GPER-induced signaling is essential for the survival of breast cancer stem cells

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER⁻/PR⁺ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.     

A population-based study of testicular cancer risk among children and young adults from Norway and Utah,USA

Similar family-based cancer and genealogy data from Norway and Utah allowed comparisons of the incidence of testicular cancer (TC), and exploration of the role of Scandinavian ancestry and family history of TC in TC risk. Our study utilizes data from the Utah Population Database and Norwegian Population Registers. All males born during 1951–2015 were followed for TC until the age of 29 years. A total of 1,974,287 and 832,836 males were born in Norway and Utah, respectively, of whom 2,686 individuals were diagnosed with TC in Norway and 531 in Utah. The incidence per year of TC in Norway (10.6) was twice that observed in Utah (5.1) for males born in the last period (1980–1984). The incidence rates of TC in Utah did not differ according to the presence or absence of Scandinavian ancestry (p = 0.669). Having a brother diagnosed with TC was a strong risk factor for TC among children born in Norway and Utah, with HR = 9.87 (95% CI 5.68–17.16) and 6.02 (95% CI 4.80–7.55), respectively; with even higher HR observed among the subset of children in Utah with Scandinavian ancestry (HR = 12.30, 95% CI 6.78–22.31). A clear difference in TC incidence among individuals born in Norway and descendants of Scandinavian people born in Utah was observed. These differences in TC rates point to the possibility of environmental influence. Family history of TC is a strong risk factor for developing TC in both populations.     

参附注射液对猪创伤性心脏骤停复苏后肾损伤的保护作用研究

目的探讨参附注射液对猪创伤性心脏骤停复苏后肾损伤的保护作用。方法国产健康雄性白猪21头,采用随机数字表法分为假手术组(Sham组,n=5)、创伤性心脏骤停复苏(TCA组,n=9)和参附组(SFI组,n=7)。Sham组只经历气管插管及动静脉置管,不经历放血、复苏等过程。TCA组匀速释放总血容量的40%,然后经电刺激法室颤5 min,心肺复苏5 min后常规液体复苏治疗。SFI组在TCA组基础上于复苏后5 min进行参附注射液的干预。于放血前10 min、复苏后1、3、6、24 h检测血清TNF-α、IL-6、肌酐(Cr)、尿素氮(BUN)水平。复苏后24 h经右侧耳缘静脉注射10%氯化钾液20 mL处死猪,迅速获取肾组织标本,应用原位末端标记法(TNUEL法)检测细胞凋亡情况,免疫组织化学法检测半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)的蛋白表达水平。结果TCA组中有8头猪复苏成功,SFI组和Sham组中所有猪复苏成功。与Sham组比较,TCA组血清Cr水平在复苏后24 h、BUN水平在复苏后1、3、6、24 h均明显增高(均P<0.05),TNF-α、IL-6水平在复苏后3、6、24 h明显增高(均P<0.05),复苏后24 h后肾组织细胞凋亡指数及Caspase-3表达增加(均P<0.05)。与TCA组比较,SFI组BUN水平复苏后3、6 h明显降低(均P<0.05),TNF-α、IL-6水平在复苏后3、6、24 h明显降低(均P<0.05),肾组织细胞凋亡指数和Caspase-3蛋白表达有所降低,但差异无统计学意义(均P>0.05)。结论在猪TCA复苏模型中,早期应用参附注射液能够明显减轻复苏后肾损伤。其机制可能与抑制系统炎症反应、减轻细胞凋亡有关。     

综合疗法治疗4~5期慢性肾脏病31例临床观察

目的:观察综合疗法治疗慢性肾脏病(CKD)4~5期脾肾亏虚证的效果。方法:将CKD4~5期脾肾亏虚证患者62例随机分为2组,其中治疗组31例,对照组30例(剔除1例)。对照组予基础治疗合中药、骨化三醇及碳酸钙D3片治疗,治疗组予基础治疗合中药、骨化三醇及益肾泄浊汤保留灌肠治疗,观察时间为4周。比较2组血肌酐(Scr)、肾小球滤过率(e GFR)、尿素氮(BUN)、血钙、血磷、碱性磷酸酶(ALP)、甲状旁腺激素(i PTH)及中医证候疗效。结果:中医证候总有效率治疗组为83.87%(26/31),对照组为73.33%(22/30),组间比较,差异有统计学意义(P<0.05);2组Scr、e GFR、BUN、血磷治疗前后组内比较及治疗后组间比较,差异均有统计学意义(P<0.01或P<0.05);2组血钙、i PTH、ALP治疗前后组内比较,差异均有统计学意义(P<0.01),但治疗后组间比较,差异无统计学意义(P>0.05)。结论:综合疗法治疗慢性肾脏病4~5期脾肾亏虚证效果确切,安全可靠。     

Efficacy and Safety of the Modified EPOCH Regimen (Etoposide,Vincristine, Doxorubicin,Carboplatin, and Prednisolone) for Adult T-cell Leukemia/Lymphoma: A Multicenter Retrospective Study

BackgroundWe retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen.Patients and MethodsPatients received up to 6 mEPOCH cycles. Etoposide (50 mg/m²/day), doxorubicin (10 mg/m²/day), and vincristine (0.4 mg/m²/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m²/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert’s formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6.ResultsIn 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation.ConclusionThe mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.     

