Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia

Delayed oligodendrocyte (OL) maturation caused by hypoxia (Hx)-induced neonatal brain injury results in hypomyelination and leads to neurological disabilities. Previously, we characterized Sirt1 as a crucial regulator of OL progenitor cell (OPC) proliferation in response to Hx. We now identify Sirt2 as a critical promoter of OL differentiation during both normal white matter development and in a mouse model of Hx. Importantly, we find that Hx reduces Sirt2 expression in mature OLs and that Sirt2 overexpression in OPCs restores mature OL populations. Reduced numbers of Sirt2+ OLs were also observed in the white matter of preterm human infants. We show that Sirt2 interacts with p27Kip1/FoxO1, p21Cip1/Cdk4, and Cdk5 pathways, and that these interactions are altered by Hx. Furthermore, Hx induces nuclear translocation of Sirt2 in OPCs where it binds several genomic targets. Overall, these results indicate that a balance of Sirt1 and Sirt2 activity is required for developmental oligodendrogenesis, and that these proteins represent potential targets for promoting repair following white matter injury

Effect of Src Kinase inhibition on Cytochrome c, Smac/DIABLO and Apoptosis Inducing Factor (AIF) Following Cerebral Hypoxia-Ischemia in Newborn Piglets

We have previously shown that cerebral Hypoxia-ischemia (HI) results in activation of Src kinase in the newborn piglet brain. We investigated the regulatory mechanism by which the pre-Apoptotic proteins translocate from mitochondria to the cytosol during HI through the Src kinase. Newborn piglets were divided into 3 groups (n = 5/group): normoxic (Nx), HI and HI pre-Treated with Src kinase inhibitor PP2 (PP2 + HI). Brain tissue HI was verified by neuropathological analysis and by Adenosine Triphosphate (ATP) and Phosphocreatine (PCR) levels. We used western blots, immunohistochemistry, H&E and biochemical enzyme assays to determine the role of Src kinase on mitochondrial membrane apoptotic protein trafficking. HI resulted in decreased ATP and PCR levels, neuropathological changes and increased levels of cytochrome c, Smac/DIABLO and AIF in the cytosol while their levels were decreased in mitochondria compared to Nx. PP2 decreased the cytosolic levels of pre-Apoptotic proteins, attenuated the neuropathological changes and apoptosis and decreased the HI-induced increased activity of caspase-3. Our data suggest that Src kinase may represent a potential target that could interrupt the enzymatic activation of the caspase dependent cell death pathway. © 2017 The Author(s)

Single stage repair for aortic root aneurysm in a patient with coexisting coarctation incorporating the Cabrol technique: a case report

Background A 44 year old man who presented with a history of chest pain and dyspnoea was found to have an aneurysm of the aortic root, aortic valve insufficiency, and coarctation of the aorta. Case presentation The patient underwent a single stage procedure to treat the aortic root, valve and coarctation with a composite valved conduit and extra-anatomic bypass of the coarctation. The modified Cabrol technique was necessary to attach the coronary buttons due to grossly abnormal anatomy. The patient made a remarkable recovery and was discharged on the 8th post-operative day. Conclusion This case report highlights the feasibility and efficacy of performing a single stage procedure on complex coarctation with associated cardiac defects. To the best of our knowledge, this is the first report of the modified Cabrol technique being used in this particular setting

FAK-Src-paxillin system expression and disease outcome in human neuroblastoma

Background: Neuroblastoma (NB) often presents with metastatic disease and poor survival. The need for new prognostic markers remains invaluable. The FAK-Src-Paxillin protein system is associated with aggressive phenotype in adult malignancies but is largely unexplored in pediatric NB. Objective: To assess FAK-Src-Paxillin protein expression in human NB cell lines and clinical cytology material and to delineate its association with survival. Design/Methods: Western blot and immunohistochemistry were applied for FAK-Src-Paxillin expression in NB cell lines and 23 human cytology specimens, respectively. Protein expression in human clinical samples was correlated with clinicopathological parameters, MYCN amplification and survival. Results: FAK, Src and Paxillin proteins are expressed in human NB cells lines, and can be detected in clinical cytology specimens from NB patients, (59%, 32% and 33% respectively). Simultaneous FAK-Src-Paxillin expression was noted in 30% of NB patients. Children with concomitant positivity FAK, Src, and Paxillin tumors, as well as MYCN amplification, had increased mortality compared to those without. Conclusions: FAK-Src-Paxillin system is a marker of unfavorable prognosis for human NB patients but also a promising therapeutic target. © 2017 Taylor & Francis Group, LLC

Multi-targeted molecular therapeutic approach in aggressive neuroblastoma: the effect of Focal Adhesion Kinase-Src-Paxillin system

Introduction: Nonreceptor tyrosine kinases play key roles in the integrin system. Located at the focal adhesions, they consist of large protein complexes through which the cytoskeleton connects to the extracellular matrix. The focal adhesion kinase (FAK)-Src-paxillin complex, a major mediator of the integrin pathway, contributes to cell migration and motility. Its overexpression is increased in children with advanced neuroblastoma (NB), one of the most common malignancies of childhood, with poor survival. Areas covered: We review the most recent data on FAK-Src-paxillin and their implications in NB, the molecular structure and the regulatory mechanisms of each molecule and their interactions and up-to-date information on their use as the newest biomarkers and their potential use as therapeutic targets in NB. Expert opinion: Based on the current literature, we hypothesize that combined and concurrent inhibition of the FAK-Src-Paxillin system may result in significant tumor suppression and prevention or delay of metastasis