Publications by authors named "Brian Walker"

461 Publications

Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial.

Elife 2021 Apr 6;10. Epub 2021 Apr 6.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action.

Methods: In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis.

Results: We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05).

Conclusions: We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity.

Funding: The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura's Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association.

Clinical Trial Number: NCT02152553.
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http://dx.doi.org/10.7554/eLife.62236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024021PMC
April 2021

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

Mol Metab 2021 Mar 27:101225. Epub 2021 Mar 27.

British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, United Kingdom. Electronic address:

Objective: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to the cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue, and impacts glucose homeostasis in the lean and obese state.

Methods: The actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding.

Results: 20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect which was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding.

Conclusions: Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue which influences glucose homeostasis in lean mice.
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http://dx.doi.org/10.1016/j.molmet.2021.101225DOI Listing
March 2021

Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities.

Nat Commun 2021 03 25;12(1):1861. Epub 2021 Mar 25.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient's life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.
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http://dx.doi.org/10.1038/s41467-021-22140-0DOI Listing
March 2021

Our future in the Anthropocene biosphere.

Ambio 2021 Apr 14;50(4):834-869. Epub 2021 Mar 14.

CSIRO, Canberra, Australia.

The COVID-19 pandemic has exposed an interconnected and tightly coupled globalized world in rapid change. This article sets the scientific stage for understanding and responding to such change for global sustainability and resilient societies. We provide a systemic overview of the current situation where people and nature are dynamically intertwined and embedded in the biosphere, placing shocks and extreme events as part of this dynamic; humanity has become the major force in shaping the future of the Earth system as a whole; and the scale and pace of the human dimension have caused climate change, rapid loss of biodiversity, growing inequalities, and loss of resilience to deal with uncertainty and surprise. Taken together, human actions are challenging the biosphere foundation for a prosperous development of civilizations. The Anthropocene reality-of rising system-wide turbulence-calls for transformative change towards sustainable futures. Emerging technologies, social innovations, broader shifts in cultural repertoires, as well as a diverse portfolio of active stewardship of human actions in support of a resilient biosphere are highlighted as essential parts of such transformations.
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http://dx.doi.org/10.1007/s13280-021-01544-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955950PMC
April 2021

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

J Hum Genet 2021 Jan 20. Epub 2021 Jan 20.

BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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http://dx.doi.org/10.1038/s10038-020-00895-6DOI Listing
January 2021

The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma.

Nat Commun 2021 01 12;12(1):293. Epub 2021 Jan 12.

Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA.

Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.
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http://dx.doi.org/10.1038/s41467-020-20524-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804406PMC
January 2021

Corridors of Clarity: Four Principles to Overcome Uncertainty Paralysis in the Anthropocene.

Bioscience 2020 Dec 28;70(12):1139-1144. Epub 2020 Oct 28.

Economics, Athens University of Economics and Business, Athens, Greece, and at the University of Bologna, Bologna, Italy.

Global environmental change challenges humanity because of its broad scale, long-lasting, and potentially irreversible consequences. Key to an effective response is to use an appropriate scientific lens to peer through the mist of uncertainty that threatens timely and appropriate decisions surrounding these complex issues. Identifying such corridors of clarity could help understanding critical phenomena or causal pathways sufficiently well to justify taking policy action. To this end, we suggest four principles: Follow the strongest and most direct path between policy decisions on outcomes, focus on finding sufficient evidence for policy purpose, prioritize no-regrets policies by avoiding options with controversial, uncertain, or immeasurable benefits, aim for getting the big picture roughly right rather than focusing on details.
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http://dx.doi.org/10.1093/biosci/biaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750100PMC
December 2020

Effects of Obesity and Insulin on Tissue-Specific Recycling Between Cortisol and Cortisone in Men.

J Clin Endocrinol Metab 2021 Mar;106(3):e1206-e1220

University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Context: 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11βHSD1 transcripts are more abundant in adipose, but the consequences for oxidation vs reduction remain unknown.

Objective: This work aimed to determine whether 11βHSD1 equilibrium in metabolic tissues is regulated by insulin and obesity.

Methods: A 2-phase, randomized, crossover, single-blinded study in a clinical research facility was conducted of 10 lean and obese healthy men. 11β-Reductase and 11β-dehydrogenase activities were measured during infusion of 9,11,12,12-[2H]4-cortisol and 1,2-[2H]2-cortisone, respectively, on 2 occasions: once during saline infusion and once during a hyperinsulinemic-euglycemic clamp. Arterialized and venous samples were obtained across forearm skeletal muscle and abdominal subcutaneous adipose. Steroids were quantified by liquid chromatography-tandem mass spectrometry and adipose tissue transcripts by quantitative polymerase chain reaction.

Results: Neither whole-body nor tissue-specific rates of production of cortisol or cortisone differed between lean and obese men, however insulin attenuated the diurnal decrease. Whole-body 11β-HSD1 reductase activity tended to be higher in obesity (~ 10%) and was further increased by insulin. Across adipose tissue, 11β-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.99 ± 9.62 vs placebo 11.68 ± 3.63 pmol/100 g/minute; P < .05). Across skeletal muscle, 11β-dehydrogenase activity was reduced by insulin in lean men only (2.55 ± 0.90 vs 4.50 ± 1.42 pmol/100 g/minute, P < .05).

Conclusions: Regeneration of cortisol is upregulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11β-reductase and 11β-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences.
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http://dx.doi.org/10.1210/clinem/dgaa896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947841PMC
March 2021

Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials.

PLoS Med 2020 11 4;17(11):e1003323. Epub 2020 Nov 4.

Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.

Background: The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases.

Methods And Findings: Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies.

Conclusions: In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.
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http://dx.doi.org/10.1371/journal.pmed.1003323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641353PMC
November 2020

Monitoring treatment response and disease progression in myeloma with circulating cell-free DNA.

Eur J Haematol 2021 Feb 10;106(2):230-240. Epub 2020 Nov 10.

Division of Hematology Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, USA.

Circulating cell-free DNA (cfDNA) has the potential to capture spatial genetic heterogeneity in myeloma (MM) patients. We assessed whether cfDNA levels vary according to risk status defined by the 70 gene expression profile (GEP70). cfDNA levels in 77 patients were significantly higher in the GEP70 high-risk (HR) group compared to the low-risk (LR) group and correlated weakly with clinical markers including lactate dehydrogenase, β -microglobulin, and ISS. Patients with high cfDNA levels were associated with a worse PFS (hazard ratio 6.4; 95% CI of ratio 1.9-22) and OS (hazard ratio 4.4; 95% CI of ratio 1.2-15.7). Circulating tumor DNA (ctDNA) was elevated in the HR group and ctDNA correlated strongly with GEP70 risk score (Spearman r = .69, P = .0027). cfDNA concentrations were significantly elevated between days 3-5 after chemotherapy before falling back to baseline levels. ctDNA in two patients showed a similar spike in levels between days 3 and 5 after chemotherapy with a concomitant increase in allele fraction of KRAS mutations. We assessed cfDNA levels in 25 patients with smoldering myeloma with serial samples and showed increased allele fraction of mutated KRAS at progression in cfDNA. Our study shows that cfDNA is a dynamic tool to capture genetic events in myeloma.
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http://dx.doi.org/10.1111/ejh.13541DOI Listing
February 2021

Development of a reef fish biological condition gradient model with quantitative decision rules for the protection and restoration of coral reef ecosystems.

Mar Pollut Bull 2020 Oct 19;159:111387. Epub 2020 Aug 19.

U.S. Environmental Protection Agency, Office of Water, Washington, DC, USA.

Coral reef ecosystems are declining due to multiple interacting stressors. A bioassessment framework focused on stressor-response associations was developed to help organize and communicate complex ecological information to support coral reef conservation. This study applied the Biological Condition Gradient (BCG), initially developed for freshwater ecosystems, to fish assemblages of U.S. Caribbean coral reef ecosystems. The reef fish BCG describes how biological conditions changed incrementally along a gradient of increasing anthropogenic stress. Coupled with physical and chemical water quality data, the BGC forms a scientifically defensible basis to prioritize, protect and restore water bodies containing coral reefs. Through an iterative process, scientists from across the U.S. Caribbean used fishery-independent survey data and expert knowledge to develop quantitative decision rules to describe six levels of coral reef ecosystem condition. The resultant reef fish BCG provides an effective tool for identifying healthy and degraded coral reef ecosystems and has potential for global application.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111387DOI Listing
October 2020

The functional epigenetic landscape of aberrant gene expression in molecular subgroups of newly diagnosed multiple myeloma.

J Hematol Oncol 2020 08 6;13(1):108. Epub 2020 Aug 6.

Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

Background: Multiple Myeloma (MM) is a hematological malignancy with genomic heterogeneity and poor survival outcome. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease.

Methods: Alterations in the DNA methylome were mapped in 52 newly diagnosed MM (NDMM) patients of six molecular subgroups and matched with loci-specific chromatin marks to define their impact on gene expression. Differential DNA methylation analysis was performed using DMAP with a ≥10% increase (hypermethylation) or decrease (hypomethylation) in NDMM subgroups, compared to control samples, considered significant for all the subsequent analyses with p<0.05 after adjusting for a false discovery rate.

Results: We identified differentially methylated regions (DMRs) within the etiological cytogenetic subgroups of myeloma, compared to control plasma cells. Using gene expression data we identified genes that are dysregulated and correlate with DNA methylation levels, indicating a role for DNA methylation in their transcriptional control. We demonstrated that 70% of DMRs in the MM epigenome were hypomethylated and overlapped with repressive H3K27me3. In contrast, differentially expressed genes containing hypermethylated DMRs within the gene body or hypomethylated DMRs at the promoters overlapped with H3K4me1, H3K4me3, or H3K36me3 marks. Additionally, enrichment of BRD4 or MED1 at the H3K27ac enriched DMRs functioned as super-enhancers (SE), controlling the overexpression of genes or gene-cassettes.

Conclusions: Therefore, this study presents the underlying epigenetic regulatory networks of gene expression dysregulation in NDMM patients and identifies potential targets for future therapies.
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http://dx.doi.org/10.1186/s13045-020-00933-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409490PMC
August 2020

KTP Laser Treatment of Early Glottic Cancer: A Multi-Institutional Retrospective Study.

Ann Otol Rhinol Laryngol 2021 Jan 4;130(1):47-55. Epub 2020 Jul 4.

Department of Otorhinolaryngology-Head and Neck Surgery, Mayo Clinic Arizona, Phoenix, AZ, USA.

Objectives: The primary objectives were to report oncologic outcomes of transoral laser microsurgery with potassium-titanyl-phosphate (KTP) laser (TLM-KTP) ablation of early glottic cancer (EGC). The secondary objectives were to report vocal outcomes and to analyze factors that might influence outcomes.

Methods: A multi-institutional, retrospective analysis of consecutive patients treated for T1 or T2 glottic squamous cell carcinoma undergoing TLM-KTP ablation with at least 2 years of follow-up was performed. Patients with prior radiation or surgery for laryngeal disease were excluded.

Primary Outcome Measures Included: surgical failures requiring radiation or laryngectomy, disease-specific survival (DSS), and overall survival (OS). Secondary outcome measures included: pre- and postoperative Voice Handicap Index-10 (VHI-10) scores. The effects of smoking status, stage, and anterior commissure involvement on outcomes were analyzed.

Results: Overall 88 patients met inclusion criteria (83% male, 79.5% current or former smokers). Mean age was 68 (standard deviation (SD): 12). Mean follow-up was 39.5 months (SD: 15.3). Staging included 50 T1a, 21 T1b, and 20 T2 tumors, including three metachronous second primaries. Radiation and/or laryngectomy avoidance was achieved in 87/88 (98.9%) of patients, inclusive of 24 patients requiring KTP re-treatments. Two patients had biopsy-proven recurrence (2.3%), but only 21 of 24 re-treated patients received a formal biopsy. No patients died from laryngeal cancer. DSS and OS were 100% and 92.3%, respectively. The mean VHI-10 scores were 19.3 preoperatively, 3.8 at 6-months postop, and 3.8 at 2-years postop. Smokers had a longer interval to re-treatment ( = .03), patients with T2 lesions had a shorter interval to re-treatment (0.02), and patients with T2 lesions presented with worse initial VHI-10 scores (0.002).

Conclusions: A multi-institutional, retrospective case series of TLM-KTP ablation of EGC demonstrated excellent oncologic outcomes when close surveillance and proactive re-treatments were utilized. Disease-specific survival, overall survival, and vocal function were excellent. Additional studies are necessary to further analyze the merits and risks of this treatment approach.
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http://dx.doi.org/10.1177/0003489420938100DOI Listing
January 2021

Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high-risk mutational patterns.

Blood Cancer J 2020 06 19;10(6):70. Epub 2020 Jun 19.

Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by the presence of ≥20% circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood and, given the rarity of the disease, are challenging to study. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype, we performed whole-exome sequencing and gene expression analysis in 23 and 41 patients with newly diagnosed pPCL, respectively. The results reveal an enrichment of complex structural changes and high-risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular, pPCL patients with traditional low-risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group. Furthermore, gene expression profiling showed upregulation of adverse risk modifiers in pPCL compared to non-pPCL MM, while adhesion molecules and extracellular matrix proteins became increasingly downregulated. In conclusion, this is one of the largest studies to dissect pPCL on a genomic and molecular level.
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http://dx.doi.org/10.1038/s41408-020-0336-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303180PMC
June 2020

Two Cases of Vancomycin-Resistant Bacteremia With Development of Daptomycin-Resistant Phenotype and its Detection Using Oxford Nanopore Sequencing.

Open Forum Infect Dis 2020 Jun 23;7(6):ofaa180. Epub 2020 May 23.

Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

In this work, we report 2 cases of vancomycin-resistant bacteremia with development of daptomycin resistance in 2 patients with acute myeloid leukemia and myelodysplastic syndrome. Mutations related to daptomycin-nonsusceptible phenotype in genes were found in all strains of the study, including those with a minimum inhibitory concentration <1 µg/mL collected before daptomycin therapy. Epidemiological investigation using core genome single nucleotide polymorphism and core genome multilocus sequence typing revealed clonality of all the isolates. In this study, we conclude that real-time genome sequencing of clinical isolates can provide rapid access to timely information on daptomycin-resistant genotypes that would help clinicians speed up and optimize the selection of the antibiotic for treatment.
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http://dx.doi.org/10.1093/ofid/ofaa180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291683PMC
June 2020

Exploring the Temporal Relation between Body Mass Index and Corticosteroid Metabolite Excretion in Childhood.

Nutrients 2020 May 23;12(5). Epub 2020 May 23.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Childhood obesity is associated with alterations in hypothalamus-pituitary-adrenal (HPA) axis activity. However, it is unknown whether these alterations are a cause or a consequence of obesity. This study aimed to explore the temporal relationship between cortisol production and metabolism, and body mass index (BMI). This prospective follow-up study included 218 children (of whom 50% were male), born between 1995 and 1996, who were assessed at the ages of 9, 12 and 17 years. Morning urine samples were collected for assessment of cortisol metabolites by gas chromatography-tandem mass spectrometry, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolic pathways. A cross-lagged regression model was used to determine whether BMI at various ages during childhood predicted later cortisol production and metabolism parameters, or vice versa. The cross-lagged regression coefficients showed that BMI positively predicted cortisol metabolite excretion ( = 0.03), and not vice versa ( = 0.33). In addition, BMI predicted the later balance of 11β-hydroxysteroid dehydrogenase (HSD) activities ( = 0.07), and not vice versa ( = 0.55). Finally, cytochrome P450 3A4 activity positively predicted later BMI ( = 0.01). Our study suggests that changes in BMI across the normal range predict alterations in HPA axis activity. Therefore, the alterations in HPA axis activity as observed in earlier studies among children with obesity may be a consequence rather than a cause of increased BMI.
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http://dx.doi.org/10.3390/nu12051525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284460PMC
May 2020

Sexual dimorphism in cortisol metabolism throughout pubertal development: a longitudinal study.

Endocr Connect 2020 Jun;9(6):542-551

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, The Netherlands.

Objective: Sex differences in disease susceptibility might be explained by sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. However, studies conducted thus far lacked an assessment of Tanner pubertal stage. This study aimed to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism.

Methods: Participants (n = 218) were enrolled from a population-based Netherlands Twin Register. At the ages of 9, 12 and 17 years, Tanner pubertal stage was assessed and early morning urine samples were collected. Cortisol metabolites were measured with GC-MS/MS and ratios were calculated, representing cortisol metabolism enzyme activities, such as A-ring reductases, 11β-HSDs and CYP3A4. Cortisol production and metabolism parameters were compared between sexes for pre-pubertal (Tanner stage 1), early pubertal (Tanner stage 2-3) and late-pubertal (Tanner stage 4-5) stages.

