No abstract

Background and Purpose-Downregulation of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is thought to be a novel neuroprotective strategy in ischemic stroke, but the underlying mechanisms remain unclear. In this study, we aimed to validate the use of PTEN regulation of ␥-aminobutyric acid subtype A receptors (GABA A Rs) as a molecular target for the treatment of ischemic stroke. Because suppression of GABA A Rs contributes to ischemic neuron death, describing the intracellular signaling that interacts with GABA A Rs in ischemic neurons would provide a molecular basis for novel stroke therapies. Methods-We measured surface GABA A R expression by immunocytochemical labeling and surface protein biotinylation assay. Knockdown and overexpression approaches were used to test the effects of PTEN on the expression and function of GABA A Rs. Neuronal death was detected in both in vitro and in vivo stroke models. Results-The knockdown and overexpression approaches provided the first evidence that PTEN negatively regulated membrane expression and function of GABA A Rs in rat hippocampal neurons. Importantly, we demonstrated that a PTEN inhibitor prevented the reduction of surface GABA A Rs in injured hippocampal neurons subjected to oxygen-glucose deprivation, an in vitro insult that mimics ischemic injury, whereas a GABA A R antagonist significantly reduced this PTEN inhibitor-induced neuroprotection in both the in vitro and in vivo ischemic stroke models. Conclusions-Our study provides direct evidence that downregulation of PTEN protects against ischemic neuron death by preserving GABA A R function. Targeting this pathway may be an effective strategy for development of selective, potent stroke treatments.

Background: A precise and consistent definition of return to sport (RTS) after anterior cruciate ligament (ACL) injury is lacking, and there is controversy surrounding the process of returning patients to sport and their previous activity level. Purpose: The aim of the Panther Symposium ACL Injury Return to Sport Consensus Group was to provide a clear definition of RTS after ACL injury and a description of the RTS continuum as well as provide clinical guidance on RTS testing and decision-making. Study Design: Consensus statement. Methods: An international, multidisciplinary group of ACL experts convened as part of a consensus meeting. Consensus statements were developed using a modified Delphi method. Literature review was performed to report the supporting evidence. Results: Key points include that RTS is characterized by achievement of the preinjury level of sport and involves a criteria-based progression from return to participation to RTS and, ultimately, return to performance. Purely time-based RTS decision-making should be abandoned. Progression occurs along an RTS continuum, with decision-making by a multidisciplinary group that incorporates objective physical examination data and validated and peer-reviewed RTS tests, which should involve functional assessment as well as psychological readiness. Consideration should be given to biological healing, contextual factors, and concomitant injuries. Conclusion: The resultant consensus statements and scientific rationale aim to inform the reader of the complex process of RTS after ACL injury that occurs along a dynamic continuum. Research is needed to determine the ideal RTS test battery, the best implementation of psychological readiness testing, and methods for the biological assessment of healing and recovery.

Pancreatic cancer is an aggressive disease with dismal prognosis. It is of paramount importance to understand the underlying etiological mechanisms and identify novel, consistent, and easy-to-apply prognostic factors for precision therapy. TUSC3 (tumor suppressor candidate 3) was identified as a potential tumor suppressor gene and previous study showed TUSC3 is decreased in pancreatic cancer at mRNA level, but its putative tumor suppressor function remains to be verified. In this study, TUSC3 expression was found to be suppressed both at mRNA and protein levels in cell line models as well as in clinical samples; decreased TUSC3 expression was associated with higher pathological TNM staging and poorer outcome. In three pairs of cell lines with different NF-κB activity, TUSC3 expression was found to be reversely correlated with NF-κB activity. TUSC3-silenced pancreatic cancer cell line exhibited enhanced potential of proliferation, migration and invasion. In an orthotopic implanted mice model, TUSC3 silenced cells exhibited more aggressive phenotype with more liver metastasis. In conclusion, the current study shows that decreased immunological TUSC3 staining is a factor prognostic of poor survival in pancreatic cancer patients and decreased TUSC3 promotes pancreatic cancer cell proliferation, invasion and metastasis. The reverse correlation between NF-κB activity and TUSC3 expression may suggest a novel regulation pattern for this molecule.