Publications by authors named "David L Corcoran"

81 Publications

A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

Ann Surg 2022 Mar 3. Epub 2022 Mar 3.

Department of Surgery, Duke University; Durham, North Carolina, USA Department of Head and Neck Surgery & Communication Sciences, Duke University; Durham, North Carolina, USA Department of Obstetrics and Gynecology, Duke University; Durham, North Carolina, USA Department of Medicine, Duke University; Durham, North Carolina, USA Duke Molecular Physiology Institute, Duke University; Durham, North Carolina, USA Duke Center for Genomic and Computational Biology, Duke University; Durham, North Carolina, USA Department of Molecular Genetics and Microbiology, Duke University; Durham, North Carolina, USA Department of Electrical and Computer Engineering, Duke University; Durham, North Carolina, USA Department of Biostatistics and Bioinformatics, Duke University; Durham, North Carolina, USA.

Objective: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing.

Summary Background Data: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes.

Methods: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing fourteen surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury.

Results: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and post-operative time points and are already seeing evidence of physiologic perturbation between timepoints.

Conclusions: This repository allows for longitudinal, state-of-the-art genomic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.
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http://dx.doi.org/10.1097/SLA.0000000000005429DOI Listing
March 2022

Thymic stromal lymphopoietin controls hair growth.

Stem Cell Reports 2022 Mar 24;17(3):649-663. Epub 2022 Feb 24.

Department of Dermatology, Duke University, P.O. Box 103052, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

Skin tissue regeneration after injury involves the production and integration of signals by stem cells residing in hair follicles (HFSCs). Much remains unknown about how specific wound-derived factors modulate stem cell contribution to hair growth. We demonstrate that thymic stromal lymphopoietin (TSLP) is produced in response to skin injury and during the anagen phase of the hair cycle. Intradermal injection of TSLP promoted wound-induced hair growth (WIHG), whereas neutralizing TSLP receptor (TSLPR) inhibited WIHG. Using flow cytometry and fluorescent immunostaining, we found that TSLP promoted proliferation of transit-amplifying cells. Lgr5-mediated deletion of Tslpr in HFSCs inhibited both wound-induced and exogenous TSLP-induced hair growth. Our data highlight a novel function for TSLP in regulation of hair follicle activity during homeostasis and wound healing.
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http://dx.doi.org/10.1016/j.stemcr.2022.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9039851PMC
March 2022

An integrated comparative physiology and molecular approach pinpoints mediators of breath-hold capacity in dolphins.

Evol Med Public Health 2021 28;9(1):420-430. Epub 2021 Oct 28.

Department of Medicine, Duke University Medical Center, Durham, NC, USA.

Background And Objectives: Ischemic events, such as ischemic heart disease and stroke, are the number one cause of death globally. Ischemia prevents blood, carrying essential nutrients and oxygen, from reaching tissues, leading to cell and tissue death, and eventual organ failure. While humans are relatively intolerant to ischemic events, other species, such as marine mammals, have evolved a unique tolerance to chronic ischemia/reperfusion during apneic diving. To identify possible molecular features of an increased tolerance for apnea, we examined changes in gene expression in breath-holding dolphins.

Methodology: Here, we capitalized on the adaptations possesed by bottlenose dolphins () for diving as a comparative model of ischemic stress and hypoxia tolerance to identify molecular features associated with breath holding. Given that signals in the blood may influence physiological changes during diving, we used RNA-Seq and enzyme assays to examine time-dependent changes in gene expression in the blood of breath-holding dolphins.

Results: We observed time-dependent upregulation of the arachidonate 5-lipoxygenase (ALOX5) gene and increased lipoxygenase activity during breath holding. ALOX5 has been shown to be activated during hypoxia in rodent models, and its metabolites, leukotrienes, induce vasoconstriction.

Conclusions And Implications: The upregulation of ALOX5 mRNA occurred within the calculated aerobic dive limit of the species, suggesting that ALOX5 may play a role in the dolphin's physiological response to diving, particularly in a pro-inflammatory response to ischemia and in promoting vasoconstriction. These observations pinpoint a potential molecular mechanism by which dolphins, and perhaps other marine mammals, respond to the prolonged breath holds associated with diving.
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http://dx.doi.org/10.1093/emph/eoab036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833867PMC
October 2021

DunedinPACE, a DNA methylation biomarker of the pace of aging.

Elife 2022 01 14;11. Epub 2022 Jan 14.

Department of Psychology and Neuroscience, Duke University, Durham, United States.

Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously, we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al., 2020). Here, we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).

Methods: We used data from the Dunedin Study 1972-1973 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.

Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.

Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.

Funding: This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.
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http://dx.doi.org/10.7554/eLife.73420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853656PMC
January 2022

Developmental nicotine exposure and masculinization of the rat preoptic area.

Neurotoxicology 2022 03 10;89:41-54. Epub 2022 Jan 10.

Duke University Nicholas School of the Environment, Durham, NC, 27708, USA; Duke University Medical Center, Department of Obstetrics & Gynecology, Durham, NC, 27701, USA. Electronic address:

Nicotine is a neuroteratogenic component of tobacco smoke, e-cigarettes, and other products and can exert sex-specific effects in the developing brain, likely mediated through sex hormones. Estradiol modulates expression of nicotinic acetylcholine receptors in rats, and plays critical roles in neurodevelopmental processes, including sexual differentiation of the brain. Here, we examined the effects of developmental nicotine exposure on the sexual differentiation of the preoptic area (POA), a brain region that normally displays robust structural sexual dimorphisms and controls adult mating behavior in rodents. Using a rat model of gestational exposure, developing pups were exposed to nicotine (2 mg/kg/day) via maternal osmotic minipump (subcutaneously, sc) throughout the critical window for brain sexual differentiation. At postnatal day (PND) 4, a subset of offspring was analyzed for epigenetic effects in the POA. At PND40, all offspring were gonadectomized, implanted with a testosterone-releasing capsule (sc), and assessed for male sexual behavior at PND60. Following sexual behavior assessment, the area of the sexually dimorphic nucleus of the POA (SDN-POA) was measured using immunofluorescent staining techniques. In adults, normal sex differences in male sexual behavior and in the SDN-POA area were eliminated in nicotine-treated animals. Using novel analytical approaches to evaluate overall masculinization of the adult POA, we identified significant masculinization of the nicotine-treated female POA. In neonates (PND4), nicotine exposure induced trending alterations in methylation-dependent masculinizing gene expression and DNA methylation levels at sexually-dimorphic differentially methylated regions, suggesting that developmental nicotine exposure is capable of triggering masculinization of the rat POA via epigenetic mechanisms.
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http://dx.doi.org/10.1016/j.neuro.2022.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917982PMC
March 2022

Skin Injury Activates a Rapid TRPV1-Dependent Antiviral Protein Response.

J Invest Dermatol 2022 Jan 7. Epub 2022 Jan 7.

Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.

The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins (AVPs) are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate AVP production remains largely unknown. In this study, we characterized the induction and regulation of AVPs after skin injury and identified a key role of TRPV1 in this process. Transcriptional and phenotypic profiling of cutaneous wounds revealed that skin injury induces high levels of AVPs in both mice and humans. Remarkably, pharmacologic and genetic ablation of TRPV1-mediated nociception abrogated the induction of AVPs, including Oas2, Oasl2, and Isg15 after skin injury in mice. Conversely, stimulation of TRPV1 nociceptors was sufficient to induce AVP production involving the CD301b cells‒IL-27‒mediated signaling pathway. Using IL-27 receptor‒knockout mice, we show that IL-27 signaling is required in the induction of AVPs after skin injury. Finally, loss of TRPV1 signaling leads to increased viral infectivity of herpes simplex virus. Together, our data indicate that TRPV1 signaling ensures skin antiviral competence on wounding.
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http://dx.doi.org/10.1016/j.jid.2021.11.041DOI Listing
January 2022

Altered gut ecosystems plus the microbiota's potential for rapid evolution: A recipe for inevitable change with unknown consequences.

Comput Struct Biotechnol J 2021 30;19:5969-5977. Epub 2021 Oct 30.

Institute of Parasitology, Biology Centre, Czech Academy of Sciences, 370 05 České Budějovice, Czech Republic.

