BackgroundChemoradiotherapy is the major means in the treatment of gliomas followed by surgery. Ferroptosis has been shown to play an important role in carcinogenesis by many studies. However, its underlying effect on chemoradiotherapy sensitivity in gliomas remains unclear.MethodsThe genetic and clinical information and ferroptosis-related genes were downloaded from The Cancer Genome Atlas (TCGA) database. Gene Expression Profiling Interactive Analysis (GEPIA) was used to perform hub gene expression and survival analysis. Cell Counting Kit 8 (CCK-8), colony formation, 5-Ethynyl-2 '-Deoxyuridine (EdU), Transwell and chemoradiotherapy sensitivity experiments were performed to confirm the biological function of RGS4 in glioma cells. The molecular mechanism of RGS4 on ferroptosis in gliomas was explored in vitro.Results385 ferroptosis-related genes were identified via bioinformatics analysis. 16 differential expressed genes (DEGs) were identified as radiation-related genes. Among them, RGS4, HSPA5, and SLC40A1 had prognostic values in further analysis. The calculated risk score could significantly distinguish the high-risk population. Moreover, RGS4 expression was closely related with immune infiltration and regulators. RGS4 knockdown could inhibit the proliferation and migration of glioma cells. Down-regulation of RGS4 expression induced ferroptosis to promote cancer sensitivity to chemoradiotherapy.ConclusionsA three-gene signature was developed in a risk-score model, which could be used to predict the prognosis of glioma patients. RGS4 is dysregulated in many types of cancers, and is a candidate prognostic biomarker for many types of cancers. Moreover, RGS4 may be a target for predicting and enhancing the chemoradiotherapy sensitivity of gliomas.

Regulatory B (Breg) cells is a type of immune cell that exhibit immunosuppressive behavior within the tumor microenvironment. However, the differentiation and regulatory mechanisms of these Breg cells remain unexplored. Single-cell transcriptome sequencing analysis of human nasopharyngeal carcinoma (NPC) revealed a significant enrichment of B cell subset characterized by high expression of EGR1 and EGR3 in the tumor microenvironment. Notably, in the hypoxic microenvironment, these B cells induce MAPK pathway activation, subsequently triggering the activation of transcription factors EGR1 and EGR3, which further modulate the expression of immunosuppressive factors like TGFB1 and IL10. In transplant experiments using primary B cells induced under hypoxia and co-transplanted with cancer cells, a significant increase in tumor growth was observed. Mechanism experiments demonstrated that EGR1hi and EGR3+ B cells further activate the maturation and immunosuppressive function of Treg cells through the secretion of IL16 and TNF-α. Hence, this study identifies the key transcription factors EGR1 and EGR3 as essential regulators and elucidates the differentiation of Breg cells under hypoxic conditions.

Abstract Temozolomide is a major chemotherapeutic agent in the clinical treatment of gliomas. Unfortunately, patients usually develop drug resistance. Pyroptosis is recently considered as a new type of programmed cell death, however, the effect and mechanism of the pyroptosis pathway in glioma are unclarified. Gene expression profiles were obtained from the public databases. A total of 37 differentially expressed genes related to pyroptosis were identified, and the molecular subgroups were prognostically different. A risk-score model of 11 pyroptosis-related genes was constructed and effectively classified glioma patients into high- and low-risk groups, which were significantly distinct in prognosis and immune cell infiltration. PRKACA was differentially expressed in 20 of 33 cancer types. The expression was also associated with tumor stage and prognosis. In addition, PRKACA was active and correlated with immune markers. Experimentally, PRKACA knockdown inhibited the malignant phenotypes and induced pyroptosis, as well as sensitized glioma cells to TMZ. In conclusions, a risk-score model was constructed to perform risk classification and prognostic prediction for glioma patients. Moreover, PAKACA was identified as a promising therapeutic candidate for treating patients who are resistant or less responsive to TMZ.

