Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in Chinese

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HLA-B evolutionary divergence is associated with outcomes after SARS-CoV-2 infection

We examined the correlation between class I HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of 234 adult inpatients with confirmed SARS-CoV-2 infection. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HED scores for HLA class I (HLA-A, -B, and -C) genotypes were calculated using Grantham’s distance. Higher HED scores for HLA-B, but not HLA-A or -C, are significantly associated with a decreased probability of poor outcomes including ICU admission, mechanical ventilation, and death (OR = 0.93; P = 0.04) in the univariate analysis. In the multivariate analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). This finding is consistent with the notion that broader peptide repertoires presented by class I HLA may be beneficial in infection control.     

Harmonization and Standardization of Panel-Based Tumor Mutational Burden Measurement: Real-World Results and Recommendations of the Quality in Pathology Study

IntroductionTumor mutational burden (TMB) is a quantitative assessment of the number of somatic mutations within a tumor genome. Immunotherapy benefit has been associated with TMB assessed by whole-exome sequencing (wesTMB) and gene panel sequencing (psTMB). The initiatives of Quality in Pathology (QuIP) and Friends of Cancer Research have jointly addressed the need for harmonization among TMB testing options in tissues. This QuIP study identifies critical sources of variation in psTMB assessment.MethodsA total of 20 samples from three tumor types (lung adenocarcinoma, head and neck squamous cell carcinoma, and colon adenocarcinoma) with available WES data were analyzed for psTMB using six panels across 15 testing centers. Interlaboratory and interplatform variation, including agreement on variant calling and TMB classification, were investigated. Bridging factors to transform psTMB to wesTMB values were empirically derived. The impact of germline filtering was evaluated.ResultsSixteen samples had low interlaboratory and interpanel psTMB variation, with 87.7% of pairwise comparisons revealing a Spearman’s ρ greater than 0.6. A wesTMB cut point of 199 missense mutations projected to psTMB cut points between 7.8 and 12.6 mutations per megabase pair; the corresponding psTMB and wesTMB classifications agreed in 74.9% of cases. For three-tier classification with cut points of 100 and 300 mutations, agreement was observed in 76.7%, weak misclassification in 21.8%, and strong misclassification in 1.5% of cases. Confounders of psTMB estimation included fixation artifacts, DNA input, sequencing depth, genome coverage, and variant allele frequency cut points.ConclusionsThis study provides real-world evidence that all evaluated panels can be used to estimate TMB in a routine diagnostic setting and identifies important parameters for reliable tissue TMB assessment that require careful control. As complex or composite biomarkers beyond TMB are likely playing an increasing role in therapy prediction, the efforts by QuIP and Friends of Cancer Research also delineate a general framework and blueprint for the evaluation of such assays.     

不同地理居群新塔花的ITS2和psbA-trnH序列及聚类分析

目的:分析18个不同地理居群新塔花的内转录间隔区(ITS)2和psbA-trnH序列,为其种质资源评价和基原药用植物遗传多样性分析提供参考。方法:试剂盒法提取新塔花基因组DNA,聚合酶链式反应(PCR)扩增ITS2和psbA-trnH间隔区序列,双向测序,拼接,基于Kimura两参数模型(K2P)构建邻接法(NJ)系统发育树。结果:不同地理居群新塔花ITS2和psbA-trnH序列均有种内差异。ITS2序列长度平均为236 bp,检测有9个单倍型,遗传距离为0～0. 022,不同地理居群新塔花聚为两支,XTH3,XTH6,XTH9等10个地理居群聚为一支,XTH4,XTH5,XTH10等8个地理居群聚为另一支。除XTH6的psbAtrnH序列存在6 bp缺失外,其他地理居群的psbA-trnH序列长度均为355 bp,检测有4个单倍型,遗传距离为0～0. 023,不同地理居群新塔花聚为两支,XTH1,XTH3,XTH4等12个地理居群聚为一支,XTH14,XTH17,XTH18聚为另一支。基于ITS2+psbA-trnH组合序列的系统发育(NJ)树显示,不同地理居群的新塔花可分为两支,XTH11,XTH12,XTH16等12个地理居群聚为一支,XTH14,XTH17,XTH18聚为另一支。结论:不同地理居群的新塔花地理位置接近或相似,相对遗传距离较小,亲缘关系较为接近,说明不同地理居群新塔花的亲缘关系及其遗传多样性与地理位置相关。     

Aberrant expression of Wnt/β-catenin signaling pathway genes in aggressive malignant gastric gastrointestinal stromal tumors

IntroductionRecent reports on gene expression profiling (GEP) show several genes associated with malignant progression of GIST. However, genes associated with malignant transformation have not been clarified. Here, we aimed to reveal distinct genes in aggressive malignant GIST, using comprehensive gene expression analysis.Materials and methodsWe investigated GEP obtained by microarrays for 43 gastric GISTs, which mostly harbored KIT and PDGFRA mutations and integrated clinicopathological risk information. RT-PCR and immunohistochemistry were performed for FZD7, a receptor of Wnt ligands.ResultsGEP divided 43 gastric GISTs into two clusters. A cluster included seven of eight high-risk GISTs (88%) in modified NIH classification and was defined as high-risk cluster; the other cluster was defined as low-risk cluster. The number of probes with over 3-fold changes between the two clusters was 1,177, in which probes corresponding to 16 oncogenes were included. Genes involved in the Wnt signaling pathway were the most abundant among the 16 oncogenes. Focusing on 73 Wnt signaling pathway genes of the 21,578 probes, 12 upregulated and 5 downregulated genes were found in the high-risk cluster. Major cascade genes promoting the Wnt/β-catenin signaling pathway, including WNT11, FZD family, and DVL2, were upregulated in the high-risk cluster. SNAI1, SNAI2, and BIRC5, which are activated by this pathway and increase cell proliferation, were also upregulated. These gene expression alterations were consistent in the positive direction of this pathway. GISTs in high-risk cluster strongly expressed FZD7.ConclusionWnt/β-catenin signaling pathway may play an important role in malignant transformation of indolent GIST.     

Le fil institutionnel en période Covid : utilisation de la plateforme Discord au CMPA

The COVID crisis led hospitals to reorganize care services and to develop innovative strategies to provide care at a distance. In our health care and education centre for adolescents, which provides both long-term psychiatric care and high school education, inpatients and outpatients were mostly confined at home. In order to ensure continuity of care as well as maintain institutional ties, different communication tools were used. Among them, we particularly relied upon Discord (social network initially designed for gamers) which allowed us to set up an entire virtual ward, maintain individual and group care programmes as well as team meetings. This innovation generated a number of preliminary questions and precautions which guided our decisions regarding the server settings. The outcome of this experiment is globally positive, both quantitatively and qualitatively, even if care at a distance showed its limits. Despite the involvement and creativity of health professionals, the confinement period disrupted and even led to the discontinuation of some care projects.     