In a single human gut, which is estimated to produce 1000-times more bacteria in a single day than the entire human population on Earth as of 2020, the potential for evolution is vast. In addition to the sheer volume of reproductive events, prokaryotes can transfer most genes horizontally, greatly accelerating their potential to evolve. In the face of this evolutionary potential, Westernization has led to profound changes in the ecosystem of the gut, including increased chronic inflammation in many individuals and dramatically reduced fiber consumption and decreased seasonal variation in the diet of most individuals. Experimental work using a variety of model systems has shown that bacteria will evolve within days to weeks when faced with substantial environmental changes. However, studies evaluating the effects of inflammation of the gut on the microbiota are still in their infancy and generally confounded by the effects of the microbiota on the immune system. At the same time, experimental data indicate that complete loss of fiber from the diet constitutes an extinction-level event for the gut microbiota. However, these studies evaluating diet may not apply to Westernized humans who typically have reduced but not absent levels of fiber in their diet. Thus, while it is expected that the microbiota will evolve rapidly in the face of Westernization, experimental studies that address the magnitude of that evolution are generally lacking, and it remains unknown to what extent this evolutionary process affects disease and the ability to treat the disease state.
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http://dx.doi.org/10.1016/j.csbj.2021.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598968PMC
October 2021

IL-27 Derived From Macrophages Facilitates IL-15 Production and T Cell Maintenance Following Allergic Hypersensitivity Responses.

Front Immunol 2021 30;12:713304. Epub 2021 Sep 30.

Department of Dermatology, Duke University, Durham, NC, United States.

Crosstalk between T cells, dendritic cells, and macrophages in temporal leukocyte clusters within barrier tissues provides a new concept for T cell activation in the skin. Activated T cells from these leukocyte clusters play critical roles in the efferent phase of allergic contact hypersensitivity (CHS). However, the cytokines driving maintenance and survival of pathogenic T cells during and following CHS remain mostly unknown. Upon epicutaneous allergen challenge, we here report that macrophages produce IL-27 which then induces IL-15 production from epidermal keratinocytes and dermal myeloid cells within leukocyte clusters. In agreement with the known role of IL-15 as a T cell survival factor and growth cytokine, this signaling axis enhances BCL2 and survival of skin T cells. Genetic depletion or pharmacological blockade of IL-27 in CHS mice leads to abrogated epidermal IL-15 production resulting in a decrease in BCL2 expression in T cells and a decline in dermal CD8 T cells and T cell cluster numbers. These findings suggest that the IL-27 pathway is an important cytokine for regulating cutaneous T cell immunity.
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http://dx.doi.org/10.3389/fimmu.2021.713304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515907PMC
December 2021

Refraining from use diminishes cannabis-associated epigenetic changes in human sperm.

Environ Epigenet 2021 21;7(1):dvab009. Epub 2021 Sep 21.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 2608 Erwin Road, Durham, NC, USA.

Cannabis use alters sperm DNA methylation, but the potential reversibility of these changes is unknown. Semen samples from cannabis users and non-user controls were collected at baseline and again following a 77-day period of cannabis abstinence (one spermatogenic cycle). Users and controls did not significantly differ by demographics or semen analyses. Whole-genome bisulfite sequencing identified 163 CpG sites with significantly different DNA methylation in sperm between groups ( < 2.94 × 10). Genes associated with altered CpG sites were enriched with those involved in development, including cardiogenesis and neurodevelopment. Many of the differences in sperm DNA methylation between groups were diminished after cannabis abstinence. These results indicate that sustained cannabis abstinence significantly reduces the number of sperm showing cannabis-associated alterations at genes important for early development.
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http://dx.doi.org/10.1093/eep/dvab009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455898PMC
September 2021

Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: Exploratory analyses from CALERIE™ phase 2.

Exp Gerontol 2021 11 20;155:111555. Epub 2021 Sep 20.

Pennington Biomedical Research Center, Baton Rouge, LA, USA.

Caloric restriction (CR) improves markers of aging in humans; but it is not known if the fat mass and obesity-associated gene (FTO) rs9939609 single nucleotide polymorphism (SNP), which is associated with appetite and energy intake, influences adherence to prolonged CR. Utilizing data from the two-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 randomized controlled trial, we tested whether the FTO rs9939609 SNP was associated with adherence to CR in healthy adults without obesity. As secondary aims, we assessed whether the FTO rs9939609 SNP was associated with changes in body composition, biomarkers of aging, and eating behaviors. Participants were randomized into either a CR group that targeted a 25% reduction in energy intake compared to the habitual energy intake at baseline, or an ad libitum (AL) control group. Participants were genotyped for the FTO rs9939609 SNP. Dietary adherence was determined through changes in energy intake using doubly labeled water and changes in body composition at baseline, month 12, and month 24 in both the CR and AL condition. Weight, body composition, resting metabolic rate (RMR), adiponectin, insulin, leptin, and eating behaviors were measured at the same timepoints. A total of 144 participants (91 CR and 53 AL, age: 38.6 ± 7.1 years; body mass index: 25.3 ± 1.7 kg/m) were studied. Of these, 27 were homozygous for the 'obesity-risk' A allele (AA), while 44 were homozygous for the T allele (TT) and 73 were heterozygotes (AT). By design, the CR group exhibited greater percent CR compared to the AL group during the trial (P < 0.01), but no genotype-by-treatment interaction was observed for change in energy intake or percent CR (P ≥ 0.40). The FTO rs9939609 SNP was also negligibly associated with change in most other endpoints (P ≥ 0.13), though AAs showed a reduction in RMR adjusted for body composition change over the 24 months relative to TTs (genotype-by-treatment interaction: P = 0.03). In a two-year CR intervention delivered to healthy individuals without obesity, the FTO rs9939609 SNP was not associated with adherence to CR and did not alter improvements in most aging biomarkers.
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http://dx.doi.org/10.1016/j.exger.2021.111555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720865PMC
November 2021

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa.

Front Med (Lausanne) 2021 24;8:665873. Epub 2021 Aug 24.

Department of Dermatology, School of Medicine, Duke University, Durham, NC, United States.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent abscesses, nodules, and sinus tracts in areas of high hair follicle and sweat gland density. These sinus tracts can present with purulent drainage and scar formation. Dysregulation of multiple immune pathways drives the complexity of HS pathogenesis and may account for the heterogeneity of treatment response in HS patients. Using transcriptomic approaches, including single-cell sequencing and protein analysis, we here characterize the innate inflammatory landscape of HS lesions. We identified a shared upregulation of genes involved in interferon (IFN) and antimicrobial defense signaling through transcriptomic overlap analysis of differentially expressed genes (DEGs) in datasets from HS skin, diabetic foot ulcers (DFUs), and the inflammatory stage of normal healing wounds. Overlap analysis between HS- and DFU-specific DEGs revealed an enrichment of gene signatures associated with monocyte/macrophage functions. Single-cell RNA sequencing further revealed monocytes/macrophages with polarization toward a pro-inflammatory M1-like phenotype and increased effector function, including antiviral immunity, phagocytosis, respiratory burst, and antibody-dependent cellular cytotoxicity. Specifically, we identified the STAT1/IFN-signaling axis and the associated IFN-stimulated genes as central players in monocyte/macrophage dysregulation. Our data indicate that monocytes/macrophages are a potential pivotal player in HS pathogenesis and their pathways may serve as therapeutic targets and biomarkers in HS treatment.
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http://dx.doi.org/10.3389/fmed.2021.665873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421606PMC
August 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 09 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612069PMC
September 2021

Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia.

Cancers (Basel) 2021 Jun 7;13(11). Epub 2021 Jun 7.

Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.

Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS).

Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of , patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): -mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment.

Results: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as -mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy.

Conclusions: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.
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http://dx.doi.org/10.3390/cancers13112847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201008PMC
June 2021

Resource profile and user guide of the Polygenic Index Repository.

Nat Hum Behav 2021 12 17;5(12):1744-1758. Epub 2021 Jun 17.

McCourt School of Public Policy, Georgetown University, Washington, DC, USA.

Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs' prediction accuracies, we constructed them using genome-wide association studies-some not previously published-from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the 'additive SNP factor'. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available.
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http://dx.doi.org/10.1038/s41562-021-01119-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678380PMC
December 2021

Urine and Plasma Metabolome of Healthy Adults Consuming the DASH (Dietary Approaches to Stop Hypertension) Diet: A Randomized Pilot Feeding Study.

Nutrients 2021 May 22;13(6). Epub 2021 May 22.

Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.

We aimed to identify plasma and urine metabolites altered by the Dietary Approaches to Stop Hypertension (DASH) diet in a post-hoc analysis of a pilot feeding trial. Twenty adult participants with un-medicated hypertension consumed a Control diet for one week followed by 2 weeks of random assignment to either Control or DASH diet. Non-missing fasting plasma (n = 56) and 24-h urine (n = 40) were used to profile metabolites using untargeted gas chromatography/mass spectrometry. Linear models were used to compare metabolite levels between the groups. In urine, 19 identifiable untargeted metabolites differed between groups at < 0.05. These included a variety of phenolic acids and their microbial metabolites that were higher during the DASH diet, with many at false discovery rate (FDR) adjusted < 0.2. In plasma, eight identifiable untargeted metabolites were different at < 0.05, but only gamma-tocopherol was significantly lower on DASH at FDR adjusted < 0.2. The results provide insights into the mechanisms of benefit of the DASH diet.
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http://dx.doi.org/10.3390/nu13061768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224662PMC
May 2021

ENTPD1 (CD39) Expression Inhibits UVR-Induced DNA Damage Repair through Purinergic Signaling and Is Associated with Metastasis in Human Cutaneous Squamous Cell Carcinoma.

J Invest Dermatol 2021 10 20;141(10):2509-2520. Epub 2021 Apr 20.

Department of Duke Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Pinnell Center for Investigative Dermatology, Department of Duke Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina, USA; Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA. Electronic address:

UVR and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells promote cSCC carcinogenesis, and in other solid tumors, infiltrating regulatory T cells and CD8 T cells express ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39), an ectoenzyme that catalyzes the rate-limiting step in converting extracellular adenosine triphosphate (ATP) to extracellular adenosine (ADO). We previously showed that extracellular purine nucleotides influence DNA damage repair. In this study, we investigate whether DNA damage repair is modulated through purinergic signaling in cSCC. We found increased ENTPD1 expression on T cells within cSCCs when compared with the expression on T cells from blood or nonlesional skin, and accordingly, concentrations of derivative extracellular adenosine diphosphate (ADP), adenosine monophosphate (AMP), and ADO are increased in tumors compared with those in normal skin. Importantly, ENTPD1 expression is significantly higher in human cSCCs that metastasize than in those that are nonmetastatic. We also identify in a mouse model that ENTPD1 expression is induced by UVR in an IL-27-dependent manner. Finally, increased extracellular ADO is shown to downregulate the expression of NAP1L2, a nucleosome assembly protein we show to be important for DNA damage repair secondary to UVR. Together, these data suggest a role for ENTPD1 expression on skin-resident T cells to regulate DNA damage repair through purinergic signaling to promote skin carcinogenesis and metastasis.
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http://dx.doi.org/10.1016/j.jid.2021.02.753DOI Listing
October 2021

Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.

Am J Kidney Dis 2021 07 31;78(1):38-47. Epub 2021 Mar 31.

Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA. Electronic address:

Rationale & Objective: Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participants with and without CKD, as well as the NAE, blood pressure (BP), and metabolomic response to bicarbonate supplementation.

Study Design: Randomized order, cross-over study with controlled feeding.

Setting & Participants: Participants consisted of 8 patients with CKD (estimated glomerular filtration rate 30-59mL/min/1.73m or 60-70mL/min/1.73m with albuminuria) and 6 patients without CKD. All participants had baseline serum bicarbonate concentrations between 20 and 28 mEq/L; they did not have diabetes mellitus and did not use alkali supplements at baseline.

Intervention: Participants were fed a fixed-acid-load diet with bicarbonate supplementation (7 days) and with sodium chloride control (7 days) in a randomized order, cross-over fashion.

Outcomes: Urine NAE, 24-hour ambulatory BP, and 24-hour urine and plasma metabolomic profiles were measured after each period.

Results: During the control period, mean NAE was 28.3±10.2 mEq/d overall without differences across groups (P=0.5). Urine pH, ammonium, and citrate were significantly lower in CKD than in non-CKD (P<0.05 for each). Bicarbonate supplementation reduced NAE and urine ammonium in the CKD group, increased urine pH in both groups (but more in patients with CKD than in those without), and increased; urine citrate in the CKD group (P< 0.2 for interaction for each). Metabolomic analysis revealed several urine organic anions were increased with bicarbonate in CKD, including 3-indoleacetate, citrate/isocitrate, and glutarate. BP was not significantly changed.

Limitations: Small sample size and short feeding duration.

Conclusions: Compared to patients without CKD, those with CKD had lower acid excretion in the form of ammonium but also lower base excretion such as citrate and other organic anions, a potential compensation to preserve acid-base homeostasis. In CKD, acid excretion decreased further, but base excretion (eg, citrate) increased in response to alkali. Urine citrate should be evaluated as an early and responsive marker of impaired acid-base homeostasis.

Funding: National Institute of Diabetes and Digestive and Kidney Diseases and the Duke O'Brien Center for Kidney Research.

Trial Registration: Registered at ClinicalTrials.gov with study number NCT02427594.
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http://dx.doi.org/10.1053/j.ajkd.2020.10.015DOI Listing
July 2021

Male obesity impacts DNA methylation reprogramming in sperm.

Clin Epigenetics 2021 01 25;13(1):17. Epub 2021 Jan 25.

Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Duke University Medical Center, 501 W. Main Street, Suite 510, The Chestefield Building, PO Box 90534, Durham, NC, 27701, USA.

Background: Male obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the next generation. DNA methylation contributes to gene regulation and is erased and re-established during gametogenesis. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental influences, including the obesogenic environment, that could disrupt reprogramming fidelity. Here we conducted an exploratory analysis that showed that overweight/obesity (n = 20) is associated with differences in mature spermatozoa DNA methylation profiles relative to controls with normal BMI (n = 47).

Results: We identified 3264 CpG sites in human sperm that are significantly associated with BMI (p < 0.05) using Infinium HumanMethylation450 BeadChips. These CpG sites were significantly overrepresented among genes involved in transcriptional regulation and misregulation in cancer, nervous system development, and stem cell pluripotency. Analysis of individual sperm using bisulfite sequencing of cloned alleles revealed that the methylation differences are present in a subset of sperm rather than being randomly distributed across all sperm.

Conclusions: Male obesity is associated with altered sperm DNA methylation profiles that appear to affect reprogramming fidelity in a subset of sperm, suggestive of an influence on the spermatogonia. Further work is required to determine the potential heritability of these DNA methylation alterations. If heritable, these changes have the potential to impede normal development.
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http://dx.doi.org/10.1186/s13148-020-00997-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831195PMC
January 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 06 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction.

Nat Genet 2021 01 7;53(1):35-44. Epub 2021 Jan 7.

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.
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http://dx.doi.org/10.1038/s41588-020-00754-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116735PMC
January 2021

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid.

J Alzheimers Dis 2021 ;79(2):511-530

Duke Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.

Background: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.

Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number.

Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction.

Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.

Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.
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http://dx.doi.org/10.3233/JAD-200747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902966PMC
September 2021

Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement.

Patterns (N Y) 2020 05 23;1(2). Epub 2020 Apr 23.

Department of Psychology and Neuroscience, Duke University, Grey Building, 2020 West Main Street, Suite 201, Durham, NC 27705, USA.

DNA methylation plays an important role in both normal human development and risk of disease. The most utilized method of assessing DNA methylation uses BeadChips, generating an epigenome-wide "snapshot" of >450,000 observations (probe measurements) per assay. However, the reliability of each of these measurements is not equal, and little consideration is paid to consequences for research. We correlated repeat measurements of the same DNA samples using the Illumina HumanMethylation450K and the Infinium MethylationEPIC BeadChips in 350 blood DNA samples. Probes that were reliably measured were more heritable and showed consistent associations with environmental exposures, gene expression, and greater cross-tissue concordance. Unreliable probes were less replicable and generated an unknown volume of false negatives. This serves as a lesson for working with DNA methylation data, but the lessons are equally applicable to working with other data: as we advance toward generating increasingly greater volumes of data, failure to document reliability risks harming reproducibility.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467214PMC
http://dx.doi.org/10.1016/j.patter.2020.100014DOI Listing
May 2020

Efficacy of osimertinib against EGFRvIII+ glioblastoma.

Oncotarget 2020 Jun 2;11(22):2074-2082. Epub 2020 Jun 2.

Departments of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both and . Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib's efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (<100 nM) while also inhibiting its downstream signaling. Further, osimertinib inhibited D317's growth and in both heterotopic and orthotopic xenograft models. Additional preclinical studies are warranted to identify EGFRvIII+ GBM's molecular signature most responsive to osimertinib.
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http://dx.doi.org/10.18632/oncotarget.27599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275784PMC
June 2020

Association of Neighborhood Disadvantage in Childhood With DNA Methylation in Young Adulthood.

JAMA Netw Open 2020 06 1;3(6):e206095. Epub 2020 Jun 1.

Department of Psychology and Neuroscience, Duke University, Durham, North Carolina.

Importance: DNA methylation has been proposed as an epigenetic mechanism by which the childhood neighborhood environment may have implications for the genome that compromise adult health.