Results: Cortisol metabolite excretion rate decreased with pubertal maturation in both sexes, but did not significantly differ between sexes at any pubertal stage, although in girls a considerable decrease was observed between early and late-pubertal stage (P < 0.001). A-ring reductase activity was similar between sexes at pre- and early pubertal stages and was lower in girls than in boys at late-pubertal stage. Activities of 11β-HSDs were similar between sexes at pre-pubertal stage and favored cortisone in girls at early and late-pubertal stages. Cytochrome P450 3A4 activity did not differ between sexes.

Conclusions: Prepubertally, sexes were similar in cortisol parameters. During puberty, as compared to boys, in girls the activities of A-ring reductases declined and the balance between 11β-HSDs progressively favored cortisone. In addition, girls showed a considerable decrease in cortisol metabolite excretion rate between early and late-pubertal stages. Our findings suggest that the sexual dimorphism in cortisol may either be explained by rising concentrations of sex steroids or by puberty-induced changes in body composition.
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http://dx.doi.org/10.1530/EC-20-0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354723PMC
June 2020

TarPan: an easily adaptable targeted sequencing panel viewer for research and clinical use.

BMC Bioinformatics 2020 Apr 15;21(1):144. Epub 2020 Apr 15.

Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA.

Background: The study of cancer genomics continually matures as the number of patient samples sequenced increases. As more data is generated, oncogenic drivers for specific cancer types are discovered along with their associated risks. This in turn leads to potential treatment strategies that pave the way to precision medicine. However, significant financial and analytical barriers make it infeasible to sequence the entire genome of every patient. In contrast, targeted sequencing panels give reliable information on relevant portions of the genome at a fiscally responsible cost. Therefore, we have created the Targeted Panel (TarPan) Viewer, a software tool, to investigate this type of data.

Results: TarPan Viewer helps investigators understand data from targeted sequencing data by displaying the information through a web browser interface. Through this interface, investigators can easily observe copy number changes, mutations, and structural events in cancer samples. The viewer runs in R Shiny with a robust SQLite backend and its input is generated from bioinformatic algorithms reliably described in the literature. Here we show the results from using TarPan Viewer on publicly available follicular lymphoma, breast cancer, and multiple myeloma data. In addition, we have tested and utilized the viewer internally, and this data has been used in high-impact peer-reviewed publications.

Conclusions: We have designed a flexible, simple to setup viewer that is easily adaptable to any type of cancer targeted sequencing, and has already proven its use in a research laboratory environment. Further, we believe with deeper sequencing and/or more targeted application it could be of use in the clinic in conjunction with an appropriate targeted sequencing panel as a cost-effective diagnostic test, especially in cancers such as acute leukemia or diffuse large B-cell lymphoma that require rapid interventions.
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http://dx.doi.org/10.1186/s12859-020-3477-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158102PMC
April 2020

Long-Term Stability of Cortisol Production and Metabolism Throughout Adolescence: Longitudinal Twin Study.

Twin Res Hum Genet 2020 02 25;23(1):33-38. Epub 2020 Mar 25.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, the Netherlands.

Life-course experiences have been postulated to program hypothalamus-pituitary-adrenal (HPA) axis activity, suggesting that HPA axis activity is, at least partially, stable over time. Yet, there is paucity of data on the long-term stability of cortisol production and metabolism. We performed a prospective follow-up study in twins recruited from a nationwide register to estimate the stability of cortisol production and metabolism over time, and the contribution of genetic and environmental factors to this stability. In total, 218 healthy mono- and dizygotic twins were included. At the ages of 9, 12 and 17 years, morning urine samples were collected for assessment (by gas chromatography-tandem mass spectrometry) of cortisol metabolites, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolism activity. Our results showed a low stability for both cortisol metabolite excretion rate (with correlations <.20) and cortisol metabolism activity indices (with correlations of .25 to .46 between 9 and 12 years, -.02 to .15 between 12 and 17 years and .09 to .28 between 9 and 17 years). Because of the low stability over time, genetic and environmental contributions to this stability were difficult to assess, although it seemed to be mostly determined by genetic factors. The low stability in both cortisol production and metabolism between ages 9 and 17 years reflects the dynamic nature of the HPA axis.
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http://dx.doi.org/10.1017/thg.2020.6DOI Listing
February 2020

Antibiotic Resistance in Marine Microbial Communities Proximal to a Florida Sewage Outfall System.

