SIRPA delivers an anti-phagocytic “don’t-eat-me” signal through its expression on macrophage membrane surface and promotes tumor progression via membrane-independent mechanism. However, current CD47- and SIRPA-targeting agents only disrupt cell-surface inhibitory signaling, highlighting the therapeutic potential of degrading SIRPA. Here, we identified that E3 ubiquitin ligase TRIM2 interacted with SIRPA in vitro. Clinically, elevated TRIM2 expression is associated with prolonged overall and progression-free survival in renal-cell carcinoma (RCC) patients. Mechanistically, TRIM2 catalyzes K48-linked poly-ubiquitination of SIRPA, promoting its proteasomal degradation and reducing SIRPA protein levels. CRISPR/Cas9-mediated deletion of TRIM2 in macrophages upregulated SIRPA, significantly impairing phagocytosis of tumor cells. TRIM2 deficiency also promoted tumor growth by increasing intratumoral infiltration of M2-type macrophage, reducing accumulation of anti-tumor M1-like and antigen-presenting macrophages, and impairing effector CD8 + T-cell recruitment. Importantly, combined TRIM2 overexpression and PD-L1 blockade synergistically enhance anti-tumor immunity. Together, these results suggest that targeting TRIM2 may represent a novel therapeutic strategy against RCC by degrading SIRPA in macrophage and provide a roadmap for clinical application.

e15004 Background: ZV0203, a first in class (FIC) pertuzumab antibody-drug conjugate (ADC), targets HER2 positive tumor cells with tubulin inhibitor DUO5 as its payload via a stable and protease-cleavable valine-citrulline linker. In preclinical studies, ZV0203 demonstrated superior antitumor activity compared to Kadcyla in multiple tumor cell line xenograft models with no noticeable toxicity. GLP toxicity studies indicated that ZV0203 was well tolerated with an estimated therapeutic index of 35. Methods: This was an open-label, multicenter, phase 1, dose-escalation study in patients (pts) with HER2+ advanced solid tumors. Primary objectives were safety, tolerability and RP2D. Secondary objectives included PK, immunogenicity and preliminary clinical efficacy. ZV0203 was administered intravenously Q3W on a 21-day cycle. An accelerated titration design was used for the 0.3 and 0.6 mg/kg doses, followed by a 3+3 design for 1.2, 1.8, 2.7 and 3.6 mg/kg dose levels. Results: As of January 18, 2024, 15 pts with solid tumors (breast [11], colorectal [2], gastric [1], lung [1]) were enrolled across doses of 0.3-3.6 mg/kg with a median age of 52 years old (range 35-65), of which 9 pts received prior HER2-targeted therapy (trastuzumab ± pertuzumab) and 14 pts completed 21-day DLT assessment (0.3 mg/kg and 0.6 mg/kg [1 each], 1.2 mg/kg, 1.8 mg/kg, 2.7 mg/kg and 3.6mg/kg [3 each]) with no DLT incidence. Treatment-related adverse events (TRAE) occurred in 14 (93.3%) pts. The most frequent TRAEs were corneal epitheliopathy [9], elevated liver enzymes [6], dry eyes [6], neutropenia [4], anemia [4], leukopenia [3], and proteinuria [3], and most were grade 1-2 in severity. 5 pts experienced grade 3 TRAEs: lymphocytopenia (1.8mg/kg [1]) , corneal epitheliopathy (3.6 mg/kg [1]) and blurred vision (2.7 mg/kg [2], 3.6 mg/kg [1]), which were manageable during treatment. No unexpected safety signals were reported. TRAEs led to 13.3% (2/15) treatment discontinuation. Among 14 pts evaluated, 5 pts achieved a best tumor response of PR; 4 pts had SD; 1 pt had Non-CR/Non-PD per RECIST v1.1. Thus, disease control rate was 71.4% (10/14). PK results demonstrated that the PK profile of total antibody was similar to that of ZV0203 ADC, whose systematic exposure increased in a dose-dependent manner and remained stable after repeated administration. Concentration of DUO5 remained scarce, suggesting good stability of ZV0203. Conclusions: ZV0203 was well tolerated and showed clinically encouraging anti-tumor activity in heavily pretreated pts with HER2 positive cancer. Clinical trial information: NCT05423977 .

