Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

血府逐瘀汤合温胆汤加减联合西药治疗高血压颈动脉硬化的临床观察

目的:观察血府逐瘀汤合温胆汤加减联合西药治疗高血压颈动脉硬化的效果。方法:选取2017年6月至2018年6月聊城市中医院收治的高血压颈动脉硬化患者92例作为研究对象,按照随机数字表法随机分为对照组与观察组,每组46例。对照组患者给予左旋氨氯地平+阿托伐他汀口服,观察组在对照组基础上加用血府逐瘀汤合温胆汤加减口服。观察患者血压、血脂控制情况,测定颈动脉内膜中层厚度(IMT)、斑块面积、血管皮内皮功能、血清蛋白酶分子水平。结果:与对照组比较,观察组治疗后的血压SBP、DBP及血脂TG、TC、LDL-C等指标更低(P<0.05);颈动脉粥样硬化斑块IMT厚度、斑块面积明显缩小(P<0.05),血管内皮功能指标ET-1、AngⅡ、TXB2水平明显降低,NO水平明显升高(P<0.05);血清CatK、MMP-9水平明显降低(P<0.05);观察组不良反应发生率8.70%明显低于对照组不良反应发生率21.74%(P<0.05)。结论:血府逐瘀汤合温胆汤加减联合西药更利于控制高血压颈动脉硬化患者的血压,调节脂质代谢,改善血管内皮功能,降低血清蛋白酶分子的含量,用药安全。     

基于LC-MS的甘草炮制雷公藤降低肝毒性的代谢组学研究

目的 观察甘草炮制雷公藤Tripterygium wilfordii后对小鼠血清中代谢产物的影响，初步探讨其降低肝毒性的可能代谢通路。方法 将C57BL/6小鼠随机分为对照（Con）组、雷公藤（Raw）组、甘草炮制雷公藤（Pro）组，观察小鼠肝组织病理变化，检测小鼠肝功能生化指标、炎症因子水平；利用液质联用（LC-MS）技术结合代谢组学方法，对各组间的代谢差异进行表征。结果 与Raw组相比，Pro组小鼠肝组织损伤显著改善，肝功能生化指标、炎症因子水平显著降低，表明甘草炮制雷公藤后可以降低小鼠肝毒性；共筛选出脂肪酸、磷脂酸、甘油酯、磷脂酰胆碱、胆酸等12个潜在生物标志物，主要涉及脂肪酸生物合成、甘油磷脂代谢、花生四烯酸代谢等9个代谢通路。结论 甘草炮制雷公藤可有效降低小鼠的肝毒性，其机制可能与调节脂肪酸代谢等通路相关，为其临床合理应用提供参考依据。     

Constructing robust selves after brain injury: positive identity work among members of a female self-help group

Despite common experiences of identity damage, decline, and deterioration, many brain injury survivors succeed in reconstructing robust identities in the wake of injury. Yet, while this accomplishment greatly benefits survivors’ quality of life, little is known about how positive identity work might be facilitated or enhanced in therapeutic institutions. Drawing on data from a women’s self-help group, we argue that an egalitarian, reflective, strength-focused, and gender-segregated environment can provide female ABI (acquired brain injury) survivors with a fertile scene for identity enhancement and offer unique opportunities for collective identity development. Sociolinguistic interactional analysis revealed four types of positive identity work undertaken within the group: constructing competent selves; tempering the threat of loss and impairment; resisting infantilisation and delegitimisation; and asserting a collective gender identity. This identity work was facilitated by specific programme attributes and activities and contributed to the global project of decentring disability and destigmatising impairments and losses. We call for increased attention to identity issues in brain injury rehabilitation and argue that gender-segregated programming can provide a unique space for female survivors to construct empowering individual and collective identities after injury.