Hyperprogressive Disease in Patients With Urothelial Carcinoma or Renal Cell Carcinoma Treated With PD-1/PD-L1 Inhibitors

BackgroundA rapid progression pattern called hyperprogressive disease (HPD) has been observed during early cycles of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. Data regarding HPD in patients with genitourinary cancer are limited.Patients and MethodsWe included 203 patients with genitourinary cancer treated with PD-1/PD-L1 inhibitors between February 2015 and June 2018. HPD was defined as a greater than 50% increase in tumor burden, greater than 2-fold increase in tumor growth rate, or development of extensive (10 or more) new lesions.ResultsPatients (n = 102) with renal cell carcinoma (RCC) and patients (n = 101) with urothelial carcinoma (UC) were included. HPD was observed in 13 (6.4%) patients. The median overall survival for patients with progressive disease and HPD was 7.3 months and 3.5 months, respectively. HPD occurred more frequently in patients with UC than in those with RCC (11.9% vs. 0.9%; P = .01). Multivariate analysis showed that UC and creatinine above 1.2 mg/dL were independent predictive factors for HPD. A 30% increase in lymphocyte number following PD-1/PD-L1 inhibitor treatment was a negative predictor of HPD. The incidence of HPD in patients with UC treated with paclitaxel-based chemotherapy was one-third of those treated with PD-1/PD-L1 inhibitors.ConclusionHPD developed predominantly in patients with UC, and the incidence of HPD in patients with RCC was negligible. Treatment with PD-1/PD-L1 inhibitors should be prescribed with caution in patients with UC and creatinine above 1.2 mg/dL.     

α7 nAChRs expressed on antigen presenting cells are insensitive to the conventional antagonists α-bungarotoxin and methyllycaconitine

Expression of α7 nicotinic acetylcholine receptors (nAChRs) on antigen presenting cells (APCs), such as macrophages and dendritic cells, is now well established. We have shown that GTS-21, a selective α7 nAChR agonist, downregulates APC-dependent CD4⁺ T cell differentiation into regulatory T cells (Tregs) and effector Th1, Th2 and Th17 cells by inhibiting antigen processing, thereby interfering with antigen presentation. α7 nAChRs on Jurkat human leukemic T cells require functional T cell receptors (TCRs)/CD3 and leukocyte-specific tyrosine kinase to mediate nicotine-induced Ca²⁺-signaling via Ca²⁺ release from intracellular stores, and are insensitive to two conventional α7 nAChR antagonists, α-bungarotoxin (α-BTX) and methyllycaconitine (MLA). We investigated the effects of GTS-21, α-BTX and MLA on ovalbumin (OVA)-induced Th cytokine release from spleen cells isolated from OVA-specific TCR transgenic DO11.10 mice. We found that: (1) GTS-21 dose-dependently suppresses OVA-induced IFN-γ, IL-4 and IL-17 release, but neither α-BTX nor MLA alone affected the OVA-induced cytokine release. (2) Neither α-BTX nor MLA abolished the suppressive effects of GTS-21 on IFN-γ and IL-17 release from OVA-activated DO11.10 spleen cells. (3) GTS-21 significantly suppressed OVA-induced APC-dependent CD4⁺ T cell differentiation into Tregs. Neither MLA nor mecamylamine, a non-specific nAChR antagonist, abolished the suppressive effect of GTS-21 on Treg differentiation. These results suggest that α7 nAChRs on APCs involved in cytokine synthesis and T cell differentiation are insensitive to the conventional α7 nAChR antagonists, α-BTX and MLA, and that α7 nAChRs on APCs differ pharmacologically from those in neurons.     

A prognostic signature based on immune-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the fourth commonest female malignancy worldwide. CESC progresses in immune-microenvironment mainly composed of infiltrating immune and stromal cells. Here, we performed an integrated analysis incorporating the expression profiles from the Cancer Genome Atlas (TCGA) database and scores of immune and stromal cells calculated by Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm. A two-gene signature (CD1C and CD6 genes) was established to predict the prognosis of CESC. Based on this signature, patients were divided into the high- and low-risk groups, and this signature showed good prognostic performance according to the results of Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis in train set and two validation sets. A nomogram was built for evaluating the clinical applicability of this signature. In addition, based on Tumor Immune Estimation Resource (TIMER) database, 2 hub genes showed negative correlations with tumor purity and positive correlations with infiltrating levels of immune filtrating cells. What’s more, we propose new treatment strategies for the two prognostic subtypes. Low- risk patients were found presenting with a higher level of immune checkpoint molecules and showing higher immunogenicity in immunophenoscore (IPS) analysis, which indicated a better response for immunotherapy. Meanwhile, estimated by Genomics of Drug Sensitivity in Cancer (GDSC) database, the high-risk patients showed sensitive responses to five chemotherapy drugs. Finally, 10 candidate small-molecule drugs for CESC were defined. In summary, the CD1C-CD6 signature can accurately predict the prognosis of CESC.