Abstract Background Controlling nutritional status (CONUT), prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) are new parameters that reflect the immune-nutritional status in some cancers. Purpose To investigate the relationship between preoperative nutritional status and systemic inflammatory indexes on the clinicopathological prognosis of patients with stage I-IV esophageal cancer and to clarify the predictive value of nutritional status and inflammatory indexes on tumor recurrence, metastasis and long-term survival after radical resection. Methods The clinical data of 381 patients who underwent radical esophagectomy at the First Affiliated Hospital of Zhengzhou University from August 5, 2013, to August 1, 2021, were analyzed retrospectively. The preoperative clinical characteristics and hematological examination results were collected, the data on nutritional and immune status were analyzed, tumor recurrence and survival were evaluated by telephone follow-up, and overall survival (OS) and progression-free survival (PFS) were calculated. Nutritional data and the immune status, clinical data and survival information were also analyzed. Results Analysis of the clinical data of 381 patients with esophageal cancer undergoing radical esophagectomy revealed that preoperative nutritional status was related to preoperative complications, neoadjuvant therapy, TNM stage, tumor location, pathological type, vascular invasion, nerve invasion and regional lymph node metastasis, and the indexes of systemic inflammation were related to neoadjuvant therapy, TNM stage, tumor location, pathological type and nerve invasion. In univariate analysis, vascular invasion, preoperative CONUT, PNI and SII were identified as important factors affecting prognosis. In multivariate analysis, vascular invasion, preoperative CONUT, PNI, and SII were identified as important factors showing an independent correlation with survival time. A nomogram was developed, and the statistically significant influencing factors from the multivariate Cox regression model were included to predict the 2-, 3- and 5-year overall survival rates of patients with lung metastasis from gastric cancer. Conclusion CONUT, PNI and SII are independent risk factors for predicting overall survival and recurrence-free survival after radical resection of esophageal cancer. The proposed nomogram prediction model can aid in individualized analysis of the prognosis of these patients.

目的 探讨藤梨根提取物通过白细胞介素-6/信号传导因子及转录激活因子3(IL-6/STAT3)信号通路调控食管癌EC-9706细胞生物学行为的研究.方法 本实验研究自2018年10月到2019年6月,分别用1、5、10、100、500、1000 mg/L的藤梨根提取物处理食管癌EC-9706细胞,选取100 mg/L作为最佳逆转实验浓度;用IL-6/STAT3信号通路激活剂处理食管癌EC-9706细胞.甲基噻唑基四唑(MTT)检测细胞的毒性;流式细胞术检测细胞的凋亡率;Transwell法检测细胞的迁移和侵袭;划痕实验检测细胞的运动能力;蛋白免疫印迹法(Western blotting)检测细胞周期蛋白1(Cyclin D1)、周期蛋白依赖性激酶抑制因子(P21)、B淋巴细胞瘤-2相关蛋白(Bax)、B淋巴细胞瘤-2(Bcl-2)、基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶-9(MMP-9)、信号传导及转录活化因子3(STAT3)、磷酸化的信号传导与转录激活因子-3(p-STAT3)蛋白的表达.结果 藤梨根提取物明显促进了食管癌EC-9706细胞凋亡(37.35±2.37),并抑制了细胞增殖(21.33±3.91)、迁移(106.31±3.20)和侵袭(67.29±2.99)(P<0.05);下调CyclinD1(0.25±0.01)、Bcl-2(0.26±0.03)、MMP-2(0.27±0.03)、MMP-9(0.25±0.01)、STAT3(0.34±0.03)、p-STAT3(0.20±0.01)蛋白表达,上调Bax(0.85±0.06)、P21(0.72±0.07)蛋白表达(P<0.05).激活IL-6/STAT3信号通路明显逆转了藤梨根提取物对食管癌EC-9706细胞增殖、凋亡、迁移和侵袭的作用.结论 藤梨根提取物可促进食管癌EC-9706细胞凋亡,抑制细胞增殖、迁移和侵袭,其机制与抑制IL-6/STAT3信号通路有关.