Objective: To ascertain whether childhood neighborhood socioeconomic disadvantage is associated with differences in DNA methylation by age 18 years.

Design, Setting, And Participants: This longitudinal cohort study analyzed data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative birth cohort of children born between 1994 and 1995 in England and Wales and followed up from age 5 to 18 years. Data analysis was performed from March 15, 2019, to June 30, 2019.

Exposures: High-resolution neighborhood data (indexing deprivation, dilapidation, disconnection, and dangerousness) collected across childhood.

Main Outcomes And Measures: DNA methylation in whole blood was drawn at age 18 years. Associations between neighborhood socioeconomic disadvantage and methylation were tested using 3 prespecified approaches: (1) testing probes annotated to candidate genes involved in biological responses to growing up in socioeconomically disadvantaged neighborhoods and investigated in previous epigenetic research (stress reactivity-related and inflammation-related genes), (2) polyepigenetic scores indexing differential methylation in phenotypes associated with growing up in disadvantaged neighborhoods (obesity, inflammation, and smoking), and (3) a theory-free epigenome-wide association study.

Results: A total of 1619 participants (806 female individuals [50%]) had complete neighborhood and DNA methylation data. Children raised in socioeconomically disadvantaged neighborhoods exhibited differential DNA methylation in genes involved in inflammation (β = 0.12; 95% CI, 0.06-0.19; P < .001) and smoking (β = 0.18; 95% CI, 0.11-0.25; P < .001) but not obesity (β = 0.05; 95% CI, -0.01 to 0.11; P = .12). An epigenome-wide association study identified multiple CpG sites at an arraywide significance level of P < 1.16 × 10-7 in genes involved in the metabolism of hydrocarbons. Associations between neighborhood disadvantage and methylation were small but robust to family-level socioeconomic factors and to individual-level tobacco smoking.

Conclusions And Relevance: Children raised in more socioeconomically disadvantaged neighborhoods appeared to enter young adulthood epigenetically distinct from their less disadvantaged peers. This finding suggests that epigenetic regulation may be a mechanism by which the childhood neighborhood environment alters adult health.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265095PMC
June 2020

Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm.

Elife 2020 05 5;9. Epub 2020 May 5.

Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972-1973. Rates of change in each biomarker over ages 26-38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person's pace of biological aging.
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http://dx.doi.org/10.7554/eLife.54870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282814PMC
May 2020

IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection.

Sci Adv 2020 04 1;6(14):eaay3245. Epub 2020 Apr 1.

Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.

In the skin, antiviral proteins and other immune molecules serve as the first line of innate antiviral defense. Here, we identify and characterize the induction of cutaneous innate antiviral proteins in response to IL-27 and its functional role during cutaneous defense against Zika virus infection. Transcriptional and phenotypic profiling of epidermal keratinocytes treated with IL-27 demonstrated activation of antiviral proteins OAS1, OAS2, OASL, and MX1 in the skin of both mice and humans. IL-27-mediated antiviral protein induction was found to occur in a STAT1- and IRF3-dependent but STAT2-independent manner. Moreover, using IL27ra mice, we demonstrate a significant role for IL-27 in inhibiting Zika virus morbidity and mortality following cutaneous, but not intravenous, inoculation. Together, our results demonstrate a critical and previously unrecognized role for IL-27 in cutaneous innate antiviral immunity against Zika virus.
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http://dx.doi.org/10.1126/sciadv.aay3245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112749PMC
April 2020

A polygenic score for age-at-first-birth predicts disinhibition.

J Child Psychol Psychiatry 2020 12 27;61(12):1349-1359. Epub 2020 Mar 27.

Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.

Background: A recent genome-wide association study identified molecular-genetic associations with age-at-first-birth. However, the meaning of these genetic discoveries is unclear. Drawing on evidence linking early pregnancy with disinhibitory behavior, we tested the hypothesis that genetic discoveries for age-at-first-birth predict disinhibition.

Methods: We included participants with genotype data from the two-decade-long Environmental Risk (E-Risk) Study (N = 1,999) and the four-decade-long Dunedin Study (N = 918). We calculated a genome-wide polygenic score for age-at-first-birth and tested whether it was associated with a range of disinhibitory outcomes across the life course, including low childhood self-control; risk for externalizing psychopathology; officially recorded criminal offending; substance dependence; informant reports of disinhibitory problems; and number of lifetime sexual partners. We further tested whether associations were attributable to accelerated pubertal maturation.

Results: In both cohorts, the age-at-first-birth polygenic score predicted low childhood self-control, externalizing psychopathology, officially recorded criminal offending, substance dependence, and number of sexual partners. Associations were modest, but robust across replication. Childhood disinhibition partly mediated associations between the polygenic score and reproductive behaviors. In contrast, associations were not attributable to accelerated pubertal timing.

Conclusions: Genomic discoveries for age-at-first-birth are about more than reproductive biology: They provide insight into the disinhibitory traits and behaviors that accompany early parenthood. Age-at-first-birth is a useful proxy phenotype for researchers interested in disinhibition. Further, interventions that improve self-regulation abilities may benefit young parents and their children.
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http://dx.doi.org/10.1111/jcpp.13224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529719PMC
December 2020

A transcriptional signature accurately identifies Aspergillus Infection across healthy and immunosuppressed states.

Transl Res 2020 05 20;219:1-12. Epub 2020 Feb 20.

Center for Applied Genomics and Precision Medicine, Duke University, Durham, North Carolina; Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina; Durham VA Medical Center, Durham, North Carolina.

Invasive aspergillosis (IA) is a major cause of critical illness in immunocompromised (IC) patients. However, current fungal tests are limited. Disease-specific gene expression patterns in circulating host cells show promise as novel diagnostics, however it is unknown whether such a 'signature' exists for IA and the effect of iatrogenic immunosuppression on any such biomarkers. Male BALB/c mice were separated into 6 experimental groups based on Aspergillus fumigatus inhalational exposure and IC status (no immunosuppression, cyclophosphamide, and corticosteroids). Mice were sacrificed 4 days postinfection. Whole blood was assayed for transcriptomic responses in peripheral white blood cells via microarray. An elastic net regularized logistic regression was employed to develop classifiers of IA based on gene expression. Aspergillus infection triggers a powerful response in non-IC hosts with 2718 genes differentially expressed between IA and controls. We generated a 146-gene classifier able to discriminate between non-IC infected and uninfected mice with an AUC of 1. However, immunosuppressive medications exhibited a confounding effect on this transcriptomic classifier. After controlling for the genomic effects of immunosuppression, we were able to generate a 187-gene classifier with an AUC of 0.92 in the absence of immunosuppression, 1 with cyclophosphamide, and 0.9 with steroids. The host transcriptomic response to IA is robust and conserved. Pharmacologic perturbation of the host immune response has powerful effects on classifier performance and must be considered when developing such novel diagnostics. When appropriately designed, host-derived peripheral blood transcriptomic responses demonstrate the ability to accurately diagnose Aspergillus infection, even in the presence of immunosuppression.
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http://dx.doi.org/10.1016/j.trsl.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170547PMC
May 2020

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine.

Front Oncol 2020 11;10:117. Epub 2020 Feb 11.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, United States.

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.
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http://dx.doi.org/10.3389/fonc.2020.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026496PMC
February 2020

Identification and activity of the functional complex between hnRNPL and the pseudoexfoliation syndrome-associated lncRNA, LOXL1-AS1.

Hum Mol Genet 2020 07;29(12):1986-1995

Department of Ophthalmology, Duke University, Duke Eye Center AERI Rm 4014, Durham, NC 27710, USA.

Individuals with pseudoexfoliation (PEX) syndrome exhibit various connective tissue pathologies associated with dysregulated extracellular matrix homeostasis. PEX glaucoma is a common, aggressive form of open-angle glaucoma resulting from the deposition of fibrillary material in the conventional outflow pathway. However, the molecular mechanisms that drive pathogenesis and genetic risk remain poorly understood. PEX glaucoma-associated single-nucleotide polymorphisms are located in and affect activity of the promoter of LOXL1-AS1, a long non-coding RNA (lncRNA). Nuclear and non-nuclear lncRNAs regulate a host of biological processes, and when dysregulated, contribute to disease. Here we report that LOXL1-AS1 localizes to the nucleus where it selectively binds to the mRNA processing protein, heterogeneous nuclear ribonucleoprotein-L (hnRNPL). Both components of this complex are critical for the regulation of global gene expression in ocular cells, making LOXL1-AS1 a prime target for investigation in PEX syndrome and glaucoma.
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http://dx.doi.org/10.1093/hmg/ddaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390937PMC
July 2020
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