Changes in DNA double-strand break repair during aging correlate with an increase in genomic mutations

A double -strand break (DSB) is one of the most deleterious forms of DNA damage. In eukaryotic cells, two main repair pathways have evolved to repair DSBs, homologous recombination (HR) and non-homologous end-joining (NHEJ). HR is the predominant pathway of repair in the unicellular eukaryotic organism, S. cerevisiae. However, during replicative aging the relative use of HR and NHEJ shifts in favor of end-joining repair. By monitoring repair events in the HO-DSB system, we find that early in replicative aging there is a decrease in the association of long-range resection factors, Dna2-Sgs1 and Exo1 at the break site and a decrease in DNA resection. Subsequently, as aging progressed, the recovery of Ku70 at DSBs decreased and the break site associated with the nuclear pore complex at the nuclear periphery, which is the location where DSB repair occurs through alternative pathways that are more mutagenic. End-bridging remained intact as HR and NHEJ declined, but eventually it too became disrupted in cells at advanced replicative age. In all, our work provides insight into the molecular changes in DSB repair pathway during replicative aging. HR first declined, resulting in a transient increase in the NHEJ. However, with increased cellular divisions, Ku70 recovery at DSBs and NHEJ subsequently declined. In wild type cells of advanced replicative age, there was a high frequency of repair products with genomic deletions and microhomologies at the break junction, events not observed in young cells which repaired primarily by HR.     

右美托咪定联合依托咪酯对老年直肠癌根治术患者术后炎症反应、胃肠功能恢复和认知功能的影响

摘要 目的：探讨右美托咪定联合依托咪酯对老年直肠癌根治术患者术后炎症反应、胃肠功能恢复和认知功能的影响。方法：选择2019年3月~2021年5月南京鼓楼医院收治的180例老年直肠癌患者,均接受腹腔镜下直肠癌根治术治疗。根据随机数字表法将患者分为对照组和研究组,各为90例。对照组患者麻醉选用依托咪酯,研究组患者麻醉选用右美托咪定联合依托咪酯,对比两组术中血流动力学、术后炎症反应、胃肠功能恢复和认知功能,同时记录两组围麻醉期不良反应发生情况。结果：插管即刻（T2）~拔管即刻（T4）时间点,两组心率（HR）、平均动脉压（MAP）先下降后升高,且研究组的波动幅度小于对照组（P<0.05）。两组进食时间组间对比无统计学差异（P>0.05）,研究组的肠鸣音恢复时间、首次排气时间短于对照组（P<0.05）。两组气管拔管时间、呼吸恢复时间、麻醉苏醒时间对比无统计学差异（P>0.05）。两组术后3 d白介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和C反应蛋白（CRP）水平均升高,且研究组的变化幅度小于对照组（P<0.05）。两组术后1 d、术后3 d简明智能状态量表（MMSE）评分先下降后升高,且研究组的波动幅度小于对照组（P<0.05）。两组不良反应发生率组间对比无差异（P>0.05）。结论：老年直肠癌根治术患者麻醉方案选用右美托咪定联合依托咪酯,可减轻机体炎性应激,稳定机体血流动力学,有利于胃肠功能恢复,同时还可减轻对机体认知功能的损害。     

术前AGR、NLR、FOXQ1联合检测对低位直肠癌根治性切除手术患者术后复发的预测价值

摘要 目的：探讨术前白蛋白-球蛋白比值（AGR）、中性粒细胞-淋巴细胞比值（NLR）、叉头框蛋白Q1（FOXQ1）联合检测对低位直肠癌根治性切除手术患者术后复发的预测价值。方法：选取2017年3月至2019年4月重庆市第九人民医院就诊的拟行低位直肠癌根治性切除手术患者110例,术前均检测血清AGR、NLR、FOXQ1水平。随访3~48个月,中位随访时间为25.5个月,失访9例,101例根据术后复发情况将患者分为复发组（n=16）和未复发组（n=85）。比较两组患者术前血清AGR、NLR、FOXQ1水平,收集患者的临床资料,以Logistic回归分析探讨低位直肠癌患者术后复发的危险因素,绘制受试者工作曲线（ROC）判定术前血清AGR、NLR、FOXQ1水平对低位直肠癌患者术后复发的预测价值。结果：复发组术前血清AGR水平低于未复发组,术前血清NLR、FOXQ1水平高于未复发组（P<0.05）;复发组患者肿瘤细胞分化程度为低分化、TNM分期为Ⅲ期、糖链抗原19-9（CA19-9）阳性占比高于未复发组（P<0.05）,复发组术后化疗占比低于未复发组（P<0.05）;Logistic回归分析结果显示,TNM分期为Ⅲ期、细胞分化程度为低分化、术前血清AGR降低、NLR升高、FOXQ1升高均为低位直肠癌患者术后复发的危险因素（P＜0.05）;ROC曲线结果显示,术前血清AGR、NLR、FOXQ1水平及三者联合对低位直肠癌患者术后复发的预测的曲线下面积（AUC）值分别为0.738、0.747、0.731、0.842。结论：术前检测血清AGR、NLR、FOXQ1水平对低位直肠癌根治性切除术患者术后复发预测具有一定的价值,且联合的预测价值更高。     