Radiotherapy is a primary treatment for cancer but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating evidence suggests that deubiquitinases (DUBs) play a crucial role in regulating cell sensitivity to ionizing radiation. Traditional small-molecule DUB inhibitors have demonstrated radiosensitization effects, and novel deubiquitinase-targeting chimeras (DUBTACs) provide a promising strategy for radiosensitizer development by harnessing the ubiquitin-proteasome system (UPS). This review highlights the mechanisms by which DUBs regulate radiosensitivity, including DNA damage repair (DDR), cell cycle, cell death, and hypoxia. Progress on DUB inhibitors and DUBTACs is summarized, and their potential radiosensitization effects are discussed. Developing drugs targeting DUBs and further research on their mechanisms will be an alternative approach to overcoming radioresistance.

目的 探讨偏侧鼻咽癌调强放疗原发灶临床靶区(CTV)的个体化优化方案的可行性.方法 回顾性分析2016年10月至2018年2月于江苏省肿瘤医院连续收治的偏侧鼻咽癌初诊患者87例.偏侧鼻咽癌定义为肿瘤浸润不超过健侧侧壁.根据鼻咽肿瘤侵犯趋势,对原发灶CTV进行如下优化:CTV2健侧包及翼腭窝根部,不包及健侧卵圆孔,咽旁间隙水平健侧仅充分包及咽后外侧淋巴结,健侧颈内静脉不常规包及.评估失败模式和5年生存率[局部控制率(LCR)、无进展生存(PFS)、总生存(OS)],采用Kaplan-Meier法计算;配对t检验和秩和检验法分析优化区域剂量变化及不良反应.结果 全组中位随访59.5个月,5年LCR、PFS、OS分别为98.9％、86.5％、92.1％.CTV优化区域内无1例局部复发.健侧风险结构的优化使腮腺、颞叶、耳蜗、中耳剂量分别降低了 13.45％、9.14％、38.83％、29.36％.观察到4例(4.6％)3级晚期听力损伤,均位于患侧.对比患侧,优化方案明显减轻了健侧的听力损伤(P＜0.001).其他3级晚期不良反应包括颅神经损伤、颈部皮下纤维化、视力损伤,各1例.结论 偏侧鼻咽癌原发灶CTV采取个体化优化方案是安全的,剂量学优势明显,不良反应发生率低,值得临床推广.

AIM:Cervical cancer is one of the most aggressive female cancers. RNA methylation is a necessary epigenetic modification in biological process. This study aimed to construct an RNA methylation regulator-based risk model for predicting the prognosis of cervical cancer patients.METHODS:The transcriptome profiles of cervical cancer data were obtained from The Cancer Genome Atlas (TCGA) and GSE44001. An RNA methylation-related risk model was constructed and assessed by the Least absolute shrinkage and selection operator (Lasso)-penalized Cox regression model and receiver operating characteristic (ROC). Kaplan-Meier and Cox regression analyses were used to evaluate the prognostic effect of the risk model and calculated scores. The immune infiltration difference was further analyzed between the subgroups with a single-sample gene set enrichment analysis (ssGSEA).RESULTS:A total of 63 methylation modulators were included in this study, and 618 cervical cancer patients were identified from TCGA and GSE44001. Differential expression genes profiling RNA methylation regulators between normal and tumor samples were distinct. A four-gene signature panel was constructed to predict the prognostic risk. The predictive ability was satisfactory. Cervical cancer patients were classified into high- or low-risk subgroups according to the median risk score. Moreover, the immune infiltration patterns between them differed.CONCLUSIONS:A risk model including four RNA methylation regulators was constructed, which will provide new perspectives for further investigation of the relationship between RNA methylation and cervical cancer.

Objective:To determine the safety of prophylactic irradiation dose CTV 60Gy optimized to CTV 50Gy for II b region in patients with stage N 0-N 1 nasopharyngeal carcinoma (NPC) and the dose advantage and clinical value for parotid gland protection, and to understand the diagnostic value of PET-CT and diffusion-weighted imaging (DWI) for suspicious positive lymph nodes in the neck (5 mm≤maximum short diameter<10 mm). Methods:Clinical data of 157 patients with primary non-metastatic NPC (N 0-N 1) admitted to our hospital from June 2015 to March 2017 were retrospectively analyzed. 104 patients underwent II b clinical target volume optimization guided by multimodal imaging system. Survival analysis was performed by Kaplan - Meier method. Univariate/multivariate regression analysis was performed to analyze the pattern of cervical lymph node recurrence. Paired t-test was used to compare the differences in target volume and parotid gland dose parameters before and after dose optimization. Results:Sixty patients underwent single-neck optimization in stage N 1, 25 patients received double-neck optimization (only those with retropharyngeal lymph node metastasis), and 19 patients underwent double-neck optimization in stage N 0. Three patients had cervical regional recurrence, all in-field. The 5-year overall survival rate was 93.3%. The lymph node recurrence-free survival rate, local recurrence-free survival rate, distant metastasis-free survival rate and disease-free survival rate were 97.1%, 91.3%, 88.5% and 80.8%, respectively. Cervical lymph node recurrence was associated with local recurrence in the nasopharynx, regardless of retropharyngeal lymph node status. Fourteen patients had suspicious positive cervical lymph nodes in II b region, with a mean maximum short diameter of 7.1 (5~9) mm on the largest cross-sectional plane, and 11 of them were positive on PET-CT, with a mean SUV max of 2.96 (2.5~3.3). There was no significant difference in GTV after optimization ( P>0.05). D mean, D max, D 50% and V 26Gy of parotid gland were significantly lower than those of conventional plan (all P<0.01). Conclusions:It is safe to optimize CTV 60Gy to CTV 50Gy in II b region in patients with N 0-N 1 NPC, and the exposure dose to normal tissues around the parotid gland and neck is significantly reduced. For small lymph nodes that do not meet the diagnostic criteria, it needs to be individualized in combination with multimodality imaging systems, such as PET-CT and DWI.

[目的]探讨鼻咽癌N2期患者行Ⅳ区靶区范围缩减的可行性以及对甲状腺保护的剂量优势.[方法]选取2015年3月至2017年4月收治的目前仍生存的鼻咽癌N2患者40例作为研究对象,其中根据甲状腺周围颈动脉鞘淋巴结分布以及Ⅲ区淋巴结状态进行Ⅳ区靶区内界和/或下界优化的34例患者纳入优化组.收集全部患者的一般临床特征、影像学资料、甲状腺功能资料及放疗剂量参数,分析靶区范围优化对甲状腺功能的影响.[结果] 40例患者中位随访时间为63个月,放疗后甲状腺功能减退(简称甲减)发生率为45.0％(18/40),其中亚临床型甲减15例(37.5％),临床型甲减3例(7.5％),出现时间为放疗后4～48个月(中位时间13个月);优化组甲减发生率为35.3％(12/34),均为亚临床型甲减.仅有2例(5.0％)患者甲状腺周围颈动脉鞘前方有可辨认淋巴结;分别有29例(72.5％)及38例(95.0％)患者颈动脉鞘后方及外方有可辨认淋巴结,颈动脉鞘后方、外方最内侧淋巴结距甲状腺外侧缘的中位距离分别为9.5(5～21) mm、18(10～34)mm;优化组甲状腺Dmean及V30均低于非优化组,Ⅳ区内界及下界均优化患者与未优化组患者的Dmean及V30有显著性差异(P＜0.01),全部病例均未出现颈部淋巴结复发.[结论]对鼻咽癌晚N分期患者进行合理优化颈部Ⅳ区临床靶区范围,在无淋巴结分布区域免除照射是安全可行的,可以更好地保护甲状腺功能.