Evolving insights: how DNA repair pathways impact cancer evolution

Viewing cancer as a large, evolving population of heterogeneous cells is a common perspective. Because genomic instability is one of the fundamental features of cancer, this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation, development, metastasis, and relapse. With the increased mutation rate and abundant diversity of the gene pool, this heterogeneity leads to cancer evolution, which is the major obstacle in the clinical treatment of cancer. Cells rely on the integrity of DNA repair machineries to maintain genomic stability, but these machineries often do not function properly in cancer cells. The deficiency of DNA repair could contribute to the generation of cancer genomic instability, and ultimately promote cancer evolution. With the rapid advance of new technologies, such as single-cell sequencing in recent years, we have the opportunity to better understand the specific processes and mechanisms of cancer evolution, and its relationship with DNA repair. Here, we review recent findings on how DNA repair affects cancer evolution, and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.     

Initial dosage optimization of tacrolimus in Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics

ABSTRACT

Background

The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics.     

HDAC1和CDK1在结肠癌组织中的表达及其临床意义

目的:研究组蛋白去乙酰化酶1（histone deacetylase 1,HDAC1）和细胞周期蛋白依赖性激酶1（cyclin-dependent kinase 1,CDK1）在结肠癌组织中的表达水平及其与患者临床病理特征及预后的关系。方法:收集2012年2月至2013年6月在本院普外科进行手术切除的51例结肠癌患者的肿瘤组织和癌旁非肿瘤组织，采用qRT-PCR法检测组织中HDAC1和CDK1 mRNA相对表达量，采用免疫组织化学染色法检测HDAC1和CDK1蛋白阳性表达率，分析肿瘤组织中HDAC1和CDK1表达的相关性及其与患者肿瘤直径、淋巴结转移等临床病理特征的关系，采用Kaplan-Meier生存函数分析HDAC1和CDK1不同表达情况与患者5年总生存率的关系。结果:肿瘤组织中HDAC1和CDK1 mRNA表达水平和蛋白阳性表达率均高于癌旁非肿瘤组织（P＜0.05）；肿瘤组织中HDAC1表达水平与CDK1表达水平呈显著正相关（P=0.012）；肿瘤组织中HDAC1表达与患者肿瘤直径和组织分化程度有关（P＜0.05），CDK1与肿瘤直径、TNM分期、分化程度、淋巴结转移有关（P＜0.05）；HDAC1、CDK1阳性表达患者5年总生存率均低于其相应阴性表达患者（P＜0.05），HDAC1和CDK1共阳性表达患者5年总生存率低于HDAC1和（或）CDK1阴性患者（P＜0.05）。结论:HDAC1和CDK1在结肠癌组织中高表达，与患者不良预后有关且两者呈正相关，推测两者在促进结肠癌进展中可能存在协同作用。     

LncRNA MEG3靶向miR-181a-5p调控宫颈癌细胞放射敏感性

目的 研究LncRNA MEG3对宫颈癌细胞放射敏感性的影响,并探讨其作用机制。方法 运用qRT-PCR法检测放射抗性和放射敏感性宫颈癌细胞中LncRNA MEG3的表达;将过表达对照组(转染pcDNA 3.1)、过表达LncRNA MEG3组(转染pcDNA 3.1-LncRNA MEG3)、抑制miR-NC组(转染anti-miR-NC)、抑制miR-181a-5p组(转染anti-miR-181a-5p)、过表达LncRNA MEG3+过表达miR-NC组(共转染pcDNA 3.1-LncRNA MEG3和anti-miR-NC)、过表达LncRNA MEG3+过表达miR-181a-5p组(共转染pcDNA 3.1-LncRNA MEG3和anti-miR-181a-5p),均用脂质体法转染至SiHa细胞;克隆形成实验检测细胞的存活分数;流式细胞术检测细胞的凋亡率;双荧光素酶报告基因检测实验检测细胞的荧光活性;Western blot检测细胞中PTEN、p-Akt、Akt的蛋白表达。结果 与放射敏感组相比,放射抗性宫颈癌组织中LncRNA MEG3的表达明显降低(P<0.05),其表达量与宫颈癌细胞的放射敏感性呈正相关;过表达LncRNA MEG3、抑制miR-181a-5p均可显著增强宫颈癌细胞SiHa放射敏感性,促进凋亡(P<0.05);野生型LncRNA MEG3细胞的荧光活性受miR-181a-5p的抑制。过表达miR-181a-5p逆转了LncRNA MEG3对宫颈癌细胞放射增敏和促凋亡作用及对PTEN/Akt信号通路的调控。结论 长链非编码RNA LncRNA MEG3可增强宫颈癌细胞放射敏感性,其机制可能与靶向miR-181a-5p调控PTEN/Akt 信号通路有关,可为提高宫颈癌的预后提供新方向。     

新型荧光示踪剂在乳腺癌前哨淋巴结活检术中的应用研究

背景与目的：吲哚菁绿（indocyanine green，ICG）与利妥昔单抗（rituximab，Rit）偶联可使ICG在淋巴结显像中具有靶向性。探讨ICG-Rit用于乳腺癌前哨淋巴结活检（sentinel lymph node biopsy，SLNB）的可行性。方法：入组山东省肿瘤防治研究院（山东省肿瘤医院）乳腺病中心96例原发性乳腺癌患者（100例次SLNB）。ICG与Rit质量比为93.75 μg∶375.00 μg。术前行ICG-Rit、联合示踪剂（亚甲蓝及核素示踪剂）乳房注射，联合法行SLNB，对检出淋巴结进行荧光显像检测，记录荧光显像淋巴结及灰度值，分析ICG-Rit淋巴结显像情况并评价对比联合法的一致性。观察患者过敏反应并检测术后嗜酸性粒细胞计数。结果：ICG-Rit病例显像率为97.0%（97/100）。ICG-Rit显像前哨淋巴结（sentinel lymph node，SLN）的均数为2.44，中位数为2；低于核素法检出SLN的均数（2.80）和中位数（3）。ICG-Rit对比联合法SLNB的准确率为97.0%（97/100），灵敏度为96.2%（25/26），假阴性率为3.8%（1/26），kappa值为0.973（P＜0.001）。显像淋巴结灰度值最高254，显像淋巴结灰度值集中在220~254，＜220者术中荧光不易察觉，缺乏连续性。入组患者术前未见过敏反应，术后嗜酸性粒细胞计数未增高。结论：ICG-Rit能够减少对非SLN（non-SLN，n-SLN）的显像。对比联合法，准确率和符合率高，安全性良好。     

术前低PSA的Gleason 8~10分前列腺癌患者临床特点

背景与目的:前列腺癌的发病率逐渐上升,其中有些患者在诊断为高级别前列腺癌甚至转移性前列腺癌时,其前列腺特异性抗原(prostate-specific antigen,PSA)数值却处于很低的水平。探讨术前低血清PSA的Gleason 8~10分前列腺癌患者临床特点。方法:收集2013年1月-2018年1月江苏省苏北人民医院收治的72例接受前列腺癌根治术的高Gleason评分前列腺癌患者的临床资料。根据术前血清PSA水平分为4组:A组<4.0 ng/mL(9例)、B组4.0~10.0 ng/mL(12例)、C组10.0~20.0 ng/mL(15例)和D组>20.0 ng/mL(36例)。4组平均年龄分别为(68.8±8.6)、(68.9±6.0)、(71.6±6.0)和(68.4±6.4)岁。平均随访时间分别为(21.6±12.1)、(18.8±7.2)、(25.0±13.4)和(24.8±12.5)个月。切缘阳性例数分别为3例(33.3%)、5例(41.7%)、5例(33.0%)和15例(41.7%)。精囊侵犯例数分别为6例(66.7%)、2例(16.7%)、2例(13.3%)和14例(38.9%)。淋巴结转移例数分别为2例(22.2%)、3例(25.0%)、4例(26.7%)和13例(36.1%)。预后评价指标为无生化复发天数(biochemical progression-free day,bPFD)与前列腺癌特异性死亡(prostate cancer-specific death,PCSD)。4组平均PFD分别为(90.00±38.40)、(306.17±79.00)、(223.14±63.30)和(145.03±62.50)d。PCSD例数分别为4例(44.4%)、0例(0.0%)、1例(6.7%)和5例(13.9%)。组间年龄、随访时间、PFD使用单因素方差分析,进一步两两比较采用最小显著差别(least significant difference,LSD)法;组间临床病理学特征采用χ2检验、Fisher精确检验;PCSD使用Kaplan-Meier生存分析,生存曲线间比较使用log-rank检验。结果:A组与其余3组相比,年龄、随访时间、切缘阳性、淋巴结转移的差异均无统计学意义(P>0.05)。A组与B、C两组相比,精囊侵犯、PFD的差异均有统计学意义(P<0.05)。但A组与D组相比,精囊侵犯、PFD的差异无统计学意义(P>0.05)。生存分析显示,A组相较于B组在随访时间内生存状况更差,但差异无统计学意义(P=0.092),A组与C、D两组的生存差异有统计学意义(P<0.05)。结论:具有术前低血清PSA水平的高Gleason评分前列腺癌患者相较于PSA更高水平的患者预后更差,易出现精囊侵犯、术后生化复发快且PCSD例数多。     

The extracellular matrix enriched with membrane metalloendopeptidase and insulin‐degrading enzyme suppresses the deposition of amyloid‐beta peptide in Alzheimer's disease cell models

Amyloid plaque is a typical feature of Alzheimer's disease (AD) and is one of the targets for AD therapy. Membrane metalloendopeptidase (MME) and insulin‐degrading enzyme (IDE) are two types of proteases that could cleave beta‐amyloid (Aβ) peptides generated by neuron cells of AD patients. Extracellular matrix (ECM) plays a crucial role in regulating tissue‐specific functions and is an ideal biomaterial for tissue repair. In this study, we extracted the liquid ECM enriched with collagen‐binding‐domain‐fused IDE or MME from human foreskin fibroblast cells. We found that these ECM biomaterials reduced the aggregation of Aβ peptides, prevented the formation of amyloid plaques, and also suppressed phosphorylation of Tau protein in AD cell models. Overall, our research provides a novel ECM biomaterial that can be potentially used for AD therapy.