Defining human mesenchymal stem cell efficacy in vivo

Allogeneic human mesenchymal stem cells (hMSCs) can suppress graft versus host disease (GvHD) and have profound anti-inflammatory and regenerative capacity in stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of disease. There is significant clinical hMSC variability in efficacy and the ultimate response in vivo. The challenge in hMSC based therapy is defining the efficacy of hMSC in vivo. Models which may provide insight into hMSC bioactivity in vivo would provide a means to distinguish hMSCs for clinical utility. hMSC function has been described as both regenerative and trophic through the production of bioactive factors. The regenerative component involves the multi-potentiality of hMSC progenitor differentiation. The secreted factors generated by the hMSCs are milieu and injury specific providing unique niches for responses in vivo. These bioactive factors are anti-scarring, angiogenic, anti-apoptotic as well as regenerative. Further, from an immunological standpoint, hMSC's can avoid host immune response, providing xenographic applications. To study the in vivo immuno-regulatory effectiveness of hMSCs, we used the ovalbumin challenge model of acute asthma. This is a quick 3 week in vivo pulmonary inflammation model with readily accessible ways of measuring effectiveness of hMSCs. Our data show that there is a direct correlation between the traditional ceramic cube score to hMSCs attenuation of cellular recruitment due to ovalbumin challenge. The results from these studies verify the in vivo immuno-modulator effectiveness of hMSCs and support the potential use of the ovalbumin model as an in vivo model of hMSC potency and efficacy. Our data also support future directions toward exploring hMSCs as an alternative therapeutic for the treatment of airway inflammation associated with asthma

Experiences using a multidisciplinary model for treating injection drug use associated infections: A qualitative study

Background: Over the past two decades, the United States has experienced a dramatic increase in the rate of injection drug use, injection associated infections, and overdose mortality. A hospital-based program for treating opioid use disorder in people who inject drugs presenting with invasive infections was initiated at an academic tertiary care center in 2020. The goal of this program was to improve care outcomes, enhance patient experiences, and facilitate transition from the hospital to longer term addiction care. The purpose of this study was to interview two cohorts of patients, those admitted before vs. after initiation of this program, to understand the program\u27s impact on care from the patient\u27s perspective and explore ways in which the program could be improved. Methods: Thirty patients admitted to the hospital with infectious complications of injection drug use were interviewed using a semi-structured format. Interviews were transcribed and coded. Emergent themes were reported. Limited descriptive statistics were reported based on chart review. Results: Thirty interviews were completed; 16 participants were part of the program (admitted after program implementation) while 14 were not participants (admitted prior to implementation). Common themes associated with hospitalization included inadequate pain control, access to medications for opioid use disorder (MOUD), loss of freedom, stigma from healthcare personnel, and benefits of having an interprofessional team. Participants in the program were more likely to report adequate pain control and access to MOUD and many cited benefits from receiving care from an interprofessional team. Conclusions: Patients with opioid use disorder admitted with injection related infections reported improved experiences when receiving care from an interprofessional team focused on their addiction. However, perceived stigma from healthcare personnel and loss of freedom related to hospitalization were continued barriers to care before and after implementation of this program

BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling

Objective Colorectal cancer remains the fourth most common cause of cancer-related mortality worldwide. Here we investigate the role of nuclear factor-?B (NF-?B) co-factor B-cell CLL/lymphoma 3 (BCL-3) in promoting colorectal tumour cell survival. Design Immunohistochemistry was carried out on 47 tumour samples and normal tissue from resection margins. The role of BCL-3/NF-?B complexes on cell growth was studied in vivo and in vitro using an siRNA approach and exogenous BCL-3 expression in colorectal adenoma and carcinoma cells. The question whether BCL-3 activated the AKT/protein kinase B (PKB) pathway in colorectal tumour cells was addressed by western blotting and confocal microscopy, and the ability of 5- aminosalicylic acid (5-ASA) to suppress BCL-3 expression was also investigated. Results We report increased BCL-3 expression in human colorectal cancers and demonstrate that BCL-3 expression promotes tumour cell survival in vitro and tumour growth in mouse xenografts in vivo, dependent on interaction with NF-?B p50 or p52 homodimers. We show that BCL-3 promotes cell survival under conditions relevant to the tumour microenvironment, protecting both colorectal adenoma and carcinoma cells from apoptosis via activation of the AKT survival pathway: AKT activation is mediated via both PI3K and mammalian target of rapamycin (mTOR) pathways, leading to phosphorylation of downstream targets GSK- 3 and FoxO1/3a. Treatment with 5-ASA suppressed BCL-3 expression in colorectal cancer cells. Conclusions Our study helps to unravel the mechanism by which BCL-3 is linked to poor prognosis in colorectal cancer; we suggest that targeting BCL-3 activity represents an exciting therapeutic opportunity potentially increasing the sensitivity of tumour cells to conventional therapy

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

Sudden cardiac death as a result of lethal ventricular arrhythmias is a major cause of death in cardiac diseases such as heart failure and prior myocardial infarct. Activity of the autonomic nervous system is often abnormal where sympathetic activity is upregulated and vagal activity reduced in these conditions. The abnormal autonomic state has been shown to be a strong prognostic marker of increased mortality and propensity to lethal arrhythmias, for which there is no effective prevention. Research effort over the years has established good evidence for a causal link between autonomic disturbance and ventricular arrhythmias. However, the detailed electrophysiological mechanisms by which ventricular fibrillation occurs are still not clear and molecular processes which are modulated by autonomic nerve influences that either predispose the heart to or protect it from these arrhythmias are not fully understood. This review presents data from studies investigating the link between activity of the autonomic nervous system and ventricular arrhythmias, from seminal findings in classical studies to ongoing investigations, in the quest for a better understanding of the arrhythmogenic mechanisms underlying neurocardiac interactions with a view to the development of effective preventative and therapeutic strategies which are very much needed