Simpsonhvass9652

Spinal muscular atrophy (SMA) is a motoneuron disease caused by deletions of the Survival of Motoneuron 1 gene (SMN1) and low SMN protein levels. SMN restoration is the concept behind a number of recently approved drugs which result in impressive yet limited effects. Since SMN has already been enhanced in treated patients, complementary SMN-independent approaches are needed. Previously, a number of altered signaling pathways which regulate motoneuron degeneration have been identified as candidate targets. However, signaling pathways form networks, and their connectivity is still unknown in SMA. Here, we used presymptomatic SMA mice to elucidate the network of altered signaling in SMA. The SMA network is structured in two clusters with AKT and 14-3-3 ζ/δ in their centers. Both clusters are connected by B-Raf as a major signaling hub. The direct interaction of B-Raf with 14-3-3 ζ/δ is important for an efficient neurotrophic activation of the MEK/ERK pathway and crucial for motoneuron survival. Further analyses in SMA mice revealed that both proteins were down-regulated in motoneurons and the spinal cord with B-Raf being reduced at presymptomatic stages. Primary fibroblasts and iPSC-derived motoneurons from SMA patients both showed the same pattern of down-regulation. This mechanism is conserved across species since a Caenorhabditis elegans SMA model showed less expression of the B-Raf homolog lin-45 Accordingly, motoneuron survival was rescued by a cell autonomous lin-45 expression in a C. elegans SMA model resulting in improved motor functions. This rescue was effective even after the onset of motoneuron degeneration and mediated by the MEK/ERK pathway.Severe environmental stress can trigger a plethora of physiological changes and, in the process, significant cytoplasmic reorganization. Stress-activated RNA-protein granules have been implicated in this cellular overhaul by sequestering pre-existing mRNAs and influencing their fates during and after stress acclimation. While the composition and dynamics of stress-activated granule formation has been well studied, their function and impact on RNA-cargo has remained murky. Several recent studies challenge the view that these granules degrade and silence mRNAs present at the onset of stress and instead suggest new roles for these structures in mRNA storage, transit, and inheritance. Here we discuss recent evidence for revised models of stress-activated granule functions and the role of these granules in stress survival and recovery.

To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab.

A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m

) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints.

From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported.

Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors.

EudraCT 2012-003043-29; NCT01706120.

EudraCT 2012-003043-29; NCT01706120.Microglia are the primary immune cell of the CNS, comprising 5-20% of the ∼60 billion neuroglia in the human brain. In the developing and adult CNS, they preferentially target active neurons to guide synapse maturation and remodeling. At the same time, they are the first line of defense against bacterial, fungal, and viral CNS infections. Although an extensive literature details their roles in rodents, less is known about how they function in humans because of the difficulty in obtaining tissue samples and the understandable inability to extensively study human microglia in situ. In this study, we use recent advances in the study of brain microenvironments to establish cultures of primary human microglia in a serum-free medium. Postsurgical samples of human brain were enzymatically and mechanically dissociated into single cells, and microglia were isolated at high purity by positive selection using CD11b Ab-coated microbeads. The CD11b+ cells were plated on poly-l-lysine-coated surfaces and bathed in serum-free DMEM/F12 supplemented with three essential components (TGF-β, IL-34, and cholesterol). Under these conditions, microglia assumed a ramified morphology, showed limited proliferation, actively surveyed their surroundings, and phagocytosed bacterial microparticles. check details In the presence of LPS, they assumed a more compact shape and began production of proinflammatory cytokines and reactive oxygen species. LPS on its own triggered release of TNF-α, whereas release of IL-1β required costimulation by ATP. Thus, human microglia maintained in a defined medium replicate many of the characteristics expected of native cells in the brain and provide an accessible preparation for investigations of human microglial physiology, pharmacology, and pathophysiology.