다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.

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Detection of immunogenic cell death and its relevance for cancer therapy

Mutation testing realizes the idea of using artificial defects to support testing activities. Mutation is typically used as a way to evaluate the adequacy of test suites, to guide the generation of test cases, and to support experimentation. Mutation has reached a maturity phase and gradually gains popularity both in academia and in industry. This chapter presents a survey of recent advances, over the past decade, related to the fundamental problems of mutation testing and sets out the challenges and open problems for the future development of the method. It also collects advices on best practices related to the use of mutation in empirical studies of software testing. Thus, giving the reader a “mini-handbook”-style roadmap for the application of mutation testing as experimental methodology.

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Mutation Testing Advances: An Analysis and Survey

MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy.

511 Kullback-Leibler divergence model to integrate genetic and genomic information to assess drug response for psoriatic patients

Objectives Large cell transformation (LCT) of Sezary Syndrome (SS) is associated with an aggressive clinical course. To date, there are no rigorous studies identifying risk factors for the development of this phenomenon. We aim to characterize the clinicopathologic risk factors that may predispose patients with SS to develop LCT in the largest such study to date that the authors have identified. Materials/Methods We retrospectively evaluated all SS patient records available in the Michigan Medicine Cancer Registry from 2010–2019. The Mann-Whitney U test and Fisher exact test were used to compare age, sex, race, time to diagnosis, stage, total body surface area (TBSA) involvement, pathologic features, complete blood counts, flow cytometry data, and T cell receptor rearrangements. The Kaplan-Meier method and log-rank test were used to assess overall survival (OS). Univariate analyses were conducted for endpoints of LCT and OS and visualized with Forest plots using the “survival” and “forestplot” packages in R. Results Of the 28 SS patients included in the analysis, eight patients with LCT were identified, and 20 without nonlarge cell transformation (NLCT). Mean peak LDH before LCT (p = 0.0012), mean maximum TBSA involvement before diagnosis of LCT (p = 0.0114), absolute CD8+ cell count on flow cytometry or on biopsy at diagnosis of SS (p = 0.0455), presence of Langerhans cell hyperplasia (p = 0.0171), and presence of ulceration on biopsy (p = 0.0034) were clinicopathologic variables identified as differing significantly between the two groups. On univariate analysis, increased TBSA involvement (HR 1.043 per unit increase, 95% CI 1.001 – 1.081, p = 0.018) and increased peak LDH prior to LCT diagnosis (HR 1.002 per unit increase, 95% CI 1.001 – 1.003, p = 0.002) were identified as poorly prognostic, while unit increase in CD8+ absolute cell count at diagnosis of SS (HR 0.988, 95% CI 0.976 – 0.999, p = 0.041) was identified as protective for development of LCT. There was no survival difference identified between patients with “High” vs. “Low” CD8+ cell counts, or between LCT and NLCT groups. Conclusions Maximum TBSA involvement, peak LDH, presence of ulceration, Langerhans cell hyperplasia, and decreased levels of CD8+cells in the peripheral blood may predict the development of LCT in patients with SS.

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Matthew Patrick

Papers

MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy.

511 Kullback-Leibler divergence model to integrate genetic and genomic information to assess drug response for psoriatic patients

Clinicopathologic Risk Factors for The Large Cell Transformation of Sezary Syndrome