Objectives:The study aims to summarize publication characteristics of anti-programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immunotherapy for esophageal cancer and create scientific maps to explore hotspots and emerging trends with bibliometric methods.Methods:The publications between 2012 and 2021 were retrieved from the Web of Science Core Collection (WoSCC) on June 20, 2022. Bibliometric tools including HistCite, VOSviewer, and CiteSpace were used for statistical analysis. Data on the trend of the annual output, countries/regions, institutions, journals, authors, subject categories, keywords, and co-cited references were presented in this study.Results:A total of 552 publications written by 3,623 authors of 872 institutions, 44 countries/regions in 250 journals were included in the bibliometric study. China, USA and Japan were the key countries in this field. Kato Ken, Bang Yung-Jue, Frontiers in Oncology, Journal of Clinical Oncology and Natl Canc Ctr were the top 1 productive author, co-cited author, productive journal, co-cited journal and prolific institution, respectively. The top 4 most present keywords were esophageal cancer, immunotherapy, esophageal squamous cell carcinoma and PD-L1. Neoadjuvant chemotherapy, response, PD-1 blockade and CD8+ T cell were four latest research frontiers. The keywords reflected the progress from PD-1/PD-L1 expression to the clinical application of PD-1/PD-L1 inhibitors. The current researches mainly focus on neoadjuvant immunotherapy for esophageal cancer and development of biomarkers. Further research is warranted to determine effective predictive biomarkers or models, illustrate the molecular mechanism of combined treatment, and construct the optimal therapeutic strategy.Conclusions:This study visually analyzed the global trend and hotspots of anti-PD-1/PD-L1 immunotherapy for esophageal cancer over the past decade. The results could guide scientists to comprehensively understand the global frontiers and determine future directions.

To evaluate the clinical efficacy of continuing cetuximab vs bevacizumab plus chemotherapy crossover after first progression to cetuximab regimen in wild-type KRAS, NRAS and BRAF V600E mCRC, we conducted this prospective, open-label and randomized phase 2 trial in three cancer centers from Oct 1, 2016 to July 1, 2020. Eligibility criteria included documented progressive disease during or after first-line treatment with cetuximab regimen; second biopsy confirmed as KRAS, NRAS and BRAF V600E wild-type mCRC. Patients were randomized to arm A (cetuximab+chemo) or arm B (bevacizumab+chemo) with second-line chemotherapy crossover. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS) and toxicity. Tissue VEGFA, ERBB2 and MET mRNA were examined by real time RT-PCR. A total of 104 patients (53 in arm A and 51 in arm B) were enrolled. Median PFS was 7.7 months (95% CI: 6.5-8.9) for arm A and 6.3 months (95% CI: 4.5-8.1) for arm B (p=0.931). Median OS was 18.2 months (95% CI: 14.5-21.9) for arm A and 16.4 months (95% CI: 14.2-18.6) for arm B (p=0.339). The ORR was 28.3% and 19.6% in arm A and arm B (p=0.31), respectively. MET mRNA was highly expressed in the cetuximab-progressed tumors, but treatment responsiveness to cetuximab or bevacizumab in each arm was not correlated with the MET expression level. The results showed no significant difference in PFS, OS and ORR between the two arms, but a trend in favor of the cetuximab continuation plus chemotherapy crossover was examined in all end points. High expression of MET in cetuximab-progressed tumors may indicate an existence of MET-dependent tumor cell population.

