Activating mutations in BRAF are found in 50% of melanomas and although treatment with BRAF inhibitors (BRAFi) is effective, resistance often develops. We now show that recently discovered NRAS isoform 2 is up-regulated in the setting of BRAF inhibitor resistance in melanoma, in both cell lines and patient tumor tissues. When isoform 2 was overexpressed in BRAF mutant melanoma cell lines, melanoma cell proliferation and in vivo tumor growth were significantly increased in the presence of BRAFi treatment. shRNA-mediated knockdown of isoform 2 in BRAFi resistant cells restored sensitivity to BRAFi compared with controls. Signaling analysis indicated decreased mitogen-activated protein kinase (MAPK) pathway signaling and increased phosphoinositol-3-kinase (PI3K) pathway signaling in isoform 2 overexpressing cells compared with isoform 1 overexpressing cells. Immunoprecipitation of isoform 2 validated a binding affinity of this isoform to both PI3K and BRAF/RAF1. The addition of an AKT inhibitor to BRAFi treatment resulted in a partial restoration of BRAFi sensitivity in cells expressing high levels of isoform 2. NRAS isoform 2 may contribute to resistance to BRAFi by facilitating PI3K pathway activation.
Background: Outcomes after kidney transplantation (KTx) remain limited by delayed graft function (DGF) and acute rejection. Non-invasive biomarkers may help identify patients at increased risk for these events. We examined the association between the systemic immune-inflammation index (SII), a novel inflammatory biomarker, and outcomes after KTx and evaluated its ability to predict post-transplant prognosis. Patients and Methods: Adult patients who underwent primary KTx at our institution between 2016-2019 were included. SII was calculated from pre-transplant complete blood counts as the ratio of the neutrophil count to the lymphocyte count multiplied by the platelet count. The cutoff between high and low SII was determined by maximizing the area under the curve. Multivariable logistic and Cox regression were used to identify factors associated with DGF and patient, rejectionfree, and graft survival respectively. Results: Overall, 378 KTx recipients were included; 224 (59.3%) had high SII. On unadjusted analysis, high SII was associated with reduced odds of DGF, and improved patient and rejection-free survival. After adjustment, high SII was independently associated with improved patient survival alone. Multivariable models incorporating SII performed well for the prediction of DGF (c-statistic=0.755) and patient survival (c-statistic=0.786), though rejection-free survival was more difficult to predict (c-statistic=0.635). Conclusion: SII demonstrated limited utility as an independent predictor of outcomes after KTx. However, in combination with other clinically relevant parameters, SII is a useful predictor of post-KTx prognosis. Validation of this novel inflammatory biomarker in a multi-institutional study is needed to further elucidate its practical applications in transplantation.Kidney transplantation is the standard of care for patients with end-stage renal disease (ESRD), offering significant health and quality of life benefits compared to remaining on dialysis (1). Despite a steady increase in the number of kidney transplants performed in the US, delayed graft function (DGF) and acute rejection (AR) remain prevalent, hindering optimization of patient and allograft survival (2, 3). In the past decade, research on the transplant community has given increasing attention to the development and identification of novel biomarkers that allow for rapid, safe, non-invasive, and accurate detection of immunological injury to the kidney allograft (4, 5). Of particular interest are prognostic and predictive biomarkers that can identify patients at increased risk for allograft injury, including DGF and AR (6, 7).The neutrophil-to-lymphocyte ratio (NLR) and platelet-tolymphocyte ratio (PLR) are two biomarkers that provide an indication of inflammatory status and have been shown to be strong predictors of negative prognosis in a variety of conditions including cancer (8, 9), cardiovascular disease (10, 11), ESRD (12), and, more recently, kidney and liver transplantation (13)(14)(15)(16)(17)(18). Despite a growing body o...
In the United States, an overall national decline in organ transplants has accompanied the substantial burden of COVID‐19. Amidst significant regional variations in COVID‐19, lung transplantation (LTx) remains a critical life‐saving operation. Our LTx practice during the early pandemic may provide a blueprint for managing LTx in an era of continued community prevalence. Patients who underwent LTx at our institution between March 1 and May 20, 2020 were included. Recipient, operative, and donor characteristics were compared to those from our program in 2019, and COVID‐19 testing practices were evaluated for March, April, and May to understand how our practice adapted to the pandemic. Our program performed 36 LTx, 33% more than the same period in 2019. Recipient, operative, and donor characteristics during COVID‐19 were similar to those in 2019. By April 1, all donors and recipients underwent pretransplant COVID‐19 testing, all returning negative results. To date, no recipients have developed posttransplant COVID‐19. At our institution, pretransplant COVID‐19 testing, use of local donor lungs, and avoidance of donors from areas of increased community penetration supported a safe and effective LTx practice during the early COVID‐19 pandemic. Continued follow‐up is required to ensure the long‐term safety of these newly transplanted patients.
Objective Outside pregnancy, nitrofurantoin, ciprofloxacin and sulfamethoxazole-trimethoprim (SMZ-TMP) are first-line therapy (FLT) for lower urinary tract infections (LUTIs). Optimal antibiotics for LUTI have been extrapolated based on expert opinion. Progression to pyelonephritis and adverse obstetric outcomes were compared between women who received FLT and those given alternative antibiotics. Methods This study includes a retrospective cohort of women with LUTI, including asymptomatic bacteriuria and acute cystitis at single health care system from July 2013 to May 2019. Women receiving FLT, defined as nitrofurantoin or SMZ-TMP, were compared with those receiving nonfirst-line therapy (nFLT). Primary outcome was progression to pyelonephritis. Secondary outcomes included pyelonephritis-related anemia, sepsis, length of stay, preterm birth (PTB), and low birth weight (LBW). Logistic regression was used to calculate odds of outcomes. Results Of 476 women, 336 (70.6%) received FLT and 140 (29.4%) received nFLT. Women receiving FLT were more likely having BMI ≥ 40 (p = 0.04). Progression to pyelonephritis did not differ (5.8 vs. 8.2%; p = 0.44), nor did other pyelonephritis-related outcomes. After controlling for confounders, no difference in odds of progression to pyelonephritis was seen (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 0.42, 2.49). FLT was not associated with PTB or LBW (aOR 0.60, 95% CI 0.29, 1.26) after controlling for confounders. Conclusion Receipt of antibiotics other than nitrofurantoin or SMZ-TMP for LUTI in pregnancy was not associated with increased risk of progression to pyelonephritis, PTB, or LBW.
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