Comparison of CT and Dixon MR Abdominal Adipose Tissue Quantification Using a Unified Computer-Assisted Software Framework.

PURPOSE: Reliable and objective measures of abdominal fat distribution across imaging modalities are essential for various clinical and research scenarios, such as assessing cardiometabolic disease risk due to obesity. We aimed to compare quantitative measures of subcutaneous (SAT) and visceral (VAT) adipose tissues in the abdomen between computed tomography (CT) and Dixon-based magnetic resonance (MR) images using a unified computer-assisted software framework. MATERIALS AND METHODS: This study included 21 subjects who underwent abdominal CT and Dixon MR imaging on the same day. For each subject, two matched axial CT and fat-only MR images at the L2-L3 and the L4-L5 intervertebral levels were selected for fat quantification. For each image, an outer and an inner abdominal wall regions as well as SAT and VAT pixel masks were automatically generated by our software. The computer-generated results were then inspected and corrected by an expert reader. RESULTS: There were excellent agreements for both abdominal wall segmentation and adipose tissue quantification between matched CT and MR images. Pearson coefficients were 0.97 for both outer and inner region segmentation, 0.99 for SAT, and 0.97 for VAT quantification. Bland-Altman analyses indicated minimum biases in all comparisons. CONCLUSION: We showed that abdominal adipose tissue can be reliably quantified from both CT and Dixon MR images using a unified computer-assisted software framework. This flexible framework has a simple-to-use workflow to measure SAT and VAT from both modalities to support various clinical research applications.

Protocol for the Stimulating ß3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial: a double-blinded, randomised, placebo-controlled study evaluating the effects of mirabegron on functional performance in patients with peripheral arterial disease.

INTRODUCTION: There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the ß3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating ß3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication. METHODS AND ANALYSIS: The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care. ETHICS AND DISSEMINATION: The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes. TRIAL REGISTRATION NUMBER: ACTRN12619000423112; Results.

Bimekizumab: a dual IL-17A and IL-17F inhibitor for the treatment of psoriasis and psoriatic arthritis.

INTRODUCTION: Interleukin (IL)-17 is critical in the pathogenesis of psoriasis and psoriatic arthritis (PsA) with most data suggesting that IL-17A alone was the key cytokine. However, in vitro and in vivo studies have suggested dual blockade of IL-17A and IL-17 F may be more effective than IL-17 A blockade alone. Bimekizumab is the first human monoclonal antibody to exert simultaneous specific inhibition of IL-17A and IL-17 F, and has been studied in several phase II/III trials for psoriasis and PsA. AREAS COVERED: Bimekizumab is not currently licensed for use. A literature search identified clinical trials examining the efficacy and safety of bimekizumab for psoriasis and PsA, and these were critically appraised. EXPERT OPINION: Clinical trials of bimekizumab have been promising, demonstrating a rapid onset of response and superior efficacy compared to three currently licensed biologics: secukinumab, ustekinumab, and adalimumab. Bimekizumab maintains a high level of efficacy with maintenance dosing intervals of 8 weeks, compared with 4 weeks for currently licensed IL-17A antagonists. No unexpected adverse events have been identified, although mild-to-moderate fungal infections occur in approximately 10%. Studies over longer time periods involving additional active comparators would be valuable in further defining the role of bimekizumab amongst currently available treatments.

Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axonal transport with functional recovery.

Gene replacement approaches are leading to a revolution in the treatment of previously debilitating monogenic neurological conditions. However, the application of gene therapy to complex polygenic conditions has been limited. Down-regulation or dysfunction of receptor expression in the disease state or in the presence of excess ligand has been shown to compromise therapeutic efficacy. Here, we offer evidence that combined overexpression of both brain-derived neurotrophic factor and its receptor, tropomyosin receptor kinase B, is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also show efficacy in experimental glaucoma and humanized tauopathy models. Simultaneous administration of a ligand and its receptor by a single gene therapy vector overcomes several problems relating to ligand deficiency and receptor down-regulation that may be relevant to multiple neurodegenerative diseases. This approach shows promise as a strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair.

CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma.

BACKGROUND: Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance. METHODS: Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. RESULTS: Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft. CONCLUSIONS: CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK-rearranged malignancies.

DKC1 is a transcriptional target of GATA1 and drives upregulation of telomerase activity in normal human erythroblasts.

Telomerase is a ribonucleoprotein complex that maintains the length and integrity of telomeres, and thereby enables cellular proliferation. Understanding the regulation of telomerase in hematopoietic cells is relevant to the pathogenesis of leukemia, in which telomerase is constitutively activated, as well as bone marrow failure syndromes that feature telomerase insufficiency. Past studies showing high levels of telomerase in human erythroblasts and a prevalence of anemia in disorders of telomerase insufficiency provide the rationale for investigating telomerase regulation in erythroid cells. Here it is shown for the first time that the telomerase RNA-binding protein dyskerin (encoded by DKC1) is dramatically upregulated as human hematopoietic stem and progenitor cells commit to the erythroid lineage, driving an increase in telomerase activity in the presence of limiting amounts of TERT mRNA. It is also shown that upregulation of DKC1 was necessary for expansion of glycophorin A+ erythroblasts and sufficient to extend telomeres in erythroleukemia cells. Chromatin immunoprecipitation and reporter assays implicated GATA1-mediated transcriptional regulation of DKC1 in the modulation of telomerase in erythroid lineage cells. Together these results describe a novel mechanism of telomerase regulation in erythroid cells which contrasts with mechanisms centered on transcriptional regulation of TERT that are known to operate in other cell types. This is the first study to reveal a biological context in which telomerase is upregulated by DKC1 and to implicate GATA1 in telomerase regulation. The results from this study are relevant to hematopoietic disorders involving DKC1 mutations, GATA1 deregulation and/or telomerase insufficiency.

Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes.

Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.

A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network.

Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.

Dietary supplement recommendations by Saskatchewan chiropractors: results of an online survey.

BACKGROUND: Chiropractors receive training in nutrition during their education, previous surveys have found that chiropractors frequently provide recommendations to patients relating to nutrition and dietary supplement intake. However, it has not been ascertained which specific supplements chiropractors recommend or the types of health conditions for which supplement recommendations are made. OBJECTIVE: The purpose of this study was to determine which dietary supplements are most commonly recommended by chiropractors in the province of Saskatchewan,Canada and the health conditions for which supplement recommendations are made. DESIGN: An online survey of licensed chiropractors practicing in the province of Saskatchewan, Canada was distributed three times following online and in-person notifications of the survey. STATISTICAL ANALYSES PERFORMED: Descriptive statistics were reported, predominantly in the form of means and proportions. RESULTS: A response rate of 45% was obtained. All of the respondents (100%) indicated providing nutritional advice or counselling to patients, while nearly all (99%) indicated providing dietary supplement recommendations to patients. Respondents estimated that they provide nutritional advice or counselling to 31% of their patients on average, and recommend dietary supplements to an average of 25% of their patients. The most commonly recommended supplements were glucosamine sulfate, multivitamins, vitamin C, vitamin D, calcium, omega-3 fatty acids, and probiotics. The most common reasons to recommend dietary supplements were for "general health and wellness" (82% of respondents), "bone health" (74%), "rheumatologic, arthritic, degenerative, or inflammatory conditions' (72%), and "acute and/or chronic musculoskeletal conditions" (65%). CONCLUSION: The majority of respondents indicated providing nutritional counselling and recommendations for dietary supplements to their patients. Respondents generally recommend a small number of dietary supplements and provide these recommendations and counselling to fewer than half of their patients on average, while tending to focus on conditions most closely related to the scope of practice of chiropractors. The findings of this study may have been limited by selection bias owing to the low response rate and as those who respond to surveys are often more likely to respond positively.