Interview on The Grange and Community Life

The Crafts, and Larry Algire discuss the Grange, which is a fraternal order of farmers founded in secret in 1868. Specifically, they discuss Wayne Grange, which was founded in 1873. The Grange system has masters, overseers and stewards as its leadership structure. They also discuss what the Grange does for the community, including square dances, and helping out the farm community.https://digital.kenyon.edu/ffp_interviews/1039/thumbnail.jp

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Dropout from interpersonal psychotherapy for mental health disorders : A systematic review and meta-analysis

Objective: Dropout is one factor that might limit the effectiveness of interpersonal psychotherapy (IPT). Improved understanding of IPT dropout is an important research priority. This meta-analysis examined dropout rates from IPT in randomized controlled trials. Method: Seventy-two trials met inclusion criteria. Results: The weighted mean dropout rate from IPT was 20.6% (95% CI = 17.4–24.2). Dropout rates were similar for depressive (20.9%; 95% CI = 17.2–25.2), anxiety (16.1%; 95% CI = 11.1–22.9), and eating disorders (18.7%; 95% CI = 11.6–28.8). Dropout was highest when more stringent definitions of dropout were applied (e.g., failure to complete the entire IPT protocol versus failure to complete at least 50% of sessions) and was lowest when adolescent patients were sampled. There was some evidence that IPT was associated with significantly lower rates of dropout than both CBT and non-specific supportive therapies. These effects were generally replicated when analysing trials that provided a clear definition of treatment (rather than study) dropout. Conclusions: Overall, findings provide preliminary evidence to suggest that IPT may be an accepted and tolerated treatment option for patients with common mental health disorders. This review also highlights the need for future trials to rigorously report detail pertaining to patient dropout

The empirical status of the third-wave behaviour therapies for the treatment of eating disorders: A systematic review

Although third-wave behaviour therapies are being increasingly used for the treatment of eating disorders, their efficacy is largely unknown. This systematic review and meta-analysis aimed to examine the empirical status of these therapies. Twenty-seven studies met full inclusion criteria. Only 13 randomized controlled trials (RCT) were identified, most on binge eating disorder (BED). Pooled within- (pre-post change) and between-groups effect sizes were calculated for the meta-analysis. Large pre-post symptom improvements were observed for all third-wave treatments, including dialectical behaviour therapy (DBT), schema therapy (ST), acceptance and commitment therapy (ACT), mindfulness-based interventions (MBI), and compassion-focused therapy (CFT). Third-wave therapies were not superior to active comparisons generally, or to cognitive-behaviour therapy (CBT) in RCTs. Based on our qualitative synthesis, none of the third-wave therapies meet established criteria for an empirically supported treatment for particular eating disorder subgroups. Until further RCTs demonstrate the efficacy of third-wave therapies for particular eating disorder subgroups, the available data suggest that CBT should retain its status as the recommended treatment approach for bulimia nervosa (BN) and BED, and the front running treatment for anorexia nervosa (AN) in adults, with interpersonal psychotherapy (IPT) considered a strong empirically-supported alternative

Identification of a T follicular helper cell subset that drives anaphylactic IgE.

Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell-derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13-producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These TFH13 cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis