3-60 RNA Splicing: A New Player in the Carbon Ion Irradiation -Induced Cell Death

Recently, RNA processing has emerged as a novel pathway that may contribute to the maintenance of genome stability[1]. Alternative splicing is a key molecular mechanism for increasing the functional diversity of the eukaryotic proteomes, but it also often altered in cancer. Mounting evidence indicates that alternative splicing, the process that allows production of multiple mRNA variants from each gene, contributes to the heterogeneity of the disease[2]. Although the mechanism of alternative splicing variant in cancer is unclear, the cancer-specific alternative splicing variants have been observed in a variety of human cancers and cancer cell lines and have been connected to tumorgenesis.

3-57 Protective Effect of Diallyl Disulfide on Carbon Ion Irradiation-induced Cell Death in Mouse Testis via p73 Signaling Pathway, But Not p53

Diallyl Disulfide (DADS) is the main organosulfur component of garlic and it is known for multiple pharmacologicalactions. Currently, DADS has been well documented to ameliorate the testis injuries caused by X-rayirradiation[1??4]. However, the effect of DADS against heavy-ion-induced testis damage, particularly cell apoptosis,is still largely unknown. In this regard, based on ground experiments at accelerators, this study has been undertakento estimate the protective mechanisms of DADS against carbon ion-induced cell apoptosis at the level ofsignal transduction pathway in mouse testis.

3-62 Impact of Carbon Ion Irradiation on Spermatogenic Cells Apoptosis in Pubertal Mice*

There has been a considerable improvement in men of child-bearing age undergoing radiotherapy which oftenconcerned about the possibility of future children[1]. In this investigation, we used TUNEL assay to analyzespermatogenic cells apoptosis in pubertal mice testes after carbon ion irradiation (CIR) that evaluate the impactof CIR on spermatogenesis in pubertal mice.The 4 weeks of Swiss-Webster mice were whole-body irradiated with 0, 1 and 4 Gy, respectively. Testes werecollected 14 d after irradiation. The histological changes in testicular tissue were observed and the apoptotictesticular cells were examined. The Johnsen score reflected the quantitative assessment of seminiferous tubules(Fig. 1(d)). Significant damage to the seminiferous tubule was observed in the irradiated groups (P < 0:001).Quantitative analysis of spermatogenic cells apoptosis is shown in Fig. 1(h). A significant increase in TUNELpositivecells was found in the seminiferous tubule in the irradiated groups (P <0:001). Our results showed TUNELpositivespermatogenic cells were mainly spermatogonia, spermatocytes, early spermatids and late spermatids, andthese cells seemed to be initially more susceptible to CIR toxicity.

3-70 Capsazepine, a TRPV1 Antagonist, Enhances Radiation Sensitivity in Human Hepatocellular Carcinoma HepG2 Cells

Transient receptor potential vanilloid 1(TRPVl) that is known as capsaicin receptor is a non-selective cationion channel[1]. TRPV1 can regulate Ca2+ influx, participate in a variety of physiological and pathological processof tumor[2]. One such agent is Capsazepine (CPZ) that is now widely used as a selective vanilloid type 1 receptor(TRPV1) antagonist. CPZ can be directly actived on the capsaicin receptor, blocked its biological effects, and abolishedosteosarcoma-induced hyperalgesia when administered subcutaneously at doses ranging from 3 to 10 mg/kg,blocked calcium channels[3]. However, the mechanisms underlying the anticancer effects of CPZ have not fully beenunderstood. Whether CPZ can induce apoptosis of human hepatocellular carcinoma cell line HepG2 is not known.Therefore, the objective of the study reported here was to determine whether CPZ can enhance radiation sensitivityin HepG2 cell, and impact on cell proliferation.

3-69 Effects of Carbon-ion Beam Irradiation on MSH2 Expression in HepG2 Cells

Primary liver cancer (namely hepatocellular carcinoma, HCC) represents the third most frequent cause of cancerdeath. National Comprehensive Cancer Network guidelines suggest that radiotherapy (RT) can be considered asan important role for unresectable HCC[1]. Heavy ion radiotherapy (e.g. carbon ion) has showed a strong role forkilling malignancies especially for radioresistant malignancies that are insensitive to conventional radiotherapy, suchas X-ray.The mismatch repair (MMR) is a highly conserved DNA repair pathway that recognizes and repairs base-pairingerrors during DNA replication or recombination. When the genes (mainly including MutS and MutL families) thatmediate MMR are mutated or epigenetically silenced, the predisposition to cancer is significantly increased. MMRdeficiency can be inherited, as in the case of Lynch syndrome also known as hereditary non-polyposis colorectalcarcinoma (HNPCC). MSH2 protein also can modulate the homologous recombination that is a prominent doublestrandbreak (DSB) repair pathway.

Molecular Mechanism of SF3b1 in Carbon Ion Irradiation-Induced A poptosis in Cancer Cells

Charged particle radiation may exert highly lethal effects even on radioresistant tumors[1].Although extensive researches are studying the carcinogenesis and carbon ion beam therapy,there is still space to improve the radiosensitivity to cervical cancer in order to reduce radiation dosage.

4-64 Selective ATP Hydrolysis Inhibition in F1Fo ATP Synthase Enhances Radiosensitivity of Non-small-cell Lung Cancer Cells(A549)

F1Fo ATP synthase,or named ATPase(EC 3.6.1.3)(referred as the same enzyme hereafter)catalyzes the phosphorylation of ADP to ATP by exploiting a the transmembrane proton motive force(Δp)produced by the oxidation of nutrient substrates in mitochondrial respiration in all organisms.However,under peculiar physiological conditions when mitochondrial respiration is impaired which lead to the electrochemical gradient across the inner membrane collapse,the F1Fo ATP synthase switches its catalytic activity from ATP synthesis to ATP hydrolysis for maintaining theΔp.

4-58 Role of Diallyl Disul de in Carbon Ion Beams{induced Cancer Cell Apoptosis

Cervical cancer represents the third most common cause of female mortality[1].Radiotherapy remains the mainstay of treatment,especially in advanced cervical cancer.The patients’survival rate can be determined by their responsiveness to radiotherapeutic treatment[2-4].Although conventional X-ray treatment is an effective modality for a wide variety of human cancers,poor results may sometimes occur.High linear energy transfer(LET)charged particle radiation has several potential advantages over the treatment with low-LET radiation,such as an inverted depth–dose distribution,a higher relative biological effectiveness,a reduction in oxygen enhancement ratio,and a lower cellular capability for repair of radiation injury,making it potentially superior to low-LET radiation,such as X-rays,in the treatment of malignant solid tumors.

外泌体在肿瘤细胞及其临床应用中的研究进展

外泌体是直径为40~130 nm的纳米级囊泡结构,是一类重要的细胞间通信分子,含有大量的蛋白质、核酸和脂质物质。外泌体不仅对肿瘤免疫、肿瘤侵袭与转移及肿瘤耐药方面有关键的调节作用,在肿瘤的诊断与治疗方面也具有重要价值。本文介绍了外泌体的定义、发生和形成过程。此外,详细总结了外泌体的提取方法。最后,深入的讨论了外泌体在载药、放疗、化疗和耐药中的临床应用,旨在为外泌体的分子机理和临床研究提供新思路。

PCBP1在肿瘤中的作用及研究进展

多聚结合蛋白1[poly(rC)-binding protein 1,PCBP1]是RNA结合蛋白家族的成员之一,它广泛表达于各种人体正常组织中,并在多种生物学过程中发挥重要的作用,比如从不同水平调控基因表达、病毒的复制、铁离子转运等。同时,PCBP1作为一种潜在的肿瘤抑制因子,参与多种肿瘤的发生、发展、转移等过程,这为理解肿瘤发生的机制提供了新思路。在本篇综述中,我们简单介绍了PCBP1的结构和功能,并从肿瘤发生发展、侵袭或转移、肿瘤干细胞及肿瘤化疗等方面着重讨论了它在多种肿瘤疾病中可能的作用机制,旨在为临床治疗肿瘤提供一种可靠的靶标基因。

三阴性乳腺癌中p53蛋白表达的Meta分析

目的:评价三阴性乳腺癌与p53蛋白表达的相关性,为提高三阴性乳腺癌个体化治疗提供参考。方法:通过PubMed、Web of Science、CNKI、WanFang data、VIP数据库检索相关文献,检索时间为2005年至2020年。由两位研究者按照文献的纳入与排除标准进行文献筛选、资料提取、质量评价,最后采用RevMan 5.3软件进行Meta分析。结果:纳入文献36篇,其中中文文献29篇,英文文献7篇。结果显示:三阴性乳腺癌组p53的阳性表达率高于非三阴性乳腺癌组[OR=2.29,95%CI(2.06,2.55)],p53阳性组的淋巴转移率高于p53阴性组[OR=1.96,95%CI(1.20,3.18)],差异具有统计学意义;而p53的阳性表达与三阴性乳腺癌的TNM分期无关[OR=0.49,95%CI(0.08,2.90)],差异没有统计学意义;三阴性乳腺癌p53阳性组的总生存率低于p53阴性组[OR=0.36,95%CI(0.23,0.56)],差异具有统计学意义;三阴性乳腺癌p53阳性组的无病生存率低于p53阴性组[OR=0.32,95%CI(0.23,0.45)],差异具有统计学意义;三阴性乳腺癌患者的年龄与p53的阳性表达没有相关性[OR=1.17,95%CI(0.83,1.65)],差异没有统计学意义。结论:p53的表达与三阴性乳腺癌的发生、发展及预后密切相关,并且可能成为预测三阴性乳腺癌发生发展的独立因子。

外泌体作为药物载体的临床应用研究

Exosomes denote a family of nano-sized membrane extracellular vesicles with a diameter in the range of 40-130 nm that are secreted by most cell types of the body[1].Initial studies suggest that this extracellular vesicle is a metabolic waste that cells secrete.However,more and more studies have shown that exosomes act as mediators of cell-to-cell signaling and participate in a variety of physiological and pathological activities in organisms[2].Due to such characteristics,analyzing the specific biomarkers[3]carried therein is expected to be a non-invasive method for diagnosis and monitoring of tumors.Additionally,exosomes are not only important for tumor immunity,tumor invasion,metastasis and tumor resistance,but also has important value in the diagnosis and treatment of tumor.Exosomes can exert important effects in various disease models[4].Overall studies give an idea that exosomes play both cancer-promoting and malignant functions in malignant tumors[5].

二烯丙基二硫协同重离子诱导的癌细胞内源性和外源性凋亡

Charged particle radiation may exert highly lethal effects even on radioresistant tumors.Although extensive researches are studying the carcinogenesis and carbon ion beam therapy,there is still space to improve the radiosensitivity to cervical cancer in order to reduce radiation dosage.The combination of particle therapy with drug is now rapidly gaining practice in clinics with great expectations for cancer cure[1􀀀3].Thus,strategies to minimize the side effects of radiotherapy while preserving their radiotherapeutic efficacy are needed.Recently,significant attention has been focused on natural radio protective agent in vegetables and fruits.DADS,a major organosulfur compound derived from garlic,induces cell death in various cancer cells but shows little or no cytotoxicity in normal cells as single drugs.Therapeutic approaches based on the combination of high-LET carbon beams and DADS aim at increasing clinical responses while lowering the radiation dosages and cancer cell resistance.The advantage of combination stems from the fact that each one can have a single target or mechanism of action or this combination may share the same target or mechanism of action against cancer cells.Therefore,in this study,we clarify the effect of DADS on the radiation-regulated cell apoptosis,as well as alterations of crucial mediator of the apoptosis pathway in HeLa cells.

二烯丙基二硫促进重离子诱导的癌细胞凋亡

Recently,significant attention has been focused on natural radiosensitive agent in vegetables and fruits[1].Diallyl disulfide(DADS;i.e,CH2=CH-CH2-S-S-CH2-CH=CH2),an oil-soluble compound extracted from garlic(Allium sativum L.)documents as a potent compound to prevent cancer,genotoxicity,nephrotoxicity,and hepatotoxicity[2].Although DADS has been reported to provide the anticancer activity in several cancer types by inhibiting cell cycle arrest and inducing apoptosis,the molecular effect of DADS on high-LET carbon beams-regulated proliferation,cell cycle arrest and cell death is currently unknown。

二烯丙基二硫辐射保护的分子机理研究

High-linear energy transfer(LET)heavy ions produce more cytotoxic and genotoxic damage to cells in comparison with low-LET ionizing irradiation,such as X-rays or-rays[1].Our previous studies demonstrated that exposure to heavy ions such as carbon ions caused decrease in testicular weight and sthenospermia,which affects the testicular development and breeding activity of males.The reason is that the organ systems with proliferating cells are very sensitive,and the testis is a radiosensitive organ.Additionally,in space travel,astronaut exposed to high-LET galactic cosmanic rays at higher radiation doses and dose rates than humans received on Earth.It is an unavoidable problem for long duration manned interplanetary missions.Furthermore,in hadrontherapy,although high-LET heavy ions as an innovative modality of high precision tool for the treatment of cancer such as testis and prostate tumor,potential damage to healthy tissues surrounding the tumor target along its penetrating path should still be considered.Given space radiation protection and cancer therapy,there is a demand for reliable agent for protection of the testis against heavy-ion radiation.

重离子辐射诱导癌细胞非p53依赖的凋亡机制研究

Radiotherapy is widely used for the definitive and adjuvant treatment of numerous cancers[1].However,resistance to radiotherapy remains an important concern[2].Various factors including p53 mutation or deletion[3],overexpression of DNA repair proteins[4],and tumor microenvironment[5]have been proposed to play roles in radioresistance.Among the radioresistant factors,p53 mutation or deletion is regarded as a good candidate for radioresistant markers[6].The tumor suppressor p53 is well established as the guardian of the genome,regulating cell cycle arrest,DNA repair,senescence,and apoptosis[7].Mutation of p53 occurs in more than 50%of human cancers,which significantly increases cellular resistance to-irradiation[8].Additionally,there is growing evidence that mutation or deletion of p53 tumors cells is inherently resistant to radiation and perhaps other conventional anticancer treatments,i.e.,chemotherapy[9].This intrinsic mechanism of resistance is responsible for a significant number of tumor recurrences[10].