Clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in Chinese population with mismatch repair deficient urothelial carcinoma: a real-world study

Urothelial carcinoma (UC) with deficient mismatch repair (dMMR) is a specific subtype of UC characterized by the loss of mismatch repair (MMR) proteins and its association with Lynch syndrome (LS). However, comprehensive real-world data on the incidence, clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in the Chinese patients with dMMR UC remains unknown. We analyzed 374 patients with bladder urothelial carcinoma (BUC) and 232 patients with upper tract urothelial carcinoma (UTUC) using tissue microarrays, immunohistochemistry, and targeted next-generation sequencing. Results showed the incidence of dMMR UC was higher in the upper urinary tract than in the bladder. Genomic analysis identified frequent mutations in KMT2D and KMT2C genes and LS was confirmed in 53.8% of dMMR UC cases. dMMR UC cases displayed microsatellite instability-high (MSI-H) (PCR method) in 91.7% and tumor mutational burden-high (TMB-H) in 40% of cases. The density of intratumoral CD8+ T cells correlated with better overall survival in dMMR UC patients. Positive PD-L1 expression was found in 20% cases, but some patients positively responded to immunotherapy despite negative PD-L1 expression. Our findings provide valuable insights into the characteristics of dMMR UC in the Chinese population and highlights the relevance of genetic testing and immunotherapy biomarkers for treatment decisions

Rational synthesis of an atomically precise carboncone under mild conditions

在已知的碳的存在形态中，还有一种锥型的碳结构，早在50年前人们在热解碳时发现了这类结构，此前也常被人们称为碳纳米锥，虽然这类碳纳米锥有望作为扫描隧道显微镜的探针、场发射头等替代材料，但始终未能找到合适方法精准地合成它们。因此，这类锥型碳材料尚未得到人们足够重视和开发。功能团簇材料创新研究群体的谢素原、张前炎课题组与美国波士顿学院的Lawrence Scott教授合作，首次通过有机合成途径，在温和的条件下合成得到了首例结构明确的碳锥单元（碳锥子）C70H20及其可溶衍生物。他们通过实验、理论计算、结构分析，最终在他们合成的碳锥子结构中，仅有1个五元环在锥顶，而在锥顶和锥缘之间（围绕着中心五元环）有2圈由六元环组成的完整的稠圈层，谢素原等将这一碳锥子命名为carboncone[1,2]。通过这一典型的碳锥子（carboncone[1,2]），有望借助气相沉积等技术不断增加稠圈层数（m）来制备具有确定锥角的系列单壁纳米碳锥（carboncone[1,m>2]）。随着研究的深入，不久的将来人类有望合成出其它四种不同锥角的碳锥子（carboncone[n=2-5,m]），完整地研究探索和开发利用这类锥型结构的碳材料。 化学化工学院2015级硕士生朱正钟（主要负责合成）和2017级博士生陈佐长（主要负责理论计算）为该论文的共同第一作者。Carboncones, a special family of all-carbon allotropes, are predicted to have unique properties that distinguish them from fullerenes, carbon nanotubes, and graphenes. Owing to the absence of methods to synthesize atomically well-defined carboncones, however, experimental insight into the nature of pure carboncones has been inaccessible. Herein, we describe a facile synthesis of an atomically well-defined carboncone[1,2] (C70H20) and its soluble penta-mesityl derivative. Identified by x-ray crystallography, the carbon skeleton is a carboncone with the largest possible apex angle. Much of the structural strain is overcome in the final step of converting the bowl-shaped precursor into the rigid carboncone under mild reaction conditions. This work provides a research opportunity for investigations of atomically precise single-layered carboncones having even higher cone walls and/or smaller apex angles.This research was supported by the National Natural Science Foundation of China (21771152, 21721001, 21390390, 21827801, 51572231, 21571151, and 21701134), the 973 Program of China (2015CB932301), the Major Science and Technology Project between University-Industry Cooperation in Fujian Province (2016H6023), and the Fundamental Research Funds for the Central Universities (20720170028 and 20720160084). This research was also supported financially by the U.S. National Science Foundation (CHE-0809494 and CHE-1149096). 研究工作得到国家自然科学基金（21771152等）、科技部重大科学研究计划项目（2015CB932301）和福建省高校产学合作项目、中央高校基本科研业务费、美国国家科学基金等的资助

An Updated Search of Steady TeV γ−\gamma-Ray Point Sources in Northern Hemisphere Using the Tibet Air Shower Array

Using the data taken from Tibet II High Density (HD) Array (1997 February-1999 September) and Tibet-III array (1999 November-2005 November), our previous northern sky survey for TeV $\gamma-$ray point sources has now been updated by a factor of 2.8 improved statistics. From $0.0^{\circ}$ to $60.0^{\circ}$ in declination (Dec) range, no new TeV $\gamma-$ray point sources with sufficiently high significance were identified while the well-known Crab Nebula and Mrk421 remain to be the brightest TeV $\gamma-$ray sources within the field of view of the Tibet air shower array. Based on the currently available data and at the 90% confidence level (C.L.), the flux upper limits for different power law index assumption are re-derived, which are approximately improved by 1.7 times as compared with our previous reported limits.Comment: This paper has been accepted by hepn

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer