Publications by authors named "Ke Hao"

219 Publications

Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes.

J Clin Invest 2021 Sep 9. Epub 2021 Sep 9.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America.

Apolipoprotein L1 (APOL1) risk-alleles in donor kidneys associate with graft loss but whether recipient risk-allele expression impacts transplant outcomes is unclear. To test whether recipient APOL1 risk-alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT1/17. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in risk-allele carriers vs. non-carriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk-alleles associating with TCMR and DCAL. This finding has broader implications for immune mediated injury to native kidneys.
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http://dx.doi.org/10.1172/JCI146643DOI Listing
September 2021

Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.

Gastroenterology 2021 Sep 2. Epub 2021 Sep 2.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background And Aims: Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension.

Methods: We performed RNA sequence analysis of biopsy specimens from patients with UC with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments.

Results: Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly-ADP ribosylation protein 14 was a predicted key driver gene of extension. Higher poly-ADP ribosylation protein 14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended.

Conclusion: Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.
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http://dx.doi.org/10.1053/j.gastro.2021.08.053DOI Listing
September 2021

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.

Nat Commun 2021 08 24;12(1):5095. Epub 2021 Aug 24.

Universitat Pompeu Fabra, Barcelona, Spain.

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.
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http://dx.doi.org/10.1038/s41467-021-24558-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384884PMC
August 2021

In-hospital use of ACE inhibitors/angiotensin receptor blockers associates with COVID-19 outcomes in African American patients.

J Clin Invest 2021 10;131(19)

Sema4, Stamford, Connecticut, USA.

BACKGROUNDThe angiotensin-converting enzyme (ACE) D allele is more prevalent among African Americans compared with other races and ethnicities and has previously been associated with severe coronavirus disease 2019 (COVID-19) pathogenesis through excessive ACE1 activity. ACE inhibitors/angiotensin receptor blockers (ACE-I/ARB) may counteract this mechanism, but their association with COVID-19 outcomes has not been specifically tested in the African American population.METHODSWe identified 6218 patients who were admitted into Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020, in New York City. We evaluated whether the outpatient and in-hospital use of ACE-I/ARB is associated with COVID-19 in-hospital mortality in an African American compared with non-African American population.RESULTSOf the 6218 patients with COVID-19, 1138 (18.3%) were ACE-I/ARB users. In a multivariate logistic regression model, ACE-I/ARB use was independently associated with a reduced risk of in-hospital mortality in the entire population (OR, 0.655; 95% CI, 0.505-0.850; P = 0.001), African American population (OR, 0.44; 95% CI, 0.249-0.779; P = 0.005), and non-African American population (OR, 0.748, 95% CI, 0.553-1.012, P = 0.06). In the African American population, in-hospital use of ACE-I/ARB was associated with improved mortality (OR, 0.378; 95% CI, 0.188-0.766; P = 0.006), whereas outpatient use was not (OR, 0.889; 95% CI, 0.375-2.158; P = 0.812). When analyzing each medication class separately, ARB in-hospital use was significantly associated with reduced in-hospital mortality in the African American population (OR, 0.196; 95% CI, 0.074-0.516; P = 0.001), whereas ACE-I use was not associated with impact on mortality in any population.CONCLUSIONIn-hospital use of ARB was associated with a significant reduction in in-hospital mortality among COVID-19-positive African American patients.FUNDINGNone.
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http://dx.doi.org/10.1172/JCI151418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483748PMC
October 2021

Comparison of Two Post Preparation Methods in Mandibular Second Molars with a C-shaped Root Canal Configuration.

Chin J Dent Res 2021 Jun;24(2):125-132

Objective: To compare the reduction of residual dentine thickness of two different post preparation methods on the mandibular second molars with a C-shaped root canal configuration.

Methods: A total of 26 extracted right mandibular second molars with a C-shaped root canal configuration were selected and paired based on similar canal morphology. Each of the paired teeth was randomly allocated to the heat and ultrasonic instruments group (HU group) or Peeso Reamer (Mani, Utsonomiya, Japan) group (PR group) (n = 13) and received post preparation with different instruments after the same endodontic treatment. The reduction of residual dentine thickness and the minimal remaining dentine thickness at the apical sections at 4 or 7 mm below the cementoenamel junction (CEJ) were recorded. The data were analysed using an independent samples t test (α = 0.05).

Results: The reduction of residual dentine thickness for the HU group was less than that for the PR group in the two sections. Moreover, at the section 7 mm below the CEJ, the teeth reduction of the distolingual wall in the HU group (0.022 ± 0.007 mm) was significantly lower than that in the PR group (0.101 ± 0.013 mm) (P < 0.01).

Conclusion: Using heat and ultrasonic instruments to perform post preparation could follow the original canal configuration to save more tooth structure in the remaining root canal wall, minimise the reduction of residual dentine thickness and decrease the incidence of root canal perforation.
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http://dx.doi.org/10.3290/j.cjdr.b1530527DOI Listing
June 2021

Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis.

J Zhejiang Univ Sci B 2021 Jun;22(6):492-503

Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou 310006, China.

Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.
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http://dx.doi.org/10.1631/jzus.B2000842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214945PMC
June 2021

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank.

Commun Biol 2021 06 8;4(1):700. Epub 2021 Jun 8.

Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec, QC, Canada.

To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (P = 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.
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http://dx.doi.org/10.1038/s42003-021-02227-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187656PMC
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Precision Medicine Approaches to Vascular Disease: JACC Focus Seminar 2/5.

J Am Coll Cardiol 2021 May;77(20):2531-2550

Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, UNSW Sydney, Kensington, New South Wales, Australia. Electronic address:

In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed "Mendelian vascular diseases," which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.
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http://dx.doi.org/10.1016/j.jacc.2021.04.001DOI Listing
May 2021

Placental gene networks at the interface between maternal PM exposure early in gestation and reduced infant birthweight.

Environ Res 2021 08 18;199:111342. Epub 2021 May 18.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Background: A growing body of evidence links maternal exposure to particulate matter <2.5 μM in diameter (PM) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM exposure prior to and during pregnancy and infant birthweight.

Methods: We evaluated PM exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package.

Results: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM exposure levels averaged across the identified growth restriction window.

Conclusion: Our findings suggest that maternal PM exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections.
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http://dx.doi.org/10.1016/j.envres.2021.111342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195860PMC
August 2021

Deep Analysis of the Peripheral Immune System in IBD Reveals New Insight in Disease Subtyping and Response to Monotherapy or Combination Therapy.

Cell Mol Gastroenterol Hepatol 2021 2;12(2):599-632. Epub 2021 Apr 2.

Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York; Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Inflammatory bowel disease (IBD) is a complex disease with variable presentation, progression, and response to therapies. Current disease classification is based on subjective clinical phenotypes. The peripheral blood immunophenome can reflect local inflammation, and thus we measured 39 circulating immune cell types in a large cohort of IBD and control subjects and performed immunotype:phenotype associations.

Methods: We performed fluorescence-activated cell sorting or CyTOF analysis on blood from 728 Crohn's disease, 464 ulcerative colitis, and 334 non-IBD patients, with available demographics, endoscopic and clinical examinations and medication use.

Results: We observed few immune cell types commonly affected in IBD (lowered natural killer cells, B cells, and CD45RA CD8 T cells). Generally, the immunophenome was distinct between ulcerative colitis and Crohn's disease. Within disease subtype, there were further distinctions, with specific immune cell types associating with disease duration, behavior, and location. Thiopurine monotherapy altered abundance of many cell types, often in the same direction as disease association, while anti-tumor necrosis factor (anti-TNF) monotherapy demonstrated an opposing pattern. Concomitant use of an anti-TNF and thiopurine was not synergistic, but rather was additive. For example, thiopurine monotherapy use alone or in combination with anti-TNF was associated with a dramatic reduction in major subclasses of B cells.

Conclusions: We present a peripheral map of immune cell changes in IBD related to disease entity and therapies as a resource for hypothesis generation. We propose the changes in B cell subsets could affect antibody formation and potentially explain the mechanism behind the superiority of combination therapy through the impact of thiopurines on pharmacokinetics of anti-TNFs.
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http://dx.doi.org/10.1016/j.jcmgh.2021.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263768PMC
April 2021

Revealing consensus gene pathways associated with respiratory functions and disrupted by PM2.5 nitrate exposure at bulk tissue and single cell resolution.

Environ Pollut 2021 Jul 19;280:116951. Epub 2021 Mar 19.

Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; College of Environmental Science and Engineering, Tongji University, Shanghai, China; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Background: Nitrate is a major pollutant component in ambient PM. It is known that chronic exposure to PM NO damages respiratory functions. We aim to explore the underlying toxicological mechanism at single cell resolution.

