Showing papers by "Wayne State University published in 2012"

A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3

Abstract: We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non-synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted. Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w1118; iso-2; iso-3 strain and the reference y1; cn1 bw1 sp1 strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non-synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in...

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression.

Abstract: The human genome contains many thousands of long noncoding RNAs (lncRNAs). While several studies have demonstrated compelling biological and disease roles for individual examples, analytical and experimental approaches to investigate these genes have been hampered by the lack of comprehensive lncRNA annotation. Here, we present and analyze the most complete human lncRNA annotation to date, produced by the GENCODE consortium within the framework of the ENCODE project and comprising 9277 manually annotated genes producing 14,880 transcripts. Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. In contrast to protein-coding genes, however, lncRNAs display a striking bias toward two-exon transcripts, they are predominantly localized in the chromatin and nucleus, and a fraction appear to be preferentially processed into small RNAs. They are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. Importantly, about one-third seem to have arisen within the primate lineage. Comprehensive analysis of their expression in multiple human organs and brain regions shows that lncRNAs are generally lower expressed than protein-coding genes, and display more tissue-specific expression patterns, with a large fraction of tissue-specific lncRNAs expressed in the brain. Expression correlation analysis indicates that lncRNAs show particularly striking positive correlation with the expression of antisense coding genes. This GENCODE annotation represents a valuable resource for future studies of lncRNAs.

A framework for human microbiome research

Abstract: A variety of microbial communities and their genes (microbiome) exist throughout the human body, playing fundamental roles in human health and disease. The NIH funded Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 to 18 body sites up to three times, which to date, have generated 5,177 microbial taxonomic profiles from 16S rRNA genes and over 3.5 Tb of metagenomic sequence. In parallel, approximately 800 human-associated reference genomes have been sequenced. Collectively, these data represent the largest resource to date describing the abundance and variety of the human microbiome, while providing a platform for current and future studies.

Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma

Abstract: Purpose Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. Patients and Methods In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin’s lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. Results The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Conclusion The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy. J Clin Oncol 30:2183-2189. © 2012 by American Society of Clinical Oncology

Globalization and its Discontents

Abstract: In this issue of the journal, William Robinson offers his analysis of the rise of transnational elites emerging outside of the traditional frame of nation-based capitalism. What is significant, in large part, is that unlike their national-capital predecessors, this new cadre has little concern for all that we refer to as social reproduction, industrialization, and local development. In its place, argues Robinson, are elites guided by a definition of global development rooted in the expansion of global markets and the integration of national economies into a global capitalist reality. This picture is a logical extension of a narrative that takes capitalism from a period of internationalization to globalization, and while the distinction between these two periods of capitalist development remains somewhat unclear we can agree significant changes are underway. The pages of this journal have recently explored the nature of class politics in globalization (Berberoglu, 2009; Kollmeyer, 2003; and Sakellaropoulos, 2009), the reconceptualization of globalization through a gender lens (Acker, 2004; Gottfried, 2004; and Ng, 2004), the impact of globalization on workers (Archibald, 2009a, 2009b) and the way the rhetoric of the core penetrates other regions of a globalizing economy (Barahona, 2011). Robinson’s article, and the critical exchange between Robinson and commentators in this issue, shifts our attention away from what we mean by globalization and its impact, and towards the question of who now manages this new global economy and what that means. The neoliberal agenda, and apparently the focus of transnational elites, is the expansion and reliance on ‘the market’ and a return to pure laissez-faire practices. The role of markets is the central piece, for example, in the current efforts to restructure the failing economies in Europe and the underpinning of the criticism that markets should be freed from the fetters of government regulations that introduce inefficiencies and are to blame for the economic ills that have befallen the major capitalist economies of the world (Fuchs, 2010). We now know all too well, so we are told, that a correction requires a heavy dose of austerity and the shrinking of the social supports provided by national governments. Otherwise local economies will fail to participate in the growing global economy and nations will fall into unimaginable poverty. The writings of Andre Gunder Frank (especially 1966, 1971) foreshadow the current argument, though I am certain not in the way he would have imagined. For Frank, while post-World War II capitalist countries may have been undeveloped at some point, the rest of the post-colonial world suffered from underdevelopment – that is, from a process that maintained poverty and economic hardship as a result of their relationships with so-called modern capitalist countries. The very forces of capitalism instituted well-documented practices of extracting resources and maintaining low wages in order to increase profits (practices that persist today, if not in the same form). At the same time, to ‘encourage’ development, governments and global financial institutions like the IMF and World Bank provided huge loans so that these countries could ‘afford’ to modernize rapidly. These loans were accompanied by massive intervention 440404 CRS0010.1177/0896920512440404EditorialCritical Sociology 2012

Workload analysis of a large-scale key-value store

Abstract: Key-value stores are a vital component in many scale-out enterprises, including social networks, online retail, and risk analysis. Accordingly, they are receiving increased attention from the research community in an effort to improve their performance, scalability, reliability, cost, and power consumption. To be effective, such efforts require a detailed understanding of realistic key-value workloads. And yet little is known about these workloads outside of the companies that operate them. This paper aims to address this gap.To this end, we have collected detailed traces from Facebook's Memcached deployment, arguably the world's largest. The traces capture over 284 billion requests from five different Memcached use cases over several days. We analyze the workloads from multiple angles, including: request composition, size, and rate; cache efficacy; temporal patterns; and application use cases. We also propose a simple model of the most representative trace to enable the generation of more realistic synthetic workloads by the community.Our analysis details many characteristics of the caching workload. It also reveals a number of surprises: a GET/SET ratio of 30:1 that is higher than assumed in the literature; some applications of Memcached behave more like persistent storage than a cache; strong locality metrics, such as keys accessed many millions of times a day, do not always suffice for a high hit rate; and there is still room for efficiency and hit rate improvements in Memcached's implementation. Toward the last point, we make several suggestions that address the exposed deficiencies.

Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study

Abstract: Purpose Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30. The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL. Patients and Methods Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion. The primary end point of the study was overall objective response rate as assessed by independent central review. Results Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. The median durations of overall respons...

Combined results of searches for the standard model Higgs boson in pp collisions at √s = 7 TeV

Abstract: Combined results are reported from searches for the standard model Higgs boson in proton-proton collisions at sqrt(s)=7 TeV in five Higgs boson decay modes: gamma pair, b-quark pair, tau lepton pair, W pair, and Z pair. The explored Higgs boson mass range is 110-600 GeV. The analysed data correspond to an integrated luminosity of 4.6-4.8 inverse femtobarns. The expected excluded mass range in the absence of the standard model Higgs boson is 118-543 GeV at 95% CL. The observed results exclude the standard model Higgs boson in the mass range 127-600 GeV at 95% CL, and in the mass range 129-525 GeV at 99% CL. An excess of events above the expected standard model background is observed at the low end of the explored mass range making the observed limits weaker than expected in the absence of a signal. The largest excess, with a local significance of 3.1 sigma, is observed for a Higgs boson mass hypothesis of 124 GeV. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-600 (110-145) GeV is estimated to be 1.5 sigma (2.1 sigma). More data are required to ascertain the origin of this excess.

Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift

Abstract: This paper describes a new program SnpSift for filtering differential DNA sequence variants between two or more experimental genomes after genotoxic chemical exposure. Here, we illustrate how SnpSift can be used to identify candidate phenotype-relevant variants including single nucleotide polymorphisms, multiple nucleotide polymorphisms, insertions, and deletions (InDels) in mutant strains isolated from genome-wide chemical mutagenesis of Drosophila melanogaster. First, the genomes of two independently isolated mutant fly strains that are allelic for a novel recessive male-sterile locus generated by genotoxic chemical exposure were sequenced using the Illumina next-generation DNA sequencer to obtain 20- to 29-fold coverage of the euchromatic sequences. The sequencing reads were processed and variants were called using standard bioinformatic tools. Next, SnpEff was used to annotate all sequence variants and their potential mutational effects on associated genes. Then, SnpSift was used to filter and select differential variants that potentially disrupt a common gene in the two allelic mutant strains. The potential causative DNA lesions were partially validated by capillary sequencing of polymerase chain reaction-amplified DNA in the genetic interval as defined by meiotic mapping and deletions that remove defined regions of the chromosome. Of the five candidate genes located in the genetic interval, the Pka-like gene CG12069 was found to carry a separate pre-mature stop codon mutation in each of the two allelic mutants whereas the other four candidate genes within the interval have wild-type sequences. The Pka-like gene is therefore a strong candidate gene for the male-sterile locus. These results demonstrate that combining SnpEff and SnpSift can expedite the identification of candidate phenotype-causative mutations in chemically mutagenized Drosophila strains. This technique can also be used to characterize the variety of mutations generated by genotoxic chemicals.

