Mutant HRas Signaling and Rationale for Use of Farnesyltransferase Inhibitors in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are often associated with poor outcomes, due at least in part to the limited number of treatment options available for those patients who develop recurrent and/or metastatic disease (R/M HNSCC). Even with the recent validation and approval of immunotherapies in the first-line setting for these patients, the need for the development of new and alternative precision medicine strategies with survival benefit is clear. Oncogenic alterations in the HRAS (Harvey rat sarcoma virus) proto-oncogene are seen in approximately 4-8% of R/M HNSCC tumors. Recently, several preclinical and clinical advancements have been made in the implementation of small-molecule inhibitors that block post-translational farnesylation of HRas, thereby abrogating its downstream oncogenic activity. In this review, we focus on the biology of wild-type and mutant HRas signaling in HNSCC, and rationale for use and outcomes of farnesyltransferase inhibitors in patients with HRAS-mutant tumors.

The Difference in Scar-Related Quality of Life in Open Versus Closed Septorhinoplasty.

INTRODUCTION: The open and closed techniques are the main surgical techniques to perform septorhinoplasty. Although the open technique offers a better view of the pertinent anatomy and facilitates surgical access, it creates an external scar that could affect patients' satisfaction and quality of life (QoL). This study aims to compare the open and closed techniques using the SCAR-Q patient-reported outcome measure. METHODS: In this retrospective study, we have included patients who had their nasal surgery one year ago, in the period between April 2020 and April 2021. The SCAR-Q assessment tool to study patients' satisfaction with appearance, symptoms, and psychological impact of open and closed septorhinoplasty techniques. RESULTS: A total of 77 patients were included in this analysis. Of these, 39 (50.6%) patients underwent a closed septorhinoplasty, and 38 (49.4%) patients underwent an open approach. The mean (SD) age was 29.6 (8.1) years, and most patients were females (59.7%). The overall SCAR-Q questionnaire responses were very positive across all scales in our cohort, the median (IQR) scores were 91.0 (73.0-100.0) for the appearance scale, 89.0 (70.0-100.0) for the symptoms scale, and 100.0 (87.0-100.0) for the psychological impact scale. However, we have found no differences in SCAR-Q scores regarding appearance, symptoms, and psychological impact between open and closed septorhinoplasty. CONCLUSION: We have found no significant differences in QoL between open and closed techniques of septorhinoplasty. Larger studies are needed to further validate this finding.

Metformin Prevents Hyperglycemia-Associated, Oxidative Stress-Induced Vascular Endothelial Dysfunction: Essential Role for the Orphan Nuclear Receptor Human Nuclear Receptor 4A1 (Nur77).

Vascular pathology is increased in diabetes because of reactive-oxygen-species (ROS)-induced endothelial cell damage. We found that in vitro and in a streptozotocin diabetes model in vivo, metformin at diabetes-therapeutic concentrations (1-50 µM) protects tissue-intact and cultured vascular endothelial cells from hyperglycemia/ROS-induced dysfunction typified by reduced agonist-stimulated endothelium-dependent, nitric oxide-mediated vasorelaxation in response to muscarinic or proteinase-activated-receptor 2 agonists. Metformin not only attenuated hyperglycemia-induced ROS production in aorta-derived endothelial cell cultures but also prevented hyperglycemia-induced endothelial mitochondrial dysfunction (reduced oxygen consumption rate). These endothelium-protective effects of metformin were absent in orphan-nuclear-receptor Nr4a1-null murine aorta tissues in accord with our observing a direct metformin-Nr4a1 interaction. Using in silico modeling of metformin-NR4A1 interactions, Nr4a1-mutagenesis, and a transfected human embryonic kidney 293T cell functional assay for metformin-activated Nr4a1, we identified two Nr4a1 prolines, P505/P549 (mouse sequences corresponding to human P501/P546), as key residues for enabling metformin to affect mitochondrial function. Our data indicate a critical role for Nr4a1 in metformin's endothelial-protective effects observed at micromolar concentrations, which activate AMPKinase but do not affect mitochondrial complex-I or complex-III oxygen consumption rates, as does 0.5 mM metformin. Thus, therapeutic metformin concentrations requiring the expression of Nr4a1 protect the vasculature from hyperglycemia-induced dysfunction in addition to metformin's action to enhance insulin action in patients with diabetes. SIGNIFICANCE STATEMENT: Metformin improves diabetic vasodilator function, having cardioprotective effects beyond glycemic control, but its mechanism to do so is unknown. We found that metformin at therapeutic concentrations (1-50µM) prevents hyperglycemia-induced endothelial dysfunction by attenuating reactive oxygen species-induced damage, whereas high metformin (>250 µM) impairs vascular function. However, metformin's action requires the expression of the orphan nuclear receptor NR4A1/Nur77. Our data reveal a novel mechanism whereby metformin preserves diabetic vascular endothelial function, with implications for developing new metformin-related therapeutic agents.