Methods: We systematically conducted exposure experiments on forty C57BL/6 mice, assessed respiratory functions, and profiled lung transcriptome. . Afterward, we estimated the cell type compositions from RNA-seq data using deconvolution analysis. The genes and pathways associated with respiratory function and dysregulated by to PM NO exposure were characterized at bulk-tissue and single-cell resolution.

Results: PM NO exposure did not significantly modify the cell type composition in lung, but profoundly altered the gene expression within each cell type. At ambient concentration (22 μg/m), exposure significantly (FDR<10%) altered 95 genes' expression. Among the genes associated with respiratory functions, a large fraction (74.6-91.7%) were significantly perturbed by PM NO exposure. For example, among the 764 genes associated with peak expiratory flow (PEF), 608 (79.6%) were affected by exposure (p = 1.92e-345). Pathways known to play role in lung disease pathogenesis, including circadian rhythms, sphingolipid metabolism, immune response and lysosome, were found significantly associated with respiratory functions and disrupted by PM NO exposure.

Conclusions: This study extended our knowledge of PM NO exposure's effect to the levels of lung gene expression, pathways, lung cell type composition and cell specific transcriptome. At single cell resolution, we provided insights in toxicological mechanism of PM NO exposure and subsequent pulmonary disease risks.
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http://dx.doi.org/10.1016/j.envpol.2021.116951DOI Listing
July 2021

Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.

Nat Commun 2021 03 12;12(1):1610. Epub 2021 Mar 12.

Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
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http://dx.doi.org/10.1038/s41467-021-21823-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955030PMC
March 2021

Intestinal Dysbiosis in Young Cystic Fibrosis Rabbits.

J Pers Med 2021 Feb 16;11(2). Epub 2021 Feb 16.

Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Individuals with cystic fibrosis (CF) often experience gastrointestinal (GI) abnormalities. In recent years, the intestinal microbiome has been postulated as a contributor to the development of CF-associated GI complications, hence representing a potential therapeutic target for treatment. We recently developed a rabbit model of CF, which is shown to manifest many human patient-like pathological changes, including intestinal obstruction. Here, we investigated the feces microbiome in young CF rabbits in the absence of antibiotics treatment. Stool samples were collected from seven- to nine-week-old CF rabbits ( = 7) and age-matched wild-type (WT) rabbits ( = 6). Microbiomes were investigated by iTag sequencing of 16S rRNA genes, and functional profiles were predicted using PICRUSt. Consistent with reports of those in pediatric CF patients, the fecal microbiomes of CF rabbits are of lower richness and diversity than that of WT rabbits, with a marked taxonomic and inferred functional dysbiosis. Our work identified a new CF animal model with the manifestation of intestinal dysbiosis phenotype. This model system may facilitate the research and development of novel treatments for CF-associated gastrointestinal diseases.
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http://dx.doi.org/10.3390/jpm11020132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920415PMC
February 2021

Protein interacting with C-kinase 1 is involved in epithelial-mesenchymal transformation and suppresses progress of gastric cancer.

Med Oncol 2021 Mar 4;38(4):34. Epub 2021 Mar 4.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.

Protein interacting with C-kinase 1 (PICK1) is a 415-aa multidomain scaffold protein encoded by the PICK1 gene. Accumulating evidence suggests that PICK1 is involved in the progression of cancer. However, the role of PICK1 in gastric cancer (GC) remains largely unknown. Using integrated analysis of publicly available GC transcriptome data from the Gene Expression Omnibus (GEO) database and immunohistochemistry analysis of samples obtained from clinical GC patients, we found that PICK1 expression was significantly down-regulated in gastric tumor tissues in comparison with adjacent normal tissues. Our analyses also revealed that decreased expression of PICK1 conferred a disadvantage on overall survival time in GC patients. Additionally, PICK1 expression showed a strong association with the epithelial-mesenchymal transition (EMT) pathway, and PICK1 might represent a functional bridge for EMT. Moreover, PICK1 expression was significantly decreased in the EMT subtype of GC and was negatively correlated with the expression of fibronectin 1 (FN1) and myosin light chain 9 (MYL9) mRNAs. Thus, our study provides evidence that PICK1 is a promising biomarker for the molecular etiology of GC.
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http://dx.doi.org/10.1007/s12032-021-01483-0DOI Listing
March 2021

Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19.

Hum Genet 2021 Jun 19;140(6):969-979. Epub 2021 Feb 19.

Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, Vancouver, BC, Canada.

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (P < 5 × 10). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (P < 5 × 10). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.
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http://dx.doi.org/10.1007/s00439-021-02264-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892327PMC
June 2021

Polygenic risk score for alcohol drinking behavior improves prediction of inflammatory bowel disease risk.

