacks (66.5 per 100 000; interval estimate, 43.5-63.1), and males (37.5 per 100 000; interval estimate, 26.8-39.5). There were 1598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100 000 (interval estimate, 3.3-7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care–associated infections in all surveillance areas.ConclusionsInvasive MRSA infection affects certain populations disproportionately. It is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.
3,803 citations
TL;DR: A unified approach is proposed that makes it possible for researchers to preprocess data with matching and then to apply the best parametric techniques they would have used anyway and this procedure makes parametric models produce more accurate and considerably less model-dependent causal inferences.
Abstract: Although published works rarely include causal estimates from more than a few model specifications, authors usually choose the presented estimates from numerous trial runs readers never see. Given the often large variation in estimates across choices of control variables, functional forms, and other modeling assumptions, how can researchers ensure that the few estimates presented are accurate or representative? How do readers know that publications are not merely demonstrations that it is possible to find a specification that fits the author's favorite hypothesis? And how do we evaluate or even define statistical properties like unbiasedness or mean squared error when no unique model or estimator even exists? Matching methods, which offer the promise of causal inference with fewer assumptions, constitute one possible way forward, but crucial results in this fast-growing methodological literature are often grossly misinterpreted. We explain how to avoid these misinterpretations and propose a unified approach that makes it possible for researchers to preprocess data with matching (such as with the easy-to-use software we offer) and then to apply the best parametric techniques they would have used anyway. This procedure makes parametric models produce more accurate and considerably less model-dependent causal inferences.
3,601 citations
TL;DR: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis.
Abstract: Background Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. Results Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patie...
3,474 citations
TL;DR: In this paper, the authors analyzed 13,023 genes in 11 breast and 11 colorectal cancers and found that individual tumors accumulate an average of 90 mutant genes but only a subset of these contribute to the neoplastic process.
Abstract: Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.
3,152 citations
TL;DR: The goal was to forecast the global burden of Alzheimer's disease and evaluate the potential impact of interventions that delay disease onset or progression.
Abstract: Background Our goal was to forecast the global burden of Alzheimer's disease and evaluate the potential impact of interventions that delay disease onset or progression. Methods A stochastic, multistate model was used in conjunction with United Nations worldwide population forecasts and data from epidemiological studies of the risks of Alzheimer's disease. Results In 2006, the worldwide prevalence of Alzheimer's disease was 26.6 million. By 2050, the prevalence will quadruple, by which time 1 in 85 persons worldwide will be living with the disease. We estimate about 43% of prevalent cases need a high level of care, equivalent to that of a nursing home. If interventions could delay both disease onset and progression by a modest 1 year, there would be nearly 9.2 million fewer cases of the disease in 2050, with nearly the entire decline attributable to decreases in persons needing a high level of care. Conclusions We face a looming global epidemic of Alzheimer's disease as the world's population ages. Modest advances in therapeutic and preventive strategies that lead to even small delays in the onset and progression of Alzheimer's disease can significantly reduce the global burden of this disease.
3,106 citations
TL;DR: The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway, and this review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.
Abstract: Keap1-Nrf2-ARE signaling plays a significant role in protecting cells from endogenous and exogenous stresses. The development of Nrf2 knockout mice has provided key insights into the toxicological importance of this pathway. These mice are more sensitive to the hepatic, pulmonary, ovarian, and neurotoxic consequences of acute exposures to environmental agents and drugs, inflammatory stresses, as well as chronic exposures to cigarette smoke and other carcinogens. Under quiescent conditions, the transcription factor Nrf2 interacts with the actin-anchored protein Keap1, largely localized in the cytoplasm. This quenching interaction maintains low basal expression of Nrf2-regulated genes. However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival. This review highlights the key elements in this adaptive response to protection against acute and chronic cell injury provoked by environmental stresses.
TL;DR: Initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with pac litaxel alone.
Abstract: vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001), headache (2.2% vs. 0.0%, P = 0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P = 0.02) were more frequent in patients receiving paclitaxel plus bevacizumab. Infection was more common in patients receiving paclitaxel plus bevacizumab (9.3% vs. 2.9%, P<0.001), but febrile neutropenia was uncommon (<1% overall). Conclusions Initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with paclitaxel alone. (ClinicalTrials.gov number, NCT00028990.)
