哇巴因抑制乳腺癌细胞增殖与雌激素受体亚型介导的信号通路有关

目的在确定哇巴因是否经雌激素受体(estrogen re-ceptor,ER)途径发挥抗乳腺癌细胞增殖作用的基础上,进一步探讨ER亚型在哇巴因介导的增殖抑制中的作用。方法选择兼有两种ER亚型表达的人乳腺癌细胞株MCF-7为研究对象,采用MTT法、RNA干扰技术及蛋白印迹检测技术,观察ER亚型对哇巴因介导的细胞增殖抑制作用的影响。结果在0.1～1 000 nmol.L-1浓度范围内,哇巴因以剂量依赖性方式明显抑制MCF-7细胞的增殖活性,该抑制作用可被ER阻断剂ICI 182,780部分阻断。应用RNA干扰技术沉默ERα或ERβ基因表达,进一步证实哇巴因对MCF-7细胞的增殖抑制作用主要由ERα介导。结论哇巴因可通过ERα信号通路对乳腺癌发挥抗肿瘤效应。NKA结合ER可能是未来开发抗乳癌药物的潜在重要靶点。     

Acute inhibitory effects of clenbuterol on force, Ca²⁺ transients and action potentials in rat soleus may not involve the β₂-adrenoceptor pathway

1. Clenbuterol, a β₂‐adrenoceptor agonist, can have inhibitory and myotoxic effects on slow‐twitch muscles. Clenbuterol is lipophilic and may enter into the intracellular compartment, and because of this, it is likely that clenbuterol will have different effects to classical β₂‐adrenoceptor agonists such as terbutaline. The aim of the present study is to investigate clenbuterol’s effect on force, intracellular [Ca²⁺] and electrophysiology, and the role of the β₂‐adrenoceptor pathway in these effects. 2. Simultaneous measurements of isometric force and [Ca²⁺]_i were made from small bundles of rat soleus muscle fibres in which several superficial fibres had been pressure‐injected with the fluorescence Ca²⁺ indicator Indo‐1. The muscle’s electrophysiological response was measured using glass intracellular microelectrodes. 3. The most robust effect of clenbuterol was a concentration‐ (10–50 μmol/L) and frequency‐dependent (10–80 Hz) loss of force and [Ca²⁺]_i maintenance during tetanic stimulation of muscle fibres. None of these effects were reduced in the presence of the β₂‐antagonist ICI 118551. 4. In addition clenbuterol had a significant effect on muscle electrophysiology, with action potentials measured during tetanic trains being inhibited in a concentration‐ and frequency‐dependent manner. This response was also unchanged by pre‐treatment with the β₂‐antagonist ICI 118551. 5. These results indicate that some of clenbuterol’s effects are mediated through a pathway other than the β₂‐adrenoceptors.     

Overcoming resistance to fulvestrant (ICI182,780) by downregulating the c-ABL proto-oncogene in breast cancer

Inhibiting estrogen receptor (ER) function with specific estrogen receptor modulators (SERM) can achieve a primary response in cancer patients; however, intrinsic or subsequently acquired resistance to the therapy remains a major obstacle in treatment. The pure anti-estrogen fulvestrant has been shown to be a promising antagonist of ERα in treating advanced breast cancer. However, our knowledge of the mechanisms governing cellular responsiveness to this agent is limited. Here we show that down-regulation of the nonreceptor tyrosine kinase c-ABL enhanced sensitization to fulvestrant in breast cancer cells. Blocking c-ABL kinase activity with the inhibitor imatinib further increased ERα downregulation induced by fulvestrant, decreased the number of proliferating cells entering the cell cycle, and increased cellular sensitivity to fulvestrant treatment. Conversely, introducing kinase-activated c-ABL can rescue fulvestrant-induced ERα downregulation. Consistent with the effects of imatinib, the silencing of endogenous c-ABL increased the sensitivity of breast cancer cells to fulvestrant treatment. These results demonstrate a role for c-ABL in mediating resistance to the pure anti-estrogen fulvestrant.     

Androgen receptor or estrogen receptor-beta blockade alters DHEA-, DHT-, and E(2)-induced proliferation and PSA production in human prostate cancer cells

BACKGROUND: Dehydroepiandrosterone (DHEA) is an endogenous steroid that is metabolized to androgens and/or estrogens in the human prostate. DHEA levels decline with age, and use of DHEA supplements to retard the aging process is of unproved effectiveness and safety. LNCaP and LAPC-4 prostate cancer cells were used to determine whether DHEA-modulated proliferation and prostate specific antigen (PSA) production were mediated via the androgen receptor (AR) and/or ERbeta. METHODS: Cells were treated with DHEA, DHT, or E(2) and antagonists to AR (Casodex-bicalutamide) or ER (ICI 182,780) or siRNA to the respective receptors. Proliferation was assessed by MTT assay and PSA mRNA and protein secretion were measured by quantitative real-time PCR and ELISA. Associations of AR and ERbeta were analyzed by co-immunoprecipitation studies and fluorescent confocal microscopy. RESULTS: DHEA-, T-, and E(2)-induced proliferation of LNCaP cells was blunted by Casodex but not by ICI treatment. In LNCaP cells, Casodex and ICI suppressed hormone-induced PSA production. In LAPC-4 cells, DHT-stimulated PSA mRNA was inhibited by Casodex and ICI, and the minimal stimulation by DHEA was inhibited by ICI. Use of siRNAs confirmed involvement of AR and ERbeta in hormone-induced PSA production while AR-ERbeta co-association was suggested by immunoprecipitation and nuclear co-localization. CONCLUSIONS: These findings support involvement of both AR and ERbeta in mediating DHEA-, DHT-, and E(2)-induced PSA expression in prostate cancer cells.     

