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

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

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

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility

Real Life Account of PBIS at the Primary/Elementary Level

Real Life Account of PBIS at the Primary/Elementary Level: Implementation and Sustainability of Tier I Behavior Support PBIS implementation began with administrative support. Coach and PBIS team were formed and action plan was created. A tentative action plan was introduced to all school staff. Staff input was needed for a successful implementation. Timeline was created and everyone was given an opportunity to take an active role with implementation. Schoolwide expectations and positive reinforcements were developed: PBIS language, lesson plans, tickets, celebrations… Collected data soon guided the instruction and adjusted the re-teaching of school expectations. We found it very important for students to receive immediate feedback of expected behavior. Negative behavior was addressed with a positive statement or correction (re-teaching of expectation). A specific plan was developed to guide teacher managed/office managed behavior schoolwide. PBIS instruction was data driven through the SWISS data system with documentation and accountability. PBIS team analyzed data and developed a plan for future behavioral success. The plan addressed the problem areas in the building, days of the week, and times of the day. Data and plan was shared with staff for schoolwide implementation. We expanded our expectations through media with a school TV show and face book postings. PBIS expectations were also shared with parents and the community. Family nights and other community events focused on expanding our goal of positive behaviors. We connected all projects and school efforts to PBIS: café and outdoor area, community luncheon… We found that persistence was the key for both students and faculty. Creating a PBIS school by using the state guidelines was a important but sustainability happened when we made it “our own.” We are very proud to be a PBIS school and we encourage staff to be positive, proud, personable, and to always SMILE

Anterior EEG asymmetry and the Modifier Model of Autism.

Individual differences in the expression of autism complicate research on the nature and treatment of this disorder. In the Modifier Model of Autism (Mundy et al. 2007), we proposed that individual differences in autism may result not only from syndrome specific causal processes, but also from variability in generic, non-syndrome specific modifier processes that affect the social and emotional development of all people. One study supporting this model found that measures of resting anterior EEG asymmetry, a measure reflecting complex brain processes associated with generic individual differences in approach and avoidance motivation, may help explain differences in the expression of autism in children without intellectual disabilities (Sutton et al. 2005). In the current study, we partially replicated the observation that children with autism who exhibited a pattern of left frontal EEG asymmetry tended to display milder levels of social symptoms, although in the current sample this pattern applied only to HFA children with relatively lower verbal IQs. New observations indicated that left frontal EEG asymmetry was also associated with retrospective parent reports of significantly later age of onset of symptoms, but also higher levels of self-reported outward expressions of anger as well as symptoms of obsessive compulsive disorder in school-age higher functioning children with ASD. Therefore, the results of this study provide a new and fully independent set of observations, which indicate that individual differences in anterior EEG asymmetry may significantly moderate the expression and developmental course of autism. This observation may have clinical implications for identifying meaningful diagnostic sub-groups among children with autism