In silico repurposing the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing clear cell renal carcinoma

The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.     

Ribociclib plus letrozole in subgroups of special clinical interest with hormone receptor–positive,human epidermal growth factor receptor 2–negative advanced breast cancer: Subgroup analysis of the phase IIIb CompLEEment-1 trial

BackgroundThe phase IIIb CompLEEment-1 study evaluated ribociclib plus letrozole in patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). Outcomes were investigated in the following subgroups: central nervous system (CNS) metastases, prior chemotherapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and visceral metastases plus prior chemotherapy for advanced disease or ECOG PS 2.Patients and methodsPatients with HR+, HER2– ABC without prior hormonal treatment for advanced disease received oral ribociclib (600 mg once daily, 3 weeks on/1 week off) plus letrozole (2.5 mg once daily, continuous). Primary endpoint was safety/tolerability, assessed via occurrence of adverse events (AEs); key secondary endpoints included time to progression (TTP), overall response rate, and clinical benefit rate.Results51 patients had CNS metastases, 194 received prior chemotherapy for advanced disease, 112 had ECOG PS 2, 146 had visceral metastases plus prior chemotherapy, and 77 had visceral metastases plus ECOG PS 2. Safety results were consistent with those in the overall CompLEEment-1 population; no new safety concerns were identified. The AE profile was manageable with low rates of discontinuations due to AEs. TTP in patients with CNS metastases was consistent with the overall study population and shorter for other patient subgroups. Each patient subgroup achieved meaningful clinical benefit from treatment, consistent with the overall population.ConclusionThese findings confirm the clinical benefit of ribociclib plus endocrine therapy in high-risk patient subgroups of clinical interest commonly underrepresented in clinical trials.     

p-MAPK、CyclinD1和CDK4蛋白在大肠癌中的表达及相关性

目的 检测p-MAPK、CyclinD1和CDK4蛋白在大肠癌中的表达,并探讨其相关性.方法 选取78例大肠癌组织,距癌灶3 cm以外的癌旁组织,进行组织切片,HE染色进行病理分型,应用S-P免疫组化法对组织中的p-MAPK、Cyclin D1和CDK4进行检测.结果 病理分型后,78例大肠癌中p-MAPK、Cycli...     

重型肝炎的中西医结合治疗

重型肝炎（重肝）是由嗜肝病毒引发的低发病率、高死亡率的凶险肝炎，其发病率约占黄疸型肝炎的3％。我国每年死于重型肝炎的人数以数十万计，随着预防的普及，治疗观念和方法的改进，重型肝炎发生和病死率将逐步下降。     

人CDK2-AP1(DOC-1)酵母双杂交诱饵质粒自激活作用鉴定

目的验证诱饵质粒pBD—DOC-1在酵母双杂交系统的自激活性及毒性作用,为应用酵母双杂交系统（yeasttwo—hybrid system）筛选与p12DOC-1／CDK2-AP1相互作用的蛋白建立实验基础。方法将诱饵质粒pBD—DOC-1转化到酵母细胞MAV203中,检测诱饵蛋白有无毒性和自激活作用。同时利用对照质粒组筛选组氨酸（His）本底表达抑制剂3AT（3-氨基．1,2,4-三唑）的合适工作浓度。结果诱饵质粒pBD．DOC—1成功转化到酵母细胞MAV203中,对宿主酵母细胞无毒性,对报告基因无自激活作用。确定了组氨酸（His）本底表达抑制剂3AT（3-氨基-1,2,4-三唑）的合适工作浓度。结论诱饵质粒pBD—DOC-1可以用于酵母双杂交实验,为进-步运用酵母双杂交技术在人类组织cDNA文库中筛选与之相互作用的蛋白奠定了基础。     

Safety and efficacy of cyclin-dependent kinase inhibitor rechallenge following ribociclib-induced limiting hypertransaminasemia

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity.