132例晚期非小细胞肺癌胸腔积液EGFR基因突变检测结果及其临床意义:一项来自单中心的回顾性研究

背景与目的恶性胸腔积液表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变检测缺乏病理质控,导致对检测结果解释及指导临床EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)使用造成困惑。因此,提出质控标准,并按此标准进行胸水EGFR突变检测尤为重要。本研究拟回顾性分析按照严格病理质控标准进行的胸水沉渣切片EGFR基因突变检测结果以及据此结果指导EGFR-TKIs治疗的疗效。方法回顾性分析中国医学科学院北京协和医院病理科2012年1月-2018年6月收到的胸腔积液标本的患者临床资料,其中具有临床资料相对完整,且按照制定的质控标准进行了胸水沉渣石蜡包埋切片EGFR基因突变检测的患者132例。根据EGFR基因突变检测结果,分为阳性组和阴性组,比较不同组别使用EGFR-TKIs的疗效。结果胸腔积液经离心后,沉渣石蜡包埋、切片,HE染色后镜下观察,若肿瘤细胞数目≥100个,即满足病理质控标准,可用于后续EGFR基因突变检测。132例患者中,72例(54.5%)患者胸水中检出EGFR基因突变。72例突变阳性患者中,69例患者使用了EGFR-TKIs。60例EGFR突变阴性患者中,仅15例使用EGFR-TKIs。EGFR突变阳性组的疾病控制率(disease control rate,DCR)为95.8%,中位无疾病进展生存时间(progression-free survival,PFS)为11个月;EGFR突变阴性组的DCR为0%,中位PFS为1个月,两组患者DCR和PFS均有显著差异(P<0.05)。结论经病理质控的胸水沉渣包埋切片可用于EGFR基因突变检测,其结果可指导临床EGFR-TKIs使用。

Application of next-generation sequencing technology to precision medicine in cancer: joint consensus of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology

Next-generation sequencing(NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously.Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology(CSCO) and the China Actionable Genome Consortium(CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians,pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure(SOP), data analysis, report, and NGS platform certification and validation.

Numerical Simulation of the Thin Film Coating Flow in Two-Dimension

Thin film coating is a process of making liquid film cover and deposit base body surface by the way of dipping, spraying, sliding or spin coating, which is a kind of modern surface engineering. It plays an important role in the actual processing, such as improving the surface properties, fine processing, and new surface properties. Analysis of the influence of substrating morphology and fluid flow properties itself on coating fluid motion has an important significance to optimize the thin film coating and improve the quality of the final film. The influence from uneven substrate surface’s geometry configuration on internal motion of the flow field in slip-coating is analyzed by using the FLUENT software as a calculation platform. A two-dimension model of slip coating under isosceles triangle and isosceles trapezoid substrate was established, and thin film coating fluid motions under different configuration parameters were simulated. It is pointed out that the key factor determining the turbulence generation and evolution is the parameter of substrating surface nature. The effects of the change of Reynolds number on turbulent appearance and action area are studied. The velocity contours of fluid field on different substrate surfaces are shown, and the impact of substrate geometry on the backwater region is analyzed.

Dynamics of non-metal-regulated FeCo bimetal microenvironment on oxygen reduction reaction activity and intrinsic mechanism

The change in the coordination environment of the active sites of a fuel cell cathode catalyst provides a new modulation strategy for stimulating the catalyst’s oxygen reduction reaction activity.The thermodynamic and electronic properties of the FeCoN5A and FeCoN6A catalyst structures with nonmetallic A-doped(A=B,N,O,P,and S)coordination were calculated and analyzed based on density functional theory.The modulation order of G*OH by different A-doped FeCo bimetal pairs(BMPs)was as follows:S>P>O>N/C>B.There was a dynamic distribution of charges in the coordination environment during the adsorption of OH,which resulted in inversely proportional relationship with the charge transfer between the adsorbate OH,active site,first coordination layer,and second coordination layer in turn.Descriptors of the orbital energy levels of neighboring nonmetal atoms were constructed based on the p-electron number and electronegativity of the doped nonmetal A.The change of the orbital energy levels of the first coordination atom during the adsorption process caused the structure to exhibit different adsorption energies.This study provides new insights on the non-metallic modulation of the M-N-C coordination environment to improve the oxygen reduction reaction activity.

