Systematic analysis of DNA polymerases as therapeutic targets in pan-cancers

Introduction:DNA polymerases are crucial for maintaining genome stability and influencing tumorigenesis.However,the clinical implications of DNA polymerases in tumorigenesis and their potential as anti-cancer therapy targets are not well understood.Methods:We conducted a systematic analysis using TCGA Pan-Cancer Atlas data and Gene Set Cancer Analysis results to examine the expression profiles of 15 DNA polymerases(POLYs)and their clinical correlations.We also evaluated the prognostic value of POLYs by analyzing their expression levels in relation to overall survival time(OS)using Kaplan-Meier survival curves.Additionally,we investigated the correlations between POLY expression and immune cells,DNA damage repair(DDR)pathways,and ubiquitination.Drug sensitivity analysis was performed to assess the relationship between POLY expression and drug response.Results:Our analysis revealed that 14 out of 15 POLYs exhibited significantly distinct expression patterns between tumor and normal samples across most cancer types,except for DNA nucleotidylexotransferase(DNTT).Specifically,POLD1 and POLE showed elevated expression in almost all cancers,while POLQ exhibited high expression levels in all cancer types.Some POLYs showed heightened expression in specific cancer subtypes,while others exhibited low expression.Kaplan-Meier survival curves demonstrated significant prognostic value of POLYs in multiple cancers,including PAAD,KIRC,and ACC.Cox analysis further validated these findings.Alteration patterns of POLYs varied significantly among different cancer types and were associated with poorer survival outcomes.Significant correlations were observed between the expression of POLY members and immune cells,DDR pathways,and ubiquitination.Drug sensitivity analysis indicated an inverse relationship between POLY expression and drug response.Conclusion:Our comprehensive study highlights the significant role of POLYs in cancer development and identifies them as promising prognostic and immunological biomarkers for various cancer types.Additionally,targeting POLYs therapeutically holds promise for tumor immunotherapy.

基于真实世界数据的食管鳞癌在新辅助治疗联合PD-1/PD-L1抑制剂的安全性及疗效分析

目的:免疫检查点抑制剂联合化疗在食管癌的治疗中具有较好的疗效,然而免疫治疗在局部晚期食管癌围手术期的应用尚缺乏共识。本研究通过分析真实世界的数据,为免疫检查点抑制剂在食管癌新辅助治疗中的临床应用提供借鉴和依据。方法:本研究分析2020年3月至2021年8月就诊于河北医科大学第四医院,经病理证实为食管鳞癌的局部晚期患者,经评估建议行新辅助治疗联合免疫检查点抑制剂,后接受规范的食管癌根治手术,共纳入患者152例。观察终点为病理完全缓解(pathologic complete response,pCR)率,主要病理缓解(major pathologic response,MPR)率,显微镜下无残留(R0)切除率、术后并发症、肿瘤退缩分级、无病生存(disease-free survival,DFS)率,并探索最优的新辅助化免联合治疗的周期数。结果:R0切除94.1%(143/152),术后病理评估发现按照美国病理学家协会(CAP)肿瘤退缩分级标准,0级、1级、2级、3级的比例分别为29.6%、11.2%、25.7%、33.5%;pCR率25%。16.4%出现新辅助治疗相关不良反应;术后降期率62.5%。术后并发症:90天术后死亡率为0,发生术后并发症25%,吻合口瘘的发生率7.8%,肺炎发生率9.2%。术前免疫周期数为2~3次的患者,术后病理类型为CAP分级0~2级的占比92.1%,而其他周期数的患者术后病理类型为CAP分级0~2级的占比7.9%(P=0.007)。全组患者中位随访时间16.4(15.0~7.8)个月,1年DFS率96.7%,2年DFS率87.5%。结论:程序性细胞死亡因子-1/配体-1(programmed death-1/programmed cell death-ligand 1,PD-1/PD-L1)抑制剂在局部晚期食管鳞癌患者的新辅助治疗中安全可行,R0切除率满意,pCR率满意,新辅助化疗联合免疫检查点抑制剂治疗明显达到降期的目的。多数患者术后治疗受限,建议辅助治疗尽可能放到术前。术前2~3个周期患者可能有更高的病理缓解率。

Detrital zircon U-Pb dating in the southern Hefei Basin: Evidence for exhumation of HP-UHP rocks of the Dabie Orogen

The Hefei Basin of eastern China developed in response to uplift of the Dabie Orogen,and zircon dating can be used to assess the exhumation history of the orogen.Zircons were collected from samples of the Lower Jurassic Fanghushan Formation and Middle Jurassic Sanjianpu Formation in the southern Hefei Basin,and mica-quartz schist and biotite granite gneiss from the Susong Complex of the Dabie Orogen.The zircon U-Pb dating was undertaken using laser ablation-inductively coupled plasma-mass spectrometry.The detrital zircons from conglomerates of the Fanghushan Formation and from clasts within the conglomerates have age-frequency distributions with the main clusters between 2.0 and 1.8 Ga,similar to age data of the Susong Complex.On the other hand,the zircons of the Fanghushan Formation do not show the age cluster at 1000–900 Ma that characterizes zircons in the underlying metasediments of the lower Paleozoic Foziling Group.A cluster of Triassic zircon ages also appears in the arkosic sandstones of the Fanghushan Formation.These data indicate that the provenance of the Fanghushan Formation was a mixture of high-pressure(HP)and ultrahigh-pressure(UHP)Triassic metamorphic rocks,Paleozoic magmatic rocks,and the Susong Complex,but not the lower Paleozoic Foziling Group even though it directly underlies the sediments of the Hefei Basin.Two samples from the Sanjianpu Formation show zircon age clusters at 797 and 791 Ma(middle Neoproterozoic)and 226 Ma(Triassic),and again,these are markedly different from the age clusters that characterize the Foziling Group.It seems,therefore,that despite the Foziling Group being at the surface in the underwater depositional area of the Hefei Basin,it was not exposed in the source area of the Hefei basinal sediments during the Jurassic,and there are two possible reasons for this.First,the exhumation of the Dabie Orogen was directed partly towards the north,in the process of which some of the Foziling Group was covered.Second,the Susong Complex rocks became involved in the development of an accretionary wedge,thus covering some of the Foziling Group during the process of subduction.

Comparisons of minimally invasive esophagectomy and open esophagectomy in lymph node metastasis/dissection for thoracic esophageal cancer

Background:The study aimed to clarify the characteristics of lymph node metastasis(LNM)and to compare the oncologic outcomes of minimally invasive esophagectomy(MIE)with open esophagectomy(OE)in terms of lymph node dissection(LND)in thoracic esophageal cancer patients.Methods:The data from esophageal cancer patients who underwent MIE or OE from January 2016 to January 2019 were retrospectively reviewed.The characteristics of LNM in thoracic esophageal cancer were discussed,and the differences in numbers of LND,LND rate,and LNM rate/degree of upper mediastinum between MIE and OE were compared.Results:For overall characteristics of LNM in 249 included patients,the highest rate of LNM was found in upper mediastinum,while LNM rate in middle and lower mediastinum,and abdomen increased with the tumor site moving down.The patients were divided into MIE(n=204)and OE groups(n=45).In terms of number of LND,there were significant differences in upper mediastinum between MIE and OE groups(8[5,11]vs.5[3,8],P<0.001).The comparative analysis of regional lymph node showed there was no significant difference except the subgroup of upper mediastinal 2L and 4L group(3[1,5]vs.0[0,2],P<0.001 and 0[0,2]vs.0,P=0.012,respectively).Meanwhile,there was no significant difference in terms of LND rate except 2L(89.7%[183/204]vs.71.1%[32/45],P=0.001)and 4L(41.2%[84/204]vs.22.2%[10/45],P=0.018)groups.For LNM rate of T3 stage,there was no significant difference between MIE and OE groups,and the comparative analysis of regional lymph node showed that there was no significant difference except 2L group(11.1%[5/45]vs.38.1%[8/21],P=0.025).The LNM degree of OE group was significantly higher than that of MIE group(27.2%[47/173]vs.7.6%[32/419],P<0.001),and the comparative analysis of regional LNM degree showed that there was no significant difference except 2L(34.7%[17/49]vs.7.7%[13/169],P<0.001)and 4L(23.8%[5/21]vs.3.9%[2/51],P=0.031)subgroups.Conclusion:MIE may have an advantage in LND of upper mediastinum 2L and 4L groups,while it was similar to OE in other stations of LND.