免疫检查点抑制剂治疗黑色素瘤相关不良反应及其管理策略

近年来,免疫检查点抑制剂(ICI)在黑色素瘤治疗中取得了显著的成效,但是T细胞功能的活化也引起了一系列免疫相关不良反应(ir AE)。不同于传统化疗的不良反应,ir AE有着独特的临床表现和处理要求。虽然ir AE的发生和管理逐渐得到临床医生的重视,但一些常见ir AE的发生机制、临床表现、诊断和鉴别及其综合监测管理仍需进一步总结和归纳,以便提高临床医生工作水平和临床试验设计质量。而且不同ir AE的发生机制、糖皮质激素的治疗影响、原有自身免疫疾病患者的治疗风险等问题仍存在争议。本文阐述ICI治疗黑色素瘤引起的ir AE相关临床表现特点和诊疗管理措施,旨在对ir AE管理策略和研究方向提出具有指导意义的意见。     

免疫检查点抑制剂治疗非小细胞肺癌产生免疫相关不良反应和肺炎的特点及其危险因素分析

目的：探讨免疫检查点抑制剂(ICI)治疗非小细胞肺癌(NSCLC)产生的免疫相关不良反应(irAE)及ICI相关肺炎(ICI-P)的特点及其危险影响因素。方法：回顾性分析2019年1月到2021年12月间在山西白求恩医院胸部肿瘤科接受至少1次ICI治疗的114例NSCLC患者的一般性资料和临床特征的基线特征、治疗细节和发生irAE、ICI-P的数据,分析患者临床特征与irAE及ICI-P的关系,分析ICI-P发生的危险因素。观察ICI-P患者临床特点和治疗效果。结果：114例接受ICI治疗的NSCLC患者中有48例(42.11%)发生68次irAE,整体和严重irAE的发生率分别是59.65%、9.65%;从高到低排列发生率(仅列出前四位)：消化系统>呼吸系统>皮肤>内分泌系统;使用信迪利单抗>度伐利尤单抗>卡瑞利珠单抗=帕博利珠单抗;临床特征中的年龄与irAE发生有关联。15例患者发生ICI-P,整体发生率为13.16%,占irAE患者的31.25%,其中4例为重症,占irAE数的8.33%、ICI-P数的26.66%;发生于联合治疗的多于单药治疗(73...     

胃肠道间质肿瘤：微环境特点及免疫治疗思路

胃肠道间质肿瘤(GIST)是胃肠道最常见的间充质来源的肿瘤,对放化疗敏感性低。近二十年来,以伊马替尼为代表的酪氨酸激酶抑制剂类药物在很大程度上改善了GIST患者的预后,但仍有相当数量的患者出现原发或继发性耐药,因此需要开拓新的治疗方法。随着肿瘤免疫治疗的基础与临床研究的进展,越来越多的肿瘤患者从免疫治疗中获益。但是,免疫治疗在GIST中的应用却较为缓慢。目前,免疫检查点抑制剂治疗在GIST中的应用取得了初步进展,未来还需要有更多的循证证据。在发展迅速的免疫细胞疗法和肿瘤疫苗领域,目前尚无相关新技术用于GIST的临床研究。尽管如此,GIST的免疫微环境具有丰富的免疫细胞浸润,提示GIST是潜在的免疫治疗优势病种。但是,免疫治疗在GIST中的应用不能“照搬”上皮来源肿瘤的特征,必须在充分了解GIST免疫特征的基础上,进行针对性研究,开发出基于GIST的免疫治疗策略,才能使免疫治疗真正改善患者的预后。     

Transarterial chemoembolization plus immune checkpoint inhibitor as postoperative adjuvant therapy for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter cohort study

PurposeThis study aimed to assess the efficacy and safety of postoperative adjuvant transarterial chemoembolization (PA-TACE) plus immune checkpoint inhibitor (ICI) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).Patients and methodsThis study was conducted on three centers from June 2018 to December 2020. Patients were divided into the PA-TACE (n = 48) and PA-TACE plus ICI groups (n = 42). The recurrence-free survival (RFS) and overall survival (OS) curves were depicted by Kaplan-Meier method, and the differences between the two groups were compared using log-rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for RFS and OS. Adverse events (AEs) were assessed according to the Common Terminology Criteria for AEs (CTCAE) version 5.0.ResultsThe median RFS of the PA-TACE plus ICI group was significantly longer than the PA-TACE group (12.76 months vs. 8.11 months; P = 0.038). The median OS of the PA-TACE plus ICI group was also significanfly better than the PA-TACE group (24.5 months vs. 19.1 months; P = 0.032). PA-TACE plus ICI treatment was an independent prognostic factor for RFS (HR: 0.54, 95% CI: 0.32–0.9, P = 0.019) and OS (HR: 0.47, 95% CI: 0.26–0.86, P = 0.014). Only one patient experienced grade ≥3 immune-related AEs in the PA-TACE plus ICI group.ConclusionsPA-TACE plus ICI treatment had better efficacy in preventing recurrence and prolonging survival than PA-TACE alone for HCC patients with PVTT after R0 resection. This novel treatment modality may be an appropriate option for HCC with PVTT.