Temsirolimus acts as additive with bendamustine in aggressive lymphoma.

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified

Occurrence, risk factors and outcome of adenovirus infection in adult recipients of allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Adenovirus (ADV) infections can have a high mortality in immunocompromised patients and are difficult to treat. OBJECTIVES AND STUDY DESIGN: We retrospectively analyzed occurrence and risk factors of ADV infection in 399 adults with hematological disorders undergoing hematopoietic stem cell transplantation (allo-HSCT), focusing on alternative donor transplantation (ADT) and disseminated disease. RESULTS: ADV infection occurred in 42 patients (10.5%). Disease was localized in 18 and disseminated in 6 patients. ADV infection was observed in 15% after ADT, performed in 29% of all recipients, and was less frequent (6%) in T-cell-replete (TCR) haploidentical transplantation using post-transplantation cyclophosphamide (PTCY) than in other ADT protocols. Lower age, the use of alternative donor grafts and acute graft-versus-host disease (GvHD)≥grade II were risk factors for ADV infection. After failure of standard antiviral treatment, three patients with disseminated ADV disease received one dose of ADV-specific T cells, resulting in virological response in 2/3 patients, clearance of ADV viremia in 2/2 patients, and survival of 1/3 patients; both patients with pneumonia died. CONCLUSIONS: ADV infection was of moderate occurrence in our adult recipients of allo-HSCT despite a high proportion of potential high-risk patients receiving ADT. TCR strategies using PTCY might limit ADV complications in haploidentical transplantation. Despite feasible adoptive therapy strategies, outcome of disseminated disease remains dismal

Enhancing discovery of genetic variants for posttraumatic stress disorder through integration of quantitative phenotypes and trauma exposure information

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.</p