Differential transcriptomic landscapes of multiple organs from SARS-CoV-2 early infected rhesus macaques

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries,how-ever,the underlying mechanism,in particular immune responses in different organs,remains elusive.In this study,comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed.Compared to normal controls,SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs,with drastic transcriptomic changes in cerebral cortex and right ventricle.Intriguingly,cerebral cortex exhibited a hyperinflammatory state evidenced by sig-nificant upregulation of inflammation response-related genes.Meanwhile,expressions of coagulation,angio-genesis and fibrosis factors were also up-regulated in cerebral cortex.Based on our findings,neuropilin 1(NRP1),a receptor of SARS-CoV-2,was significantly elevated in cerebral cortex post infection,accompanied by active immune response releasing inflammatory factors and signal transmission among tissues,which enhanced infection of the central nervous system(CNS)in a positive feedback way,leading to viral encephalitis.Overall,our study depicts a multi-tissue/organ tran-scriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2,and provides important insights into the mechanistic basis for COVID-19-asso-ciated clinical complications.

酸性pH培养条件短时阻止胚胎干细胞分化并减弱microRNA的功能

干细胞和癌细胞不同于大多终末分化细胞,更偏好利用糖酵解代谢提供能量.然而,糖酵解代谢在基因表达调控和细胞命运决定中的作用尚不清楚.本文确认了糖酵解代谢和乳酸的产生随着小鼠胚胎干细胞的分化而降低.更重要的是,作者发现乳酸积累导致的酸性环境能够在短时间内阻止小鼠和人的胚胎干细胞退出多能性状态,并且会下调miRNA调控通路中的关键蛋白AGO1的表达,从而削弱miR-290/302家族对其靶基因的抑制作用.研究同时发现,酸性pH也会下调多个癌细胞株中AGO1的表达,并减弱癌细胞中miRNA的抑制作用.该研究为酸性微环境调控胚胎干细胞的命运决定和基因表达提供了新证据和机理解释.

Investigation of the mechanism of phytate-modified biochar-catalyzed persulfate degradation of Ponceau 2R

The mechanism of oxidation and degradation effect of phytate-modified biochar catalyzed persulfate on Ponceau 2R was investigated.Chemical-structural properties of phytate-modified biochar,such as surface morphology and surface oxygen-containing functional groups were characterized.The results suggest that modified biochar has better oxidation performance than unmodified biochar,and the modified biochar generated at 500℃pyrolysis temperature can catalyze peroxymonosulfate(PMS)system with high efficiency,in large pH and temperature scope.And the degradation mechanism of Ponceau 2R by biochar-catalyzed PMS generation(BC-PMS)system was researched.It revealed that PBC300(phytate-modified biochar pyrolyzed at 300℃),PBC500(phytate-modified biochar pyrolyzed at 500℃),and PBC700(phytate-modified biochar pyrolyzed at 700℃)may have metaphosphoric acid linked to oxygen atoms and metaphosphoric acid linked in a bridging manner on the surface of biochar,catalyzing the production of hydroxyl radicals by PMS.PBC700 catalyzes the production of singlet oxygen by PMS through its structural defects,and singlet oxygen is the main catalytic product of PBC700.

Genomic characterization reveals distinctmutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract

Background:Neuroendocrine carcinomas of the gastrointestinal tract(GINECs)remain a disease of grim prognosis with limited therapeutic options.Their molecular characteristics are still undefined.This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs.Methods:Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed,paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation.Mutational signatures,somatic mutations,and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes.Survival analysis was conducted to identify the independent factors.Results:In total,143GI-NECswere examined:the stomach,87 cases(60.8%);the esophagus,29 cases(20.3%);the colorectum,20 cases(14.0%);and the small intestine,7 cases(4.9%).Eighty-three(58.0%)and 60(42.0%)cases were subclassified into small cell and large cell subtypes,respectively.GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations.Obvious heterogeneity of mutational signatures,somatic mutations,and copy number variations was revealed across anatomic locations rather than histological subtypes.Except for tumor protein p53(TP53)and retinoblastoma 1(RB1),the most frequently mutated genes in the stomach,esophagus,colorectum,and small intestine were low-density lipoprotein receptor-related protein 1B(LRP1B),notch receptor 1(NOTCH1),adenomatosis polyposis coli(APC),catenin beta 1(CTNNB1),respectively.Mutations in the WNT-β-catenin,NOTCH and erythroblastic leukemia viral oncogene B(ERBB)pathwayswere prevalently identified in gastric,esophageal,and colorectalNECs,respectively.Importantly,104(72.7%)GI-NECs harbored putative clinically relevant alterations,and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors.Furthermore,we found that tumor cells in GI-NECs first gain clonal mutations in TP53,RB1,NOTCH1 and APC,followed by subsequent wholegenome doubling(WGD)and post-WGD clonal mutations in LRP1B,CUB and Sushi multiple domains 3(CSMD3),FAT tumor suppressor homolog 4(FAT4)and erb-b2 receptor tyrosine kinase 4(ERBB4),and finally develop subclonal mutations.Conclusions:GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations.Moreover,potentially actionable alterations and prognostic factors were revealed for GI-NECs.

