Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

The roles of vicariance and isolation by distance in shaping biotic diversification across an ancient archipelago: evidence from a Seychelles caecilian amphibian

© 2020 The Authors. Published by BMC. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1186/s12862-020-01673-wBackground Island systems offer excellent opportunities for studying the evolutionary histories of species by virtue of their restricted size and easily identifiable barriers to gene flow. However, most studies investigating evolutionary patterns and processes shaping biotic diversification have focused on more recent (emergent) rather than ancient oceanic archipelagos. Here, we focus on the granitic islands of the Seychelles, which are unusual among island systems because they have been isolated for a long time and are home to a monophyletic radiation of caecilian amphibians that has been separated from its extant sister lineage for ca. 65–62 Ma. We selected the most widespread Seychelles caecilian species, Hypogeophis rostratus, to investigate intraspecific morphological and genetic (mitochondrial and nuclear) variation across the archipelago (782 samples from nine islands) to identify patterns and test processes that shaped their evolutionary history within the Seychelles. Results Overall a signal of strong geographic structuring with distinct northern- and southern-island clusters were identified across all datasets. We suggest that these distinct groups have been isolated for ca. 1.26 Ma years without subsequent migration between them. Populations from the somewhat geographically isolated island of Frégate showed contrasting relationships to other islands based on genetic and morphological data, clustering alternatively with northern-island (genetic) and southern-island (morphological) populations. Conclusions Although variation in H. rostratus across the Seychelles is explained more by isolation-by-distance than by adaptation, the genetic-morphological incongruence for affinities of Frégate H. rostratus might be caused by local adaptation over-riding the signal from their vicariant history. Our findings highlight the need of integrative approaches to investigate fine-scale geographic structuring to uncover underlying diversity and to better understand evolutionary processes on ancient, continental islands.Funding for this research was provided by two grants from the National Science Foundation (BSR 88–17453, BSR 90–24505) [funding for fieldwork and lab work], two grants from the National Geographic Society (Grants 1977: 1633, 1743) [funding for fieldwork], three grants from the University of Michigan Office of the Vice President for Research, and a Research Partnership Award from the University of Michigan to RAN [morphology work]; a joint NHM-UCL IMPACT studentship [to fund STM’s PhD, lab work and fieldwork], Mohamed Bin Zayed Species Conservation Fund [funding for fieldwork] and Systematics Research Fund [funding for fieldwork] to STM; an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant #P20GM103408 to LL [funding for lab work]; a NERC/BBSRC SynTax grant [funding for fieldwork and collaboration], and Darwin Initiative (grant 19–002) [funding for fieldwork, lab work and capacity building] with partners Bristol University, Islands Conservation Society, Seychelles Islands Foundation, Seychelles Ministry of Environment, Seychelles National Parks Authority, Seychelles Natural History Museum, University of Kent, Zoological Society of London to MW, DJG, JJD. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.Published onlin

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Sensitivity of the Advanced LIGO detectors at the beginning of gravitational wave astronomy

The Laser Interferometer Gravitational Wave Observatory (LIGO) consists of two widely separated 4 km laser interferometers designed to detect gravitational waves from distant astrophysical sources in the frequency range from 10 Hz to 10 kHz. The first observation run of the Advanced LIGO detectors started in September 2015 and ended in January 2016. A strain sensitivity of better than 10−23/Hz−−−√ was achieved around 100 Hz. Understanding both the fundamental and the technical noise sources was critical for increasing the astrophysical strain sensitivity. The average distance at which coalescing binary black hole systems with individual masses of 30  M⊙ could be detected above a signal-to-noise ratio (SNR) of 8 was 1.3 Gpc, and the range for binary neutron star inspirals was about 75 Mpc. With respect to the initial detectors, the observable volume of the Universe increased by a factor 69 and 43, respectively. These improvements helped Advanced LIGO to detect the gravitational wave signal from the binary black hole coalescence, known as GW150914

Effects of Data Quality Vetoes on a Search for Compact Binary Coalescences in Advanced LIGO's First Observing Run

The first observing run of Advanced LIGO spanned 4 months, from September 12, 2015 to January 19, 2016, during which gravitational waves were directly detected from two binary black hole systems, namely GW150914 and GW151226. Confident detection of gravitational waves requires an understanding of instrumental transients and artifacts that can reduce the sensitivity of a search. Studies of the quality of the detector data yield insights into the cause of instrumental artifacts and data quality vetoes specific to a search are produced to mitigate the effects of problematic data. In this paper, the systematic removal of noisy data from analysis time is shown to improve the sensitivity of searches for compact binary coalescences. The output of the PyCBC pipeline, which is a python-based code package used to search for gravitational wave signals from compact binary coalescences, is used as a metric for improvement. GW150914 was a loud enough signal that removing noisy data did not improve its significance. However, the removal of data with excess noise decreased the false alarm rate of GW151226 by more than two orders of magnitude, from 1 in 770 years to less than 1 in 186000 years.Comment: 27 pages, 13 figures, published versio

Methods and results of a search for gravitational waves associated with gamma-ray bursts using the GEO 600, LIGO, and Virgo detectors

Paper producido por "The LIGO Scientific Collaboration and the Virgo Collaboration". (En el registro se mencionan solo algunos autores de las decenas de personas que participan).In this paper we report on a search for short-duration gravitational wave bursts in the frequency range 64 Hz–1792 Hz associated with gamma-ray bursts (GRBs), using data from GEO 600 and one of the LIGO or Virgo detectors. We introduce the method of a linear search grid to analyze GRB events with large sky localization uncertainties, for example the localizations provided by the Fermi Gamma-ray Burst Monitor (GBM). Coherent searches for gravitational waves (GWs) can be computationally intensive when the GRB sky position is not well localized, due to the corrections required for the difference in arrival time between detectors. Using a linear search grid we are able to reduce the computational cost of the analysis by a factor of Oð10Þfor GBM events. Furthermore, we demonstrate that our analysis pipeline can improve upon the sky localization of GRBs detected by the GBM, if a high-frequency GW signal is observed in coincidence. We use the method of the linear grid in a search for GWs associated with 129 GRBs observed satellite-based gamma-ray experiments between 2006 and 2011. The GRBs in our sample had not been previously analyzed for GW counterparts. A fraction of our GRB events are analyzed using data from GEO 600 while the detector was using squeezed-light states to improve its sensitivity; this is the first search for GWs using data from a squeezed-light interferometric observatory. We find no evidence for GW signals, either with any individual GRB in this sample or with the population as a whole. For each GRB we place lower bounds on the distance to the progenitor, under an assumption of a fixed GWemission energy of 10−2M⊙c2, with a median exclusion distance of 0.8 Mpc for emission at 500 Hz and 0.3 Mpc at 1 kHz. The reduced computational cost associated with a linear search grid will enable rapid searches for GWs associated with Fermi GBM events once the advanced LIGO and Virgo detectors begin operation.http://journals.aps.org/prd/abstract/10.1103/PhysRevD.89.122004publishedVersionFil: Aasi, J. LIGO. California Institute of Technology; Estados Unidos de América.Fil: Domínguez, E. Argentinian Gravitational Wave Group; Argentina.Fil: Maglione, C. Argentinian Gravitational Wave Group; Argentina.Fil: Reula, O. Argentinian Gravitational Wave Group; Argentina.Fil: Ortega, W. Argentinian Gravitational Wave Group; Argentina.Fil: Wolovick, N. Argentinian Gravitational Wave Group; Argentina.Fil: Schilman, M. Argentinian Gravitational Wave Group; Argentina.Física de Partículas y Campo