Neural immune cell responses to clinically relevant ligands of the niacin receptor (Gpr109a): niacin and monomethyl fumarate

Background: Inflammation is a major driver, and perhaps cause, of neurodegeneration, suggesting neuroimmunomodulation as a therapeutic strategy. Microglia, the primary mediators of neuroinflammation, switch between three activation states [surveillant/unactivated (M0), proinflammatory (M1), anti-inflammatory/pro-repair (M2)], with M1 being associated with worsening pathology, while M2 is associated with reduced severity. Microglia reportedly express Gpr109a, a receptor predicted, but not demonstrated, to reduce M1 and induce M2 phenotype switching. If Gpr109a ligands do reduce M1 and promote M2 microglial activation, this may be therapeutically beneficial. Astrocytes are secondary immunocompetent glial cells, which can express Gpr109a, although most astrocytes are reportedly Gpr109a-. It remains unclear whether Gpr109a ligands induce responses in Gpr109a+ astrocytes. Methods: Primary rat cortical microglia and astrocyte cultures were assessed for Gpr109a expression, and treated with Gpr109a ligands (niacin, monomethyl fumarate). Controls included nicotinamide (similar metabolic effects to niacin, but without Gpr109a activation) and lipopolysaccharide (LPS, positive inflammatory control). Microglial and astrocyte responses were assessed by marker expression (immunostaining: Arg1, Gpr109a, Iba1, Nox2) and morphometric analyses. Results: Expression of Gpr109a was demonstrated for rat microglia and astrocytes, with the majority of cells being Gpr109a+. Clear glial responses to Gpr109a ligands were not reproducibly demonstrated for either microglia or astrocytes. For Gpr109a ligands and for LPS, no consistent dose-response effects were seen in expression of Gpr109a, Nox2, Iba1 or Arg1. Morphological measurements showed no consistent responses to Gpr109a ligands or LPS treatment (Cell area, perimeter, Feret’s max/min diameter, aspect ratio, circularity index). Conclusion: Gpr109a represents a promising target for neuroimmunomodulatory therapies, as clinically approved ligands have good safety profiles, and neural immune cells express Gpr109a. Future studies should employ more sophisticated CNS models, including injury/disease to determine whether Gpr109a ligands may generate beneficial responses in neuroimmune cells already undergoing inflammatory/pathological activation

What Resilience (Strength) Means for Australian Aboriginal and Torres Strait Islander Health Professionals and Practitioners: An Exploratory Study

This article explores the concept of resilience from the perspective of Australian Aboriginal and Torres Strait Islander health professionals and practitioners, with the aim of describing what it is and how it is practiced in the workplace. Interviews in the form of Yarns were conducted with ten Aboriginal and Torres Strait Islander health professionals in regional North Queensland. We found that for Aboriginal and Torres Strait Islander health professionals and practitioners, resilience encompasses cultural identity and an ability to manage both Indigenous and western cultures and structures. Resilience, understood as ‘Strength’, draws on strong relationships to family and Country, often nurtured through strong women, who have overcome intergenerational trauma. For Aboriginal and Torres Strait Islander health professionals and practitioners, resilience is practiced through challenging the existing structural barriers experienced by Aboriginal and Torres Strait Islander clients who must deal with racism and a system not organised to meet their needs. Further research on the relationship between culture and resilience/strength is required

Colorectal polyp outcomes after participation in the seAFOod polyp prevention trial: Evidence of rebound elevated colorectal polyp risk after short-term aspirin use

BACKGROUND: The seAFOod polyp prevention trial was a randomised, placebo-controlled, 2 × 2 factorial trial of aspirin 300 mg and eicosapentaenoic acid (EPA) 2000 mg daily in individuals who had a screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Aspirin treatment was associated with a 20% reduction in colorectal polyp number at BCSP surveillance colonoscopy 12 months later. It is unclear what happens to colorectal polyp risk after short-term aspirin use. AIM: To investigate colorectal polyp risk according to the original trial treatment allocation, up to 6 years after trial participation. METHODS: All seAFOod trial participants were scheduled for further BCSP surveillance and provided informed consent for the collection of colonoscopy outcomes. We linked BCSP colonoscopy data to trial outcomes data. RESULTS: In total, 507 individuals underwent one or more colonoscopies after trial participation. Individuals grouped by treatment allocation were well matched for clinical characteristics, follow-up duration and number of surveillance colonoscopies. The polyp detection rate (PDR; the number of individuals who had ≥1 colorectal polyp detected) after randomization to placebo aspirin was 71.1%. The PDR was 80.1% for individuals who had received aspirin (odds ratio [OR] 1.13 [95% confidence interval 1.02, 1.24]; p = 0.02). There was no difference in colorectal polyp outcomes between individuals who had been allocated to EPA compared with its placebo (OR for PDR 1.00 [0.91, 1.10]; p = 0.92). CONCLUSION: Individuals who received aspirin in the seAFOod trial demonstrated increased colorectal polyp risk during post-trial surveillance. Rebound elevated neoplastic risk after short-term aspirin use has important implications for aspirin cessation driven by age-related bleeding risk. ISRCTN05926847

