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.     

Comprehensive analysis of the relationship between competitive endogenous RNA (ceRNA) networks and tumor infiltrating-cells in hepatocellular carcinoma

BackgroundThe innovation of immune checkpoint blockade (ICB) represents a promising shift in the treatment of advanced hepatocellular carcinoma (HCC). However, response to ICB has varied largely due to the high tumor heterogeneity and complex tumor microenvironment (TME). The competitive endogenous RNA (ceRNA) network also plays an important role in tumor occurrence and progression, but its relation with tumor-infiltrating immune cells (TICs) remains largely unexplored in HCC. The overriding objective of our study was thus to construct a prognosis-related risk model and to further evaluate the relationship between ceRNA networks and TICs.MethodsDifferentially expressed gene (DEG) analysis was performed to identify the differentially expressed RNAs. Lasso and multivariable Cox regression analyses were used to construct risk models, which were assessed by the area under the receiver operating characteristic curve (AUC of ROC) and Kaplan-Meier (K-M) curves. Then, a single-sample gene set enrichment analysis (ssGSEA) algorithm was adopted to dissect the TICs in HCC samples. Nomograms were constructed and calibration curves were used to verify the discrimination and accuracy of the nomograms. Finally, integration analysis was performed to validate the correlation of ceRNA and TICs.ResultsIn the study, 7 differentially expressed RNAs [5 messenger RNA s (mRNAs) and 2 micro RNAs (miRNAs)] were incorporated to construct a ceRNA risk model. The AUC of the 1-, 3-, and 5-year overall survival (OS) were 0.784, 0.685, and 0.691 respectively. Likewise, 7 types TICs were in the TICs signature model and the AUC of the 1-, 3-, and 5-year OS were 0.706, 0.731, and 0.721 respectively. The integration analysis showed that 7 pairs of mRNA-TICs and 1 pair of miRNA-TICs had a close relation (all correlation coefficients >0.2, P<0.001).ConclusionsThrough constructing two risk models based on ceRNA network and TICs, we identified the hub RNAs and key TICs in the progression and prognosis of HCC, and further explored the relationship between ceRNA and TME. Importantly, targeting these hub RNAs may facilitate the remodeling of the TME and be a potential therapeutic alternative to enhancing the response to ICB, thus improving the prognosis of HCC patients.     

Protective role of histone deacetylase 4 from ultraviolet radiation-induced DNA lesions

Ultraviolet B (UVB) exposure is a core factor that leads to skin disease or carcinogenesis through the insufficient repair of DNA lesions. UVB-induced DNA lesions are mainly removed by the nucleotide excision repair (NER) mechanism. The expression of histone deacetylase 4 (HDAC4) is altered in the skin upon UVB exposure, indicating its possible implication in UVB-induced DNA lesions repair. Here, we investigated the role of HDAC4 in the NER removal of the main classes of UVB-induced DNA lesions consisting of cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). We found that UVB irradiation increased HDAC4 expression at both the mRNA and protein levels. HDAC4 interacted with NER factor XPC, which played an important role in effectively removing the UVB-induced DNA lesions. This study provides an understanding of the HDAC4 function in DNA repair, which will allow the development of efficient strategies to protect the skin from UVR-induced diseases.     

如何根据特异性IgM和IgG评价新型冠状病毒宫内垂直传播

新型冠状病毒能否通过宫内垂直传播感染胎儿是关注的焦点,而如何正确评价新型冠状病毒是否存在宫内垂直传播,更是问题的关键所在。病毒学和血清学证据对诊断病毒宫内垂直传播都有价值。单纯将血清学结果用于确定新型冠状病毒宫内传播时,应至少对新生儿随访3~6个月,动态观察IgM和IgG滴度变化,同时随访其母亲,与母亲特异性抗体的滴度进行比较。     

汽车制造工人颈部职业性肌肉骨骼疾患及危险因素探讨

目的调查汽车制造工人职业性肌肉骨骼疾患(WMSDs)发病情况，探讨其颈部WMSDs的危险因素。方法采用整群抽样方法，选择广州市1家汽车整车及1家零部件生产企业共8356名作业人员为研究对象，采用《北欧肌肉骨骼疾患问卷(修改版)》(NMQ)调查WMSDs患病情况，多因素Logistic回归分析颈部WMSDs影响因素，并对危险因素接触情况进行调査分析。结果研究对象WMSDs年患病率为44.6%，其中颈部WMSDs患病率为25.4%(2126/8356)，以发动机生产及总装岗位作业工人的颈部WMSDs较高，年患病率分别为30.6%、26.3%。多因素Logistic回归分析结果显示，颈部WMSDs的主要危险因素包括年龄、工龄、以不舒服的姿势工作、每天从事同样的工作、涉及到寒冷凉风或气温变化、经常加班、腰背部经常重复同一动作、颈部前倾或后仰、颈部长时间保持同一姿势。调查发现，84.9%的研究对象每天从事同样的工作，总装岗位最高(89.0%)；83.5%的作业工人经常加班；81.6%的作业工人工作中颈部前倾或后仰，以发动机生产岗位最为突出(87.5%)。结论汽车制造作业人员WMSDs患病率较高，尤以颈部最为常见，其危险因素主要包括不良工作姿势及不合理的劳动组织，发动机生产及总装岗位是颈部WMSDs的重点风险岗位，应开展有效的工效学干预措施。     

临床医学专业“5+3”一体化本科全程导师制创新人才培养的实践与探索

以培养创新型人才为目标，大连医科大学制定实施了“5+3”创新人才培养改革方案，以导师制培养为载体，在医学本科教育全过程中，制定分阶段创新能力培养体系，涵盖课程、讲座、实验设计、论文等基本科研能力训练，强化本科生科研能力培养。通过对首届“5+3”学生阶段性培养成果的统计学分析发现，“5+3”学生发表中文期刊、SCI，主持国家级创新项目、省级创新项目的比例均显著高于普通5年制学生，差异具有统计学意义（P<0.05）。虽然实施过程中存在一些问题和不足，但以导师制为核心的科研基础训练对提高学生科研思维和创新能力效果显著，对培养医学创新型人才具有可实施性。     

TAS-102 has a tumoricidal activity in multiple myeloma

TAS-102/Lonsurf is a new oral anti-tumor drug consisting of trifluridine and tipiracil in a 1:0.5 molar ratio. Lonsurf has been approved globally, including US, Europe Union, and China, to treat patients with advanced colorectal cancer. Ongoing clinical trials are currently conducted for the treatment of other solid cancers. However, the therapeutic potential of TAS-102 in hematological malignancies has not been explored. In this study, we investigate the therapeutic efficacy of TAS-102 in multiple myeloma both in vitro and in vivo. We demonstrate that TAS-102 treatment inhibits tumor cell proliferation in six human myeloma cell lines with IC₅₀ values in a range from 0.64 to 9.10 μM. Dot blotting and immunofluorescent staining show that trifluridine is predominately incorporated into genomic DNAs of myeloma cells. TAS-102 treatment induces myeloma cell apoptosis through cell cycle arrest in G1 phase and activation of cGAS-STING signaling in myeloma cells. In the human myeloma xenograft models, TAS-102 treatment reduces tumor progression and prolongs mouse survival. TAS-102 has shown its efficacies in the drug-resistant myeloma cells, and the combination of TAS-102 and bortezomib has a synergistic anti-myeloma activity. Our preclinical studies indicate that TAS-102 is a potential novel agent for myeloma therapy.