Publications by authors named "David Scott"

1,278 Publications

  • Page 1 of 1

Discovery of sterically-hindered phenol compounds with potent cytoprotective activities against ox-LDL-induced retinal pigment epithelial cell death as a potential pharmacotherapy.

Free Radic Biol Med 2021 Nov 26. Epub 2021 Nov 26.

Harvard Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, USA. Electronic address:

Late-stage dry age-related macular degeneration (AMD) or geographic atrophy (GA) is an irreversible blinding condition characterized by degeneration of retinal pigment epithelium (RPE) and the associated photoreceptors. Clinical and genetic evidence supports a role for dysfunctional lipid processing and accumulation of harmful oxidized lipids in the pathogenesis of GA. Using oxidized low-density lipoprotein (ox-LDL)-induced RPE death assay, we screened and identified sterically-hindered phenol compounds with potent protective activities for RPE. The phenol-containing PPARγ agonist, troglitazone, protected against ox-LDL-induced RPE cell death, whereas other more potent PPARγ agonists did not protect RPE cells. Knockdown of PPARγ did not affect the protective activity of troglitazone in RPE, confirming the protective function is not due to the thiazolidine (TZD) group of troglitazone. Prototypical hindered phenol trolox and its analogs potently protected against ox-LDL-induced RPE cell death whereas potent antioxidants without the phenol group failed to protect RPE. Hindered phenols preserved lysosomal integrity against ox-LDL-induced damage and FITC-labeled trolox was localized to the lysosomes in RPE cells. Analogs of trolox inhibited reactive oxygen species (ROS) formation induced by ox-LDL uptake in a dose-dependent fashion and were effective at sub-micromolar concentrations. Treatment with trolox analog 2,2,5,7,8-pentamethyl-6-chromanol (PMC) significantly induced the expression of the lysosomal protein NPC-1 and reduced intracellular cholesterol level upon ox-LDL uptake. Our data indicate that the lysosomal-localized hindered phenols are uniquely potent in protecting the RPE against the toxic effects of ox-LDL, and may represent a novel pharmacotherapy to preserve the vision in patients with GA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2021.11.026DOI Listing
November 2021

Digital clock drawing test metrics in older patients before and after endoscopy with sedation: An exploratory analysis.

Acta Anaesthesiol Scand 2021 Nov 23. Epub 2021 Nov 23.

University of Melbourne, Melbourne, Victoria, Australia.

Background: In the postoperative period, clinically feasible instruments to monitor elderly patients' neurocognitive recovery and discharge-readiness, especially after short-stay procedures, are limited. Cognitive monitoring may be improved by a novel digital clock drawing test (dCDT). We screened for cognitive impairment with the 4 A Test (4AT) and then administered the dCDT pre and post short-stay procedure (endoscopy). The primary aim was to investigate whether the dCDT was sensitive to a change in cognitive status postendoscopy. We also investigated if preoperative cognitive status impacted postendoscopy dCDT variables.

Methods: We recruited 100 patients ≥65 years presenting for endoscopy day procedures at a single metropolitan hospital. Participants were assessed after admission and immediately before discharge from the hospital. We administered the 4AT, followed by both command and copy clock conditions of the dCDT. We analysed the total drawing time (dCDT time), as well as scored the drawn clock against the established Montreal Cognitive Assessment (MoCA) criteria both before and after endoscopy.

Results: Linear regression showed higher 4AT test scores (poorer performance) were associated with longer postoperative dCDT time (β = 5.6, p = 0.012) for the command condition after adjusting for preoperative baseline dCDT metrics, sex, age, and years of education.

Conclusion: Postoperative dCDT time-based variables slowed in those with baseline cognitive impairment detected by the 4AT, but not for those without cognitive impairment. Our results suggest the dCDT, using the command mode, may help detect cognitive impairment in patients aged >65 years after elective endoscopy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aas.14003DOI Listing
November 2021

Associations between socioeconomic status and obesity, sarcopenia, and sarcopenic obesity in community-dwelling older adults: The Tasmanian Older Adult Cohort Study.

Exp Gerontol 2021 Dec 14;156:111627. Epub 2021 Nov 14.

Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia; Australian Institute of Musculoskeletal Science, Melbourne Medical School - Western Campus, The University of Melbourne, St Albans, Victoria, Australia.

Background: Social disadvantage may contribute to increased prevalence of sarcopenia and obesity. This study investigated if socioeconomic factors are associated with obesity, sarcopenia, or sarcopenic obesity (SO), in community-dwelling older adults.

Methods: This was a cross-sectional analysis of data from the Tasmanian Older Adult Cohort study. Obesity was defined by body fat percentage (Men: ≥25%; Women: ≥35%) and sarcopenia was defined as the lowest 20% of sex-specific appendicular lean mass (ALM)/height (m) and handgrip strength. Socioeconomic factors investigated were education (tertiary degree, secondary or no secondary school), occupation (high skilled white-collar, low skilled white-collar, or blue-collar) and residential area (advantaged or disadvantaged area). Multinomial logistic regression analyses yielding odds ratios (95% confidence intervals) were performed and adjusted for potential confounders. Mediation analysis was performed.

Results: 1099 older adults (63.0 ± 7.5 years; 51.1% women) participated. Older adults with a tertiary degree were significantly less likely to have obesity (0.68; 0.47, 0.98) and SO (0.48; 0.24, 0.94) compared with those who had no secondary schooling. No associations were found for occupation. Similarly, older adults living in advantaged areas were significantly less likely to have obesity (0.61; 0.39, 0.95). Steps per day mediated the association between residential area and body fat percentage by 51%.

Conclusion: Lower educational attainment, but not occupation, was associated with increased likelihood for both obesity and SO in community-dwelling older adults. Low physical activity levels in disadvantaged areas substantially contributed to higher obesity prevalence in this population. Further research is necessary to confirm whether similar associations exist in populations with greater levels of social disadvantage and to design effective community-based interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exger.2021.111627DOI Listing
December 2021

Adherence to Mediterranean diet and its associations with circulating cytokines, musculoskeletal health and incident falls in community-dwelling older men: The Concord Health and Ageing in Men Project.

Clin Nutr 2021 Dec 23;40(12):5753-5763. Epub 2021 Oct 23.

Centre for Education and Research on Ageing, Concord Hospital, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; The ARC Centre of Excellence in Population Ageing Research, University of Sydney, Sydney, New South Wales, Australia; School of Life and Environmental Sciences, Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia.

Background & Aims: Mediterranean dietary patterns may exert favourable effects on various health conditions. This study aimed to determine associations of adherence to Mediterranean diet as well as its components, with circulating cytokine levels, musculoskeletal health and incident falls in community-dwelling older men.

Methods: Seven hundred ninety-four (794) community-dwelling men with mean age 81.1 ± 4.5 years, who participated in the five-year follow-up of the Concord Health and Ageing in Men Project (CHAMP) were included in the cross-sectional analysis, and 616 attended follow-up three years later. Adherence to Mediterranean diet was assessed using MEDI-LITE (literature-derived Mediterranean diet) score which was obtained using a validated diet history questionnaire. Twenty-four evaluable circulating cytokines were analyzed using Bio-Plex Pro Human Cytokine 27-plex Assay kit. Appendicular lean mass (ALM) and bone mineral density (BMD) were measured using dual-energy x-ray absorptiometry (DXA). Three-year changes in gait speed and hand grip strength were assessed by walking a 6-m course and using a dynamometer respectively and analyzed using linear mixed-effects models. Incident falls over three years were determined through telephone interviews every four months. Multivariable linear regression was utilized to determine the cross-sectional associations between MEDI-LITE scores and circulating cytokines, bone mineral density, ALM, and ALM. Linear mixed-effects models were performed to estimate associations between MEDI-LITE scores and three-year change in hand grip strength and gait speed while negative binomial regression was applied to estimate associations between MEDI-LITE scores and three-year incident falls as well as associations between each MEDI-LITE component and three-year incident falls. Adjustments for multiple comparisons were performed using Benjamini-Hochberg adjustment for multiple testing.

Results: A higher MEDI-LITE score, indicating greater adherence to Mediterranean diet, was associated with higher appendicular lean mass adjusted for body mass index (ALM) (β: 0.004 kg; 95% CI: 0.000, 0.008), and lower incident falls rates (IRR: 0.94; 95% CI: 0.89, 0.99). Higher consumption of monounsaturated fatty acids (IRR: 0.76; 95% CI: 0.59, 0.98) and monounsaturated fatty acids to saturated fatty acids ratio (IRR: 0.72; 95% CI: 0.57, 0.90) were associated with 24%, and 28% lower falls risk in older men respectively. MEDI-LITE scores were not associated with BMD or physical function parameters.

Conclusions: Adherence to a Mediterranean diet is associated with higher ALM, and fewer falls in community-dwelling older men. Monounsaturated and saturated fatty acids were the most important contributors to the association between Mediterranean diet and falls risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnu.2021.10.010DOI Listing
December 2021

Data-sharing practices in publications funded by the Canadian Institutes of Health Research: a descriptive analysis.

CMAJ Open 2021 Oct-Dec;9(4):E980-E987. Epub 2021 Nov 9.

Leslie & Irene Dubé Health Sciences Library (Read), University of Saskatchewan, Saskatoon, Sask.; Taylor Family Digital Library (Ganshorn), University of Calgary, Calgary, Alta.; University Library (Rutley), University of Saskatchewan, Saskatoon, Sask.; University Library (Scott), University of Lethbridge, Lethbridge, Alta.

Background: As Canada increases requirements for research data management and sharing, there is value in identifying how research data are shared and what has been done to make them findable and reusable. This study aimed to understand Canada's data-sharing landscape by reviewing how data funded by the Canadian Institutes of Health Research (CIHR) are shared and comparing researchers' data-sharing practices to best practices for research data management and sharing.

Methods: We performed a descriptive analysis of CIHR-funded publications from PubMed and PubMed Central published between 1946 and Dec. 31, 2019, that indicated that the research data underlying the results of the publication were shared. We analyzed each publication to identify how and where data were shared, who shared data and what documentation was included to support data reuse.

Results: Of 4144 CIHR-funded publications identified, 1876 (45.2%) included accessible data, 935 (22.6%) stated that data were available via request or application, and 300 (7.2%) stated that data sharing was not applicable or possible; we found no evidence of data sharing in 1558 publications (37.6%). Frequent data-sharing methods included via a repository (1549 [37.4%]), within supplementary files (1048 [25.3%]) and via request or application (935 [22.6%]). Overall, 554 publications (13.4%) included documentation that would facilitate data reuse.

Interpretation: Publications funded by the CIHR largely lack the metadata, access instructions and documentation to facilitate data discovery and reuse. Without measures to address these concerns and enhanced support for researchers seeking to implement best practices for research data management and sharing, much CIHR-funded research data will remain hidden, inaccessible and unusable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.9778/cmajo.20200303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580829PMC
November 2021

Baseline predictors of remission, pain and fatigue in rheumatoid arthritis: the TITRATE trial.

Arthritis Res Ther 2021 11 4;23(1):278. Epub 2021 Nov 4.

Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Cutcombe Road, London, SE5 9RJ, UK.

Background: Clinical trials show intensive treatment to induce remission is effective in patients with highly active rheumatoid arthritis (RA). The TITRATE trial showed that the benefits of intensive treatment also extend to moderately active RA. However, many patients failed to achieve remission or show improvements in pain and fatigue. We investigated whether baseline predictors could identify treatment non-responders.

Methods: The impact of obesity, depression, anxiety and illness perception on RA outcomes, including disease activity, remission, pain and fatigue were determined using a pre-planned secondary analysis of the TITRATE trial data.

Results: Body mass index was associated with disease activity levels and remission: obese patients had a higher overall disease activity and fewer obese patients achieved remission. Intensive management was not associated with increased remission in these patients. Obesity was also associated with increased overall pain and fatigue. Anxiety, depression and health perceptions had no discernible impact on disease activity but were associated with high levels of pain and fatigue. There was a strong association between anxiety and high pain scores; and between depression and high fatigue scores; and health perception was strongly related to both. None of the predictors had an important impact on pain and fatigue reduction in cross-sectional analysis.

Conclusions: Disease activity is higher in obese patients and they have fewer remissions over 12 months. Anxiety, depression and health perceptions were associated with higher pain and fatigue scores. Intensive management strategies need to account for these baseline features as they impact significantly on clinical and psychological outcomes.

Trial Registration: ISRCTN 70160382 ; date registered 16 January 2014.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-021-02653-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567573PMC
November 2021

The Economic Burden of Lupus Nephritis: A Systematic Literature Review.

Rheumatol Ther 2021 Nov 3. Epub 2021 Nov 3.

Value Evidence and Outcomes, GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK.

Introduction: Few studies have evaluated the economic burden of lupus nephritis (LN). The aim of this systematic literature review (SLR) was to assess the economic burden (direct and indirect costs, and healthcare resource utilization [HCRU]) associated with LN, with particular focus on the burden of renal flares and end-stage kidney disease (ESKD).

Methods: This SLR (GSK study 213531) was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches of the MEDLINE and Embase databases were conducted for English language publications reporting cost or HCRU data in patients with LN (regardless of age or LN histological class) until December 10, 2019. Handsearching of conference proceedings and keyword-based searches in PubMed, Google, and Google Scholar were also conducted.

Results: Twenty-two studies were identified from 28 publications reporting the cost (n = 19) and HCRU (n = 13) associated with LN. Most studies were from North America (n = 13) and many used administrative claims data (n = 9). LN was associated with substantially higher direct costs (e.g., total annual, hospitalization, and ESKD-related direct costs), total indirect costs, and HCRU (e.g., hospitalization, outpatient services, and medication use) compared with patients without systemic lupus erythematosus (SLE) or non-renal SLE controls. ESKD and dialysis were significant contributors to economic burden. No studies described the cost of renal flares.

Conclusions: The consensus across the 22 studies was that the economic burden of LN is substantial, particularly in active or severe disease, or if there is progression to ESKD. Total direct cost may be underestimated in claims data given the challenges of identifying patients with LN. Further studies are vital to ascertain the cost of renal flares; a renal flare is likely to result in a period of increased HCRU, which could be mitigated by treatments that extend renal remission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40744-021-00368-yDOI Listing
November 2021

The dietary inflammatory index, obesity, type 2 diabetes, and cardiovascular risk factors and diseases.

Obes Rev 2022 Jan 27;23(1):e13349. Epub 2021 Oct 27.

Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.

An unhealthy diet is a recognized risk factor in the pathophysiology of numerous chronic noncommunicable diseases (NCD), including obesity, type 2 diabetes (T2DM), and cardiovascular diseases (CVD). This is, at least in part, due to unhealthy diets causing chronic low-grade inflammation in the gut and systemically. To characterize the inflammatory potential of diet, we developed the Dietary Inflammatory Index (DII®). Following this development, around 500 papers have been published, which examined the association between the DII, energy-adjusted DII (E-DII™), and the children's DII (C-DII™) and many chronic NCDs including obesity and cardiometabolic diseases. Although a previous narrative review published in 2019 briefly summarized the evidence in this area, there was a significant increase in papers on this topic since 2020. Therefore, the purpose of this narrative review is to provide an in-depth updated review by including all papers until July 2021 on DII and its relationship with obesity, T2DM, and CVD. Furthermore, we aim to identify potential gaps in the literature and provide future directions for research. Most studies found that DII was associated with an increased risk of obesity, T2DM, and CVD with some relationships being sex-specific. However, we identified the paucity of papers describing associations between dietary inflammation and T2DM and its risk factors. Few studies used gold-standard measures of cardiometabolic risk factors. We also identified the lack of interventional studies designed to change the inflammatory potential of diets and study its effect on cardiometabolic risk factors and diseases. We recommend that such interventional studies are needed to assess if changes in DII, representing the inflammatory potential of diet, independently of changes in body composition can modulate cardiometabolic risk factors and diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/obr.13349DOI Listing
January 2022

Inconsistent and incomplete retraction of published research: A cross-sectional study on Covid-19 retractions and recommendations to mitigate risks for research, policy and practice.

PLoS One 2021 27;16(10):e0258935. Epub 2021 Oct 27.

Southampton Health Technology Assessments Centre (SHTAC), Wessex Institute, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Background: Retraction of published research can reduce the dissemination of incorrect or misleading information, but concerns have been raised about the clarity and rigor of the retraction process. Failure to clearly and consistently retract research has several risks, for example discredited or erroneous research may inform health research studies (e.g. clinical trials), policies and practices, potentially rendering these unreliable.

Objective: To investigate consistency and clarity of research retraction, based on a case study of retracted Covid-19 research.

Study Design: A cross-sectional study of retracted Covid-19 articles reporting empirical research findings, based on searches of Medline, Embase and Scopus on 10th July and 19th December 2020.

Key Results: We included 46 retracted Covid-19 articles. The number eligible for inclusion nearly doubled, from 26 to 46, in five months. Most articles (67%) were retracted from scientific journals and the remainder from preprint servers. Key findings: (1) reasons for retraction were not reported in 33% (15/46) of cases; (2) time from publication to retraction could not be determined in 43% (20/46) of cases; (3) More than half (59%) of retracted Covid-19 articles (27/46) remained available as original unmarked electronic documents after retraction (33% as full text and 26% as an abstract only). Sources of articles post-retraction were preprint servers, ResearchGate and, less commonly, websites including PubMed Central and the World Health Organization. A retracted journal article which controversially claimed a link between 5G technology and Covid-19 remains available in its original full text from at least 60 different websites.

Conclusions: The retraction process is inconsistent and often ambiguous, with more than half of retracted Covid-19 research articles remaining available, unmarked, from a wide range of online sources. There is an urgent need to improve guidance on the retraction process and to extend this to cover preprint servers. We provide structured recommendations to address these concerns and to reduce the risks that arise when retracted research is inappropriately cited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258935PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550405PMC
November 2021

Gene expression-based model predicts outcome in children with intermediate-risk classical Hodgkin lymphoma.

Blood 2021 Oct 18. Epub 2021 Oct 18.

University of British Columbia, Canada.

Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, determine molecular correlates of treatment failure, and develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared to adult cHL data. Eosinophils, B-cells, and mast cell signatures were enriched in children, while macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs. 90.3%; log-rank P = .0138) independent of interim response, stage, fever and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. ClinicalTrials.gov Identifier: NCT00025259.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021011941DOI Listing
October 2021

Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma.

Proc Natl Acad Sci U S A 2021 10;118(41)

Centre for Lymphoid Cancer, British Columbia (BC) Cancer, Vancouver, BC, Canada V5Z 1L3;

Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4 helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1CXCL13 T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5 normal B cells in close proximity to CXCL13 T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1CXCL13 T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL ( = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1CXCL13 T cells as a treatment target in LR-CHL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2105822118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521678PMC
October 2021

Thermodynamics of semi-specific ligand recognition: the binding of dipeptides to the E.coli dipeptide binding protein DppA.

Eur Biophys J 2021 Dec 5;50(8):1103-1110. Epub 2021 Oct 5.

School of Biosciences, University of Nottingham, Sutton Bonington Campus, LE12 5RD, UK.

This investigation of the temperature dependence of DppA interactions with a subset of three dipeptides (AA. AF and FA) by isothermal titration calorimetry has revealed the negative heat capacity ([Formula: see text]) that is a characteristic of hydrophobic interactions. The observation of enthalpy-entropy compensation is interpreted in terms of the increased structuring of water molecules trapped in a hydrophobic environment, the enthalpic energy gain from which is automatically countered by the entropy decrease associated with consequent loss of water structure flexibility. Specificity for dipeptides stems from appropriate spacing of designated DppA aspartate and arginine residues for electrostatic interaction with the terminal amino and carboxyl groups of a dipeptide, after which the binding pocket closes to become completely isolated from the aqueous environment. Any differences in chemical reactivity of the dipeptide sidechains are thereby modulated by their occurrence in a hydrophobic environment where changes in the structural state of entrapped water molecules give rise to the phenomenon of enthalpy-entropy compensation. The consequent minimization of differences in the value of ΔG for all DppA-dipeptide interactions thus provides thermodynamic insight into the biological role of DppA as a transporter of all dipeptides across the periplasmic membrane.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00249-021-01572-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566422PMC
December 2021

Long-standing donor diabetes and pathologic findings are associated with shorter allograft survival in recipients of kidney transplants from diabetic donors.

Mod Pathol 2021 Sep 28. Epub 2021 Sep 28.

Department of Pathology, Oregon Health & Science University, Portland, OR, USA.