Polymorphisms in Cyclooxygenase, Lipoxygenase and TP53 genes predict colorectal polyp risk reduction by aspirin in the seAFOod polyp prevention trial

Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 single nucleotide polymorphisms (SNPs) in oxylipin metabolism genes such as cyclooxygenase [PTGS] and lipoxygenase [ALOX], as well as 7 SNPs already associated with colorectal cancer (CRC) risk reduction by aspirin (eg. TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomised 2x2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. Five hundred and forty-two (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with non-aspirin users was restricted to rs4837960 (PTGS1) common homozygotes (IRR 0.69 [95%CI 0.53,0.90]; q=0.06), rs2745557 (PTGS2) compound heterozygote-rare homozygotes (IRR 0.60 [0.41,0.88]; q=0.06), rs7090328 (ALOX5) rare homozygotes (IRR 0.27 [0.11,0.64]; q=0.05), rs2073438 (ALOX12) common homozygotes (IRR 0.57 [0.41,0.80]; q=0.05), and rs104522 (TP53) rare homozygotes (IRR 0.37 [0.17,0.79]; q=0.06). No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalised, predictive models of CRC chemoprevention by aspirin

Systems Analysis of miRNA Biomarkers to Inform Drug Safety

microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems

miR-22 and miR-205 Drive Tumor Aggressiveness of Mucoepidermoid Carcinomas of Salivary Glands

Publisher Copyright: Copyright © 2022 Naakka, Barros-Filho, Adnan-Awad, Al-Samadi, Marchi, Kuasne, Korelin, Suleymanova, Brown, Scapulatempo-Neto, Lourenço, Castilho, Kowalski, Mäkitie, Araújo, Leivo, Rogatto, Salo and Passador-Santos.Objectives: To integrate mRNA and miRNA expression profiles of mucoepidermoid carcinomas (MECs) and normal salivary gland (NSGs) tissue samples and identify potential drivers. Material and Methods: Gene and miRNA expression arrays were performed in 35 MECs and six NSGs. Results: We found 46 differentially expressed (DE) miRNAs and 3,162 DE mRNAs. Supervised hierarchical clustering analysis of the DE transcripts revealed two clusters in both miRNA and mRNA profiles, which distinguished MEC from NSG samples. The integrative miRNA-mRNA analysis revealed a network comprising 696 negatively correlated interactions (44 miRNAs and 444 mRNAs) involving cell signaling, cell cycle, and cancer-related pathways. Increased expression levels of miR-205-5p and miR-224-5p and decreased expression levels of miR-139-3p, miR-145-3p, miR-148a-3p, miR-186-5p, miR-338-3p, miR-363-3p, and miR-4324 were significantly related to worse overall survival in MEC patients. Two overexpressed miRNAs in MEC (miR-22 and miR-205) were selected for inhibition by the CRISPR-Cas9 method. Cell viability, migration, and invasion assays were performed using an intermediate grade MEC cell line. Knockout of miR-205 reduced cell viability and enhanced ZEB2 expression, while miR-22 knockout reduced cell migration and invasion and enhanced ESR1 expression. Our results indicate a distinct transcriptomic profile of MEC compared to NSG, and the integrative analysis highlighted miRNA-mRNA interactions involving cancer-related pathways, including PTEN and PI3K/AKT. Conclusion: The in vitro functional studies revealed that miR-22 and miR-205 deficiencies reduced the viability, migration, and invasion of the MEC cells suggesting they are potential oncogenic drivers in MEC.Peer reviewe

Review: A Publication of LMDA, the Literary Managers and Dramaturgs of the Americas, volume 17, issue 1

Contents include: Editor\u27s Page: A Note from New LMDA President, Brian Quirt; Think Dramaturgically, Act Locally! A Conference Overview; I Was Mugged at My First LMDA Conference; First-Timer Fragments; Conference Photos; Introducing the Lessing (and Joe and Michael); A Message Faxed from Romania; Acceptance Speech, Michael Lupu; Producing The Belle\u27s Stratagem; Dramaturging Justice: The Exonerated Project at the Alley Theatre; Past President Liz Engeleman: Some Appreciations; The Toronto Mini-Conference (reprinted from the LMDA Canada newsletter); Gateway to the Americas, The LMDA Delegation, A Report from Mexico; Imag[in]ing Poverty: Creative Critical Dramaturgy for Suzan-Lori Parks\u27s In the Blood; Hester, La Negrita in Iowa City, Staging Spells and Homelessness in Suzan-Lori Parks\u27s In the Blood; The Future of Theatre is...(a creative contest); Seventh Annual Call for LMDA Residency Proposals. Issue editors: D.J. Hopkins, Madeleine Oldham, Carlenne Lacostahttps://soundideas.pugetsound.edu/lmdareview/1034/thumbnail.jp

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

Acknowledgements We are grateful for the assistance provided by both the Microscopy and Histology Core Facility, and the Iain Fraser Cytometry Centre, at the University of Aberdeen. We thank Ann Wheeler and Matt Pearson from Edinburgh Super-Resolution Imaging Consortium for technical support with 3D SIM microscopy. We also thank Janet A. Willment and Bernard Kerscher, supervised by G.D.B., for providing the Fc fusion proteins, Jeanette A. Wagener, supervised by Neil A.R.G. Gow, for providing high purity chitin, Jan Westland for obtaining blood samples and Paul Crocker for useful discussions. Principal funding for this project was provided by Wellcome Trust grant 094847 (R.N.B, L.P.E, M.A.V). In addition, support was provided by Biotechnology and Biological Sciences Research Council grants BBF0083091 (A.D. and S.M.H.) and BBK0161641 (A.D. and S.M.H.), Wellcome Trust grant 082098 (A.D.), Wellcome Trust grants 97377, 102705 (G.D.B) and funding for the MRC Centre for Medical Mycology at the University of Aberdeen MR/N006364/1 (G.D.B).Non peer reviewe

Implementing an mHealth system for substance use disorders in primary care: a mixed methods study of clinicians’ initial expectations and first year experiences

Background: Millions of Americans need but don’t receive treatment for substance use, and evidence suggests that addiction-focused interventions on smart phones could support their recovery. There is little research on implementation of addiction-related interventions in primary care, particularly in Federally Qualified Health Centers (FQHCs) that provide primary care to underserved populations. We used mixed methods to examine three FQHCs’ implementation of Seva, a smart-phone app that offers patients online support/discussion, health-tracking, and tools for coping with cravings, and offers clinicians information about patients’ health tracking and relapses. We examined (a) clinicians’ initial perspectives about implementing Seva, and (b) the first year of implementation at Site 1. Methods: Prior to staggered implementation at three FQHCs (Midwest city in WI vs. rural town in MT vs. metropolitan NY), interviews, meetings, and focus groups were conducted with 53 clinicians to identify core themes of initial expectations about implementation. One year into implementation at Site 1, clinicians there were re-interviewed. Their reports were supplemented by quantitative data on clinician and patient use of Seva. Results: Clinicians anticipated that Seva could help patients and make behavioral health appointments more efficient, but they were skeptical that physicians would engage with Seva (given high caseloads), and they were uncertain whether patients would use Seva. They were concerned about legal obligations for monitoring patients’ interactions online, including possible “cries for help” or inappropriate interactions. One year later at Site 1, behavioral health care providers, rather than physicians, had incorporated Seva into patient care, primarily by discussing it during appointments. Given workflow/load concerns, only a few key clinicians monitored health tracking/relapses and prompted outreach when needed; two researchers monitored the discussion board and alerted the clinic as needed. Clinician turnover/leave complicated this approach. Contrary to clinicians’ initial concerns, patients showed sustained, mutually supportive use of Seva, with few instances of misuse. Conclusions: Results suggest the value of (a) focusing implementation on behavioral health care providers rather than physicians, (b) assigning a few individuals (not necessarily clinicians) to monitor health tracking, relapses, and the discussion board, (c) anticipating turnover/leave and having designated replacements. Patients showed sustained, positive use of Seva. Trial registration: ClinicalTrials.gov (NCT01963234)

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy