Targeting the MAPK pathway by combined inhibition of BRAF and MEK has increased overall survival in advanced BRAF-mutant melanoma in both therapeutic and adjuvant clinical settings. However, a significant proportion of tumors develop acquired resistance, leading to treatment failure. We have previously shown p63 to be an important inhibitor of p53-induced apoptosis in melanoma following genotoxic drug exposure. Here we investigated the role of p63 in acquired resistance to MAPK inhibition and show that p63 isoforms are upregulated in melanoma cell lines chronically exposed to BRAF and MEK inhibition, with consequent increased resistance to apoptosis. This p63 upregulation was the result of its reduced degradation by the E3 ubiquitin ligase FBXW7. FBXW7 was itself regulated by MDM2, and in therapy-resistant melanoma cell lines, nuclear accumulation of MDM2 caused downregulation of FBXW7 and consequent upregulation of p63. Consistent with this, both FBXW7 inactivating mutations and MDM2 upregulation were found in melanoma clinical samples. Treatment of MAPK inhibitor-resistant melanoma cells with MDM2 inhibitor Nutlin-3A restored FBXW7 expression and p63 degradation in a dose-dependent manner and sensitized these cells to apoptosis. Collectively, these data provide a compelling rationale for future investigation of nutlin-3A as an approach to abrogate acquired resistance of melanoma to MAPK inhibitor targeted therapy. SIGNIFICANCEUpregulation of p63, an unreported mechanism of MAPK inhibitor resistance in melanoma, can be abrogated by treatment with the MDM2 inhibitor Nutlin-3A, which may serve as a strategy to overcome resistance.Research.
Background. Knee osteoarthritis (KOA) is a significant cause of disability in a globally ageing population. Knee replacement surgery has been shown to improve function and quality of life. Access to this intervention can be limited for a number of reasons including rationing of care, lack of healthcare provision in austere environments, and more recently, due to the cessation of elective orthopaedic care as a result of the COVID pandemic. Referral for knee replacement surgery is often guided by the patient’s Oxford Knee Score (OKS). Recent therapies including treatment with microfragmented adipose tissue (MFAT) have emerged as alternatives to relieve pain and improve function in such patients. Method. We identified all patients with KOA Kellgren-Lawrence grade 3 and 4 in our dataset of patients treated with a single injection of MFAT and applied published OKS thresholds for referral for TKR to separate them into 3 cohorts according to their functional impairment. 220 patients (95 females, 125 males) with KOA were given one MFAT injection. The function (OKS) and quality of life (EuroQol-5) prior to and 24 months after therapy were compared. Results. MFAT injection provided a statistically significant improvement in the quality of life (EQ-5D) at 24 months in patients with a baseline OKS of 39 or less ( p value: <0.001) as well as those with OKS of 27 or less who are deemed suitable for a knee replacement ( p value: <0.001). Conclusion. MFAT injection improves quality of life in patients with KOA who are deemed suitable for the knee replacement. MFAT is a low-morbidity alternative biological treatment and can delay the need for total knee replacement in suitable patients.
Knee osteoarthritis is a major cause of disability worldwide. Newer modalities of treatment with less morbidity, such as intra-articular injection of microfragmented fat (MFAT), are showing promise. We report on our novel observation that women show a greater improvement in pain and function to MFAT than men. Traditionally, women have been underrepresented in studies and studies with both sexes regularly fail to analyze the results by sex. To mitigate for this bias and quantify it, we describe a technique using reproducible statistical analysis and replicable results with Open Access statistical software R to calculate the magnitude of this difference. Genetic, hormonal, environmental, and age factors play a role in our observed difference between the sexes. There is a need for further studies to identify the molecular basis for this difference and be able to utilize it to improve outcome for both women and men.
Background Augmented reality (AR) uses a set of technologies that overlays digital information into the real world, giving the user access to both digital and real-world environments in congruity. AR may be specifically fruitful in reconstructive microsurgery due to the dynamic nature of surgeries performed and the small structures encountered in these operations. The aim of this study was to conduct a high-quality preferred reporting items for systematic reviews and meta-analyses (PRISMA) and assessment of multiple systematic reviews 2 (AMSTAR 2) compliant systematic review evaluating the use of AR in reconstructive microsurgery. Methods A systematic literature search of Medline, EMBASE, and Web of Science databases was performed using appropriate search terms to identify all applications of AR in reconstructive microsurgery from inception to December 2018. Articles that did not meet the objectives of the study were excluded. A qualitative synthesis was performed of those articles that met the inclusion criteria. Results A total of 686 articles were identified from title and abstract review. Five studies met the inclusion criteria. Three of the studies used head-mounted displays, one study used a display monitor, and one study demonstrated AR using spatial navigation technology. The augmented reality microsurgery score was developed and applied to each of the AR technologies and scores ranged from 8 to 12. Conclusion Although higher quality studies reviewing the use of AR in reconstructive microsurgery is needed, the feasibility of AR in reconstructive microsurgery has been demonstrated across different subspecialties of plastic surgery. AR applications, that are reproducible, user-friendly, and have clear benefit to the surgeon and patient, have the greatest potential utility. Further research is required to validate its use and overcome the barriers to its implementation.
Background Climate change is a major public health threat worldwide. Operating theaters are responsible for extensive waste production due to the resource-intensive nature of surgery, including hand surgery. Methods An online literature search was performed to ascertain the approaches that surgeons may undertake to positively impact the environment. Results Surgeons can make hand surgery more carbon neutral through various measures that have been categorized as pre-, intra-, and postoperative interventions. With all changes, the aims are to minimize waste and costs while optimizing patient outcomes. Conclusions Administrative obstacles to implementing pro-climate hospital changes may be overcome by also considering likely cost benefits with many environmentally friendly measures. New measures in hand surgery should consider patient safety, clinical efficacy, cost effectiveness, and the environmental impact.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.