Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities

Neoadjuvant Therapy for Resectable Pancreatic Cancer: A New Standard of Care. Pooled Data from Three Randomized Controlled Trials

OBJECTIVE The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome.Summary Background Data: Few underpowered studies have suggested benefits from neoadjuvant chemo (± radiation) for strictly resectable PDAC without offering conclusive recommendations. METHODS Three RCTs were identified comparing neoadjuvant chemo (± radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, while OS, postoperative morbidity and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards. RESULTS 130 patients were randomized (56 in the neoadjuvant and 74 in the control groups). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only (hazard ratio (HR 0.6, 95% CI 0.4 to 0.9) (p= 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35 to 0.9, p = 0.045). While post-operative complications (CCI) occurred less frequently (p =0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters. CONCLUSION Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen

Search for evidence of the type-III seesaw mechanism in multilepton final states in proton-proton collisions at s=13\sqrt{s} = 13 TeV

A search for a signal consistent with the type-III seesaw mechanism in events with three or more electrons or muons is presented. The data sample consists of proton-proton collisions at $\sqrt{s} = 13$ TeV collected by the CMS experiment at the LHC in 2016 and corresponds to an integrated luminosity of 35.9 inverse femtobarns. Selection criteria based on the number of leptons and the invariant mass of opposite-sign lepton pairs are used to distinguish the signal from the standard model background. The observations are consistent with the expectations from standard model processes. The results are used to place limits on the production of heavy fermions of the type-III seesaw model as a function of the branching ratio to each lepton flavor. In the scenario of equal branching fractions to each lepton flavor, heavy fermions with masses below 840 GeV are excluded. This is the most sensitive probe to date of the type-III seesaw mechanism