Emerging from their burrow: Hedgehog pathway inhibitors for cancer

Introduction: Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins and mechanisms important to cancer development or survival. The Hedgehog Pathway (HhP) is a signal transduction pathway and its constitutive activation is tumorigenic in basal cell carcinoma (BCC). The HhP enables phenotypic flexibility, and channels tumor-stroma interactions. As a result, it is over-expressed in numerous cancers as well as in the tumor microenvironment and may represent a promising therapeutic target.

Areas covered: In this article, we review the rationale for targeting HhP and its role as an oncogenic driver, in tumor epithelial-to-mesenchymal transition (EMT), and in the tumor microenvironment and describe the results of preclinical and clinical studies involving HhP inhibitors.

Expert opinion: HhP activation plays an important role in both the tumor microenvironment and tumor EMT which can lead to treatment resistance for a number of different malignancies. In addition to standard use in BCC, several HhP inhibitors are in preclinical, early, and mid-stage clinical development for other solid and hematologic malignancies.     

The comparative effects of metabolic surgery,SGLT2i,or GLP-1RA in patients with obesity and type 2 diabetes: a retrospective cohort study

BackgroundNew antidiabetic agents (sodium-glucose cotransporter-2 inhibitor [SGLT2i] and glucagon-like peptide-1 receptor agonist [GLP-1RA]) and metabolic surgery have protective effects on metabolic syndromes.ObjectivesTo compare the changes of metabolic parameters and costs among patients with obesity and type 2 diabetes undergoing metabolic surgery and initiating new antidiabetic agents over 12 months.SettingHong Kong Hospital Authority database from 2006–2017.MethodsThis is a population-wide retrospective cohort study consisting of 2616 patients (1810 SGLT2i, 528 GLP-1RA, 278 metabolic surgery). Inverse probability treatment weighting of propensity score was applied to balance baseline covariates of patients with obesity and type 2 diabetes who underwent metabolic surgery, or initiated SGLT2i or GLP-1RA. Metabolic parameters and direct medical costs were measured and compared from baseline to 12 months in metabolic surgery, SGLT2i, and GLP-1RA groups.ResultsPatients in all 3 groups had improved metabolic parameters over a 12-month period. Patients with metabolic surgery achieved significantly better outcomes in BMI (?5.39, ?.56, ?.40 kg/m², P < .001), % total weight loss (15.16%, 1.34%, 1.63%, P < .001), systolic (?2.21, ?.59, 1.28 mm Hg, P < .001) and diastolic (?1.16, .50, ?.13 mm Hg, P < .001) blood pressure, HbA1c (?1.80%, ?.77%, ?.80%, P < .001), triglycerides (?.64, ?.11, ?.09 mmol/L, P < .001), and estimated glomerular filtration rate (3.08, ?1.37, ?.41 mL/min/1.73m², P < .001) after 12 months compared with patients with SGLT2i and GLP1-RA. Although the metabolic surgery group incurred the greatest direct medical costs (US$33,551, US$10,945, US$10,627, P < .001), largely due to the surgery itself and related hospitalization, the total monthly direct medical expenditure of metabolic surgery group became lower than that of SGLT2i and GLP-1RA groups at 7 months.ConclusionBeneficial weight loss and metabolic outcomes at 12 months were observed in all 3 groups, among which the metabolic surgery group showed the most remarkable effects but incurred the greatest medical costs. However, studies with a longer follow-up period are warranted to show long-term outcomes.     

Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma

Among the numerous signaling pathways involved in tumorigenesis, PI3K‐AKT‐mTOR is a key one that regulates diverse cellular functions. However, its prognostic value in esophageal carcinoma remains unclear. In our study, we examined the immunohistochemical expression of phosphorylated (p‐) AKT, mTOR, p70S6K and 4E‐BP1 along with the mutational status of PIK3CA and AKT1 genes by High Resolution Melting Analysis and Pyrosequencing in 44 esophageal carcinomas. The results were correlated with the clinicopathological characteristics of the patients in an effort to define their possible prognostic significance. Total p‐mTOR cytoplasmic expression, assessed in 10 random areas, was positively correlated with tumor stage (Kruskal–Wallis ANOVA, I/II vs III/IV, p = 0.0500). Μoreover, maximum p‐mTOR cytoplasmic immunoexpression, estimated in hot spot areas, was positively associated with tumor grade (Mann–Whitney U test, I/II vs III, p = 0.0565). Interestingly, p‐4E‐BP1 immunoreactivity was negatively correlated with tumor histological grade (Mann–Whitney U test, I/II vs III, p = 0.0427). No mutation was observed in exons 9 and 20 of PIK3CA gene and in exon 4 of AKT1 gene. In conclusion, our findings depict the presence of activated PI3K/AKT/mTOR pathway in esophageal cancer bringing forward p‐mTOR and p‐4E‐BP1 for their potential role in esophageal carcinogenesis. Additional studies are warranted to validate our findings.     

