Pathogenesis and therapeutic implications of EBV-associated epithelial cancers.

Epstein-Barr virus (EBV), one of the most common human viruses, has been associated with both lymphoid and epithelial cancers. Undifferentiated nasopharyngeal carcinoma (NPC), EBV associated gastric cancer (EBVaGC) and lymphoepithelioma-like carcinoma (LELC) are amongst the few common epithelial cancers that EBV has been associated with. The pathogenesis of EBV-associated NPC has been well described, however, the same cannot be said for primary pulmonary LELC (PPLELC) owing to the rarity of the cancer. In this review, we outline the pathogenesis of EBV-associated NPC and EBVaGCs and their recent advances. By drawing on similarities between NPC and PPLELC, we then also postulated the pathogenesis of PPLELC. A deeper understanding about the pathogenesis of EBV enables us to postulate the pathogenesis of other EBV associated cancers such as PPLELC.

Clinical outcomes in end stage renal disease on dialysis and severe coronary artery disease: A real-world study.

BACKGROUND: The optimal management of patients with end-stage renal disease (ESRD) on dialysis with severe coronary artery disease (CAD) has not been determined. METHODS: Between 2013 and 2017, all patients with ESRD on dialysis who had left main (LM) disease, triple vessel disease (TVD) and/or severe CAD for consideration of coronary artery bypass graft (CABG) were included. Patients were divided into 3 groups based on final treatment modality: CABG, percutaneous coronary intervention (PCI), optimal medical therapy (OMT). Outcome measures include in-hospital, 180-day, 1-year and overall mortality and major adverse cardiac events (MACE). RESULTS: In total, 418 patients were included (CABG 11.0%, PCI 65.6%, OMT 23.4%). Overall, 1-year mortality and MACE rates were 27.5% and 55.0% respectively. Patients who underwent CABG were significantly younger, more likely to have LM disease and have no prior heart failure. In this non-randomized setting, treatment modality did not impact on 1-year mortality, although the CABG group had significantly lower 1-year MACE rates (CABG 32.6%, PCI 57.3%, OMT 59.2%; CABG vs. OMT p < 0.01, CABG vs. PCI p < 0.001). Independent predictors of overall mortality include STEMI presentation (HR 2.31, 95% CI 1.38-3.86), prior heart failure (HR 1.84, 95% CI 1.22-2.75), LM disease (HR 1.71, 95% CI 1.26-2.31), NSTE-ACS presentation (HR 1.40, 95% CI 1.03-1.91) and increased age (HR 1.02, 95% CI 1.01-1.04). CONCLUSION: Treatment decisions for patients with severe CAD with ESRD on dialysis are complex. Understanding independent predictors of mortality and MACE in specific treatment subgroups may provide valuable insights into the selection of optimal treatment options.

HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing.

Heterogeneous nuclear ribonucleoproteins (HnRNPs) are a group of ubiquitously expressed RNA-binding proteins implicated in the regulation of all aspects of nucleic acid metabolism. HnRNP K is a member of this highly versatile hnRNP family. Pathological redistribution of hnRNP K to the cytoplasm has been linked to the pathogenesis of several malignancies but, until now, has been underexplored in the context of neurodegenerative disease. Here we show hnRNP K mislocalisation in pyramidal neurons of the frontal cortex to be a novel neuropathological feature that is associated with both frontotemporal lobar degeneration and ageing. HnRNP K mislocalisation is mutually exclusive to TDP-43 and tau pathological inclusions in neurons and was not observed to colocalise with mitochondrial, autophagosomal or stress granule markers. De-repression of cryptic exons in RNA targets following TDP-43 nuclear depletion is an emerging mechanism of potential neurotoxicity in frontotemporal lobar degeneration and the mechanistically overlapping disorder amyotrophic lateral sclerosis. We silenced hnRNP K in neuronal cells to identify the transcriptomic consequences of hnRNP K nuclear depletion. Intriguingly, by performing RNA-seq analysis we find that depletion of hnRNP K induces 101 novel cryptic exon events. We validated cryptic exon inclusion in an SH-SY5Y hnRNP K knockdown and in FTLD brain exhibiting hnRNP K nuclear depletion. We, therefore, present evidence for hnRNP K mislocalisation to be associated with FTLD and for this to induce widespread changes in splicing.

Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases.

Heterogenous nuclear ribonucleoproteins (hnRNPs) are a complex and functionally diverse family of RNA binding proteins with multifarious roles. They are involved, directly or indirectly, in alternative splicing, transcriptional and translational regulation, stress granule formation, cell cycle regulation, and axonal transport. It is unsurprising, given their heavy involvement in maintaining functional integrity of the cell, that their dysfunction has neurological implications. However, compared to their more established roles in cancer, the evidence of hnRNP implication in neurological diseases is still in its infancy. This review aims to consolidate the evidences for hnRNP involvement in neurological diseases, with a focus on spinal muscular atrophy (SMA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), congenital myasthenic syndrome (CMS), and fragile X-associated tremor/ataxia syndrome (FXTAS). Understanding more about hnRNP involvement in neurological diseases can further elucidate the pathomechanisms involved in these diseases and perhaps guide future therapeutic advances.

Localisation of Formyl-Peptide Receptor 2 in the Rat Central Nervous System and Its Role in Axonal and Dendritic Outgrowth.

Arachidonic acid and docosahexaenoic acid (DHA) released by the action of phospholipases A2 (PLA2) on membrane phospholipids may be metabolized by lipoxygenases to the anti-inflammatory mediators lipoxin A4 (LXA4) and resolvin D1 (RvD1), and these can bind to a common receptor, formyl-peptide receptor 2 (FPR2). The contribution of this receptor to axonal or dendritic outgrowth is unknown. The present study was carried out to elucidate the distribution of FPR2 in the rat CNS and its role in outgrowth of neuronal processes. FPR2 mRNA expression was greatest in the brainstem, followed by the spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The brainstem and spinal cord also contained high levels of FPR2 protein. The cerebral neocortex was moderately immunolabelled for FPR2, with staining mostly present as puncta in the neuropil. Dentate granule neurons and their axons (mossy fibres) in the hippocampus were very densely labelled. The cerebellar cortex was lightly stained, but the deep cerebellar nuclei, inferior olivary nucleus, vestibular nuclei, spinal trigeminal nucleus and dorsal horn of the spinal cord were densely labelled. Electron microscopy of the prefrontal cortex showed FPR2 immunolabel mostly in immature axon terminals or 'pre-terminals', that did not form synapses with dendrites. Treatment of primary hippocampal neurons with the FPR2 inhibitors, PBP10 or WRW4, resulted in reduced lengths of axons and dendrites. The CNS distribution of FPR2 suggests important functions in learning and memory, balance and nociception. This might be due to an effect of FPR2 in mediating arachidonic acid/LXA4 or DHA/RvD1-induced axonal or dendritic outgrowth.