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     

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.     

Egg Intake Has No Adverse Association With Blood Lipids Or Glucose In Adolescent Girls

Objective: Longitudinal data on cardiometabolic effects of egg intake during adolescence are lacking. The current analyses aim to evaluate the impact of usual adolescent egg consumption on lipid levels, fasting glucose, and insulin resistance during late adolescence (age 17–20?years).

Methods: Data from 1392 girls, aged 9 to 10 at baseline and followed for 10?years, in the National Heart, Lung, and Blood Institute’s National Growth and Health Study were used to examine the association between usual egg intake alone and in combination with other healthy lifestyle factors and late adolescent lipid levels, fasting glucose, and insulin resistance, measured as homeostasis model assessment of insulin resistance (HOMA-IR). Diet was assessed using 3-day food records during eight examination cycles. Girls were classified according to usual weekly egg intake, ages 9–17?years:?<1 egg/wk (n?=?361), 1 to <3 eggs/wk (n?=?703), and ≥3 eggs/wk (n?=?328). Analysis of covariance modeling was used to control for confounding by other behavioral and biological risk factors.

Results: Girls with low, moderate, and high egg intakes had adjusted low-density lipoprotein cholesterol levels of 99.7, 98.8, and 95.5 mg/dL, respectively (p?=?0.0778). In combination with higher intakes of fiber, dairy, or fruits and vegetables, these beneficial effects were stronger and statistically significant. There was no evidence that ≥3 eggs/wk had an adverse effect on lipids, glucose, or HOMA-IR. More active girls who consumed ≥3 eggs/wk had the lowest levels of insulin resistance.

Conclusion: These results suggest that eggs may be included as part of a healthy adolescent diet without adverse effects on glucose, lipid levels, or insulin resistance.     

Künstliche Intelligenz — Fluch oder Segen?

Der Freie Zahnarzt - Risiken und Nebenwirkungen im Gesundheitswesen. Wer sich heute mit Digitalisierung beschäftigt, kommt am Thema „Künstliche Intelligenz (KI)“ nicht vorbei....     

Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck

Summary Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m² intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.     

Quantitatively distinct requirements for signaling-competent cell spreading on engineered versus natural adhesion ligands.

To design synthetic microenvironments that elicit desired cell behaviors, we must better understand the molecular mechanisms by which cells interact with candidate biomaterials. Using cell lines with distinct alpha5beta1 integrin expression profiles, we demonstrate that this integrin mediates cell spreading on substrata coated with genetically engineered artificial extracellular matrix (aECM) proteins containing the RGD sequence (RGD-containing aECM protein [aRGD]) but lacking the PHSRN synergy site. Furthermore, aRGD-mediated adhesion stimulates an intracellular focal adhesion kinase (FAK) signal that is indicative of integrin tethering. Although both aRGD and the natural ECM protein fibronectin (FN) support alpha5beta1 integrin-mediated cell spreading, quantitative single-cell analysis revealed that aRGD-mediated spreading requires ten-fold greater threshold amount of integrin expression than FN-mediated spreading. Our analysis demonstrates that aRGD-based substrata mediate both biophysical (cell spreading) and biochemical (FAK signaling) events via the alpha5beta1 integrin, albeit with efficacy quantitatively distinct from that of natural ECM proteins that possess the full spectrum of adhesion and synergy domains.     

Community mental health centers and insurance reimbursements

This study represents the first of a two-stage project. The first phase of the study examined the funding sources for the 40 Community Services Boards in Virginia. Data provided from the Department of Mental Health and Mental Retardation in Virginia examined fee collections which are comprised of direct client, commercial insurance, Medicaid and Medicare. An analysis of quarterly reports from 1982 to 1984 revealed that Medicaid collections have decreased significantly, while commercial insurance reimbursements have increased significantly. These results, although limited to data from Virginia, point to the need to examine if these shifts are occurring nation-wide, and to determine if the shift toward commercial insurance is impacting upon the delivery of services in Community Mental Health Centers.