左金丸抗幽门螺杆菌感染的分子网络调控机制研究

目的基于网络药理学和生物信息学方法探究左金丸抗幽门螺杆菌(Hp)感染的分子网络调控机制。方法通过中药系统药理学数据库和分析平台(TCMSP)检索左金丸化学成分,筛选并预测其入血活性成分和作用靶点,检索疾病数据库中与Hp感染相关的作用靶点,构建左金丸成分靶点与疾病靶点的交互网络,获得左金丸抗Hp的特征性基因;通过DAVID6.8数据库对上述特征性基因进行GO功能富集和KEGG通路富集分析;利用Cytohubba筛选出左金丸抗Hp感染的关键靶点。结果通过TCMSP筛选、预测得到左金丸32个入血活性成分和197个作用靶点。GO分析共得到199条富集结果,其中生物过程包含炎症反应、RNA信号转录、信号传导等152条,细胞组分包含细胞核、细胞外基质、蛋白复合物等19条,分子功能包含细胞因子活性、DNA结合、ATP结合等28条。KEGG分析结果显示,Jak-STAT信号通路、T细胞受体信号通路、细胞周期信号通路、Wnt信号通路等65条通路与左金丸抗Hp感染密切相关。经Cytohubba筛选得到CXCL8、IL10、IL4、VEGFA、MMP9等10个关键基因。结论左金丸抗Hp感染具有多成分、多靶点、多通路协同作用的特点,可为其活性成分研究和抗Hp药效及机制研究提供依据。     

Biomarkers of cardiometabolic health are associated with body composition characteristics but not physical activity in persons with spinal cord injury

Objective: To examine (i) the associations between physical activity dimensions, cardiorespiratory fitness and body composition and, (ii) the associations between physical activity dimensions, cardiorespiratory fitness, body composition and biomarkers of cardiometabolic health in persons with spinal cord injury (SCI).

Methods: A cross-sectional prospective cohort study with 7-day follow-up was conducted. Body composition, cardiorespiratory fitness and biomarkers of cardiometabolic health were measured in thirty-three participants with SCI (> 1 year post injury). Physical activity dimensions were objectively assessed over 7-days.

Results: Activity energy expenditure (r =.43), physical activity level (r =.39), and moderate-to-vigorous physical activity (MVPA) (r =.48) were significantly (P < 0.001) associated with absolute (L/min) peak oxygen uptake (?O₂ peak). ?O₂ peak was significantly higher in persons performing ≥150 MVPA minutes/week compared to <40 minutes/week (P?=?0.003). Individual physical activity dimensions were not significantly associated with biomarkers of cardiometabolic health. However, body composition characteristics (BMI, waist and hip circumference) showed significant (P < 0.04), moderate (r >.30) associations with parameters of metabolic regulation, lipid profiles and inflammatory biomarkers. Relative ?O₂ peak (ml/kg/min) was moderately associated with only insulin sensitivity (r?=?0.37, P?=?0.03).

Conclusions: Physical activity dimensions are associated with cardiorespiratory fitness; however, stronger and more consistent associations suggest that poor cardiometabolic health is associated with higher body fat content. Given these findings, the regulation of energy balance should be an important consideration for researchers and clinicians looking to improve cardiometabolic health in persons with SCI.     

基于TCGA数据初步探查肝内胆管癌预后相关基因

目的 分析tCGA数据库中肝内胆管癌（ICC）高通量测序数据，寻找其预后相关基因，构建风险模型，并研究其在ICC组织中表达及作用通路。方法 下载tCGA数据库中33例ICC组织和8例癌旁组织中的RNA-seq表达矩阵数据和患者临床资料信息，利用edgeR软件包进行基因差异表达分析，通过单因素Cox回归分析筛选出预后相关差异基因，对差异基因绘制生存曲线，筛选出具有临床意义的基因，经多因素Cox回归分析并构建风险模型，通过京都基因与基因组百科全书（KEGG）通路富集分析了解预后相关基因的作用通路。结果 通过edgeR分析后得到6 617个差异基因（筛选标准为|log2 Fold Change|＞1，P＜0.05），其中高表达组4 094个，低表达组2 523个。通过功能富集发现，这些基因主要集中在化学物致癌作用、药物代谢-细胞色素P450系统、细胞色素P450对异生物质的代谢影响以及视黄醇代谢通路。经单因素Cox回归、R软件“survival”包生存曲线分析显示，UCN2、CST1、PROS1、SLC35E4、PEMT五个基因对ICC患者预后存在显著性影响。通过多因素Cox回归分析，CST1、PEMT、PROS1构建的风险模型对ICC患者预后具有判断作用。结论 UCN2、CST1、PROS1、SLC35E4、PEMT基因可能成为ICC预后判断指标，为后续临床试验提供数据支持。     

△LuxS的表型分析及其在GBS毒力调控机制研究中的应用

目的采用LuxS缺失突变株模型对B型链球菌中数量感应相关分子LuxS的功能及与其相关的自诱导因子-2数量感应通路进行研究，以探索其毒力调控机制。方法采用RT-PCR法、菌落印迹分析、生长曲线测定、cAMP因子测定等方法对该缺失突变菌株的表型特性进行了研究。最后应用哈氏弧菌作为报告菌株，通过生物发光测定法分析了突变株对B型链球菌诱导报告菌株中的生物发光活性的影响。结果发现此缺失突变可导致B型链球菌中scpB基因表达的上调；与野生株相比，突变株的生物发光诱导活性比野生株降低了大约两倍。结论本研究结果证实了LuxS在GBS中AI-2数量感应通路中的重要性，并为GBS中毒力调控机制的进一步研究提供了新的线索。