针对肿瘤的早期检测,提出基于希尔伯特曲线-卷积神经网络(H-CNN)的肿瘤类型预测模型.该模型首先使用变分自编码器对32种肿瘤类型病人的RNA表达量和DNA甲基化数据进行融合,然后通过使用希尔伯特曲线将融合数据可视化后送到CNN进行训练.基于以上过程,可以实施关于新样本的肿瘤类型预测.实验结果表明,基于融合数据的H-CNN模型在肿瘤分类问题上具有优秀的性能,并且对肿瘤病人的早期诊断和治疗具有重要的指导意义.

目的 探讨主动脉瓣重度狭窄患者TAVR术前升主动脉延长与近端主动脉整体形态相关变化的联系.方法 回顾性分析2016年2月一2020年1月郑州大学第一附属医院21例经导管主动脉瓣置换术患者.比较患者TAVR术前近端主动脉的结构解剖,重点观察了其延长、扩张、倾斜、旋转、主动脉瓣功能.结果 ①TAVR延长(+)组主动脉近端在延长(P ＜0.001)、扩张(P = 0.012)、倾斜(P ＜0.001)数据高于TAVR延长(一)组,差异有统计学意义.TAVR延长(+)组升主动(P = 0.009)、窦管交界径(P = 0.045)、主动脉窦部凹陷指数(P = 0.043)数据高于TAVR组延长(～)组,差异有统计学意义.但TAVR组延长(+)组Valsalva窦(P=0.465)、虚拟瓣环(P = 0.601)与TAVR组延长(一)组数据比较差异无统计学意义.②一名患有重度主动脉狭窄的老年人,升主动脉的延长与近端主动脉的扩张相关(r= 0.382,P = 0.013).升主动脉的延长与向右倾(r=0.729,P＜ 0.001)显著相关.升主动脉的延长与顺时针旋转相关(r = 0.468,P=0.032).结论 在老年重度主动脉瓣狭窄患者中,升主动脉的延长与主动脉窦部水平以上的主动脉扩张有关,而Valsalva窦或虚拟瓣环的扩张无关.升主动脉的延长还与近端主动脉向右倾斜、顺时针旋转相关.

目的 探讨腹腔镜结直肠癌肝转移同期切除术治疗结直肠癌肝转移的效果及对患者免疫功能的影响.方法 根据治疗方式将106例结直肠癌患者分为腔镜组和传统组,各53例,腔镜组患者给予腹腔镜结直肠癌根治术+肝切除术治疗,传统组患者给予传统开腹结直肠癌根治术+肝切除术治疗.比较两组患者一般手术指标、炎性因子[白细胞介素-6(IL-6)、白细胞介素-10(IL-10)、γ干扰素(IFN-γ)]水平、外周血T淋巴细胞亚群(包括CD3+、CD4+、CD8+,计算CD4+/CD8+)水平、并发症发生情况和2年总生存率.结果 腹腔镜组患者手术时间明显长于传统组(P﹤0.01),术中出血量明显少于传统组(P﹤0.01),术后下床活动时间、术后肛门首次排气时间、术后引流时间、术后住院时间均明显短于传统组(P﹤0.01).术后48 h,腔镜组患者血清IL-10、IL-6水平均明显低于传统组,IFN-γ水平明显高于传统组(P﹤0.01),血清CD3+、CD4+水平和CD4+/CD8+均明显高于传统组(P﹤0.01),CD8+水平明显低于传统组(P﹤0.01).腔镜组患者术后并发症总发生率为11.32％,低于传统组患者的26.42％(P﹤0.05).随访2年,腔镜组患者的总生存率为39.62％,与传统组患者的50.94％无明显差异(P﹥0.05).结论 腹腔镜结直肠癌根治性术+腹腔镜肝部切除术治疗结直肠癌肝转移患者的疗效与传统开腹手术相当,但具有创伤小、术后恢复快、对患者免疫功能影响小的优势.

