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相似文献
Introduction: Current research suggests that pediatric stroke is associated with a reduction in intellectual functioning. However, less is known about academic achievement and the contribution of specific executive functions to math and literacy in this population. The current study investigates behavioral ratings of executive functioning and their relationship to math and spelling performance in children with a history of unilateral arterial ischemic stroke.
Method: Thirty-two pediatric patients with stroke (Mage = 9.5 ± 2.7 years) and 32 demographically equivalent, healthy controls were tested on standardized measures of arithmetic, spelling, and intelligence. Executive functioning data were collected via standardized parent questionnaire.
Results: Relative to controls, stroke participants demonstrated significantly poorer functioning in math, spelling, metacognition, and behavioral-regulation. Pencil and paper arithmetic was particularly challenging for the stroke group, with 40% of patients reaching levels of clinical impairment. Hierarchical regression in stroke participants further revealed that metacognition was a robust predictor of academic deficits. Stroke occurring in later childhood and affecting cortical and subcortical brain regions also presented as potential clinical risk factors.
Conclusions: Children with stroke were especially vulnerable to math achievement deficits. Metacognition made a substantial contribution to academic achievement abilities among stroke patients, and results underscore the importance of early metacognitive skills in the completion of schoolwork. Results also emphasize that pediatric stroke patients are a heterogeneous group with regard to functioning and that there is value in examining standard score distributions of clinical participant samples. 相似文献
While the family's primacy in the patient's adaptation to chronic illness increasingly is being recognized by health professionals and social scientists, the reverse side of the coin, that is, the impact of chronicity on the family, has received little attention. A life-span development perspective is used to enrich the more traditional frameworks employed to study family development and also as a unifying framework from which to view the impact of illness on individual family members and the family as a unit. A review of selected literature reveals a profile of families most at risk for serious disruption in situations involving chronic illness. Propositions suggesting interventions directed at patients and families experiencing chronicity are derived. 相似文献
Glioblastoma multiforme is the most malignant form of brain tumor. Despite treatment including surgical resection, adjuvant
chemotherapy, and radiation, these tumors typically recur. The recurrent tumor is often resistant to further therapy with
the same agent, suggesting that the surviving cells that repopulate the tumor mass have an intrinsic genetic advantage. We
previously demonstrated that cells selected for resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are near-diploid,
with over-representation of part or all of chromosomes 7 and 22. While cells from untreated gliomas often have over-representation
of chromosome 7, chromosome 22 is typically under-represented. 相似文献