有限元评估尖顶距与股距尖顶距对股骨转子间骨折髓内钉内固定术后稳定性的影响

文题释义：尖顶距：是指术后即刻的正、侧位X射线片上拉力螺钉尖至股骨头颈中轴线与股骨头关节面交点的距离之和，并校正放大率后所得值，以毫米为单位。目前较为主流的观点是尖顶距值≤25 mm可有效减少拉力螺钉切出股骨头的可能性。股距尖顶距：股距尖顶距是在尖顶距的基础上提出的。正位片上，于内侧皮质做一条平行于股骨颈中轴线的切线，该线与股骨头关节面的交点至螺钉尖端的距离即为正位片上的股距尖顶距；侧位片上，为拉力螺钉尖至股骨头颈中轴线与股骨头关节面交点的距离；将正、侧位片上的股距尖顶距相加再予以校正后得到股距尖顶距的值。股距尖顶距更强调正位片上偏下的螺钉位置。 背景：尖顶距被广泛应用于预测拉力螺钉切出的可能性，但是一些临床研究发现在正位片上当拉力螺钉位于股骨头中心偏下的位置时更稳定，于是为了更准确评估拉力螺钉位置, 提出了股距尖顶距的概念，但是其应用价值还需要进一步验证。 目的：利用尖顶距和股距尖顶距的标准公式，将拉力螺钉放入股骨头内不同的区域，应用有限元方法对模型的稳定性进行评估并对比。 方法：利用CT影像数据建立左股骨有限元模型，用3D扫描加建模建立捷迈解剖型髓内钉内置物有限元模型，按照尖顶距15，20，25，30，35 mm将拉力螺钉分别放入股骨头内中间区域和前上、前下、后上、后下5个对应的象限，建立24个内固定模型。同时计算当拉力螺钉位于股骨头中间时对应的股距尖顶距，将拉力螺钉放入后上、后下、前上、前下4个象限，建立16个股距尖顶距模型。然后给模型垂直向下的力，比较以尖顶距和股距尖顶距为标准建立的有限元模型的稳定性。结果与结论：①以尖顶距为标准置入拉力螺钉，当拉力螺钉位于前上象限，尖顶距为35 mm时，股骨头最大轴向位移与无拉力螺钉时差值最小，为0.008 205 5 mm，当拉力螺钉位于股骨头后下象限，尖顶距为20 mm时，股骨头最大轴向位移与无拉力螺钉时差值最大，为0.023 524 0 mm。以股距尖顶距为标准置入拉力螺钉，当拉力螺钉位于前上象限，股距尖顶距为37.886 mm时，股骨头最大轴向位移与无拉力螺钉时差值最小，为0.008 794 1 mm，当拉力螺钉位于股骨头后下象限，股距尖顶距为25.256 mm时，股骨头最大轴向位移与无拉力螺钉时差值最大，为0.023 183 2 mm。②将拉力螺钉按照尖顶距和股距尖顶距的标准放入股骨头内，拉力螺钉位于股骨头中心偏后上方时，股骨骨折近端的最大主应力增高明显，平均值分别为82.339 4，79.118 8 MPa；拉力螺钉位于股骨头中心偏后下方时，股骨骨折近端的平均最大主应力值减小，分别为49.535 9，49.642 8 MPa。提示：在评估尖顶距和股距尖顶距对股骨转子间骨折髓内钉内固定模型稳定性的影响时，股距尖顶距并未较尖顶距表现出明显优势；股骨骨折近端的稳定性受到拉力螺钉位置的影响更大，当拉力螺钉位于股骨头下后象限时，稳定性最好。ORCID: 0000-0002-7707-3553(乔文) 中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程     

Next-generation sequencing through multigene panel testing for the diagnosis of hereditary epidermolysis bullosa in Chinese population

Epidermolysis bullosa (EB) is a heritable blistering disorder. We performed a next-generation sequencing-based multigene panel test and successfully predicted 100% of the EB types, including, 36 EB simplex (EBS), 13 junctional EB (JEB), 86 dystrophic EB (DEB), and 3 Kindler EB. Chinese JEB and recessive DEB (RDEB) patients have relatively mild phenotypes; for severe type separately accounts for 45.5% and 23.8%, respectively. We identified 96 novel and 49 recurrent pathogenic variants in 11 genes, although we failed to detect the second mutation in one JEB and five RDEB patients. We identified one novel p.E475K mosaic mutation in the clinically normal mother of one out of 13 EBS patients with KRT5 mutations, one recurrent p.G2034R mosaic mutation, and one novel p.G2043R mosaic mutation in the clinically normal relatives of two out of 19 dominant DEB patients. This study shows that next-generation technology could be an effective tool in diagnosing EB.