Hum Mol Genet 2021 04;30(6):514-523

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Epidemiological studies have long recognized risky behaviors as potentially modifiable factors for the onset and flares of inflammatory bowel disease (IBD); yet, the underlying mechanisms are largely unknown. Recently, the genetic susceptibilities to cigarette smoking, alcohol and cannabis use [i.e. substance use (SU)] have been characterized by well-powered genome-wide association studies (GWASs). We aimed to assess the impact of genetic determinants of SU on IBD risk. Using Mount Sinai Crohn's and Colitis Registry (MSCCR) cohort of 1058 IBD cases and 188 healthy controls, we computed the polygenic risk score (PRS) for SU and correlated them with the observed IBD diagnoses, while adjusting for genetic ancestry, PRS for IBD and SU behavior at enrollment. The results were validated in a pediatric cohort with no SU exposure. PRS of alcohol consumption (DrnkWk), smoking cessation and age of smoking initiation, were associated with IBD risk in MSCCR even after adjustment for PRSIBD and actual smoking status. One interquartile range decrease in PRSDrnkWk was significantly associated to higher IBD risk (i.e. inverse association) (with odds ratio = 1.65 and 95% confidence interval: 1.32, 2.06). The association was replicated in a pediatric Crohn's disease cohort. Colocalization analysis identified a locus on chromosome 16 with polymorphisms in IL27, SULT1A2 and SH2B1, which reached genome-wide statistical significance in GWAS (P < 7.7e-9) for both alcohol consumption and IBD risk. This study demonstrated that the genetic predisposition to SU was associated with IBD risk, independent of PRSIBD and in the absence of SU behaviors. Our study may help further stratify individuals at risk of IBD.
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http://dx.doi.org/10.1093/hmg/ddab045DOI Listing
April 2021

Chronic Exposure to PM Nitrate, Sulfate, and Ammonium Causes Respiratory System Impairments in Mice.

Environ Sci Technol 2021 03 10;55(5):3081-3090. Epub 2021 Feb 10.

Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.

Water-soluble inorganic (WSI) ions are major components of ambient air PM (particulate matter of diameter ≤2.5 μm); however, their potential health effects are understudied. On C57BL/6 mice, we quantified the effect of three major PM WSIs (NO, SO, and NH) on respiratory systems. Exposure scenarios include different WSI types, concentrations, animal development stages (young vs adult), and sex. The exposure effects were comprehensively assessed, with special focus on the respiratory function and tissue/cell level changes. Chronic PM NO exposure produced significant respiratory function decline, mainly presented as airflow obstruction. The decline was more profound in young mice than in adult mice. In young mice, exposure to 22 μg/m PM NO reduced FEV (forced expiratory volume in 0.05 s) by 11.3% ( = 9.6 × 10) and increased pulmonary neutrophil infiltration by 7.9% ( = 7.1 × 10). Causality tests identified that neutrophil infiltration was involved in the biological mechanism underlying PM NO toxicity. In contrast, the effects of PM SO were considerably weaker than NO. PM NO exposure was 3.4 times more potent than PM SO in causing reduction of the peak expiratory flow. PM NH exposure had no statistically significant effects on the respiratory function. In summary, this study provided strong evidence on the adverse impacts of PM WSIs, where the impacts were most profound in young mice exposed to PM NO. If confirmed in humans, toxicity of PM WSI will have broad implications in environment health and policy making.
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http://dx.doi.org/10.1021/acs.est.0c05814DOI Listing
March 2021

Sex-Stratified Gene Regulatory Networks Reveal Female Key Driver Genes of Atherosclerosis Involved in Smooth Muscle Cell Phenotype Switching.

Circulation 2021 Feb 27;143(7):713-726. Epub 2021 Jan 27.

Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, The Netherlands (R.J.G.H., M.M., H.M.d.R.).

Background: Although sex differences in coronary artery disease are widely accepted with women developing more stable atherosclerosis than men, the underlying pathobiology of such differences remains largely unknown. In coronary artery disease, recent integrative systems biological studies have inferred gene regulatory networks (GRNs). Within these GRNs, key driver genes have shown great promise but have thus far been unidentified in women.

Methods: We generated sex-specific GRNs of the atherosclerotic arterial wall in 160 women and age-matched men in the STARNET study (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task). We integrated the female GRNs with single-cell RNA-sequencing data of the human atherosclerotic plaque and single-cell RNA sequencing of advanced atherosclerotic lesions from wild type and Klf4 knockout atherosclerotic smooth muscle cell (SMC) lineage-tracing mice.

Results: By comparing sex-specific GRNs, we observed clear sex differences in network activity within the atherosclerotic tissues. Genes more active in women were associated with mesenchymal cells and endothelial cells, whereas genes more active in men were associated with the immune system. We determined that key drivers of GRNs active in female coronary artery disease were predominantly found in (SMCs by single-cell sequencing of the human atherosclerotic plaques, and higher expressed in female plaque SMCs, as well. To study the functions of these female SMC key drivers in atherosclerosis, we examined single-cell RNA sequencing of advanced atherosclerotic lesions from wild type and Klf4 knockout atherosclerotic SMC lineage-tracing mice. The female key drivers were found to be expressed by phenotypically modulated SMCs and affected by Klf4, suggesting that sex differences in atherosclerosis involve phenotypic switching of plaque SMCs.

Conclusions: Our systems approach provides novel insights into molecular mechanisms that underlie sex differences in atherosclerosis. To discover sex-specific therapeutic targets for atherosclerosis, an increased emphasis on sex-stratified approaches in the analysis of multi-omics data sets is warranted.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930467PMC
February 2021

An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease.

Nat Commun 2021 01 22;12(1):547. Epub 2021 Jan 22.

Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.
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http://dx.doi.org/10.1038/s41467-020-20750-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822923PMC
January 2021

Meta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn's disease.

Hum Genet 2021 Jun 16;140(6):865-877. Epub 2021 Jan 16.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA.

To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci that confer genetic risk for 19 common diseases and traits on body height, type 2 diabetes (T2D), and myocardial infarction (MI). In a meta-analysis of 20,021 subjects, we identified shared genetic determinants of Crohn's Disease (CD), a type of inflammatory bowel disease, and body height (p = 5.5 × 10). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 × 10) and an independent cohort of 510 CD cases and controls (1.57 cm shorter height per PRS-CD interquartile increase, p = 5.0 × 10 and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 × 10, with the effect independent of CD diagnosis). A pathway analysis of the variants overlapping between PRS-height and PRS-CD detected significant enrichment of genes from the inflammatory, immune-mediated and growth factor regulation pathways. This finding supports the clinical observation of growth failure in patients with childhood-onset CD and demonstrates the value of using individual-level data from dbGaP in searching for shared genetic determinants. This information can help provide a refined insight into disease pathogenesis and may have major implications for novel therapies and drug repurposing.
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http://dx.doi.org/10.1007/s00439-020-02250-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102349PMC
June 2021

Characterization of a novel brain cell line from Jian carp (Cyprinus carpio var. Jian).

Fish Physiol Biochem 2021 Apr 6;47(2):439-449. Epub 2021 Jan 6.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.

Jian carp (Cyprinus carpio var. Jian) is an economically important cultured fish in China. Currently, it is facing threats from infectious diseases including koi herpesvirus (KHV). Here, we established a new cell line, designated CCB-J, derived from the brain tissue of the Jian carp. CCB-J cells grew well in Leibovitz's L-15 medium containing 20% fetal bovine serum at 25 °C and have been subcultured for more than 60 passages. At the 30th passage, analysis showed that the number of chromosomes was 100, which is identical to that of other carp variants. Sequencing of the 18S ribosomal DNA confirmed that CCB-J originated from Jian carp. After transfection with the pEGFP-N1 plasmid, green fluorescence was observed in CCB-J. The replication of KHV in CCB-J cells was confirmed by RT-PCR and transmission electron microscopy. The viral titers of KHV in CCB-J cells and CCB cells, which have been widely used in the study of KHV, reached 10 and 10 median tissue culture infectious dose (TCID/mL), respectively, within 14 days. The result of TaqMan PCR revealed that CCB-J cells were more sensitive to KHV than CCB cells. Meanwhile, a cytopathic effect (CPE) was also observed in the CCB-J cells in a shorter time post-infection compared with CCB cells. In summary, the CCB-J cell line will be a useful tool in the study of viral pathogenesis and vaccine research.
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http://dx.doi.org/10.1007/s10695-020-00923-4DOI Listing
April 2021

ACE inhibition and cardiometabolic risk factors, lung and gene expression, and plasma ACE2 levels: a Mendelian randomization study.

R Soc Open Sci 2020 Nov 18;7(11):200958. Epub 2020 Nov 18.