经尿道等离子前列腺剜除术与经尿道前列腺电切术治疗良性前列腺增生症的临床疗效对比研究

摘要 目的：对比经尿道等离子前列腺剜除术（TUKEP）与经尿道前列腺电切术（TURP）治疗良性前列腺增生症（BPH）的临床疗效。方法：回顾性分析我院2018年1月1日至2021年3月17日期间收治的200例BPH患者的临床资料。根据手术方式的不同将患者分为A组（n=83）和B组（n=117）,A组手术方式为TURP,B组手术方式为TUKEP,比较两组围术期指标,随访6个月,对比两组性功能、尿流动力学变化及并发症发生情况。结果：B组手术时间、术中出血量、尿管留置时间、住院时间、术后冲洗时间短于A组（P<0.05）。术后6个月,两组患者的最大尿流速（Qmax）、膀胱顺应性（BC）升高,剩余尿量（PVR）降低（P<0.05）,且B组患者的Qmax、BC高于A组,PVR低于A组（P<0.05）。术后6个月,两组患者的勃起功能评分表（IIEF-5）、射精功能评分表（CIPE-5）评分降低（P<0.05）,但B组、A组IIEF-5、CIPE-5评分组间对比无明显统计学差异（P>0.05）。B组的并发症发生率小于A组（P<0.05）。结论：TUKEP、TURP治疗BPH,疗效相当,TUKEP在缩短手术时间、尿管留置时间、术后冲洗时间、住院时间,降低术中出血量,减少并发症发生率,改善尿流动力学方面更有优势。     

右美托咪定联合七氟醚对老年腹腔镜胃肠肿瘤切除术患者应激反应和脑氧代谢的影响

摘要 目的：观察老年腹腔镜胃肠肿瘤切除术患者使用七氟醚联合右美托咪定复合麻醉后,机体应激反应和脑氧代谢的变化情况。方法：将我院2020年1月至2020年12月期间收治的100例老年腹腔镜胃肠肿瘤切除术患者根据随机数字表法分为对照组（n=50,七氟醚麻醉）和研究组（n=50,右美托咪定联合七氟醚麻醉）。观察两组血流动力学、应激反应、脑氧代谢、认知功能和不良反应。结果：两组手术60 min（T1）~手术后30 min（T3）时间点较麻醉诱导前（T0）时间点心率（HR）先下降后升高,平均动脉压（MAP）先升高后下降（P<0.05）。研究组T1~T3时间点HR及MAP低于对照组（P<0.05）。两组术后3 d多巴胺（DA）、肾上腺素（AD）、去甲肾上腺素（NE）水平升高,但研究组低于对照组（P<0.05）。两组术后3 d血氧含量差（DajvO₂）和脑氧摄取率（CERO₂）下降,且研究组低于对照组（P<0.05）。研究组术后6 h、术后1 d、术后3 d简易精神状态检查量表（MMSE）评分高于对照组（P<0.05）。两组不良反应发生率,对比无显著性差异（P>0.05）。结论：七氟醚联合右美托咪定应用于老年腹腔镜胃肠肿瘤切除术患者,可有效减轻机体应激反应,减轻机体认知功能损伤,维持血流动力学稳定和脑氧代谢。     

不同剂量右美托咪定辅助麻醉对老年结肠癌根治术患者麻醉效果和术后谵妄的影响及谵妄的相关因素分析

摘要 目的：探讨不同剂量右美托咪定辅助麻醉对老年结肠癌根治术患者麻醉效果,并分析术后谵妄的影响因素。方法：选取2019年4月~2021年1月期间我院收治的160例老年结肠癌根治术患者,根据随机数字表法将患者分为A组（53例）、B组（53例）和C组（54例）。A组和B组均于麻醉诱导前给予0.5 μg/kg右美托咪定,以0.2 μg/kg?h速率静脉输注至手术结束前30 min,A组术后镇痛时再给予右美托咪定0.05 μg/kg?h。C组给予等容量和等速率的生理盐水。观察三组的应激反应、麻醉效果、不良反应发生率、谵妄发生率。根据是否发生谵妄分为谵妄组（n=28）和无谵妄组（n=132）。采用Logistic回归分析术后谵妄的影响因素。结果：三组术后第3 d C反应蛋白（CRP）、白介素-6（IL-6）、多巴胺、肾上腺素均较手术结束升高（P<0.05）。A组、B组术后第3 d CRP、IL-6、多巴胺、肾上腺素低于C组（P<0.05）。A组、B组术后第3dCRP、IL-6、多巴胺、肾上腺素组间对比,无明显差异（P>0.05）。A组、B组、C组的不良反应总发生率组间的对比无明显差异（P>0.05）。B组的谵妄发生率明显低于A组、C组（P<0.05）。A组、C组谵妄发生率组间对比无明显差异（P>0.05）。单因素分析结果显示,术后谵妄的发生与年龄、术前抑郁、术前合并基础疾病数量、术中低氧血症、气腹后PaCO₂、白蛋白有关（P<0.05）。多因素Logistic回归分析结果显示：术前抑郁、年龄≥70岁、术前合并基础疾病数量≥3、术中低氧血症、气腹后PaCO₂偏高、白蛋白偏低是导致老年结肠癌根治术患者术后谵妄的危险因素（P<0.05）。结论：小剂量右美托咪定辅助麻醉可提高老年结肠癌根治术患者的麻醉效果,减少谵妄的发生率,同时术前抑郁、年龄≥70岁、术前合并基础疾病数量≥3、术中低氧血症、气腹后PaCO₂偏高、白蛋白偏低是引起谵妄发生的危险因素。     

术前中性粒细胞绝对值/淋巴细胞比值联合血清瘦素、睾酮对前列腺癌根治术后生化复发的评估价值

摘要 目的：探讨术前中性粒细胞绝对值/淋巴细胞比值（NLR）联合血清瘦素、睾酮对前列腺癌（PCa）根治术后生化复发的评估价值。方法：选取2018年1月～2020年1月于我院接受根治性切除术治疗的82例PCa患者。术前均检测NLR、血清瘦素、睾酮水平。术后对所有患者均进行2年随访观察,按照是否发生生化复发分为复发组（n=34）以及无复发组（n=48）。比较两组NLR、血清瘦素、睾酮水平差异。收集患者临床资料,采用多因素Logistic回归分析PCa根治术后生化复发的影响因素。采用受试者工作特征（ROC）曲线分析NLR以及血清瘦素、睾酮预测PCa根治术后生化复发的评估价值。结果：复发组术前NLR以及瘦素水平均高于无复发组（P＜0.05）,而睾酮水平低于无复发组（P＜0.05）。复发组术前前列腺特异抗原（PSA）≥10 ng/mL、TNM分期T2期人数占比以及Gleason评分均高于无复发组（P＜0.05）。多因素Logistic回归分析显示,术前PSA≥10 ng/mL、TNM分期T2期、Gleason评分较高、术前NLR较高、瘦素水平较高、睾酮水平较低是PCa根治术后生化复发的危险因素（P＜0.05）。ROC曲线分析显示,联合检测术前NLR、血清瘦素、睾酮水平预测PCa根治术后生化复发的ROC曲线下面积为0.897,高于三项指标单独检测的0.678、0.712、0.733。结论：PCa根治术后生化复发受术前PSA、NLR、血清瘦素、睾酮水平、TNM分期、Gleason评分等因素影响,术前NLR联合血清瘦素、睾酮对PCa根治术后生化复发的预测价值较高。     

不同CO2气腹压力对老年腹腔镜结直肠癌根治术患者苏醒质量、应激反应和术后认知功能的影响

目的:观察不同二氧化碳(CO₂)气腹压力对老年腹腔镜结直肠癌根治术患者苏醒质量、应激反应和术后认知功能的影响。方法:选择2018年5月~2020年12月期间我院收治的择期行腹腔镜结直肠癌根治术患者91例,按入院奇偶号顺序将患者分为低CO₂气腹压力组(低压力组,10 mmHg,45例)和高CO₂气腹压力组(高压力组,15 mmHg,46例)。对比两组苏醒质量、应激反应、呼吸功能指标和认知功能变化情况。结果:低压力组患者的苏醒期躁动发生率低于高压力组(P<0.05)。两组患者注气针穿刺时(T1)、气腹成功建立时(T2)、放气后10 min(T3)时间点C反应蛋白(CRP)、皮质醇均高于入室时(T0)时间点(P<0.05),低压力组T1、T2、T3时间点CRP、皮质醇均低于高压力组(P<0.05)。与气腹前相比,两组气腹20 min后动脉血氧分压(PaO₂)降低,动脉血二氧化碳分压(PaCO₂)升高(P<0.05),与低压力组相比,高压力组PaO₂更低,PaCO₂更高(P<0.05)。术后第1 d、术后第3 d、术后第7 d,低压力组简易精神状态检查量表(MMSE)评分均高于同时间点的高压力组(P<0.05)。结论:老年腹腔镜结直肠癌根治术中,采用较低的CO₂气腹压力可提升苏醒质量,减轻机体应激反应、呼吸系统损害和认知功能损害。     

The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion

Objective and backgroundActivation of sterile inflammation after hepatic ischemia/reperfusion (I/R) culminates in liver injury. The route to liver damage starts with mitochondrial oxidative stress and cell death during early reperfusion. The link between mitochondrial oxidative stress, damage-associate molecular pattern (DAMP) release, and sterile immune signaling is incompletely understood and lacks clinical validation. The aim of the study was to validate this relation in a clinical liver I/R cohort and to limit DAMP release using a mitochondria-targeted antioxidant in I/R-subjected mice.MethodsPlasma levels of the DAMPs high-mobility group box 1 (HMGB1), mitochondrial DNA, and nucleosomes were measured in 39 patients enrolled in an observational study who underwent a major liver resection with (N = 29) or without (N = 13) intraoperative liver ischemia. Circulating cytokine and neutrophil activation markers were also determined. In mice, the mitochondria-targeted antioxidant MitoQ was intravenously infused in an attempt to limit DAMP release, reduce sterile inflammation, and suppress I/R injury.ResultsIn patients, HMGB1 was elevated following liver resection with I/R compared to liver resection without I/R. HMGB1 levels correlated positively with ischemia duration and peak post-operative transaminase (ALT) levels. There were no differences in mitochondrial DNA, nucleosome, or cytokine levels between the two groups. In mice, MitoQ neutralized hepatic oxidative stress and decreased HMGB1 release by ±50%. MitoQ suppressed transaminase release, hepatocellular necrosis, and cytokine production. Reconstituting disulfide HMGB1 during reperfusion reversed these protective effects.ConclusionHMGB1 seems the most pertinent DAMP in clinical hepatic I/R injury. Neutralizing mitochondrial oxidative stress may limit DAMP release after hepatic I/R and reduce liver damage.     

Caspase-3 immunohistochemical expression is a marker of apoptosis,increased grade and early recurrence in intracranial meningiomas

Caspase-3 is the ultimate executioner caspase that is essential for the nuclear changes associated with apoptosis. We investigated caspase-3 immunohistochemical expression in 58 primary intracranial meningiomas, using one monoclonal antibody detecting both precursor and cleaved caspase-3 (CPP32) and a second recognizing only the cleaved activated form (ASP175). Caspase-3 expression was analyzed in relation to baseline apoptosis—as illustrated by the expression of anti-single stranded DNA (ss-DNA), the antiapoptotic protein bcl-2, proliferation indices (Ki-67, PCNA, topoisomerase IIa, mitosin C), hormonal status (estrogen, progesterone, androgen receptors), standard clinicopathological parameters and patients’ disease-free survival. Caspase-3 immunostaining was observed in 62% of cases for CPP32 and in 24% for ASP175. In both instances, the labeling index (LI) was significantly correlated with ss-DNA LI (p=0.038 and p=0.018). CPP32 but not ASP175 LI positively correlated with the mitotic index (p=0.001) and PCNA LI (p=0.004). Both CPP32 and ASP175 LIs were increased in nonbenign meningiomas (p<0.0001 and p=0.0035 respectively). In univariate and multivariate survival analyses, caspase-3 predicted meningioma recurrence, independently affecting disease-free survival (p=0.011 and p=0.047 respectively for CPP32; p<0.0001 and p=0.012 respectively for ASP175). Caspase-3 may prove to be a useful predictor of early recurrence in a group of neoplasms characterized by the frequent discordance between histology and clinical behavior.