Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Producción CientíficaBackground: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.Asociación Española Contra el Cáncer (Proyecto AIOA110296BLAN).Gerencia Regional de Salud de Castilla y León (Proyecto GRS 726/A13

The Role of Epigenetic Regulation and Pluripotency‐Related MicroRNAs in Differentiation of Pancreatic Stem Cells to Beta Cells

In this study, we aimed to research the effects of class-I HDACs and glucose on differentiation of pancreatic islet derived mesenchymal stem cells (PI-MSCs) to beta cells. Beta cell differentiation determined by flow cytometric analysis and gene expression levels of PDX1, PAX4, PAX6, NKX6.1, NGN3, INS2, and GLUT2. As a result the valproic acid, is an inhibitor of class-I HDACs, caused the highest beta cell differentiation in PI-MSCs. However, the cells in this group were at early stages of differentiation. Glucose co-administration to this group carried the differentiation to higher levels, but these newly formed beta cells were not functional. Moreover, reduction in the levels of pluripotency factors that Oct3/4, c-Myc, and Nanog were parallel to beta cell differentiation. Also, the levels of HDAC1 and acetylated H3/H4 were increased and methylated H3 was decreased by VPA treatment. In addition, we have detected over expression in genes of miR-18a-5p, miR-19b-5p, miR-30d-3p, miR-124, miR-146a-5p, miR-184, miR-335, and miR-433-5p in parallel to beta cell differentiation. As the conclusion, this study is important for understanding the epigenetic mechanism that controls the beta cell differentation and it suggests new molecules that can be used for diagnosis, and treatment of diabetes. J. Cell. Biochem. 119: 455-467, 2018. (c) 2017 Wiley Periodicals, Inc

Impact of delayed intervention following admission for small bowel obstruction: A contemporary analysis

Background: The optimal timing of surgical intervention for small bowel obstruction (SBO) remains debated. Methods: All adults admitted for SBO were identified in the 2018–2019 National Inpatient Sample. Patients undergoing small bowel resection or lysis of adhesion after three days were considered part of the Delayed cohort. All others were classified as Early. Multivariable regressions were used to assess independent predictors of delayed surgical intervention as well as associations between delayed management and in-hospital mortality, major adverse events (MAE), perioperative complications, postoperative length of stay (LOS), hospitalization costs and non-home discharge. Results: Among 28,440 patients who met study criteria, 52.0 % underwent delayed intervention. Black race (AOR 1.19, 95 % CI 1.03–1.36, ref.: White) and Medicare coverage (AOR 1.16, 95 % CI 1.01–1.33, ref.: private payer) were associated with increased odds of delayed surgical management. While delayed intervention was not significantly associated with death (AOR 1.27, 95 % CI 0.97–1.68), it was linked to greater odds of MAE (AOR 1.30, 95 % CI 1.16–1.45) and several perioperative complications. The Delayed cohort also faced an incremental increase in postoperative LOS (+1.29 days, 95 % CI 0.89–1.70) and hospitalization costs (+$11,000, 95 % CI 10,000-12,000). Moreover, delayed intervention was linked to increased odds of non-home discharge (AOR 1.64, 95 % CI 1.47–1.84). Conclusions: Delay in surgical management following SBO is linked to inferior clinical outcomes and increased resource use. Our findings highlight the need to ensure proper timing of surgery for SBO as well as efforts to standardize these practices across all demographics of patients