Objective:Clinicopathological features, treatment and prognosis of urinary and male reproductive system soft tissue sarcoma (STS) and sarcomatoid carcinoma in adults were compared.Methods:A retrospective analysis was performed on the clinical data of 73 patients with STS and 15 patients with sarcomatoid carcinoma in adult urinary and male reproductive system in the First Affiliated Hospital of Zhengzhou University. There were 59 males and 14 females in STS group, with a median age of 41 (18-78)years old. The maximum tumor diameter ranged from 0.5 to 19.0 cm. The primary tumors were located in testis and peritesticular (23 cases), kidney (23 cases), prostate (15 cases), bladder (8 cases), ureter(3 cases), other parts(1 case). There were 18 cases of lymph node metastasis and 8 cases of distant metastasis. Among 73 patients with STS, 66 patients underwent surgical resection, of which 31 patients underwent radical resection. Among the 66 patients who underwent surgery, 3 patients received neoadjuvant chemotherapy; 22 patients received adjuvant chemotherapy; 5 patients were treated with adjuvant radiotherapy. Among 7 patients with STS did not receive surgical treatment, 2 patients received radiotherapy combined with chemotherapy, 2 patients received chemotherapy alone, and 3 patients received symptomatic support treatment.There were 11 males and 4 females in sarcomatoid carcinoma group, with a median age of 65 (23 - 84)years old. The measurable tumor diameter ranged from 0.4 to 16.9 cm. The primary tumors were located in kidney (6 cases), bladder (5 cases), ureter(2 cases) and prostate(2 cases). There were 2 patients of lymph node metastasis and 4 patients of distant metastasis. Of the 15 patients with sarcomatoid carcinoma, 12 patients underwent surgical resection, of which 5 patients underwent radical resection. 2 patients were treated with adjuvant therapy after operation. Among the 12 patients who received surgical treatment, 2 patients had distant metastasis before operation, all of which originated from the kidney. Among the 3 patients without surgical treatment, 1 patients received systemic chemotherapy and 2 patients received symptomatic supportive treatment. There was no significant difference in gender, tumor maximum diameter, distant metastasis and operation, chemotherapy, radiotherapy and operation combined with chemotherapy ( P>0.05) and there were significant differences in age, tumor primary location and lymph node metastasis ( P<0.05) between STS and sarcomatoid carcinoma patients.The categorical variables of the two groups were compared by χ2.With Kaplan-Meier method for univariate survival analysis, the Cox was used for multivariate analysis. Results:The median follow-up time was 18.3(0.3-90.4) months.In STS group, there were 14 patients of synovial sarcoma, 11 patients of liposarcoma, 15 patients of rhabdomyosarcoma, 16 patients of leiomyosarcoma, 10 patients of other types, and 7 patients of spindle cell sarcoma without specific classification. Among 66 patients with STS, 8 patients recurred, 14 patients metastasized after operation, 4 patients recurred and metastasized after operation. The 7 patients without surgical treatment all progressed. Among the 10 patients of sarcomatoid carcinoma without distant metastasis before operation, 3 patients recurred and 3 patients metastasized after operation. Two patients of renal sarcomatoid carcinoma with distant metastasis were treated with nephrectomy and chemotherapy. One of them had overall survival (OS) up to 2 years, and one recurred 2 months after operation. The 3 patients without surgical treatment all progressed without remission. The median OS of STS patients were 59.3 (95% CI 24.1-94.5) months and that of sarcomatoid carcinoma patients were 8.7 (95% CI 6.1-11.2) months. The OS of STS patients were better than those of sarcomatoid carcinoma patients ( HR=2.874, 95% CI 1.118-7.386, P=0.022). Conclusions:The onset age of STS in adult urinary and male reproductive system was lower than that in sarcomatoid carcinoma. The primary lesions of STS were mainly in testis, peritesticular and kidney. The primary lesions of sarcomatoid carcinoma were mainly in kidney. Among STS, leiomyosarcoma was the most common type.STS and sarcomatoid carcinoma should be diagnosed and treated with surgery quickly, and systemic therapy should be performed for patients who cannot be treated with surgery.