Tonghua Liu:A life dedicated to clinical pathology

Professor Tonghua Liu(刘彤华)was an academician of the Chinese Academy of Engineering,a renowned medical scientist,pathologist,medical educator and professor of the Pathology Department in Peking Union Medical College Hospital(PUMCH)(Fig.1).She passed away from illness on July 8th,2018 at PUMCH.She was 89(PUMCH,2018).Prof.Liu was born on November 13th,1929 in Wuxi,Jiangsu Province.She studied at the Medical School of Saint John's University in Shanghai from 1947 to 1953(Fang et al.,2009).

Genomic evolution during locoregional recurrence in colorectal cancer determined by whole-exome sequencing: a retrospective observational study

Objective:The genomic landscapes of metastatic colorectal cancer(mCRC)have been extensively studied;however,the genetic mechanisms underlying the locoregional recurrence(LR)of CRC remain unclear.The objective of our study was to investigate genomic evolution during LR in CRC using high-throughput sequencing.Methods:Twenty-three CRC patients with matched primary and LR tissues were recruited from Nanfang Hospital and Zhejiang Cancer Hospital between January 2011 and December 2018.The last date of follow-up was March 2020.Tissue samples were analyzed by whole-exome sequencing and the genomic profiles were depicted by single nucleotide variation,mutational signature,copy number variation,clonal architecture,and other features.The evolutionary process was speculated with comparison of the genetic variations between primary and LR lesions.The disseminating clusters from primary to LR lesions were identified by variant allele frequency dynamics.Furthermore,the early-recurrent biomarker was explored by comparing the indel signature between early-and late-recurrent patients.The study was approved by the Institutional Review Board of Nanfang Hospital of Southern Medical University(approval No.2020010)on September 11,2020.Results:The results highlighted distinct origins of LR between patients with high microsatellite instability and microsatellite stability.LR lesions evolved independently in patients with high microsatellite instability,while LR lesions were highly clonally related to the primary lesions in patients with microsatellite stability.Late-acquired variations in LR lesions encompassed a wide range of driver genes involved in histone methylation,DNA replication,T cell activation,PDCD1 gain,and LMNA loss.Furthermore,clonal analysis of the disseminating cells identified a dominant polyclonal seeding pattern during LR.The indel signature ID4 was associated with significantly shorter disease-free survival in patients with relapsed CRC according to a public dataset.Conclusion:These findings pose a challenge for the development of new approaches targeting the interactions of multiple clones in the establishment of LR and in terms of optimizing the clinical management of susceptible patients.

Fast Target Tracking Based on Improved Deep Sort and YOLOv3 Fusion Algorithm

Aiming at fast moving targets, such as ships, high-speed vehicles andathletes, this paper discusses a series of target detection algorithms based on neuralnetwork, YOLOv3 and background modeling. Compared KCF tracking with SSDtracking, Gaussian filter was applied to remove noise from pictures, and edgepreserving filter was used to preserve edge features. Moreover, the algorithmcombining deepsort tracking algorithm with YOLOv3 detection algorithm canimprove the accuracy of YOLOv3 target detection, solve the problem of targetloss during target tracking, adjust the frame size in real time, and improve the fitwith the target position. Experiments show that the proposed algorithm based ondetection before tracking has strong learning ability and robustness to unknownenvironment.