Detecting and Deterring Insufficient Effort Responding to Surveys

Abstract: Responses provided by unmotivated survey participants in a careless, haphazard, or random fashion can threaten the quality of data in psychological and organizational research. The purpose of this study was to summarize existing approaches to detect insufficient effort responding (IER) to low-stakes surveys and to comprehensively evaluate these approaches. In an experiment (Study 1) and a nonexperimental survey (Study 2), 725 undergraduates responded to a personality survey online. Study 1 examined the presentation of warnings to respondents as a means of deterrence and showed the relative effectiveness of four indices for detecting IE responses: response time, long string, psychometric antonyms, and individual reliability coefficients. Study 2 demonstrated that the detection indices measured the same underlying construct and showed the improvement of psychometric properties (item interrelatedness, facet dimensionality, and factor structure) after removing IE respondents identified by each index. Three approaches (response time, psychometric antonyms, and individual reliability) with high specificity and moderate sensitivity were recommended as candidates for future application in survey research. The identification of effective IER indices may help researchers ensure the quality of their low-stake survey data. This study is a first attempt to comprehensively evaluate IER detection methods using both experimental and nonexperimental designs. Results from both studies corroborated each other in suggesting the three more effective approaches. This study also provided convergent validity evidence regarding various indices for IER.

The Mechanism(s) of Neighbourhood Effects: Theory, Evidence, and Policy Implications

Abstract: Although there is now a large body of empirical research on neighbourhood effects, we know relatively little about the causal mechanisms responsible for relationships between neighbourhood attributes and individual outcomes. A list of 15 potential causal pathways which may lead to neighbourhood effects is given, grouped into four categories: social-interactive mechanisms, environmental mechanisms, geographical mechanisms, and institutional mechanisms. The ultimate goal of neighbourhood effects research is not only to identify which mechanisms are responsible for neighbourhood effects, but also to quantitatively ascertain their relative contributions to the outcome under investigation. A pharmacological metaphor of “dosage-response” is used to understand how the theoretical mechanisms could be causally linked to individual outcomes. This metaphor refers to questions regarding the composition and the administration of the neighbourhood dosage, and the neighbourhood dosage-response relationship. This chapter concludes that despite the ever growing literature on neighbourhood effects, there is far too little scholarship to make many claims about which causal links dominate for which outcomes for which people in which national contexts and any conclusions on the existence of such effects should be treated as provisional at best.

Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials

Abstract: Background. Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy. Methods. We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of $2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes. Results. Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00‐1.02; P 5 .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08‐1.14; P 5 .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18‐2.44; P 5 .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11‐2.39; P 5 .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35‐.72; P 5 .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45‐.94; P 5 .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point. Conclusions. Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC.

Childhood Obesity in Developing Countries: Epidemiology, Determinants, and Prevention

Abstract: Rapidly changing dietary practices and a sedentary lifestyle have led to increasing prevalence of childhood obesity (5-19 yr) in developing countries recently: 41.8% in Mexico, 22.1% in Brazil, 22.0% in India, and 19.3% in Argentina. Moreover, secular trends indicate increasing prevalence rates in these countries: 4.1 to 13.9% in Brazil during 1974-1997, 12.2 to 15.6% in Thailand during 1991-1993, and 9.8 to 11.7% in India during 2006-2009. Important determinants of childhood obesity include high socioeconomic status, residence in metropolitan cities, female gender, unawareness and false beliefs about nutrition, marketing by transnational food companies, increasing academic stress, and poor facilities for physical activity. Childhood obesity has been associated with type 2 diabetes mellitus, the early-onset metabolic syndrome, subclinical inflammation, dyslipidemia, coronary artery diseases, and adulthood obesity. Therapeutic lifestyle changes and maintenance of regular physical activity through parental initiative and social support interventions are the most important strategies in managing childhood obesity. Also, high-risk screening and effective health educational programs are urgently needed in developing countries.

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

Abstract: The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta)<2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.

Prolonged myelination in human neocortical evolution

Abstract: Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the human neocortex is evolutionarily exceptional. In this study, we quantified myelinated axon fiber length density and the expression of myelin-related proteins throughout postnatal life in the somatosensory (areas 3b/3a/1/2), motor (area 4), frontopolar (prefrontal area 10), and visual (areas 17/18) neocortex of chimpanzees (N = 20) and humans (N = 33). Our examination revealed that neocortical myelination is developmentally protracted in humans compared with chimpanzees. In chimpanzees, the density of myelinated axons increased steadily until adult-like levels were achieved at approximately the time of sexual maturity. In contrast, humans displayed slower myelination during childhood, characterized by a delayed period of maturation that extended beyond late adolescence. This comparative research contributes evidence crucial to understanding the evolution of human cognition and behavior, which arises from the unfolding of nervous system development within the context of an enriched cultural environment. Perturbations of normal developmental processes and the decreased expression of myelin-related molecules have been related to psychiatric disorders such as schizophrenia. Thus, these species differences suggest that the human-specific shift in the timing of cortical maturation during adolescence may have implications for vulnerability to certain psychiatric disorders.

Childhood outcomes after hypothermia for neonatal encephalopathy.

Abstract: Background We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available. Methods In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70. Results Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) ...