目的探讨苏芬太尼对人肺癌A549细胞增殖、凋亡、迁移和侵袭的影响及对PI3K/Akt信号通路的调控作用。方法采用不同浓度的苏芬太尼干预肺癌A549细胞,CCK-8法检测苏芬太尼对A549细胞活力的影响,流式细胞术检测苏芬太尼对A549细胞凋亡的影响,Transwell实验检测苏芬太尼对A549细胞迁移和侵袭能力的影响,Western blot检测A549细胞中Bax、Bcl-2、MMP-2、MMP-9及PI3K/Akt信号通路关键蛋白的表达水平。结果 CCK-8实验结果显示,苏芬太尼能够显著抑制A549细胞活力,且与处理浓度呈依赖关系;流式细胞术检测结果显示,苏芬太尼能够诱导A549细胞凋亡;Transwell实验结果显示,苏芬太尼能够抑制A549细胞迁移和侵袭能力;Western blot结果显示,苏芬太尼能够上调A549细胞中Bax的表达,下调Bcl-2、MMP-2、MMP-9和p-PI3K和p-Akt蛋白的表达。结论苏芬太尼可能通过阻断PI3K/Akt信号通路抑制肺癌A549细胞增殖、迁移和侵袭,诱导细胞凋亡。

目的 探讨基于免疫相关基因构建食管腺癌预后评分模型的方法和临床价值.方法 从癌症基因组图谱计划数据库下载获得食管腺癌样本及正常食管组织样本的基因表达谱以及性别、年龄、分化程度、TNM分期、生存时间、生存状态信息.使用Wilcox检验对食管腺癌样本与正常食管组织样本的免疫相关基因表达进行差异分析,继续使用Cox回归分析模型分析筛选出与患者预后显著相关的免疫相关基因构建预后评分模型,使用受试者工作特征(ROC)曲线评估所建模型预测能力.使用Cox回归分析模型分析评估预后评分与临床病理特征对患者总生存期的影响.结果 筛选出HSPA6、ULBP1、MAPT、CACYBP、DLL4、CCL26、RAC2、BMP8B、CSF2、OSM、OXTR等11个免疫相关基因构建食管腺癌预后评分模型,该模型是独立预后因素,1 a、3 a的ROC曲线的曲线下面积分别为0.859、0.919.结论 基于免疫相关基因构建的食管腺癌预后评分模型具有较好准确性,有助于临床决策的制定.

对于可切除食管癌患者,手术切除是最重要的治疗方式,但由于食管癌术后复发转移机率较高,因而根据个体情况选择围手术期治疗十分重要.随着人们对肿瘤免疫治疗方式的认可,免疫检查点抑制剂逐渐从后线、二线前移至一线乃至围手术期,其原理是通过抗体阻断免疫检查点,抵抗肿瘤免疫抑制,起到缩小肿瘤及防止复发的作用.抗PD-1/PD-L1抗体是最常用的免疫检查点抑制剂.多项临床试验正在探索新辅助免疫治疗联合化疗或放化疗治疗食管癌患者的应用模式,现有数据显示将免疫治疗应用于食管癌新辅助领域极具潜力,但仍需在更大样本量的临床试验中加以验证.当前仍有诸多问题亟待研究,如治疗的时机与疗程、生物标志物筛选等.本文就目前新辅助免疫治疗在食管癌中的临床研究进行综述.

Objective:To investigate the influencing factors of second primary carcinoma (SPM) in patients with transitional cell carcinoma of bladder without distant metastasis.Methods:Patients diagnosed with transitional cell carcinoma of the bladder without distant metastasis were selected from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2016. The single factor analysis was conducted to select the factors influencing the occurrence of second primary cancer by using the cumulative incidence function (CIF) in the competitive risk model. Multivariate analysis was conducted by using the Fine-Gray model.Results:In total, 154 725 patients with transitional cell carcinoma of bladder without distant metastasis were identified. Multivariate analysis showed that marital status, age, race, gender, tumor invasion, radiotherapy, surgery and chemotherapy were the influencing factors of SPM ( P<0.05). Conclusions:Transitional cell carcinoma of bladder patients without distant metastasis should undergo risk screening for SPM to guide treatment, testing and follow-up plans.

食管癌的发生、发展是多因素、多步骤相互作用的复杂过程.表皮生长因子受体(EGFR)在多种上皮性肿瘤中过表达,其异常活化与恶性肿瘤的发生、发展密切相关.目前国内外多项研究表明EGFR在部分食管癌组织中存在过表达,而在正常黏膜组织中低表达或无表达,提示EGFR信号通路在食管鳞癌的发生、发展及治疗中扮演着重要的角色.本文就近年来EGFR信号通路在食管癌发生、发展方面的研究进展进行综述.

Objective: To investigate the effects of microRNA-182-5p (miR-182-5p) on cell proliferation and invasion of esophageal squamous cell carcinoma (ESCC) and its related molecular mechanisms. Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) was employed to detect the miR-182-5p expression in ESCC tissues and cells. MiR-182-5p inhibitor, miR-182-5p mimic and negative control (NC) were transfected into ESCC Eca109 and TE1 cells, and miR-182-5p expression after transfection was examined using RT-qPCR. Cell counting kit-8 (CCK-8) was utilized to investigate the cell proliferation and Transwell chamber was used to detect the cell invasion ability. Dual-luciferase reporter assay was used to detect the direct interaction of miR-182-5p and cell adhesion molecule 2 (CADM2), RT-qPCR was employed to detect CADM2 expression in ESCC tissues, the correlation between CADM2 and miR-182-5p was also examined. Finally, western blot was used to detect the protein expressions of CADM2, focal adhesion kinase (FAK), p-Akt and Akt after transfection. Results: The miR-182-5p level in ESCC tissues was (2.180±1.295), significantly higher than (0.890±0.284) in normal esophageal epithelial tissues (P<0.001). The survival ratio of ESCC patients with high miR-182-5p level was evidently lower than that of ESCC patients with low miR-182-5p level (P<0.05). MiR-182-5p expression was significantly associated with TNM staging and lymph node metastasis (P<0.05). The expressions of miR-182-5p in ESCC cells including EC9706, Eca109, TE1, KYSE450 and KYSE70 were (2.449±0.082), (2.965±0.088), (4.873±0.258), (1.338±0.045) and (1.999±0.082), respectively, obviously higher than (0.989±0.087) in normal esophageal epithelial cell Het-1A (all P<0.01). Besides, miR-182-5p inhibitor significantly downregulated the miR-182-5p expression in Eca109 and TE1, and suppressed cell proliferation and invasion ability. Conversely, miR-182-5p mimic significantly upregulated the miR-182-5p expression in Eca109 and TE1, and promoted cell proliferation and invasion ability. Dual-luciferase reporter assay revealed that co-transfection of CADM2-3'UTR-WT and miR-182-5p mimic significantly reduced the luciferase activities in Eca109 and TE1 cells (P<0.01), and CADM2 was the direct target of miR-182-5p. The expression of CADM2 in ESCC tissues was (0.190±0.143), markedly lower than (0.845±0.327) in normal esophageal epithelial tissues (P<0.001). The miR-182-5p level exhibited negative correlation with CADM2 level in ESCC tissues (r=-0.5004, P<0.001). In addition, CADM2 expression was closely correlated with TNM staging and lymph node metastasis (P<0.05). The survival ratio of ESCC patients with high CADM2 level was evidently higher than that of ESCC patients with low CADM2 level (P<0.05). MiR-182-5p inhibitor significantly upregulated the expression of CADM2 protein, but suppressed the protein expressions of FAK, p-Akt and Akt, whereas miR-182-5p mimic markedly downregulated the expression of CADM2 protein, but promoted the protein expressions of FAK, p-Akt and Akt. Conclusion: MiR-182-5p is implicated in the carcinogenesis and development of ESCC, and thus may be a potential molecular target for ESCC patients.

