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

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

Web-based alcohol screening and brief intervention for Māori and non-Māori: the New Zealand e-SBINZ trials

BACKGROUND: Hazardous alcohol consumption is a leading modifiable cause of mortality and morbidity among young people. Screening and brief intervention (SBI) is a key strategy to reduce alcohol-related harm in the community, and web-based approaches (e-SBI) have advantages over practitioner-delivered approaches, being cheaper, more acceptable, administrable remotely and infinitely scalable. An efficacy trial in a university population showed a 10-minute intervention could reduce drinking by 11% for 6 months or more among 17-24 year-old undergraduate hazardous drinkers. The e-SBINZ study is designed to examine the effectiveness of e-SBI across a range of universities and among Māori and non-Māori students in New Zealand. METHODS/DESIGN: The e-SBINZ study comprises two parallel, double blind, multi-site, individually randomised controlled trials. This paper outlines the background and design of the trial, which is recruiting 17-24 year-old students from seven of New Zealand's eight universities. Māori and non-Māori students are being sampled separately and are invited by e-mail to complete a web questionnaire including the AUDIT-C. Those who score >4 will be randomly allocated to no further contact until follow-up (control) or to assessment and personalised feedback (intervention) via computer. Follow-up assessment will occur 5 months later in second semester. Recruitment, consent, randomisation, intervention and follow-up are all online. Primary outcomes are (i) total alcohol consumption, (ii) frequency of drinking, (iii) amount consumed per typical drinking occasion, (iv) the proportions exceeding medical guidelines for acute and chronic harm, and (v) scores on an academic problems scale. DISCUSSION: The trial will provide information on the effectiveness of e-SBI in reducing hazardous alcohol consumption across diverse university student populations with separate effect estimates for Māori and non-Māori students. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12610000279022

To Eat and To Be : food as Differenciation Policy in Spanish America, 16th and 17th Centuries

ABSTRACT: This paper demonstrates that food served as a marker of social differentiation during the 16th and 17th centuries in the Spanish possessions in America, not only in economic terms but also in the sense that food was associated with the social stratum to which a person belonged. Each one was oblidged to eat foods associated with his or her "natural" stratum. This complex hierarchical model of society was based on European patterns coming from the Middle Ages, such as the Great Chain of Being and humoral theory. This model was reinforced in the early modern period, and it took on new characteristics in America, where it was used to differentiate Spaniards, Creoles, Mestizos and Indians.RESUMEN: Este artículo muestra cómo la alimentación servía como un elemento de diferenciación social durante los siglos XVI y XVII, en la América española, no solo como un factor económico, sino asociado a la calidad o estado al que pertenecieran las personas. En este sentido, a cada uno le correspondía comer aquello que era propio de su condición estamental. Este complejo modelo de jerarquización social estaba basado en principios europeos que venían desde la Edad Media, como la gran cadena del ser y la teoría humoral. En la edad moderna, el modelo se reforzó y en América tomó nuevas características, por la forma en que se buscó diferenciar entre españoles, criollos, mestizos e indios

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe