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     

Introduction: Novel Frontiers in Cancer Metastasis

Clinical & Experimental Metastasis -     

Stitching the fabric back together: child fostering attitudes in the transition to a chronic HIV epidemic

There are an estimated 56 million orphans and vulnerable children across sub-Saharan Africa. Communities typically care for orphan children through informal caring arrangements – either within or outside of kinship networks. Within Kenya, an estimated 250,000 children live on the streets. There is less research related to fostering attitudes of this special population than orphans and vulnerable children generally. Important research over the past decade has illuminated multiple ways in which children are made more vulnerable because of HIV, including parental death and street-migration from HIV-affected households. As HIV transitions from a terminal illness to a chronic, manageable one, research is also required to establish how parents living with HIV can be an asset to children. In this study, we assess whether mothers living with HIV were very willing to foster biologically-related children, and street-involved children, how these fostering attitudes differed from mothers not living with HIV, and whether differences in fostering attitudes by reported HIV status were mediated by social support, family functioning and general self-rated health. Approximately 40% of mothers living with HIV were very willing to provide long-term foster care to biologically-related or street-involved children. This was less than the percentage of mothers not living with HIV, who were very willing to foster biologically-related children (61%) or street-involved children (58%). Significant portions of these differences were explained by social support, family functioning and general self-rated health. Multi-sectoral approaches are suggested by these findings in order to improve the child-fostering capacity of mothers living with HIV. Improving social support, family functioning and general self-rated health among HIV-infected mothers may not only provide protective benefits for the mothers and their children, but also expand the community’s capacity to care for orphan and vulnerable children.     

使用棱镜重新定位双侧中心暗点患者视网膜物像的预试验

目的 本研究使用激光扫描检眼镜(SLO)评价双侧中央暗点患者使用棱镜后的眼球运动反应.方法 本预试验共招募6例有双侧中央暗点的年龄相关性黄斑变性(AMD)患者以及6例正常视力的志愿者.首先用Nidek MP-1微视野仪确认患者的中央暗点和优选视网膜注视点(PRL),然后用Rodenstock SLO,在将视标投射在优选视网膜注视点时拍下实时视网膜像,接着在受检者眼前加入6～8 PD的棱镜,要求受检者保持注视视标,这时通过视网膜标记来测量视网膜像的移位量,以及随后发生的优选视网膜注视点的再次注视.过程中平均移位量和再次注视时间通过图像软件(ImageJ software)来计算.结果 实验组再次注视时的移位量在3个像素点或11.66个弧分之内(x轴:2.90±3.92,y轴:2.53±4.18).对照组再次注视时的移位会准确些(x轴:0.33±1.15,y轴:0.89±2.50),但与实验组差异无统计学意义(tx=1.32,Px＞0.05;ty=0.80,Py＞0.05).对照组再次注视时间(0.98±0.19)s较实验组(2.83±1.63)s要短,差距有统计学意义(t=5.03,P＜0.01).其中有1例实验组受检者没有发生再次注视,其结果被排除并单独分析.结论 研究发现,双眼中央暗点患者对棱镜物像转移后的再注视反应与正常人接近,但实验组再注视明显较对照组慢,并有1例受检者没有发生再注视.该数据说明双侧中央暗点患者无论眼前有没有棱镜,都会利用相同的视网膜位置视物,因此,通过棱镜物像再定位的意义不大.     

Epilepsie,Schlaf und plötzlicher unerwarteter Tod

Clinical Epileptology - Der plötzliche unerwartete Tod stellt eine seltene, aber schwerwiegende Komplikation für Epilepsiepatienten dar. Das Risiko hierfür ist u. a. nachts und...     

Dexamethasone as an adjuvant for peripheral nerve blockade: a randomised,triple-blinded crossover study in volunteers

Background

The efficacy of dexamethasone in extending the duration of local anaesthetic block is uncertain. In a randomised controlled triple blind crossover study in volunteers, we tested the hypothesis that neither i.v. nor perineurally administered dexamethasone prolongs the sensory block achieved with ropivacaine.