Detectable clonal mosaicism and its relationship to aging and cancer

Abstract: In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response

Abstract: Glioblastoma (GBM) is distinguished by a high degree of intratumoral heterogeneity, which extends to the pattern of expression and amplification of receptor tyrosine kinases (RTKs). Although most GBMs harbor RTK amplifications, clinical trials of small-molecule inhibitors targeting individual RTKs have been disappointing to date. Activation of multiple RTKs within individual GBMs provides a theoretical mechanism of resistance; however, the spectrum of functional RTK dependence among tumor cell subpopulations in actual tumors is unknown. We investigated the pattern of heterogeneity of RTK amplification and functional RTK dependence in GBM tumor cell subpopulations. Analysis of The Cancer Genome Atlas GBM dataset identified 34 of 463 cases showing independent focal amplification of two or more RTKs, most commonly platelet-derived growth factor receptor α (PDGFRA) and epidermal growth factor receptor (EGFR). Dual-color fluorescence in situ hybridization was performed on eight samples with EGFR and PDGFRA amplification, revealing distinct tumor cell subpopulations amplified for only one RTK; in all cases these predominated over cells amplified for both. Cell lines derived from coamplified tumors exhibited genotype selection under RTK-targeted ligand stimulation or pharmacologic inhibition in vitro. Simultaneous inhibition of both EGFR and PDGFR was necessary for abrogation of PI3 kinase pathway activity in the mixed population. DNA sequencing of isolated subpopulations establishes a common clonal origin consistent with late or ongoing divergence of RTK genotype. This phenomenon is especially common among tumors with PDGFRA amplification: overall, 43% of PDGFRA-amplified GBM were found to have amplification of EGFR or the hepatocyte growth factor receptor gene (MET) as well.

Effects of biotic disturbances on forest carbon cycling in the United States and Canada

Abstract: Forest insects and pathogens are major disturbance agents that have affected millions of hectares in North America in recent decades, implying significant impacts to the carbon (C) cycle. Here, we review and synthesize published studies of the effects of biotic disturbances on forest C cycling in the United States and Canada. Primary productivity in stands was reduced, sometimes considerably, immediately following insect or pathogen attack. After repeated growth reductions caused by some insects or pathogens or a single infestation by some bark beetle species, tree mortality occurred, altering productivity and decomposition. In the years following disturbance, primary productivity in some cases increased rapidly as a result of enhanced growth by surviving vegetation, and in other cases increased slowly because of lower forest regrowth. In the decades following tree mortality, decomposition increased as a result of the large amount of dead organic matter. Net ecosystem productivity decreased immediately following attack, with some studies reporting a switch to a C source to the atmosphere, and increased afterward as the forest regrew and dead organic matter decomposed. Large variability in C cycle responses arose from several factors, including type of insect or pathogen, time since disturbance, number of trees affected, and capacity of remaining vegetation to increase growth rates following outbreak. We identified significant knowledge gaps, including limited understanding of carbon cycle impacts among different biotic disturbance types (particularly pathogens), their impacts at landscape and regional scales, and limited capacity to predict disturbance events and their consequences for carbon cycling. We conclude that biotic disturbances can have major impacts on forest C stocks and fluxes and can be large enough to affect regional C cycling. However, additional research is needed to reduce the uncertainties associated with quantifying biotic disturbance effects on the North American C budget.

Study of high-p(T) charged particle suppression in PbPb compared to pp collisions at root s(NN)=2.76 TeV

Abstract: The transverse momentum spectra of charged particles have been measured in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV by the CMS experiment at the LHC. In the transverse momentum range pt = 5-10 GeV/c, the charged particle yield in the most central PbPb collisions is suppressed by up to a factor of 5 compared to the pp yield scaled by the number of incoherent nucleon-nucleon collisions. At higher pt, this suppression is significantly reduced, approaching roughly a factor of 2 for particles with pt in the range pt=40-100 GeV/c.

Mutations in the colony stimulating factor 1 receptor ( CSF1R ) gene cause hereditary diffuse leukoencephalopathy with spheroids

Abstract: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS In one kindred, we confirmed the de novo occurrence of the mutation Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis

ATM Mutations in Patients with Hereditary Pancreatic Cancer

Abstract: Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated ( ATM ) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls ( P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families ( P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. Significance: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes. Cancer Discovery; 2(1) : 41–6. ©2011 AACR . Read the Commentary on this article by Bakker and de Winter, [p. 14][1] This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/2/14?iss=1 [2]: /lookup/volpage/2/1?iss=1

Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.

Abstract: Context Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. Design, Setting, and Participants A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Main Outcome Measures Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P Conclusion Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration clinicaltrials.gov Identifier: NCT00079274