SHIP inhibition mediates select TREM2-induced microglial functions.

Microglia play a pivotal role in the pathology of Alzheimer's Disease (AD), with the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) central to their neuroprotective functions. The R47H variant of TREM2 has emerged as a significant genetic risk factor for AD, leading to a loss-of-function phenotype in mouse AD models. This study elucidates the roles of TREM2 in human microglia-like HMC3 cells and the regulation of these functions by SH2-containing inositol-5'-phosphatase 1 (SHIP1). Using stable cell lines expressing wild-type TREM2, the R47H variant, and TREM2-deficient lines, we found that functional TREM2 is essential for the phagocytosis of Aß, lysosomal capacity, and mitochondrial activity. Notably, the R47H variant displayed increased phagocytic activity towards apoptotic neurons. Introducing SHIP1, known to modulate TREM2 signaling in other cells, revealed its role as a negative regulator of these TREM2-mediated functions. Moreover, pharmacological inhibition of both SHIP1 and its isoform SHIP2 amplified Aß phagocytosis and lysosomal capacity, independently of TREM2 or SHIP1 expression, suggesting a potential regulatory role for SHIP2 in these functions. The absence of TREM2, combined with the presence of both SHIP isoforms, suppressed mitochondrial activity. However, pan-SHIP1/2 inhibition enhanced mitochondrial function in these cells. In summary, our findings offer a deeper understanding of the relationship between TREM2 variants and SHIP1 in microglial functions, and emphasize the therapeutic potential of targeting the TREM2 and SHIP1 pathways in microglia for neurodegenerative diseases.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Adapting the World Health Organization's Surgical Safety Checklist to High-Income Settings: A Hybrid Effectiveness-Implementation Trial Protocol.

Objectives: The proposed study aims to assess users' perceptions of a surgical safety checklist (SSC) reimplementation toolkit and its impact on SSC attitudes and operating room (OR) culture, meaningful checklist use, measures of surgical safety, and OR efficiency at 3 different hospital sites. Background: The High-Performance Checklist toolkit (toolkit) assists surgical teams in modifying and implementing or reimplementing the World Health Organization's SSC. Through the explore, prepare, implement, and sustain implementation framework, the toolkit provides a process and set of tools to facilitate surgical teams' modification, implementation, training on, and evaluation of the SSC. Methods: A pre-post intervention design will be used to assess the impact of the modified SSC on surgical processes, team culture, patient experience, and safety. This mixed-methods study includes quantitative and qualitative data derived from surveys, semi-structured interviews, patient focus groups, and SSC performance observations. Additionally, patient outcome and OR efficiency data will be collected from the study sites' health surveillance systems. Data analysis: Statistical data will be analyzed using Statistical Product and Service Solutions, while qualitative data will be analyzed thematically using NVivo. Furthermore, interview data will be analyzed using the Consolidated Framework for Implementation Research and reach, effectiveness, adoption, implementation, maintenance implementation frameworks. Setting: The toolkit will be introduced at 3 diverse surgical sites in Alberta, Canada: an urban hospital, university hospital, and small regional hospital. Anticipated impact: We anticipate the results of this study will optimize SSC usage at the participating surgical sites, help shape and refine the toolkit, and improve its usability and application at future sites.

Pembrolizumab plus Abiraterone Acetate and Prednisone in Patients with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Results from KEYNOTE-365 Cohort D.

BACKGROUND AND OBJECTIVE: Abiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC. METHODS: In cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-naïve, had disease progression ≤6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3-modified RECIST v1.1 by BICR and overall survival (OS). KEY FINDINGS AND LIMITATIONS: For the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26-31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1-measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2-22) and median OS was 30 mo (95% confidence interval 23-not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3-5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design. CONCLUSIONS: Pembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-naïve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents. PATIENT SUMMARY: For patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety.

Sistemas de planificación y control de la fabricación / Manufacturing planning and control systems

Los múltiples cambios en competencia, demanda y oportunidades del mercado, fuerzas globales y tecnología de fabricación significa que muchas empresas se enfrentan con la necesidad de cambiar sus sistemas MPC (Manufacturing Planning and Control). Esto requiere una dirección adecuada de la transición de una configuración de planificación y control de fabricación a otra. En consecuencia, hemos incluido un nuevo capítulo en el que se describe cómo los cambios en las necesidades del mercado conducen a la necesidad de hacer cambios en los sistemas MPC. Cada vez más empresas de vanguardia mejoran su competitividad integrando sus sistemas MPC a sus necesidades estratégicas. También hacemos referencia a la integración de los enfoques de planificación de requerimiento (MRP) y al justo a tiempo (JIT), ya que ambos se pueden necesitar en la transición