Approximately 6% of deceased kidney donors (DKDs) are diabetic; their kidneys may be associated with worse allograft survival, but published studies suggest that recipient diabetes status has a greater impact on mortality and survival. Since biopsy findings are the most common reason for organ discard, we sought to understand histologic and clinical factors that influence graft survival in patients who receive a kidney from a diabetic DKD. We retrospectively reviewed our institutional experience from 2005 to 2019, and re-evaluated pre-implantation and earliest post-transplant biopsies. Histologic findings were compared against a control cohort of non-diabetic DKD. Of 829 adult DKD transplants, 37 (4.5%) came from diabetic donors. There was no significant difference in diabetic vs. non-diabetic DKD graft survival for all-comers; however, when stratified by duration of donor diabetes, donor diabetes ≥6 years was associated with graft failure. In 25 patients with post-transplant biopsies available, diabetic DKD allografts had significantly greater non-glomerular chronic injury than non-diabetic DKD allografts. Moderate arteriolar hyalinosis (in 24%), moderate tubular atrophy and interstitial fibrosis (IFTA, in 36%), and diabetic glomerulopathy (in 24%) on early post-transplant biopsy were associated with allograft failure. Pre-implantation frozen section discrepancies were more common in long-standing donor diabetes, and arteriolar hyalinosis and IFTA scores on frozen accurately prognosticated graft loss. There was no morphologic improvement in lesions of diabetic nephropathy on short-term follow-up. In conclusion, donor diabetes ≥6 years, and histologic findings on frozen section and early post-transplant biopsy are associated with diabetic DKD allograft loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-021-00927-2DOI Listing
September 2021

Driving CARs to BARs: The Winding Road to Specific Regulatory T Cells for Tolerance.

Authors:
David W Scott

Front Immunol 2021 6;12:742719. Epub 2021 Sep 6.

Department of Medicine (MED), Uniformed Services University of the Health Sciences, Bethesda, MD, United States.

Chimeric antigen receptor (CAR) transduced T cells have significantly improved cancer immunotherapy. Similarly, engineering regulatory T cells (Treg) with specific receptors to endow specificity and increase efficacy of Tregs holds great promise for therapy of a variety of adverse immune responses. In this review, we focus on our approaches using retroviral transduction of specific T-cell receptors, single chain variable fragments (scFv) or antigen in models of monogenic diseases, autoimmunity and allergy. The advantages of each of these for different targets diseases are discussed as well as their potential for clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.742719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450509PMC
September 2021

Muscle function, quality, and relative mass are associated with knee pain trajectory over 10.7 years.

Pain 2021 Jun 17. Epub 2021 Jun 17.

Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia Department of Epidemiology and Preventive Medicine, Monash University Medical School, Melbourne, Australia.

Abstract: Periarticular muscle plays an important role in the pathogenesis of musculoskeletal pain. We recently reported that pain population consists of distinct subgroups of which the causes and mechanisms may differ. This study aimed to examine the association of lean mass, muscle strength, and quality with 10.7-year pain trajectory. Nine hundred forty-seven participants from a population-based cohort study were analysed. Dual-energy X-ray absorptiometry was used to assess lean and fat mass. Leg strength, knee extensor strength, and lower-limb muscle quality were measured/calculated. Knee pain was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire. Radiographic knee osteoarthritis was assessed by X-ray. Three distinct pain trajectories were identified: "Minimal pain" (53%), "Mild pain" (34%), and "Moderate pain" (13%). Higher total and lower-limb lean mass were associated with an increased risk of "Mild pain" and "Moderate pain" trajectories relative to the "Minimal pain" trajectory group, but these associations became nonsignificant after further adjustment for fat mass. Total lean mass percentage was associated with a lower risk of "Mild pain" (relative risk ratio [RRR]: 0.95, 95% confidence interval 0.92-0.98) and "Moderate pain" trajectory (RRR: 0.92, 95% confidence interval 0.87-0.96). Greater leg and knee extensor strength and muscle quality were associated with "Mild pain" and "Moderate pain" trajectories (RRR: 0.52-0.65, all P < 0.05). Similar results were found in those with radiographic knee osteoarthritis. Higher lower-limb muscle strength and quality, and relative lean mass, are associated with a reduced risk of severe knee pain trajectories, suggesting that improving muscle function and composition may protect against persistent unfavourable knee pain courses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/j.pain.0000000000002383DOI Listing
June 2021

Meta-analysis of randomised controlled trials of perioperative dexmedetomidine to reduce delirium and mortality after cardiac surgery.

Br J Anaesth 2021 11 3;127(5):e168-e170. Epub 2021 Sep 3.

Monash Health School of Clinical Sciences, Monash University, Melbourne, VIC, Australia; Prince of Wales Clinical School of Medicine, University of New South Wales, Randwick, NSW, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2021.08.009DOI Listing
November 2021

Comparing the effect of xenon and sevoflurane anesthesia on postoperative neural injury biomarkers: a randomized controlled trial.

