Association between Helicobacter pylori infection,mismatch repair,HER2 and tumor-infiltrating lymphocytes in gastric cancer

BACKGROUND The influence of Helicobacter-pylori(H.pylori)infection and the characteristics of gastric cancer(GC)on tumor-infiltrating lymphocyte(TIL)levels has not been extensively studied.Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.AIM To determine the rates of deficient mismatch-repair(dMMR),HER2-status and H.pylori infection and their association with TIL levels in GC.METHODS Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral(IT),stromal(ST)and invasive-border(IB)compartments.The density of CD3,CD8 and CD163 immune cells,and dMMR and HER2-status were determined by immunohistochemistry(IHC).H.pylori infection was evaluated by routine histology and quantitative PCR(qPCR)in a subset of samples.RESULTS dMMR was found in 34.4%,HER2+in 5%and H.pylori-positive in 55.7%of samples.High IT-TIL was associated with grade-3(P=0.038),while ST-TIL with grade-1(P<0.001),intestinal-histology(P<0.001)and no-recurrence(P=0.003).dMMR was associated with high TIL levels in the ST(P=0.019)and IB(P=0.01)compartments,and STCD3(P=0.049)and ST-CD8(P=0.05)densities.HER2-was associated with high IT-CD8(P=0.009).H.pylorinegative was associated with high IT-TIL levels(P=0.009)when assessed by routine-histology,and with high TIL levels in the 3 compartments(P=0.002-0.047)and CD8 density in the IT and ST compartments(P=0.001)when assessed by qPCR.A longer overall survival was associated with low IT-CD163(P=0.003)and CD8/CD3(P=0.001 in IT and P=0.002 in ST)and high IT-CD3(P=0.021),ST-CD3(P=0.003)and CD3/CD163(P=0.002).CONCLUSION TIL levels were related to dMMR and H.pylori-negativity.Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients

BACKGROUND RAS,BRAF,and mismatch repair(MMR)/microsatellite instability(MSI)are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer(CRC).However,their characteristics and influencing factors in Chinese patients have not been thoroughly described.AIM To analyze the clinicopathological features of KRAS,NRAS,BRAF,and PIK3CA mutations and the DNA MMR status in CRC.METHODS We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital.MMR proteins were tested using immunohistochemical analysis,and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction.Microsatellite status was determined using an MSI detection kit.Statistical analyses were conducted using SPSS software and logistic regression.RESULTS The KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 44.6%,3.4%,3.7%,and 3.9% of CRC patients,respectively.KRAS mutations were more likely to occur in patients with moderate-to-high differentiation.BRAF mutations were more likely to occur in patients with right-sided CRC,poorly differentiated,or no perineural invasion.Deficient MMR(dMMR)was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas.KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 29.6%,1.1%,8.1%,and 22.3% of patients with dMMR,respectively.The dMMR was more likely to occur in patients with a family history of CRC,aged<50 years,right-sided CRC,poorly differentiated histology,no perineural invasion,and with carcinoma in situ,stage I,or stage II tumors.CONCLUSION This study analyzed the molecular profiles of KRAS,NRAS,BRAF,PIK3CA,and MMR/MSI in CRC,identifying key influencing factors,with implications for clinical management of CRC.

Tislelizumab in previously treated,locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors

Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Spatial Mismatch of Tourism Resources and Tourism Economy:A Case Study of Ice and Snow Tourism in Altay Region

The coordinated development of tourism resources and tourism economy is vital improve the quality and efficiency of regional tourism.Taking the ice and snow tourism in Altay region as an example,this study constructed an evaluation indicator system and used the methods of gravity center model,spatial mismatch index model and obstacle degree model to calculate the spatial mismatch index and influencing factors of ice and snow tourism resources and tourism economy in Altay region as a whole and in each county and city.It found in the study period:(i)the ice and snow tourism resources and tourism economy in Altay region was synchronous in the development of time sequence,while the spatial distribution pattern was characterized by regional imbalance;(ii)at the macro scale,the spatial mismatch degree of the ice-snow tourism resource center and the tourism economic center in Altay region was gradually reduced,but they were always separated from the spatial geometric center of Altay region;(iii)at the micro scale,the spatial mismatch index of counties and cities in Altay region was mainly negative mismatch,and the types of spatial mismatch changed in different degrees;(iv)the factors showed certain spatial differentiation characteristics in different counties of Altay region,and there were some differences in the obstacles of different mismatch level areas,and the economic basis was the most frequent obstacle in different mismatch level areas of Altay region.

Impacts of Model Mismatch and Array Scale on Channel Estimation for XL-HRIS-Aided Systems

Extremely large-scale hybrid reconfigurable intelligence surface(XL-HRIS),an improved version of the RIS,can receive the incident signal and enhance communication performance.However,as the RIS size increases,the phase variations of the received signal across the whole array are nonnegligible in the near-field region,and the channel model mismatch,which will decrease the estimation accuracy,must be considered.In this paper,the lower bound(LB)of the estimated parameter is studied and the impacts of the distance and signal-tonoise ratio(SNR)on LB are then evaluated.Moreover,the impacts of the array scale on LB and spectral efficiency(SE)are also studied.Simulation results verify that even in extremely large-scale array systems with infinite SNR,channel model mismatch can still limit estimation accuracy.However,this impact decreases with increasing distance.

一种前后台结合的Pipelined ADC校准技术

针对Pipelined模数转换器(ADC)中采样电容失配和运放增益误差带来的非线性问题,提出了一种前后台结合的Pipelined ADC校准技术。前台校准技术通过对ADC量化结果的余量分析,补偿相应流水级的量化结果,后台校准技术基于伪随机(PN)注入的方式,利用PN的统计特性校准增益误差。本校准技术在系统级建模和RTL级电路设计的基础上,实现了现场可编程门阵列(FPGA)验证并成功流片。测试结果显示,在1 GS/s采样速率下,校准精度为14 bit的Pipelined ADC的有效位数从9.30 bit提高到9.99 bit,信噪比提高约4 dB,无杂散动态范围提高9.5 dB,积分非线性(INL)降低约10 LSB。

微卫星不稳定型胃癌免疫治疗的研究进展

微卫星不稳定(microsatellite instability,MSI)型胃癌是一种特殊类型的胃癌,约占总病例数的22%。微卫星是基因组中短串联重复序列的区域,而稳定性指的是这些序列在细胞分裂和DNA复制过程中保持不变。在MSI型胃癌中,这种不稳定性通常是由DNA错配修复基因(如MLH1、MSH2、MSH6等)突变或失活引起的,导致DNA修复能力降低,结果是肿瘤细胞的基因组发生大量的微卫星序列变异和突变。尽管MSI型胃癌的发病率相对较低,但多项研究表明它对免疫治疗显示出良好的治疗效果,同时作为良好预后的预测因子也得到了广泛认可。本文对MSI型胃癌患者基于免疫治疗的综合治疗研究现状进行全面总结和综述,旨在为这类患者的临床治疗提供更多可靠依据。

货币政策不确定性如何影响企业投资效率——来自中国上市企业的经验证据

为应对当今世界经济复杂变化,我国货币政策调整速度和频次有所加快,市场主体的预期与行为将不可避免地受到影响。文章基于我国2007—2022年沪深A股上市企业数据样本,采用TVP-SV-FAVAR模型、主成分分析法与MCMC算法估计中国货币政策不确定性,并结合实物期权理论框架,实证分析对企业投资效率的影响。研究发现,货币政策不确定性提升会显著增大企业非效率投资,企业可能出现投资过度或投资不足的现象,导致经济效率的损失。经过替换关键变量、排除系统性偏差和剔除经济波动后,结果依旧支持初步发现,并通过工具变量法和双重差分法缓解了内生性问题。作用机制分析表明,货币政策不确定性提升,通过降低融资便捷度、恶化金融资源配置、提高现金流不确定性水平三条路径增加企业非效率投资,拓展了货币政策传导的研究边界。异质性分析显示,货币政策不确定性会同时引起企业投资过度与不足,对民营企业、东中部地区企业及高科技企业非效率投资的影响更为显著,深化对货币政策执行效果的理论研究。在此基础上,提出构建常态化沟通机制、创新多元化融资方式、完善层级化政策评估、实行差异化因应策略等政策建议,为正确评价货币政策效果、促进货币当局精准施策与推进金融高质量发展提供理论依据和实践借鉴。

数字普惠金融对企业数字化转型的影响——基于A股上市公司的研究

数字普惠金融对企业数字化发挥引导和促转作用。本文将数字普惠金融2013~2023年市级数据与中国上市企业数据进行匹配,深入研究数字普惠金融对企业数字化转型的影响。研究发现:数字普惠金融的发展对企业数字化转型有显著驱动作用,二者之间的非线性影响存在门槛效应,这种作用在非国有企业、小型企业和高科技企业中更为明显。进一步研究二者之间的传导机制,发现数字普惠金融通过3个渠道助力企业数字化转型:缓解融资约束、优化金融错配、加大研发投入。据此,本文提出了数字普惠金融服务实体经济促进企业数字化转型的政策建议。

Effect of Lattice Mismatch on Luminescence of ZnO/Si Hetero-Structure

The photoluminescence （PL） and Raman spectra of undoped ZnO films deposited directly on Si substrate （sample A）,on Si substrate through a SiC buffer layer （sample B）,and on a ZnO crystal wafer （sample C） are investigated. There are emission peaks centered at 3.18eV （ultraviolet,UV） and 2.38eV （green） in these sampies. Comparing the Raman spectra and the variation of the PL peak intensities with annealing atmosphere, we conclude that the luminescence of the samples is related to the tensile strain in the ZnO film due to the lattice mismatch between the film and the substrate. In particular, the tensile strain reduces the formation energy of OZn antisite oxygen defects,which generate the green emission center. After annealing in oxygen-rich atmosphere, many OZn defects are generated. Thus, the intensity of green emission in ZnO/Si hetero-structure materials increases due to tensile strain in ZnO films.

基建融资错配与“重生产轻消费”下的经济运行态势分析——展望中国经济增长新周期

中国经济潜在需求和供给大,长期增长潜力巨大,但目前面临基建融资错配与“重生产轻消费”两大基础性问题,导致实际经济增速低于潜在水平。必须尽快通过进一步全面深化改革解决这两大问题,才能确保到2035年基本实现现代化。基建融资错配指的是基建投资的长期资产与短期要还款的负债不匹配,迫使地方政府在短期内需筹措足够财政资金以偿还到期债务,引致经济收缩;“重生产轻消费”指的是地方政府长期重投资、重生产、重供给、轻消费、轻需求的偏好,导致重复投资、产能过剩、产业迭代缓慢等一系列问题。党的二十届三中全会和2024年中央经济工作会议已经明确提出调整改革的方向,各部门和地方政府亟须加力加快落地实施具体改革政策,包括全面取消房地产限购,争取在三年内彻底解决地方债问题,短期内扩大消费补贴力度和范围,构建充分重视消费和需求的管理体制。

MSC模块光纤与PLC波导耦合特性分析

光器件与输入输出光纤的耦合损耗因素较多,主要包括温度、应力、模场失配等引起附加损耗。文章以电力系统光控换流阀中多模星型耦合器(MSC)模块为例,利用简化的定量分析得知,可忽略热膨胀效应对光纤阵列与波导阵列的耦合损耗的影响。基于波导理论和模式耦合理论,利用数值计算方法分析了MSC模块输入输出波导结构对耦合性能的影响——波导与光纤的模场面积和模式失配带来较大的耦合损耗。因此设计优化倒锥结构,变换模场大小,减小波导与光纤的模式失配,降低了波导光纤耦合损耗。

带Mismatch算子的高阶π演算

主要研究带mismatch的高阶进程演算的公理化问题.首先,建立存在mismatch时高阶进程的开弱高阶互模拟理论,证明了等价关系、同余性等重要性质;其次,沿用线性的方法,构建得到带mismatch的有限进程上的公理系统;最后,基于对开弱高阶互模拟的刻画,证明了该公理系统的完备性定理.该工作为带mismatch的高阶进程上互模拟判定的有效算法的设计与实现,进而为相关的应用建模工作提供了理论借鉴.

基于Smith预估器的永磁电机自抗扰控制研究

针对永磁同步电机矢量控制系统存在抗干扰能力差和延时的问题,设计了一种基于Smith预估器的自抗扰控制策略。该策略首先采用预估器补偿数字控制器和逆变器带来的延时影响,然后采用改进型自抗扰控制器代替传统PI控制器。仿真实验结果表明:该策略相对于传统PI策略提高了电机转速和电流的抗干扰能力,有效地减少了延时环节带来的影响,并提高了系统在参数失配下的鲁棒性,进而有助于提高永磁同步电机数字控制系统的性能。

G-CSF动员的HLA-Mismatched-BPSC输注联合化疗治疗恶性血液病安全性观察

目的观察G-CSF(粒细胞集落刺激因子)动员的HLA-Mismatched-BPSC(活化HLA错配的外周血造血干细胞)输注联合化疗治疗恶性血液病的安全性。方法 10例恶性血液病患者G-CSF动员的HLA-Mismatched-BPSC输注联合化疗,观察其嵌合度、不良反应及血细胞恢复时间。结果 10例恶性血液病患者于化疗24~48 h后输注G-CSF动员的HLA-MismatchedBPSC,仅1例患者出现短暂嵌合,其余9例未检测出嵌合,干细胞输注后24 h内10例患者均出现发热,经对症处理后均能缓解,4例患者出现一过性皮疹经抗过敏治疗2 d内消退;无肝、肾功能损害、出血及腹泻等GVHD表现。4例自身对照患者血细胞恢复时间较仅接受化疗有缩短倾向。结论 G-CSF动员的HLA-Mismatched-BPSC输注联合化疗,仅1例有短暂嵌合,无GVHD发生及严重不良反应。

Evaluating the predictive value of endoscopic findings for residual colorectal cancer following neoadjuvant combination immunotherapy

BACKGROUND Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain limited.AIM To examine the predictive value of endoscopic findings of primary tumors for responses to neoadjuvant immunotherapy.METHODS This retrospective study,conducted at a tertiary center in China,evaluated 74 patients with colorectal cancer,including 17 with deficient mismatch repair(dMMR)and 15 with proficient mismatch repair(pMMR)tumors.Patients underwent neoadjuvant immunotherapy followed by surgery.Endoscopic findings before and after neoadjuvant immunotherapy were reviewed and compared with the pathology of the resected specimens.RESULTS In the pMMR group(n=57 evaluable patients),endoscopy identified 11/17 patients who achieved a complete response(CR),while misidentifying 1/40 patients with residual disease as CR(64.7%vs 2.5%,P<0.01).Conversely,22/40 patients with residual disease were accurately identified as achieving a partial response(PR),with 1/17 patients who achieved CR misclassified as PR(55.0%vs 5.9%,P<0.01).The sensitivity,specificity,and accuracy of endoscopic diagnosis for pathological CR were 64.7%,97.5%,and 87.7%,respectively.In the dMMR cohort,endoscopy classified 9/17 patients as CR and 2 of the remaining patients with residual tumors as PR(64.3%vs 66.7%,P=0.73).The method demonstrated 100%sensitivity and 82.4%accuracy in diagnosing pathological CR.CONCLUSION Endoscopic evidence of CR or PR was well correlated with postoperative pathological outcomes in the pMMR cohort.Despite endoscopic indications of tumor residue,a complete pathological response post-surgery was possible in the dMMR cohort.

媒体关注、投资者情绪与企业资金期限错配

为缓解企业债务“爆雷”背后的资金期限错配,文章以2008—2022年中国A股上市公司为研究样本,分析媒体关注、投资者情绪与企业资金期限错配三者的关系。研究发现:媒体关注能缓解企业资金期限错配,投资者情绪会抑制媒体关注对企业资金期限错配的缓解作用;机制分析表明,媒体关注通过缓解融资约束和抑制管理层短视来降低企业资金期限错配;异质性分析显示,媒体关注对企业资金期限错配的缓解作用在非负面媒体报道、长期借款占比低、非国有以及内部控制质量高的企业中更显著。研究结论为缓解企业资金期限错配提供理论依据和政策参考,有助于降低市场系统性金融风险,更好支撑实体企业高质量发展。

能源错配研究进展——特征事实、影响因素与效应评估

在“双碳”目标驱动下,能源错配问题引起了学界和政界广泛关注。利用VOSviewer可视化软件,基于中国知网和Web of Science核心合辑所收录的期刊文章,系统梳理了能源错配相关研究的发展脉络。发现研究重点集中于能源错配的特征事实分析、影响因素识别及影响效应评估等方面,能源错配测度方法主要有生产函数法、前沿技术分析法和影子价格测算法。研究认为,政府对能源价格的干预和供需失衡加剧了能源错配,技术能力的进步有助于缓解这一问题;能源错配对资源利用、经济发展和环境保护产生了负面影响,并具有显著的区域异质性。最后,研究指出了需要进一步补充完善的研究方向和领域,以期丰富相应研究成果,为我国能源优化配置的政策设计提供理论指导。

KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients

AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded.Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used.Expression of MMR proteins including MHL1,MSH2,MSH6 and PMS2 was evaluated by immunohistochemistry.Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age,gender,cancer stage,location,and histology were analyzed.Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.RESULTS:The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%,respectively.KRAS mutations were more common in patients ≥ 50 years old(39.8% vs 22% in patients < 50 years old,P < 0.05).The frequencies of BRAF mutants were higher in tumors from females(6.6% vs males 2.8%,P < 0.05),located in the right colon(9.6% vs 2.1% in the left colon,1.8% in the rectum,P < 0.01),with mucinous differentiation(9.8% vs 2.8% without mucinous differentiation,P < 0.01),or being poorly differentiated(9.5% vs 3.4% well/moderately differentiated,P < 0.05).MMR deficiency was strongly associated with proximal location(20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum,P < 0.001),early cancer stage(15.0% in stages Ⅰ-Ⅱ vs 7.7% in stages Ⅲ-Ⅳ,P < 0.05),and mucinous differentiation(20.2% vs 9.2% without mucin,P < 0.01).A higher frequency of MLH1/PMS2 loss was found in females(9.2% vs 4.4% in males,P < 0.05),and MSH2/MSH6 loss tended to be seen in younger(<50 years old) patients(12.0% vs 4.0% ≥ 50 years old,P < 0.05).MMR deficient tumors were less likely to have KRAS mutations(18.8% vs 41.7% in MMR proficient tumors,P < 0.05) and tumorswith abnormal MLH1/PMS2 tended to harbor BRAF mutations(15.4% vs 4.2% in MMR proficient tumors,P < 0.05).CONCLUSION:The frequency of sporadic CRCs having BRAF mutation,MLH1 deficiency and MSI in Chinese population may be lower than that in the Western population.

ARID1A expression in gastric adenocarcinoma:Clinicopathological significance and correlation with DNA mismatch repair status

AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas.The results were further correlated with clinicopathological variables.RESULTS:The loss of any MMR protein expression,indicative of MMR deficiency,was observed in 38cases(7.8%)and was significantly associated with an older age(68.6±9.2 vs 60.4±11.7,P<0.001),a female sex(55.3%vs 31.3%,P=0.004),an antral location(44.7%vs 25.7%,P=0.021),and a differentiated histology(57.9%vs 39.7%,P=0.023).Abnormal ARID1A expression,including reduced or loss of ARID1A expression,was observed in 109 cases(22.3%)and was significantly correlated with lymphatic invasion(80.7%vs 69.5%,P=0.022)and lymph node metastasis(83.5%vs 73.7%,P=0.042).The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency(47.4%vs 20.2%,P<0.001).A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor(HR=1.36,95%CI:1.01-1.84;P=0.040).CONCLUSION:Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion,lymph node metastasis,poor prognosis,and MMR deficiency in gastric adenocarcinomas.