Rad51在同源重组中作用及其与肿瘤关系的研究进展

目的：总结国内外关于同源重组因子Rad51在人类肿瘤发生、发展中的作用,以及其在肿瘤治疗中应用的研究现状。方法：应用Medline及CNKI期刊全文数据库检索系统,以＂同源重组、Rad51和肿瘤＂为关键词,检索1993-01-2009-05的相关文献,共检索到英文文献374篇和中文文献14篇。纳入标准：1）同源重组在DNA修复中的作用;2）Rad51及其相关蛋白在同源重组中的作用和机制;3）Rad51蛋白的表达调控,4）Rad51在人类肿瘤发生、发展中的作用和机制以及以Rad51为靶点的治疗策略。根据纳入标准,精选86篇文献,最后32篇文献纳入分析。结果：Rad51蛋白是参与DNA同源重组性修复的关键因子,Rad51蛋白的高水平表达会导致体内DNA同源重组性修复能力的增强,而同源重组机制的功能失调常会导致基因组不稳定和肿瘤的发生。还有许多研究发现,Rad51蛋白表达升高所导致DNA修复能力的增强会导致肿瘤细胞对放疗、化疗和靶向治疗等多种治疗产生耐受。体外研究表明,下调Rad51蛋白表达水平可有效逆转肿瘤耐药和对放疗产生耐受。结论：Rad51是体内参与同源重组性DNA修复的关键因子,Rad51的功能失调与肿瘤的发生、发展以及治疗耐受密切相关,Rad51将会是未来肿瘤临床治疗中重要的潜在靶点。     

REIC抑制肿瘤细胞生长机制研究进展

目的：总结REIC抑制人类肿瘤细胞生长的机制。方法：应用PubMed、CNKI期刊全文数据库检索系统,以＂REIC、细胞凋亡＂等为关键词,检索2005-2012年的相关文献。纳入标准：1）REIC的一般特性;2）REIC的细胞免疫学特性;3）REIC诱导肿瘤细胞凋亡;4）REIC细胞内作用配体。排除标准：REIC抑制肿瘤细胞生长的病理意义。符合要求纳入分析的文献25篇。结果：REIC是新近发现的肿瘤抑制基因,具有诱导细胞凋亡和抑制肿瘤生长的作用。其机制为a型REIC/DKK-3启动子高度甲基化导致REIC/DKK-3表达下调;REIC蛋白诱导CD14＋单核细胞分化募集树突状细胞,加强脾抗肿瘤溶细胞活性从而抑制肿瘤细胞的生长;REIC激发内质网紧张度诱导IL-7上调进而作用于自然杀伤细胞产生间接抗肿瘤作用;REIC/DKK-3高表达下调分化抑制蛋白促使JNK激酶磷酸化,进而诱导细胞凋亡;REIC蛋白的过表达激活TGF-β受体,从而导致Smad蛋白磷酸化。结论：在肿瘤中REIC启动子高甲基化致其表达水平降低,造成其诱导细胞分化、下调分化抑制蛋白和激活TGF-β受体的能力下降,致肿瘤细胞凋亡水平降低,增殖能力增高。     

小细胞肺癌蛋白质组学研究进展

目的总结蛋白质组学在小细胞肺癌中的研究进展。方法应用PubMed、EMBASE及CNKI期刊数据库检索系统,以＂肺癌,小细胞肺癌、蛋白质组学和研究进展＂等为关键词,检索1995-01-2013-12的相关文献,共检索到英文文献556条,中文文献317条。纳入标准：1）小细胞肺癌;2）蛋白质组学研究;3）蛋白质组学技术。剔除标准：非小细胞肺癌。最后符合分析的文献24篇。结果目前蛋白质组学在小细胞肺癌中的研究主要集中于细胞、组织和血清三个方面,并且已发现多种不同的候选肿瘤标志。结论蛋白质组学研究已广泛深入到小细胞肺癌发病机制、临床早期诊断和治疗等各个方面,为发现小细胞肺癌诊断、治疗及预后判断的潜在生物标志提供了新的思路。     

微小RNA与肿瘤

目的：总结国内外关于微小RNA与肿瘤的发生发展,以及诊断和治疗相关的研究进展。方法：应用PubMed及CNKI期刊全文数据库检索系统,以＂微小RNA、肿瘤＂为关键词,检索2005-01-2010-01的文献,共检索到英文文献541篇,中文文献37篇。纳入标准：1）miRNA在肿瘤的诊断和预后判断中的作用;2）miRNA在肿瘤发生发展中的作用;3）miRNA在肿瘤治疗中的应用。共96篇文献符合纳入标准,最后纳入分析27篇文献。结果：微小RNA在细胞的多种生命活动,如增殖、分化、凋亡中发挥着重要的调节作用,因而在不同肿瘤中能够发挥癌基因或者抑癌基因的作用。通过检测组织或者患者血液及血清中微小RNA表达情况的变化可以作为肿瘤诊断和预后的指标。结论：深入研究微小RNA在肿瘤的发生发展中所起的作用,有望在肿瘤的诊断和靶向治疗以及预后判断方面提供新的思路。     

化疗药物所致周围神经病变防治研究的现状

目的:总结化疗所致周围神经病变(CIPN)研究的历史、现状及面临的问题。方法:应用PubMed全文数据库检索系统,以"周围神经病变、周围神经毒性、化疗和癌症"等为关键词,检索2006-01-2012-09相关文献。纳入标准:1)CIPN发生机制;2)临床表现;3)评估以及防治现状。根据纳入标准符合分析的文献24篇。结果:化疗所致周围神经病变是抗肿瘤药物最常见毒副作用之一,其中紫杉烷类和顺铂治疗人群发生率为60%。CIPN导致患者活动功能受限,严重影响生活质量,限制化疗剂量甚至终止化疗。其发病机制、发生率、表现类型以及严重程度的多样性归咎于药物毒性成分不同。目前探索CIPN危险因素的研究日益增多,通过基因型确认患者是否为高风险人群为未来研究热点。CIPN权威评价标准尚未确立。结论:临床尚无有效药物预防CIPN发生或改善病程,只能通过调整化疗方案甚至停用限制神经毒性。通过对CIPN发生机制、临床特征和严重程度的研究,进一步了解其病理生理变化,发现预测因子、早期神经病变标志、更敏感的诊断技术和有效的神经保护策略,提高患者生存质量。     

晚期胃癌药物治疗策略和展望

目的:总结国内外晚期胃癌药物治疗的研究现状。方法:以胃癌和药物治疗为关键词,检索Medline和中国生物医学文献数据库1989-01-2009-09的相关文献,获得英文文献1809篇,中文文献131篇。纳入标准:1)晚期胃癌患者的化疗;2)晚期胃癌的靶向治疗。根据纳入标准,精选81篇全文文献,最后纳入分析34篇。结果:晚期胃癌的药物治疗基本上是姑息性的,患者接受治疗后仅能获得部分缓解,且持续时间有限。对于晚期胃癌患者,目前国际上仍然没有统一的标准化疗方案。多个靶向药物在胃癌治疗中的效果正在观察。结论:近年对晚期胃癌治疗药物及方案的研究主要集中于以下几个方面,1)改进已有的联合化疗方案;2)评价已有有效方案;3)新的化疗药物、靶向药物的应用。     

β-tubulin与紫杉醇类耐药在肺癌中的研究进展

目的:总结国内外关于β-tubulin与紫杉醇类耐药在肺癌治疗中的基础与临床研究进展。方法:应用Medline及CNKI期刊全文数据库系统,以"肺癌"、"微管蛋白(tubulin)"、"紫杉醇"、"化疗"为关键词,检索2010-2011年前相关文献。共检索到英文文献371篇,中文文献82篇。纳入标准:1)微管蛋白分子研究;2)肺癌细胞系与tubulin及紫杉醇类化疗耐药研究;3)与tubulin及紫杉醇类化疗耐药相关肺癌临床试验研究。结果:基础与临床研究均揭示β-tubulinⅢ与紫杉醇类耐药存在明确的负相关性,其可通过突变、过表达、多药耐药等机制诱发紫杉醇类化疗耐药,β-tu-bulinⅢ高表达预示肺癌患者预后不佳。结论:β-tubulinⅢ与肺癌含紫杉醇类化疗方案耐药相关,对其抑制或逆转为肺癌提高化疗效果提供了重要新思路。     

结直肠癌化疗的研究进展

目的:对结直肠癌(CRC)化疗的新进展进行综述分析.方法:应用PubMed、CNKI数据库和ASCO论文集等检索系统,以“结肿瘤、直肠肿瘤和化疗”为检索词,检索2005-01-2012-06的相关文献,共检索到英文文献303篇,中文文献78篇.文献纳入标准:1)结直肠肿瘤;2)药物治疗;3)大型的随机对照临床试验;4)排除单中心、小样本试验结果.根据纳入标准符合分析文献31篇.结果:CRC的辅助化疗、新辅助化疗、转移性CRC的化疗及靶向治疗方面均取得了显著进展.随着新一代化疗药物的出现,奥沙利铂、氟尿嘧啶、伊立替康、希罗达及分子靶向药物西妥昔单抗、贝伐单抗等组成的多种化疗方案使得CRC患者的生存期、无病生存期及缓解率得到了明显改善,毒副作用进一步降低.结论:CRC的化疗向着规范化及基于分子靶向的个体化治疗方向发展,终将使患者更好的临床获益.     

乳腺癌化疗耐药中肿瘤干细胞的作用及其机制

目的:了解肿瘤干细胞在乳腺癌化疗耐药中的作用及其相关机制的研究进展。方法:应用检索Pubmed及CNKI数据库检索系统,以肿瘤、干细胞、乳腺癌、化疗和耐药等为关键词,检索1999-01-2011-05的相关文献,纳入标准:肿瘤干细胞与乳腺癌化疗耐药。根据纳入标准分析42篇文献。结果:肿瘤干细胞是导致乳腺癌化疗耐药和治疗失败的主要细胞,其耐药的机制包括ATP结合盒转运子的过度表达、细胞解毒酶的过度活化、细胞存活和凋亡相关信号转导通路的异常激活、肿瘤壁龛对肿瘤干细胞的保护作用以及大部分肿瘤干细胞处于静止期。通过对这些耐药机制的干预,可以逆转肿瘤干细胞的耐药性。结论:肿瘤干细胞是导致乳腺癌化疗耐药的关键细胞,对其耐药机制的研究有助于展开针对肿瘤干细胞的靶向治疗,改善患者的预后。     

人端粒酶RNA基因与肿瘤的相关研究进展

目的:总结国内外关于人端粒酶RNA基因与肿瘤的相关研究进展.方法:应用Medline和CNKI期刊全文数据库检索系统,以"人端粒酶RNA基因"和"肿瘤"为关键词,检索1995-01-2008-12相关人端粒酶RNA基因的文献,其中英文文献326篇,中文文献4篇.纳入标准:1)人端粒酶RNA基因的结构和功能;2)人端粒酶RNA基因在恶性肿瘤中的扩增和表达情况;3)人端粒酶RNA基因与致肿瘤性作用;4)人端粒酶RNA基因与肿瘤的靶向治疗研究.根据纳入标准,精选80篇文献,最后纳入分析28篇文献.结果:人端粒酶RNA基因作为人端粒酶RNA组分的编码基因,在多种恶性肿瘤中有扩增及表达增加,且它的扩增和表达水平与肿瘤的诊断和预后是相关的.结论:深入研究人端粒酶RNA基因在恶性肿瘤中的扩增、表达及致肿瘤性作用,有助于进一步理解肿瘤的发生机制,有望在肿瘤的靶向治疗上取得新的突破.     

颅脑放疗引起认知功能障碍的研究现状

目的总结国内外对颅脑放射治疗引起认知功能障碍的研究现状。方法应用检索PubMed及CNKI期刊全文数据库检索系统,以＂颅脑放疗、放射性脑损伤、认知功能障碍＂等为关键词,检索2000-01-2013-12的相关文献,共检索到英文文献2 099条,中文文献557条。纳入标准：1）先初步阅读,文章内容提示有放射性脑损伤的研究报道。2）研究中有一定数量的样本。3）文章内容主要是以放射性脑损伤（包括认知功能障碍）的临床表现、检测或诊断方法以及治疗方式为主的。剔除标准：1）重复报告。2）会议摘要。3）经验总结文献。符合纳入标准的中文文献33条,英文文献195条,根据剔除标准剔除中文文献30条,英文文献170条,最后纳入分析28篇文献。结果随着放射治疗技术方法的不断更新,颅脑肿瘤放疗患者的疗效得到一定提高,但相应潜在的放射治疗晚期并发症日渐突出。患者在接受颅脑放疗的后期会出现认知功能障碍,这可以发生在相对低剂量的照射和没有放射影像或临床证据显示脱髓鞘或脑白质坏死的情况下,而目前还缺乏有效的检测方法。因此,对于放射性脑损伤研究的重点是在减少发生及尽早发现。非侵入性的技术,如MRI、PET、pMRI等的应用为及早发现和预测放射引起的认知功能障碍奠定了基础.在治疗上,虽然颅脑放疗引起的脑损伤,包括认知功能障碍的确切机制不明,但仍有潜在的治疗策略用以防止放射性脑损伤,如消炎药、皮质醇激素、神经干细胞移植和高压氧治疗等.结论虽然颅脑放疗引起认知功能障碍已在颅脑肿瘤治疗过程中得到重视,但还需要进一步的研究及早且安全检测和评估颅脑放疗引起认知功能障碍的方法。     

Cancer-related cognitive impairment: an update on state of the art,detection, and management strategies in cancer survivors

BackgroundAdvances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. However, cancer-related cognitive impairment (CRCI) is frequently reported in patients treated for non-central nervous system cancers, particularly during and after chemotherapy.DesignThis review provides an update of the state of the art based on PubMed searches between 2012 and March 2019 on ‘cognition’, ‘cancer’, ‘antineoplastic agents’ or ‘chemotherapy’. It includes the most recent clinical, imaging and pre-clinical data and reports management strategies of CRCI.ResultsEvidence obtained primarily from studies on breast cancer patients highlight memory, processing speed, attention and executive functions as the most cognitive domains impaired post-chemotherapy. Recent investigations established that other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits. Knowledge regarding predisposing factors, biological markers or brain functions associated with CRCI has improved. Factors such as age and genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF may predispose individuals to a higher risk of cognitive impairment. Poor performance on neuropsychological tests were associated with volume reduction in grey matter, less connectivity and activation after chemotherapy. In animals, hippocampus-based memory and executive functions, mediated by the frontal lobes, were shown to be particularly susceptible to the effects of chemotherapy. It involves altered neurogenesis, mitochondrial dysfunction or brain cytokine response. An important next step is to identify strategies for managing cognitive difficulties, with primary studies to assess cognitive training and physical exercise regimens.ConclusionsCRCI is not limited to chemotherapy. A multidisciplinary approach has improved our knowledge of the complex mechanisms involved. Nowadays, studies evaluating cognitive rehabilitation programmes are encouraged to help patients cope with cognitive difficulties and improve quality of life during and after cancer.     

A meta-analysis of the effects of chemotherapy on cognition in patients with cancer

Objective

The aim of this meta-analysis was to assess whether chemotherapy-related cognitive impairment is consistently observed in cancer patients and to identify the areas of cognition affected.

Methods

The meta-analysis included 13 studies and examined the effects of chemotherapy on seven different cognitive domains, across five cancer types. It was the intention of this meta-analysis to stringently exclude many studies, allowing for examination of cognition in carefully selected studies of chemotherapy recipients who do not have current mood or anxiety diagnoses (or psychiatric or substance abuse histories), without brain cancer and who have not had radiotherapy or hormone treatment. A moderator analysis examined whether patient age, treatment duration and time since treatment end significantly contributed to chemotherapy-related cognitive impairment.

Results

Evidence for the presence of cognitive impairment following cancer treatment was established for executive function and memory. No relationship was found between cognitive impairment and time since treatment cessation but a significant negative relationship was found for treatment duration. Age had no impact on treatment-related cognitive impairment.

Conclusions

Future research must be conducted on chemotherapy-related cognitive impairment in cancer types such as lymphoma and leukaemia, which have received a moderate amount of attention and colorectal cancer, which has received little attention. This would enable us to determine the extent to which chemotherapy-related cognitive impairment is a universal phenomenon associated with the cancer experience and its treatment regardless of cancer type.     

化疗相关性认知功能损害的研究进展

化疗相关性认知功能损害（chemotherapy-related cognitive impairment,CRCI）是指脑部无原发性或转移性肿瘤的癌症患者在接受化疗期间或化疗后出现的轻微认知功能下降。CRCI的研究开始于20世纪70年代,但直到20世纪90年代国际上才出现对CRCI的一致性重要认识。研究报道CRCI的发生率为16%-75%,症状持续数月到超过20年。目前,有三种方法可以评估认知功能,即神经心理学测验、神经影像学研究和主观评估,但缺乏金标准。CRCI的发生机制在很大程度上仍然是未知的;然而,一些可能的重要机制已经被确认,包括化疗药物的直接神经毒性、DNA损伤与氧化应激、细胞因子、压力与糖皮质激素、雌激素、癌症本身及海马神经发生等。迄今,CRCI缺乏特异、安全且有效的预防和治疗方法。因此,进一步研究CRCI的确切机制及预防或逆转措施至关重要。     

A Preliminary Study on the Relationship between Serum Heparan Sulfate and Cancer-Related Cognitive Impairment: The Moderating Role of Oxidative Stress in Patients with Colorectal Cancer

Cancer-related cognitive impairment (CRCI) has been frequently reported in colorectal cancer survivors. Heparan sulfate (HS) was gradually considered to be related to cognitive disorders. The effect and potential mechanism of HS on CRCI in colorectal cancer patients were unexplored. In this study, all participants were divided into a cognitive impaired group and a cognitive normal group. The concentrations of oxidative stress factors and HS in serum were detected. Associations among HS, oxidative stress factors and CRCI were evaluated. Participants with cognitive impairment exhibited increased levels of HS, GSH, SOD and MDA, compared to the patients with normal cognitive performance. The independent significant association was found between HS and CRCI after controlling for various covariates. The higher concentrations of HS were related to the decreased cognitive performance among survivors who reported higher levels of GSH (β = 0.080, p = 0.002). Moreover, the nonlinear association between the level of HS and cognitive scores was confirmed using the restricted cubic splines (p < 0.001). These results indicated that the increased concentrations of circulating HS had a nonlinear negative connection with cognitive performance in colorectal cancer survivors, which was moderated by GSH. HS might be a new biomolecule for the identification and management of patients with CRCI.     

Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study

Purpose

Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy.

Methods

This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates.

Results

A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1–6%; p = 0.009).

Conclusions

This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.

     

Objective and subjective cognitive impairment following chemotherapy for cancer: A systematic review

Evidence suggests that some cancer survivors experience cognitive difficulties following chemotherapy. However, perceived or subjective cognitive impairment is more frequently reported than prevalence revealed by objective assessments. The aim of this review was to examine the relationship between subjective and objective measures of cognitive impairment following treatment for cancer and to determine the number of studies that found a significant relationship between these measures of cognition. A comprehensive search for articles, published between 1980 and 2012, comparing subjective and objective cognition in cancer patients treated with chemotherapy was conducted. Of 818 potentially relevant articles, 23 studies met the inclusion criteria for the current review and one article was sourced from reference lists of included studies. Only eight of 24 included studies found a significant relationship between objective and subjective measures of cognitive performance. These studies were more likely to involve breast cancer patients and to assess the relationship between memory and perceived cognitive impairment. The failure to consistently find an association between subjective and objective measures of cognition could be explained by variations in assessment methods or the definition of impairment. Alternatively, objective and perceived cognitive impairment may be unrelated because perceived impairment may be an indicator of psychological distress rather than cognitive impairment. Despite these discrepancies, patients' perceptions of impairment are important due to its significant impact on quality of life. Further research is required to explore whether objective measures of everyday functioning better predict the impact of chemotherapy related cognitive impairment on daily functioning.     

重组腺病毒p53基因治疗肝癌研究进展

目的：探讨重组腺病毒p53基因（recombinant humanAd—p53,rAd—p53）治疗肝癌的抗肿瘤机制及临床应用。方法：应用PubMed、万方和CNKI数据库,以“肝癌、重组腺病毒p53基因、基因治疗、实验研究和临床应用”为关键词,检索1994—06—01—2013—11—31文献739篇,纳入标准：1）p53基因与肝癌发生的相关性;2）重组腺病毒p53基因抗肿瘤机制;3）重组腺病毒p53治疗肝癌的实验研究;4）重组腺病毒p53治疗肝癌的临床应用研究。根据纳入标准选择符合分析的文献36篇。结果：p53基因是公认的肿瘤抑制基因,具有促使肿瘤细胞自杀和帮助缺陷细胞修复的作用。rAd—p53是复制缺陷型5型腺病毒载体与人p53基因重组的肿瘤基因治疗制品。rAd-p53通过多种途径发挥抗肿瘤作用,包括使肿瘤的细胞周期阻滞和发生程序性死亡,促进放射线对肿瘤细胞引起的细胞周期阻滞和凋亡,刺激机体产生抗肿瘤免疫反应,抑制肿瘤血管内皮生长因子,控制肿瘤的血管生成,使注射部位瘤组织产生局部血供障碍和坏死。此外,还能增加肝癌细胞的放化疗敏感性,间接增强抗肿瘤疗效。rAd-p53基因疗法为肝癌治疗开辟了崭新的途径,多项-l盘床研究疗效良好。结论：rAd—p53基因对肿瘤的作用机制体现了在抗肿瘤治疗方面的有效性,并在基础研究及临床应用中均取得了显著进展,再肝癌的防治中将取得更大的突破。