Med Gas Res 2022 Jan-Mar;12(1):10-17

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

General anesthesia and surgery are associated with an increase in neural injury biomarkers. Elevations of these neural injury biomarkers in the perioperative period are associated with postoperative delirium. Xenon has been shown to be protective against a range of neurological insults in animal models. It remains to be seen if xenon anesthesia is neuroprotective in the perioperative setting in humans. Twenty-four participants scheduled for lithotripsy were randomized to receive either xenon or sevoflurane general anesthesia. There was no statistically significant difference in the concentrations of postoperative neural injury biomarkers between the xenon and sevoflurane group. Following the procedure there was a significant increase in the concentration from baseline of all three biomarkers at 1 hour post-induction with a return to baseline at 5 hours. General anesthesia for lithotripsy was associated with a significant increase at 1 hour post-induction in the neural injury biomarkers total tau, neurofilament light and tau phosphorylated at threonine 181, a marker of tau phosphorylation. The protocol was approved by the St. Vincent's Hospital Melbourne Ethics Committee (approval No. HREC/18/SVHM/221) on July 20, 2018 and was registered with the Australia New Zealand Clinical Trials Registry (registration No. ACTRN12618000916246) on May 31, 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/2045-9912.324591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447955PMC
October 2021

Anaesthetic depth and delirium after major surgery: a randomised clinical trial.

Br J Anaesth 2021 Nov 28;127(5):704-712. Epub 2021 Aug 28.

Department of Anaesthesiology, Auckland City Hospital, Auckland, New Zealand; Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.

Background: Postoperative delirium is a serious complication of surgery associated with prolonged hospitalisation, long-term cognitive decline, and mortality. This study aimed to determine whether targeting bispectral index (BIS) readings of 50 (light anaesthesia) was associated with a lower incidence of POD than targeting BIS readings of 35 (deep anaesthesia).

Methods: This multicentre randomised clinical trial of 655 at-risk patients undergoing major surgery from eight centres in three countries assessed delirium for 5 days postoperatively using the 3 min confusion assessment method (3D-CAM) or CAM-ICU, and cognitive screening using the Mini-Mental State Examination at baseline and discharge and the Abbreviated Mental Test score (AMTS) at 30 days and 1 yr. Patients were assigned to light or deep anaesthesia. The primary outcome was the presence of postoperative delirium on any of the first 5 postoperative days. Secondary outcomes included mortality at 1 yr, cognitive decline at discharge, cognitive impairment at 30 days and 1 yr, unplanned ICU admission, length of stay, and time in electroencephalographic burst suppression.

Results: The incidence of postoperative delirium in the BIS 50 group was 19% and in the BIS 35 group was 28% (odds ratio 0.58 [95% confidence interval: 0.38-0.88]; P=0.010). At 1 yr, those in the BIS 50 group demonstrated significantly better cognitive function than those in the BIS 35 group (9% with AMTS ≤6 vs 20%; P<0.001).

Conclusions: Among patients undergoing major surgery, targeting light anaesthesia reduced the risk of postoperative delirium and cognitive impairment at 1 yr.

Clinical Trial Registration: ACTRN12612000632897.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2021.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579421PMC
November 2021

Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape.

RSC Chem Biol 2021 Aug 21;2(4):1158-1166. Epub 2021 Jun 21.

Department of Pharmacology, College of Medicine, University of Arizona 1501 North Campbell Drive, P.O. Box 245050 Tucson AZ 85724 USA +520-626-2204 +520-626-2147.

Tar DNA binding (TDP)-43 proteinopathy, typically described as cytoplasmic accumulation of highly modified and misfolded TDP-43 molecules, is characteristic of several neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 proposed proteinopathies include homeostatic imbalance between nuclear and cytoplasmic localization, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and an increase in protein truncation of cytoplasmic TDP-43. Given the therapeutic interest of targeting TDP-43, this review focuses on the current landscape of strategies, ranging from biologics to small molecules, that directly target TDP-43. Antibodies, peptides and compounds have been designed or found to recognize specific TDP-43 sequences but alleviate TDP-43 toxicity through different mechanisms. While two antibodies described here were able to induce degradation of pathological TDP-43, the peptides and small molecules were primarily designed to reduce aggregation of TDP-43. Furthermore, we discuss promising emerging therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1cb00110hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341936PMC
August 2021

Outcome of limited-stage nodular lymphocyte-predominant Hodgkin lymphoma and the impact of a PET-adapted approach.

Blood Adv 2021 09;5(18):3647-3655

Centre for Lymphoid Cancer and Department of Medical Oncology.

Radiotherapy (RT) is typically incorporated into the treatment of limited-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), although it remains unknown whether chemotherapy alone may be suitable in select patients. We evaluated outcomes of limited-stage NLPHL at BC Cancer on the basis of era-specific guidelines: routine RT era, 1995 to 2005 (n = 36), combined modality with 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by RT or RT alone; positron emission tomography (PET) era, after 2005 (n = 63), ABVD alone (4 cycles) if the PET scan after the second cycle of ABVD (PET2) is negative, or treatment is changed to RT if PET2 is positive. Median age of patients was 38 years (range, 16-82 years), 73% were male, and 43% had stage II. With a median follow-up of 10.5 years for all patients, 5-year progression-free survival (PFS) was 93% and was 97% for overall survival (OS), with no difference by treatment era (PFS, P = .13; OS, P = .35). For the 49 patients who had a PET2 scan, 86% were PET negative and 14% were PET positive by Deauville criteria with 5-year PFS rates of 92% and 80% (P = .70), respectively. This is the largest study of a PET-adapted approach in NLPHL and supports that ABVD alone may be a viable option in select patients with a negative PET2 scan, with consideration of acute and long-term toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004375DOI Listing
September 2021

Preventing Delirium and Promoting Long-Term Brain Health: A Clinical Trial Design for the Perioperative Cognitive Enhancement (PROTECT) Trial.

J Alzheimers Dis 2021 ;83(4):1637-1649

Department of Anaesthesia and Acute Pain Medicine, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.

Background: Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are common in older adults and, for many, precipitate functional decline and/or dementia.

Objective: In this protocol, we describe a novel multidisciplinary, multicomponent perioperative intervention that seeks to prevent or reduce POD and associated cognitive decline.

Methods: We will conduct a prospective, single-blind, pragmatic, randomized-controlled trial to compare our tailored multi-disciplinary perioperative pathway against current standard of care practices. We will recruit a total of 692 elective surgical patients aged 65 years or more and randomize them in a 1:1 design. Our perioperative intervention targets delirium risk reduction strategies by emphasizing the importance of early mobilization, nutrition, hydration, cognitive orientation, sensory aids, and avoiding polypharmacy. To promote healthy behavior change, we will provide a tailored psychoeducation program both pre- and postoperatively, focusing on cardiovascular and psychosocial risks for cognitive and functional decline.

Results: Our primary outcome is the incidence of any PND (encapsulating POD and mild or major postoperative neurocognitive disorder) at three months postoperative. Secondary outcomes include any incidence of POD or neurocognitive disorder at 12 months. A specialized delirium screening instrument, the Confusion Assessment Method (3D-CAM), and a neuropsychological test battery, will inform our primary and secondary outcomes.

Conclusion: Delirium is a common and debilitating postoperative complication that contributes to the cognitive and functional decline of older adults. By adopting a multicomponent, multidisciplinary approach to perioperative delirium prevention, we seek to reduce the burden of delirium and subsequent dementia in older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-210438DOI Listing
January 2021

Mutations in the transcription factor FOXO1 mimic positive selection signals to promote germinal center B cell expansion and lymphomagenesis.

Immunity 2021 08;54(8):1807-1824.e14

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

The transcription factor forkhead box O1 (FOXO1), which instructs the dark zone program to direct germinal center (GC) polarity, is typically inactivated by phosphatidylinositol 3-kinase (PI3K) signals. Here, we investigated how FOXO1 mutations targeting this regulatory axis in GC-derived B cell non-Hodgkin lymphomas (B-NHLs) contribute to lymphomagenesis. Examination of primary B-NHL tissues revealed that FOXO1 mutations and PI3K pathway activity were not directly correlated. Human B cell lines bearing FOXO1 mutations exhibited hyperactivation of PI3K and Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) signaling, and increased cell survival under stress conditions as a result of alterations in FOXO1 transcriptional affinities and activation of transcriptional programs characteristic of GC-positive selection. When modeled in mice, FOXO1 mutations conferred competitive advantage to B cells in response to key T-dependent immune signals, disrupting GC homeostasis. FOXO1 mutant transcriptional signatures were prevalent in human B-NHL and predicted poor clinical outcomes. Thus, rather than enforcing FOXO1 constitutive activity, FOXO1 mutations enable co-option of GC-positive selection programs during the pathogenesis of GC-derived lymphomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2021.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475267PMC
August 2021

Impaired cognitive performance on MoCA testing at discharge in elderly patients following day endoscopy and its relationship to preoperative mild cognitive impairment.

Anaesth Intensive Care 2021 Sep 11;49(5):357-365. Epub 2021 Aug 11.

Melbourne Medical School, University of Melbourne, Melbourne, Australia.

In patients admitted to hospital, preoperative mild cognitive impairment predicts postoperative complications. The effect of mild cognitive impairment on discharge readiness among the day stay surgery population is unknown. Our aims were to determine the incidence of impaired cognitive performance at discharge after day stay endoscopy and whether pre-existing mild cognitive impairment was associated with its development. A single-centre cohort study of elective day stay endoscopy patients was undertaken. Over a three-month period, data were collected from 69 patients aged 65 years and over. Patients were cognitively assessed on admission and discharge using the Montreal cognitive assessment tool and the three-minute diagnostic confusion assessment method. At baseline, patients who scored 1.5 or more standard deviations below age-adjusted levels on the Montreal cognitive assessment tool in conjunction with a subjective memory complaint were classified as having mild cognitive impairment. At discharge, patients were classified as having impaired cognitive performance if there was a reduction in the Montreal cognitive assessment tool score by at least two points. We also assessed delirium and subsyndromal delirium at discharge using the three-minute diagnostic confusion assessment method. We identified mild cognitive impairment in 23 patients (33.3%) on admission, and impaired performance on the Montreal cognitive assessment tool test at discharge in 35 (50.7%) patients. There was no association between mild cognitive impairment on admission and impaired cognitive performance at discharge (50.0% versus 51.1%,  = 0.94). This study demonstrates that evidence of impaired cognitive performance on the Montreal cognitive assessment tool testing is present after day stay endoscopy in over 50% of elderly patients, but this is not associated with preoperative cognitive status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0310057X21997459DOI Listing
September 2021

Prognostic significance of FCGR2B expression for the response of DLBCL patients to rituximab or obinutuzumab treatment.

Blood Adv 2021 08;5(15):2945-2957

School of Cancer Sciences, University of Southampton, Southampton, United Kingdom.

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361458PMC
August 2021

Prospective associations of chronic and intrusive pain with sarcopenia and physical disability amongst older Australian men: The Concord Health and Ageing in Men Project.

Exp Gerontol 2021 10 24;153:111501. Epub 2021 Jul 24.

School of Public Health, University of Sydney, New South Wales, Sydney, Australia; The ARC Centre of Excellence in Population Ageing Research, University of Sydney, New South Wales, Sydney, Australia.

Background: Associations of chronic and intrusive pain with sarcopenia and disability in older men are unclear.

Methods: 1452 community-dwelling men aged ≥70 years self-reported chronic pain (pain every day for ≥3 months) and intrusive pain (pain interfering with normal activities in the last 4 weeks) at baseline and five years later, and were classified as having no, prevalent (baseline only), incident (follow-up only) or persistent (both baseline and follow-up) pain. Appendicular lean mass (ALM), hand grip strength and gait speed were assessed. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People (EWGSOP2) and Sarcopenia Diagnosis and Outcomes Consortium (SDOC) definitions. Activity of daily living (ADL) and instrumental activity of daily living (IADL) impairment were assessed by questionnaires.

Results: Approximately 11% of men reported both chronic and intrusive pain. Gait speed, but not ALM or hand grip strength, significantly mediated the relationship of chronic pain and intrusive pain with ADL and IADL disability by 12-57%. Over five years, incident (odds ratio: 1.84; 95% CI: 1.10-3.10) and persistent (3.02; 1.55-5.88) intrusive pain, and persistent chronic pain (2.29; 1.30-4.04), were associated with increased likelihood of incident sarcopenia (SDOC). Incident and persistent intrusive pain were associated with incident ADL (1.91; 1.04-3.52 and 3.78; 1.90-7.51, respectively) and IADL (2.98; 1.81-4.90 and 4.63; 2.22-9.65, respectively) impairment.

Conclusions: Older men with incident and persistent intrusive pain have increased risk for incident sarcopenia and disability over five years. The association of pain with disability appears to be mediated by gait speed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exger.2021.111501DOI Listing
October 2021

Chemical Screen Identifies Diverse and Novel Histone Deacetylase Inhibitors as Repressors of NUT Function: Implications for NUT Carcinoma Pathogenesis and Treatment.

Mol Cancer Res 2021 Nov 20;19(11):1818-1830. Epub 2021 Jul 20.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

NUT carcinoma (NC), characterized most commonly by the BRD4-NUTM1 fusion, is a rare, aggressive variant of squamous carcinoma with no effective treatment. BRD4-NUT drives growth and maintains the poorly differentiated state of NC by activating pro-growth genes such as , through the formation of massive, hyperacetylated, superenhancer-like domains termed megadomains. BRD4-NUT-mediated hyperacetylation of chromatin is facilitated by the chromatin-targeting tandem bromodomains of BRD4, combined with NUT, which recruits the histone acetyltransferase, p300. Here, we developed a high-throughput small-molecule screen to identify inhibitors of transcriptional activation by NUT. In this dCAS9-based GFP-reporter assay, the strongest hits were diverse histone deacetylase (HDAC) inhibitors. Two structurally unrelated HDAC inhibitors, panobinostat and the novel compound, IRBM6, both repressed growth and induced differentiation of NC cells in proportion to their inhibition of NUT transcriptional activity. These two compounds repressed transcription of megadomain-associated oncogenic genes, such as and , while upregulating pro-differentiation, non-megadomain-associated genes, including , , and key cell-cycle regulators, such as . The transcriptional changes correlate with depletion of BRD4-NUT from megadomains, and redistribution of the p300/CBP-associated chromatin acetylation mark, H3K27ac, away from megadomains toward regular enhancer regions previously populated by H3K27ac. In NC xenograft models, we demonstrated that suppression of tumor growth by panobinostat was comparable with that of bromodomain inhibition, and when combined they improved both survival and growth suppression. IMPLICATIONS: The findings provide mechanistic and preclinical rationale for the use of HDAC inhibitors, alone or combined with other agents, in the treatment of NUT carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-21-0259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568634PMC
November 2021

GAMOGONY OF SARCOCYSTIS STRIXI IN MAMMALIAN CELL CULTURES.

J Parasitol 2021 Jul;107(4):562-565

Department of Natural Sciences and Mathematics, Johnson C. Smith University, 100 Beatties Ford Rd., Charlotte, North Carolina 28216.

We are interested in the disease ecology of Sarcocystis species that infect birds of prey as definitive and intermediate hosts. The present study was done to test our hypothesis that a laboratory model can be developed for sarcocystis infection in mammals using gamma interferon gene knockout (KO) mice as a source of Sarcocystis strixi bradyzoites and mammalian cell cultures as a source of sporulated S. strixi oocysts. Sporocysts of S. strixi from a naturally infected barred owl (Strix varia) were fed to KO mice to produce sarcocysts, and the enclosed bradyzoites were obtained by acid-pepsin digestion of abdominal and thigh muscles. Bradyzoites, metrocytes, and an unusual spherical stage were seen in digest before the inoculation of host cells. The spherical stages stained dark with Giemsa stain, but no nucleus was observed, and they were seen free and associated with the concave portion of some bradyzoites. Examination of infected cell cultures demonstrated that macrogamonts and microgamonts were present at 24 hr post-inoculation. Since sporulated oocysts were not observed, we had to reject our current hypothesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1645/20-63DOI Listing
July 2021
-->