TL;DR: In this paper, a review of recent advances in understanding the mechanical behavior of metallic glasses, with particular emphasis on the deformation and fracture mechanisms, is presented, where the role of glass structure on mechanical properties, and conversely, the effect of deformation upon glass structure, are also described.
TL;DR: This paper found that essential human genes are likely to encode hub proteins and are expressed widely in most tissues, while the vast majority of disease genes are non-essential and show no tendency to encoding hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network.
Abstract: A network of disorders and disease genes linked by known disorder-gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.
TL;DR: Obesity has increased at an alarming rate in the United States over the past three decades and the associations of obesity with gender, age, ethnicity, and socioeconomic status are complex and dynamic.
Abstract: This review of the obesity epidemic provides a comprehensive description of the current situation, time trends, and disparities across gender, age, socioeconomic status, racial/ethnic groups, and geographic regions in the United States based on national data. The authors searched studies published between 1990 and 2006. Adult overweight and obesity were defined by using body mass index (weight (kg)/height (m) 2 ) cutpoints of 25 and 30, respectively; childhood ‘‘at risk for overweight’’ and overweight were defined as the 85th and 95th percentiles of body mass index. Average annual increase in and future projections for prevalence were estimated by using linear regression models. Among adults, obesity prevalence increased from 13% to 32% between the 1960s and 2004. Currently, 66% of adults are overweight or obese; 16% of children and adolescents are overweight and 34% are at risk of overweight. Minority and low-socioeconomic-status groups are disproportionately affected at all ages. Annual increases in prevalence ranged from 0.3 to 0.9 percentage points across groups. By 2015, 75% of adults will be overweight or obese, and 41% will be obese. In conclusion, obesity has increased at an alarming rate in the United States over the past three decades. The associations of obesity with gender, age, ethnicity, and socioeconomic status are complex and dynamic. Related population-based programs and policies are needed.
TL;DR: The interpolated Markov model (IMM) DNA discriminator correctly separated 99% of the sequences in a recent genome project that produced a mixture of sequences from the bacterium Prochloron didemni and its sea squirt host, Lissoclinum patella.
Abstract: Motivation: The Glimmer gene-finding software has been successfully used for finding genes in bacteria, archaea and viruses representing hundreds of species. We describe several major changes to the Glimmer system, including improved methods for identifying both coding regions and start codons. We also describe a new module of Glimmer that can distinguish host and endosymbiont DNA. This module was developed in response to the discovery that eukaryotic genome sequencing projects sometimes inadvertently capture the DNA of intracellular bacteria living in the host.
Results: The new methods dramatically reduce the rate of false-positive predictions, while maintaining Glimmer's 99% sensitivity rate at detecting genes in most species, and they find substantially more correct start sites, as measured by comparisons to known and well-curated genes. We show that our interpolated Markov model (IMM) DNA discriminator correctly separated 99% of the sequences in a recent genome project that produced a mixture of sequences from the bacterium Prochloron didemni and its sea squirt host, Lissoclinum patella.
Availability: Glimmer is OSI Certified Open Source and available at http://cbcb.umd.edu/software/glimmer
Contact: adelcher@umiacs.umd.edu
TL;DR: Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection, and the degree of association increased with the number of vaginal-sex and oral-sex partners, among subjects with or without the established risk factors of tobacco and alcohol use.
Abstract: BACKGROUND Substantial molecular evidence suggests a role for human papillomavirus (HPV) in the pathogenesis of oropharyngeal squamous-cell carcinoma, but epidemiologic data have been inconsistent. METHODS We performed a hospital-based, case-control study of 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer. Multivariate logistic-regression models were used for case-control comparisons. RESULTS A high lifetime number of vaginal-sex partners (26 or more) was associated with oropharyngeal cancer (odds ratio, 3.1; 95% confidence interval [CI], 1.5 to 6.5), as was a high lifetime number of oral-sex partners (6 or more) (odds ratio, 3.4; 95% CI, 1.3 to 8.8). The degree of association increased with the number of vaginal-sex and oral-sex partners (P values for trend, 0.002 and 0.009, respectively). Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infection with any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to 26.4), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detected in 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens, and 64% of patients with cancer were seropositive for the HPV-16 oncoprotein E6, E7, or both. HPV-16 L1 seropositivity was highly associated with oropharyngeal cancer among subjects with a history of heavy tobacco and alcohol use (odds ratio, 19.4; 95% CI, 3.3 to 113.9) and among those without such a history (odds ratio, 33.6; 95% CI, 13.3 to 84.8). The association was similarly increased among subjects with oral HPV-16 infection, regardless of their tobacco and alcohol use. By contrast, tobacco and alcohol use increased the association with oropharyngeal cancer primarily among subjects without exposure to HPV-16. CONCLUSIONS Oral HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use.
University of Düsseldorf1, University of Pittsburgh2, University of New South Wales3, Icahn School of Medicine at Mount Sinai4, University of California, San Diego5, Washington University in St. Louis6, Children's Memorial Hospital7, University of Miami8, University of Gothenburg9, National Institutes of Health10, Columbia University11, University of Washington12, Johns Hopkins University13, University of California, San Francisco14, University of North Carolina at Chapel Hill15, University of Hawaii at Manoa16, University of Puerto Rico17
TL;DR: This report reviews the collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neuroc cognitive impairment to categorize individuals with subclinical impairment.
Abstract: In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.
28 Oct 2007
TL;DR: The provable data possession (PDP) model as discussed by the authors allows a client that has stored data at an untrusted server to verify that the server possesses the original data without retrieving it.
Abstract: We introduce a model for provable data possession (PDP) that allows a client that has stored data at an untrusted server to verify that the server possesses the original data without retrieving it. The model generates probabilistic proofs of possession by sampling random sets of blocks from the server, which drastically reduces I/O costs. The client maintains a constant amount of metadata to verify the proof. The challenge/response protocol transmits a small, constant amount of data, which minimizes network communication. Thus, the PDP model for remote data checking supports large data sets in widely-distributed storage system.We present two provably-secure PDP schemes that are more efficient than previous solutions, even when compared with schemes that achieve weaker guarantees. In particular, the overhead at the server is low (or even constant), as opposed to linear in the size of the data. Experiments using our implementation verify the practicality of PDP and reveal that the performance of PDP is bounded by disk I/O and not by cryptographic computation.
TL;DR: It is demonstrated that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway, and that its dysregulation leads to tumorigenesis, uncovering a universal size-control mechanism in metazoan.
TL;DR: Male circumcision reduced HIV incidence in men without behavioural disinhibition as well as in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups.
TL;DR: It is demonstrated that microRNAs (miRNAs) are important components of the p53 transcriptional network and miR-34a-responsive genes are highly enriched for those that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis.
Princeton University1, Goddard Space Flight Center2, University of Texas at Austin3, University of Toronto4, Johns Hopkins University5, Cornell University6, University of British Columbia7, University of Chicago8, Brown University9, University of Pennsylvania10, University of California, Los Angeles11
TL;DR: In this article, the authors presented a model of polarized foreground emission that captures the large angular scale characteristics of the microwave sky and analyzed the 3-year full-sky maps of the polarization and cosmological implications.
Abstract: The Wilkinson Microwave Anisotropy Probe (WMAP) has mapped the entire sky in five frequency bands between 23 and 94 GHz with polarization-sensitive radiometers. We present 3 year full-sky maps of the polarization and analyze them for foreground emission and cosmological implications. These observations open up a new window for understanding how the universe began and help set a foundation for future observations. WMAP observes significant levels of polarized foreground emission due to both Galactic synchrotron radiation and thermal dust emission. Synchrotron radiation is the dominant signal at l < 50 and ν 40 GHz, while thermal dust emission is evident at 94 GHz. The least contaminated channel is at 61 GHz. We present a model of polarized foreground emission that captures the large angular scale characteristics of the microwave sky. After applying a Galactic mask that cuts 25.7% of the sky, we show that the high Galactic latitude rms polarized foreground emission, averaged over l = 4-6, ranges from ≈5 μK at 22 GHz to 0.6 μK at 61 GHz. By comparison, the levels of intrinsic CMB polarization for a ΛCDM model with an optical depth of τ = 0.09 and assumed tensor-to-scalar ratio r = 0.3 are ≈0.3 μK for E-mode polarization and ≈0.1 μK for B-mode polarization. To analyze the maps for CMB polarization at l < 16, we subtract a model of the foreground emission that is based primarily on a scaling WMAP's 23 GHz map. In the foreground-corrected maps, we detect l(l + 1)C/2π = 0.086 ± 0.029 (μK)2. This is interpreted as the result of rescattering of the CMB by free electrons released during reionization at zr = 10.9 for a model with instantaneous reionization. By computing the likelihood of just the EE data as a function of τ we find τ = 0.10 ± 0.03. When the same EE data are used in the full six-parameter fit to all WMAP data (TT, TE, EE), we find τ = 0.09 ± 0.03. Marginalization over the foreground subtraction affects this value by δτ < 0.01. We see no evidence for B modes, limiting them to l(l + 1)C/2π = -0.04 ± 0.03 (μK)2. We perform a template fit to the E-mode and B-mode data with an approximate model for the tensor scalar ratio. We find that the limit from the polarization signals alone is r < 2.2 (95% CL), where r is evaluated at k = 0.002 Mpc-1. This corresponds to a limit on the cosmic density of gravitational waves of ΩGWh2 < 5 × 10-12. From the full WMAP analysis, we find r < 0.55 (95% CL) corresponding to a limit of ΩGWh2 < 1 × 10-12 (95% CL). The limit on r is approaching the upper bound of predictions for some of the simplest models of inflation, r ~ 0.3.
Ludwig Institute for Cancer Research1, University of Copenhagen2, University of Helsinki3, National Institute for Health and Welfare4, International Agency for Research on Cancer5, Norwegian University of Science and Technology6, Cayetano Heredia University7, Medical University of Warsaw8, Lund University9, Karolinska Institutet10, Boston Children's Hospital11, Emory University12, Indiana University – Purdue University Indianapolis13, Georgia Regents University14, University of Washington15, Johns Hopkins University16, Duke University17, Merck & Co.18
TL;DR: In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV- 16 or HPV -18 than did those inThe placebo group.
Abstract: BACKGROUND: Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18. METHODS: In this randomized, double-blind trial, we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. RESULTS: Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31). CONCLUSIONS: In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group.
National Institutes of Health1, Imperial College London2, Aarhus University3, University of Oxford4, University of Wisconsin-Madison5, University of Toronto6, University of California, Los Angeles7, Columbia University8, National Institute of Radiological Sciences9, University of Michigan10, University of Copenhagen11, University of Turku12, VU University Amsterdam13, Brookhaven National Laboratory14, Pfizer15, Washington University in St. Louis16, Indiana University – Purdue University Indianapolis17, University of Pittsburgh18, University of British Columbia19, Emory University20, Johns Hopkins University21, Yale University22
TL;DR: An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.
Abstract: An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.
TL;DR: In this article, the authors used the HST data to trace the history of cosmic expansion over the last 10 billion years, and found 21 new Type Ia supernovae (SNe Ia) with the Hubble Space Telescope (HST).
Abstract: We have discovered 21 new Type Ia supernovae (SNe Ia) with the Hubble Space Telescope (HST) and have used them to trace the history of cosmic expansion over the last 10 billion yr. These objects, which include 13 spectroscopicallyconfirmedSNeIaat z � 1,werediscoveredduring14epochsofreimagingoftheGOODSfieldsNorthand South over 2 yr with the Advanced Camera for Surveys on HST. Together with a recalibration of our previous HSTdiscovered SNe Ia, the full sample of 23 SNe Ia at z � 1 provides the highest redshift sample known. Combining these data with previous SN Ia data sets, we measured Hz ðÞ at discrete, uncorrelated epochs, reducing the uncertainty of Hz >1 ðÞ from 50% to under 20%, strengthening the evidence for a cosmic jerk—the transition from deceleration in the past to acceleration in thepresent. The uniqueleverage of theHSThigh-redshift SNe Ia provides thefirstmeaningful constraint on the dark energy equation-of-state parameter at z � 1. The result remains consistent with a cosmological constant [ wz ðÞ ¼� 1] and rules out rapidly evolving dark energy (dw/dz 31). The defining property of dark energy, its negative pressure, appears to be present at z > 1, in the epoch preceding acceleration, with � 98% confidenceinourprimaryfit.Moreover,thez > 1sample-averagedspectralenergydistributionisconsistentwiththat of thetypicalSNIaoverthelast10Gyr,indicatingthatanyspectralevolutionofthepropertiesof SNeIawithredshift is still below our detection threshold.
Pardis C. Sabeti1, Pardis C. Sabeti2, Patrick Varilly1, Patrick Varilly2 +255 more•Institutions (50)
TL;DR: ‘Long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population are developed.
Abstract: With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.
TL;DR: It is demonstrated that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium, and these findings suggest thatAutophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
Abstract: We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
Book•
30 Jul 2007TL;DR: In this article, the authors proposed a method to estimate causal effects by conditioning on observed variables to block backdoor paths in observational social science research, but the method is limited to the case of causal exposure and identification criteria for conditioning estimators.
Abstract: Part I. Causality and Empirical Research in the Social Sciences: 1. Introduction Part II. Counterfactuals, Potential Outcomes, and Causal Graphs: 2. Counterfactuals and the potential-outcome model 3. Causal graphs Part III. Estimating Causal Effects by Conditioning on Observed Variables to Block Backdoor Paths: 4. Models of causal exposure and identification criteria for conditioning estimators 5. Matching estimators of causal effects 6. Regression estimators of causal effects 7. Weighted regression estimators of causal effects Part IV. Estimating Causal Effects When Backdoor Conditioning Is Ineffective: 8. Self-selection, heterogeneity, and causal graphs 9. Instrumental-variable estimators of causal effects 10. Mechanisms and causal explanation 11. Repeated observations and the estimation of causal effects Part V. Estimation When Causal Effects Are Not Point Identified by Observables: 12. Distributional assumptions, set identification, and sensitivity analysis Part VI. Conclusions: 13. Counterfactuals and the future of empirical research in observational social science.
University of California, Los Angeles1, Institut d'Astrophysique de Paris2, University of Porto3, Columbia University4, Carnegie Institution for Science5, Johns Hopkins University6, California Institute of Technology7, Goddard Space Flight Center8, Yonsei University9, University of California, Berkeley10
TL;DR: In this article, the authors measured star formation rates (SFRs) of 50,000 optically selected galaxies in the local universe (z ≈ 0.1) by fitting the GALEX (ultraviolet) and SDSS photometry to a library of dustattenuated population synthesis models.
Abstract: We measure star formation rates (SFRs) of ≈50,000 optically selected galaxies in the local universe (z ≈ 0.1)—from gas-rich dwarfs to massive ellipticals. We obtain dust-corrected SFRs by fitting the GALEX (ultraviolet) and SDSS photometry to a library of dust-attenuated population synthesis models. For star-forming galaxies, our UV-based SFRs compare remarkably well with those from SDSS-measured emission lines (Hα). Deviations from perfect agreement are shown to be due to differences in the dust attenuation estimates. In contrast to Hα measurements, UV provides reliable SFRs for galaxies with weak Hα, and where Hα is contaminated with AGN emission (1/2 of the sample). Using full-SED SFRs, we calibrate a simple prescription that uses GALEX far- and near-UV magnitudes to produce dust-corrected SFRs for normal star-forming galaxies. The specific SFR is considered as a function of stellar mass for (1) star-forming galaxies with no AGNs, (2) those hosting an AGN, and (3) galaxies without Hα emission. We find that the three have distinct star formation histories, with AGNs lying intermediate between the star-forming and the quiescent galaxies. Star-forming galaxies without an AGN lie on a relatively narrow linear sequence. Remarkably, galaxies hosting a strong AGN appear to represent the massive continuation of this sequence. On the other hand, weak AGNs, while also massive, have lower SFRs, sometimes extending to the realm of quiescent galaxies. We propose an evolutionary sequence for massive galaxies that smoothly connects normal star-forming galaxies to quiescent galaxies via strong and weak AGNs. We confirm that some galaxies with no Hα show signs of star formation in the UV. We derive a cosmic star formation density at z = 0.1 with significantly smaller total error than previous measurements.