An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

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

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

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

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

Development of Tibiofemoral Angle in Korean Children

This study was performed to identify the chronological changes of the knee angle or the tibiofemoral angles in normal healthy Korean children. Full-length anteroposterior view standing radiographs of 818 limbs of 452 Korean children were analyzed. The overall patterns of the chronological changes in the knee angle were similar to those described previously in western or Asian children, but the knee angle development was delayed, i.e., genu varum before 1 yr, neutral at 1.5 yr, increasing genu valgum with maximum a value of 7.8° at 4 yr, followed by a gradual decrease to approximately 5-6° of genu valgum of the adult level at 7 to 8 yr of age. These normative data on chronological changes of knee angles should be taken into consideration when evaluating lower limb alignment in children

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

The purpose of this review is to present up-to-date pharmacological, genetic, and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine, and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein, we sought to place the P rat's behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this chapter discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general

Cross-Cultural Validation of the Perceptions of Stigmatization by Others for Seeking Help (PSOSH) Scale

Social network stigma refers to the perceived negative views about seeking help for mental health problems that are held by those closest to an individual, such as family and friends. This form of stigma predicts help-seeking attitudes and intentions beyond other forms of stigma, and is predominantly measured using the Perceptions of Stigmatization by Others for Seeking Help scale (PSOSH; Vogel, Wade, & Ascheman, 2009). However, the PSOSH was normed using samples from the United States and, until the cross-cultural validity of this measure is established, it cannot reliably be used within other countries (Miller & Sheu, 2008). As such, the current study (N = 3,440) examined the cross-cultural measurement invariance of the PSOSH using the sequential constraint imposition approach across 11 countries/regions: Australia, Brazil, Canada, Hong Kong, Portugal, Romania, Taiwan, Turkey, the United Arab Emirates (UAE), the United Kingdom (U.K.), and the United States (U.S.). Overall, findings indicate that the PSOSH measures a meaningful construct (i.e., configural and metric invariance) across the 11 countries/regions and that future cross-cultural research could use the PSOSH to examine relationships between social network stigma and other variables. Scalar invariance results also supported the examination of mean differences in Australia, Brazil, Canada, Portugal, Turkey, the U.K., and the U.S., but not in Hong Kong, Romania, Taiwan, and UAE. Implications for future cross-cultural research are discussed

Binge Drinking Effects on EEG in Young Adult Humans

Young adult (N = 96) university students who varied in their binge drinking history were assessed by electroencephalography (EEG) recording during passive viewing. Groups consisted of male and female non-binge drinkers (>1 to 5/4 drinks/ounces in under two hours), low-binge drinkers (5/4–7/6 drinks/ounces in under two hours), and high-binge drinkers (≥ 10 drinks/ounces in under two hours), who had been drinking alcohol at their respective levels for an average of 3 years. The non- and low-binge drinkers exhibited less spectral power than the high-binge drinkers in the delta (0–4 Hz) and fast-beta (20–35 Hz) bands. Binge drinking appears to be associated with a specific pattern of brain electrical activity in young adults that may reflect the future development of alcoholism

Increasing atmospheric [CO2] from glacial through future levels affects drought tolerance via impacts on leaves, xylem and their integrated function

This is the peer reviewed version of the following article: Medeiros, J. S. and Ward, J. K. (2013), Increasing atmospheric [CO2] from glacial to future concentrations affects drought tolerance via impacts on leaves, xylem and their integrated function. New Phytol, 199: 738–748. doi:10.1111/nph.12318, which has been published in final form at http://doi.org/10.1111/nph.12318. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Changes in atmospheric carbon dioxide concentration ([CO2]) affect plant carbon/water trade-offs, with implications for drought tolerance. Leaf-level studies often indicate that drought tolerance may increase with rising [CO2], but integrated leaf and xylem responses are not well understood in this respect. In addition, the influence of low [CO2] of the last glacial period on drought tolerance and xylem properties is not well understood. We investigated the interactive effects of a broad range of [CO2] and plant water potentials on leaf function, xylem structure and function and the integration of leaf and xylem function in Phaseolus vulgaris. Elevated [CO2] decreased vessel implosion strength, reduced conduit specific hydraulic conductance, and compromised leaf specific xylem hydraulic conductance under moderate drought. By contrast, at glacial [CO2], transpiration was maintained under moderate drought via greater conduit specific and leaf specific hydraulic conductance in association with increased vessel implosion strength. Our study involving the integration of leaf and xylem responses suggests that increasing [CO2] does not improve drought tolerance. We show that under glacial conditions changes in leaf and xylem properties could increase drought tolerance, while under future conditions greater productivity may only occur when higher water use can be accommodated