Antibiotics (Basel) 2020 Mar 11;9(3). Epub 2020 Mar 11.

Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, 8000 North Ocean Drive, Dania Beach, FL 33004, USA.

Water samples were collected at several wastewater treatment plants in southeast Florida, and water and sediment samples were collected along and around one outfall pipe, as well as along several transects extending both north and south of the respective outfall outlet. Two sets of samples were collected to address potential seasonal differences, including 38 in the wet season (June 2018) and 42 in the dry season (March 2019). Samples were screened for the presence/absence of 15 select antibiotic resistance gene targets using the polymerase chain reaction. A contrast between seasons was found, with a higher frequency of detections occurring in the wet season and fewer during the dry season. These data illustrate an anthropogenic influence on offshore microbial genetics and seasonal flux regarding associated health risks to recreational users and the regional ecosystem.
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http://dx.doi.org/10.3390/antibiotics9030118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148511PMC
March 2020

Social dimensions of fertility behavior and consumption patterns in the Anthropocene.

Proc Natl Acad Sci U S A 2020 03 12;117(12):6300-6307. Epub 2020 Mar 12.

Department of Agricultural and Resource Economics, University of California, Davis, CA 95616.

We consider two aspects of the human enterprise that profoundly affect the global environment: population and consumption. We show that fertility and consumption behavior harbor a class of externalities that have not been much noted in the literature. Both are driven in part by attitudes and preferences that are not egoistic but socially embedded; that is, each household's decisions are influenced by the decisions made by others. In a famous paper, Garrett Hardin [G. Hardin, 162, 1243-1248 (1968)] drew attention to overpopulation and concluded that the solution lay in people "abandoning the freedom to breed." That human attitudes and practices are socially embedded suggests that it is possible for people to reduce their fertility rates and consumption demands without experiencing a loss in wellbeing. We focus on fertility in sub-Saharan Africa and consumption in the rich world and argue that bottom-up social mechanisms rather than top-down government interventions are better placed to bring about those ecologically desirable changes.
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http://dx.doi.org/10.1073/pnas.1909857117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104011PMC
March 2020

Differential RNA splicing as a potentially important driver mechanism in multiple myeloma.

Haematologica 2021 Mar 1;106(3):736-745. Epub 2021 Mar 1.

Division of Hematology Oncology, Indiana University, Indianapolis, IN, USA.

Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple Myeloma is a molecularly heterogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We look at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in comparison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enumeration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.
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http://dx.doi.org/10.3324/haematol.2019.235424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927887PMC
March 2021

Diet-induced weight loss alters hepatic glucocorticoid metabolism in type 2 diabetes mellitus.

Eur J Endocrinol 2020 Apr;182(4):447-457

Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Context: Altered tissue-specific glucocorticoid metabolism has been described in uncomplicated obesity and type 2 diabetes. We hypothesized that weight loss induced by diet and exercise, which has previously been shown to reverse abnormal cortisol metabolism in uncomplicated obesity, also normalizes cortisol metabolism in patients with type 2 diabetes.

Objective: Test the effects of a diet intervention with added exercise on glucocorticoid metabolism.

Design: Two groups followed a Paleolithic diet (PD) for 12 weeks with added 180 min of structured aerobic and resistance exercise per week in one randomized group (PDEX).

Setting: Umeå University Hospital.

Participants: Men and women with type 2 diabetes treated with lifestyle modification ± metformin were included. Twenty-eight participants (PD, n = 15; PDEX, n = 13) completed measurements of glucocorticoid metabolism.

Main Outcome Measures: Changes in glucocorticoid metabolite levels in 24-h urine samples, expression of HSD11B1 mRNA in s.c. adipose tissue and conversion of orally administered cortisone to cortisol measured in plasma. Body composition and insulin sensitivity were measured using a hyperinsulinemic-euglycemic clamp, and liver fat was measured by magnetic resonance spectroscopy.

Results: Both groups lost weight and improved insulin sensitivity. Conversion of orally taken cortisone to plasma cortisol and the ratio of 5α-THF + 5β-THF/THE in urine increased in both groups.

Conclusions: These interventions caused weight loss and improved insulin sensitivity with concomitant increases in the conversion of cortisone to cortisol, which is an estimate of hepatic HSD11B1 activity. This suggests that dysregulation of liver glucocorticoid metabolism in these patients is a consequence rather than a cause of metabolic dysfunction.
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http://dx.doi.org/10.1530/EJE-19-0901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087495PMC
April 2020

Multiple Myeloma DREAM Challenge reveals epigenetic regulator PHF19 as marker of aggressive disease.

Leukemia 2020 07 14;34(7):1866-1874. Epub 2020 Feb 14.

Sage Bionetworks, Seattle, WA, USA.

While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients does not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involves assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post-challenge analysis identified a novel expression-based risk marker, PHF19, which has recently been found to have an important biological role in multiple myeloma. Lastly, we show that a simple four feature predictor composed of age, ISS, and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included.
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http://dx.doi.org/10.1038/s41375-020-0742-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326699PMC
July 2020

Complete Genome Sequences of Four Isolates of Vancomycin-Resistant Enterococcus faecium with the Gene and Two Daptomycin Resistance Mutations, Obtained from Two Inpatients with Prolonged Bacteremia.

Microbiol Resour Announc 2020 Feb 6;9(6). Epub 2020 Feb 6.

Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

Here, we present complete genome sequences of four isolates, obtained from two patients with apparent vancomycin-resistant bacteremia; these isolates also carried two mutations known to be associated with daptomycin resistance. Sequences were obtained using and hybrid assembly of Oxford Nanopore and Illumina sequence data.
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http://dx.doi.org/10.1128/MRA.01380-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005116PMC
February 2020

Long-term outcomes after autologous stem cell transplantation for multiple myeloma.

Blood Adv 2020 Jan;4(2):422-431

Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, NY.

As multiple myeloma (MM) treatments evolve, frequent updates are required to monitor the long-term effect of changes in approach. Traditionally, MM is considered an incurable disease, with most patients eventually relapsing. However, improvements in treatments has raised the possibility that MM might be functionally curable. To examine improvements in long-term survival, we followed 4329 patients with newly diagnosed MM treated with autologous stem cell transplantation (ASCT) at the University of Arkansas for Medical Sciences from 1989 through 2018. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis, Cox proportional hazards models, relative survival analysis, and cure modeling among different time periods, risk groups, and demographic traits. Steady improvements in OS were found, with patients treated in 2014 or later having superior OS (hazard ratio, 0.35; 95% confidence interval [CI], 0.27-0.45) and reduced excess risk for MM death (relative excess risk, 0.30; 95% CI, 0.22-0.41) compared with patients treated in 1997 or earlier. Patients treated during intervening time periods often had intermediate survival, but trends in OS, PFS, and landmarked analyses were inconsistent. Cure models support the potential for cure, ranging from 6.3% to 31.3%, depending on the year of treatment, with 10.0% to 18.6% of patients achieving their normal life expectancy across multiple periods. There was some evidence of reductions in early mortality within 3 years of diagnosis, longer complete response (CR) duration, and reductions in relapse after achieving CR. However, results differed depending on age, risk group, and cytogenetic characteristics.
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http://dx.doi.org/10.1182/bloodadvances.2019000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988393PMC
January 2020

and Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma.

Clin Cancer Res 2020 05 27;26(10):2422-2432. Epub 2020 Jan 27.

Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Purpose: Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets.

Experimental Design: We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials.

Results: As expected, the most commonly mutated genes were , and , making up 44% of patients. Double-Hit and and mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead -mutated patients showed co-occurring alterations in , or activating mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance.

Conclusions: Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1507DOI Listing
May 2020

GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement.

J Clin Endocrinol Metab 2020 05;105(5)

MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Addenbrookes Treatment Centre, UK.

Context: GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15.

Objective: To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels.

Methods And Results: We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001.

Conclusions: GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.
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http://dx.doi.org/10.1210/clinem/dgz277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105349PMC
May 2020