Incidence and prevalence of post-stroke insomnia: A systematic review and meta-analysis.

Problems with sleep are reported to be common after stroke but the incidence and prevalence of insomnia and insomnia symptoms following stroke is not yet established. The aim of this review was to conduct a systematic review and meta-analysis of the incidence and prevalence of insomnia and insomnia symptoms in individuals affected by stroke. We searched seven main electronic databases to identify studies until September 25, 2018. No studies examining incidence of post-stroke insomnia were identified. Twenty-two studies on prevalence of insomnia or insomnia symptoms including individuals with stroke were included with fourteen studies suitable for inclusion in the meta-analysis. Meta-analysis indicated pooled prevalence of 38.2% (CI 30.1-46.5) with significantly higher prevalence estimates for studies using non-diagnostic tools, 40.70% (CI 30.96-50.82) compared to studies using diagnostic assessment tools 32.21% (CI 18.5-47.64). Greater insomnia symptoms were indicated in those with comorbid depression and anxiety. The prevalence of both insomnia and insomnia symptoms are considerably higher in stroke survivors compared to the general population. Studies investigating the incidence, insomnia symptom profile and changes in insomnia prevalence over time are needed to inform clinical practice and to encourage tailored interventions that consider this symptomatology. PROSPERO registration number CRD42017065670.

Phosphorylation of a splice variant of collapsin response mediator protein 2 in the nucleus of tumour cells links cyclin dependent kinase-5 to oncogenesis.

BACKGROUND: Cyclin-dependent protein kinase-5 (CDK5) is an unusual member of the CDK family as it is not cell cycle regulated. However many of its substrates have roles in cell growth and oncogenesis, raising the possibility that CDK5 modulation could have therapeutic benefit. In order to establish whether changes in CDK5 activity are associated with oncogenesis one could quantify phosphorylation of CDK5 targets in disease tissue in comparison to appropriate controls. However the identity of physiological and pathophysiological CDK5 substrates remains the subject of debate, making the choice of CDK5 activity biomarkers difficult. METHODS: Here we use in vitro and in cell phosphorylation assays to identify novel features of CDK5 target sequence determinants that confer enhanced CDK5 selectivity, providing means to select substrate biomarkers of CDK5 activity with more confidence. We then characterize tools for the best CDK5 substrate we identified to monitor its phosphorylation in human tissue and use these to interrogate human tumour arrays. RESULTS: The close proximity of Arg/Lys amino acids and a proline two residues N-terminal to the phosphorylated residue both improve recognition of the substrate by CDK5. In contrast the presence of a proline two residues C-terminal to the target residue dramatically reduces phosphorylation rate. Serine-522 of Collapsin Response Mediator-2 (CRMP2) is a validated CDK5 substrate with many of these structural criteria. We generate and characterise phosphospecific antibodies to Ser522 and show that phosphorylation appears in human tumours (lung, breast, and lymphoma) in stark contrast to surrounding non-neoplastic tissue. In lung cancer the anti-phospho-Ser522 signal is positive in squamous cell carcinoma more frequently than adenocarcinoma. Finally we demonstrate that it is a specific and unusual splice variant of CRMP2 (CRMP2A) that is phosphorylated in tumour cells. CONCLUSIONS: For the first time this data associates altered CDK5 substrate phosphorylation with oncogenesis in some but not all tumour types, implicating altered CDK5 activity in aspects of pathogenesis. These data identify a novel oncogenic mechanism where CDK5 activation induces CRMP2A phosphorylation in the nuclei of tumour cells.

MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish.

Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP.

Ethanol production from selected lignocellulosic hydrolysates by genome shuffled strains of Scheffersomyces stipitis.

Two genome-shuffled Scheffersomyces stipitis strains, GS301 and GS302, exhibiting improved tolerance to hardwood spent sulphite liquor, were tested for growth and fermentation performance on three wood hydrolysates: (a) steam-pretreated enzymatically hydrolyzed poplar hydrolysate from Mascoma Canada, (b) steam pretreated poplar hydrolysate from University of British Columbia Forest Products Biotechnology Laboratory, and (c) mixed hardwoods pre-hydrolysate from FPInnovations (FPI). In the FPI hydrolysate, the wild type (WT) died off within 25 h, while GS301 and GS302 survived beyond 100 h. In fermentation tests, GS301 and GS302 completely utilized glucose and xylose in each hydrolysate and produced 0.39-1.4% (w/v) ethanol. In contrast, the WT did not utilize or poorly utilized glucose and xylose and produced non-detectable to trace amounts of ethanol. The results demonstrated cross tolerance of the mutants to inhibitors in three different wood hydrolysates and reinforced the utility of mating-based genome shuffling approach in industrial yeast strain improvement.

Small molecule screening in zebrafish: an in vivo approach to identifying new chemical tools and drug leads.

In the past two decades, zebrafish genetic screens have identified a wealth of mutations that have been essential to the understanding of development and disease biology. More recently, chemical screens in zebrafish have identified small molecules that can modulate specific developmental and behavioural processes. Zebrafish are a unique vertebrate system in which to study chemical genetic systems, identify drug leads, and explore new applications for known drugs. Here, we discuss some of the advantages of using zebrafish in chemical biology, and describe some important and creative examples of small molecule screening, drug discovery and target identification.

Are primary cutaneous carcinisarcomas underdiagnosed? Five cases and a review of the literature.

Primary cutaneous carcinosarcoma is a biphasic tumour containing both malignant epithelial and malignant mesenchymal elements. To date, only 26 cases have been reported in the literature. However, our findings suggest that this may reflect underreporting and possibly underdiagnosis. We present five cases and a comprehensive review of the literature: The disease most commonly presents in the eighth and ninth decades of life, is twice as common in males and may be related to sun exposure. Surgery is the primary therapeutic modality. Despite treatment, 27% of cases developed metastatic disease. Both epithelial and mesenchymal elements have been implicated in disease spread. We hope to raise awareness of this uncommon but serious disease and to assist clinicians in its management.