Gene–environment interactions in Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake

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

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

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia

Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to environmental/occupational exposure to asbestos, characterized by the presence of significant areas of hypoxia. In this study, we firstly explored the expression and the role of transglutaminase 2 (TG2) in MPM cell adaptation to hypoxia. We demonstrated that cells derived from biphasic MPM express the full-length TG2 variant at higher levels than cells derived from epithelioid MPM and normal mesothelium. We observed a significant induction of TG2 expression and activity when cells from biphasic MPM were grown as a monolayer in chronic hypoxia or packed in spheroids, where the presence of a hypoxic core was demonstrated. We described that the hypoxic induction of TG2 was HIF-2 dependent. Importantly, TGM2-v1 silencing caused a marked and significant reduction of MPM cell viability in hypoxic conditions when compared with normoxia. Notably, a TG2-selective irreversible inhibitor that reacts with the intracellular active form of TG2, but not a non-cell-permeable inhibitor, significantly compromised cell viability in MPM spheroids. Understanding the expression and function of TG2 in the adaptation to the hypoxic environment may provide useful information for novel promising therapeutic options for MPM treatment

The growth and evolution of cardiovascular magnetic resonance: a 20-year history of the Society for Cardiovascular Magnetic Resonance (SCMR) annual scientific sessions

Background and purpose: The purpose of this work is to summarize cardiovascular magnetic resonance (CMR) research trends and highlights presented at the annual Society for Cardiovascular Magnetic Resonance (SCMR) scientific sessions over the past 20 years. Methods: Scientific programs from all SCMR Annual Scientific Sessions from 1998 to 2017 were obtained. SCMR Headquarters also provided data for the number and the country of origin of attendees and the number of accepted abstracts according to type. Data analysis included text analysis (key word extraction) and visualization by ‘word clouds’ representing the most frequently used words in session titles for 5-year intervals. In addition, session titles were sorted into 17 major subject categories to further evaluate research and clinical CMR trends over time. Results: Analysis of SCMR annual scientific sessions locations, attendance, and number of accepted abstracts demonstrated substantial growth of CMR research and clinical applications. As an international field of study, significant growth of CMR was documented by a strong increase in SCMR scientific session attendance (> 500%, 270 to 1406 from 1998 to 2017, number of accepted abstracts (> 700%, 98 to 701 from 1998 to 2018) and number of international participants (42–415% increase for participants from Asia, Central and South America, Middle East and Africa in 2004–2017). ‘Word clouds’ based evaluation of research trends illustrated a shift from early focus on ‘MRI technique feasibility’ to new established techniques (e.g. late gadolinium enhancement) and their clinical applications and translation (key words ‘patient’, ‘disease’) and more recently novel techniques and quantitative CMR imaging (key words ‘mapping’, ‘T1’, ‘flow’, ‘function’). Nearly every topic category demonstrated an increase in the number of sessions over the 20-year period with ‘Clinical Practice’ leading all categories. Our analysis identified three growth areas ‘Congenital’, ‘Clinical Practice’, and ‘Structure/function/flow’. Conclusion: The analysis of the SCMR historical archives demonstrates a healthy and internationally active field of study which continues to undergo substantial growth and expansion into new and emerging CMR topics and clinical application areas

Peroxiredoxin 3 Is a Redox-Dependent Target of Thiostrepton in Malignant Mesothelioma Cells

Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in mesothelioma

Protocol for a randomized controlled study of Iyengar yoga for youth with irritable bowel syndrome

<p>Abstract</p> <p>Introduction</p> <p>Irritable bowel syndrome affects as many as 14% of high school-aged students. Symptoms include discomfort in the abdomen, along with diarrhea and/or constipation and other gastroenterological symptoms that can significantly impact quality of life and daily functioning. Emotional stress appears to exacerbate irritable bowel syndrome symptoms suggesting that mind-body interventions reducing arousal may prove beneficial. For many sufferers, symptoms can be traced to childhood and adolescence, making the early manifestation of irritable bowel syndrome important to understand. The current study will focus on young people aged 14-26 years with irritable bowel syndrome. The study will test the potential benefits of Iyengar yoga on clinical symptoms, psychospiritual functioning and visceral sensitivity. Yoga is thought to bring physical, psychological and spiritual benefits to practitioners and has been associated with reduced stress and pain. Through its focus on restoration and use of props, Iyengar yoga is especially designed to decrease arousal and promote psychospiritual resources in physically compromised individuals. An extensive and standardized teacher-training program support Iyengar yoga's reliability and safety. It is hypothesized that yoga will be feasible with less than 20% attrition; and the yoga group will demonstrate significantly improved outcomes compared to controls, with physiological and psychospiritual mechanisms contributing to improvements.</p> <p>Methods/Design</p> <p>Sixty irritable bowel syndrome patients aged 14-26 will be randomly assigned to a standardized 6-week twice weekly Iyengar yoga group-based program or a wait-list usual care control group. The groups will be compared on the primary clinical outcomes of irritable bowel syndrome symptoms, quality of life and global improvement at post-treatment and 2-month follow-up. Secondary outcomes will include visceral pain sensitivity assessed with a standardized laboratory task (water load task), functional disability and psychospiritual variables including catastrophizing, self-efficacy, mood, acceptance and mindfulness. Mechanisms of action involved in the proposed beneficial effects of yoga upon clinical outcomes will be explored, and include the mediating effects of visceral sensitivity, increased psychospiritual resources, regulated autonomic nervous system responses and regulated hormonal stress response assessed via salivary cortisol.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01107977">NCT01107977</a>.</p