目的:探讨半胱氨酸双加氧酶1(CDO1)对胃癌细胞增殖、细胞周期的调控机制.方法:用脂质体法将si-NC组(转染si-NC)、si-CDO1组(转染si-CDO1)、pcDNA组(转染pcDNA)、pcDNA-CDO1组(转染pcDNA-CDO1)、pcDNA-CDO1+DMSO组(转染pcDNA-CDO1并用DMSO处理)、pcDNA-CDO1+IGF-1组(转染pcDNA-CDO1并用IGF-1处理)转染至AKG细胞.用实时荧光定量逆转录聚合酶链反应(qRT-PCR)、免疫印迹(Western blot)、细胞计数试剂盒(CCK-8)、流式细胞术检测细胞CDO1、PI3K、Akt、p-Akt蛋白的表达、细胞增殖、细胞周期.结果:与人胃黏膜上皮细胞GES-1相比,胃腺癌细胞AKG中CDO1的表达明显降低(P<0.05);与si-NC组相比,si-CDO1组AKG细胞的增殖明显上调,细胞发生明显的S期、G2/M期阻滞,过表达CDO1则具有相反的作用.重要的是,敲减CDO1可上调PI3 K/AKT信号通路关键基因PI3 K、p-Akt的表达,而过表达CDO1具有相反的作用.激活PI3 K/AKT信号通路后,过表达CDO1对胃癌细胞的增殖、细胞周期的调控作用可被部分逆转.结论:CDO1可抑制胃癌细胞的增殖,调控细胞周期,其机制与抑制PI3 K/AKT信号通路的活性有关,将为胃癌的治疗提供参考.

目的:探讨Ⅲ型纤维连接蛋白域蛋白1(FNDC1)对食管癌发生、发展的影响及在紫杉醇(PTX)化疗中的应用前景.方法:采用免疫组化法检测食管癌及其癌旁正常组织(n=53)中FNDC1蛋白的表达.将食管癌TE13和KYSE180细胞各分为4组,空白组不做任何处理,Lipofectamine3000组、阴性对照组、FNDC1 siRNA3组分别转染Lipofectamine3000、阴性对照siRNA和FNDC1 siRNA3.48 h后,CCK-8法检测细胞增殖能力,Transwell小室实验检测细胞侵袭和转移能力.将TE13和KYSE180细胞各分为6组,分别转染阴性对照siRNA或FNDC1 siRNA3,48 h后再用不同浓度PTX(0、1.22和12.2μmol/L)处理24 h,CCK-8法检测细胞增殖能力.结果:①食管癌和癌旁正常组织中FNDC1蛋白阳性表达率分别为64.2％和24.5％,癌组织中的阳性率高于癌旁正常组织(P<0.05),且深层浸润或伴有淋巴结转移的食管癌组织中FNDC1阳性表达率高于浅层浸润或无淋巴结转移者(P<0.05).②转染FNDC1 siRNA3的TE13和KYSE180细胞增殖能力、侵袭能力和转移能力均显著降低(P<0.05).③FNDC1 siR-NA3和PTX均可抑制TE13和KYSE180细胞的增殖,两者有协同增效的作用(P<0.05).结论:FNDC1有望成为食管癌临床生物治疗的有效靶点.

Background Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy. Methods Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed. Results With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including "red-nevus-like," "pearl-like," "mulberry-like," "patch-like," and "tumor-like," according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis. Conclusions RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.