Computer Science Department and Center for Statistics and Machine Learning, Princeton University, Princeton, NJ, USA.

Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of and in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung and gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with gene expression in the Lung eQTL Consortium ( = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung gene expression in the Gene-Tissue Expression (GTEx) study ( = 4 × 10) and with circulating plasma ACE2 levels in the INTERVAL study ( = 0.03), but not with lung expression in the Lung eQTL Consortium study ( = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung and expression or plasma ACE2 levels.
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http://dx.doi.org/10.1098/rsos.200958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735342PMC
November 2020

Air pollution and chronic obstructive pulmonary disease.

Chronic Dis Transl Med 2020 Dec 11;6(4):260-269. Epub 2020 Jul 11.

Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.

There is considerable epidemiological evidence indicating that air pollution has adverse effects on human health and is closely related to respiratory diseases, including chronic obstructive pulmonary disease (COPD). These effects, which can be divided into short- and long-term effects, can manifest as an exacerbation of existing symptoms, impaired lung function, and increased hospitalization and mortality rates. Long-term exposure to air with a high concentration of pollutants may also increase the incidence of COPD. The combined effects of different pollutants may become more complex in the future; hence, there is a need for more intensive research on specific at-risk populations, and formulating corresponding protective strategies is crucial. We aimed to review the epidemiological evidence on the effect of air pollution on COPD, the possible pathophysiological mechanisms underlying this effect, as well as protective measures against the effects of air pollutants in patients with COPD.
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http://dx.doi.org/10.1016/j.cdtm.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729117PMC
December 2020

Gene expression network analysis provides potential targets against SARS-CoV-2.

Sci Rep 2020 12 14;10(1):21863. Epub 2020 Dec 14.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada.

Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets. Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions. ACE2 was in a module of 681 co-expressed genes; 10 genes with moderate-high correlation with ACE2 (r > 0.3, FDR < 0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 31 of these genes were enriched in the gene ontology biologic process 'receptor-mediated endocytosis', and 52 TMPRSS2-correlated genes had known interactions with drug compounds. Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may accelerate the development of COVID-19 therapeutics.
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http://dx.doi.org/10.1038/s41598-020-78818-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736291PMC
December 2020

Cytotoxic and Antiproliferative Effects of β-Mangostin on Rat C6 Glioma Cells Depend on Oxidative Stress Induction via PI3K/AKT/mTOR Pathway Inhibition.

Drug Des Devel Ther 2020 1;14:5315-5324. Epub 2020 Dec 1.

School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325027, People's Republic of China.

Background: Glioma is the most common malignant tumor of the nervous system, which accounts for more than 45% of central nervous system tumors and seriously threatens our health. Because of high mortality rate, limitations, and many complications of traditional treatment methods, new treatment methods are urgently needed. β-Mangostin is a natural compound derived from the fruit of L. and it has anticancer activity in several types of cancer cells. However, the antitumor effect of β-mangostin in glioma has not been clarified. Hence, this study aimed to investigate its therapeutic effects on gliomas.

Materials And Methods: To study the effect of β-mangostin on glioma cells, cell viability assay, reactive oxygen species production, cell cycle, apoptosis, and mitochondrial membrane potential were evaluated in the C6 cell line in vitro. Immunofluorescence and Western blotting were used to analyze protein expression and phosphorylation to study its mechanism of action. A subcutaneous xenograft model was used to investigate the effect of β-mangostin on tumorigenesis in vivo.

Results: We found that β-mangostin can inhibit glioma cell growth and induce oxidative damage in vitro. In addition, it reduces the phosphorylated form levels of PI3K, AKT and mTOR. Furthermore, the phosphorylated form levels of PI3K, AKT and mTOR were increased after the PI3K inhibitor was added. In vivo experiments showed that β-mangostin can inhibit tumor growth as shown by its reduced size and weight.

Conclusion: This study suggests that β-mangostin can inhibit cell proliferation and induce oxidative damage in cells. It is the first study to demonstrate that β-mangostin induces oxidative damage in glioma cells by inhibiting the PI3K/AKT/mTOR signaling pathway.
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http://dx.doi.org/10.2147/DDDT.S278414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718963PMC
September 2021

Crizotinib changes the metabolic pattern and inhibits ATP production in A549 non-small cell lung cancer cells.

Oncol Lett 2021 Jan 19;21(1):61. Epub 2020 Nov 19.

Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China.

Crizotinib, an inhibitor of the hepatocyte growth factor receptor oncogene, has been studied extensively regarding its antitumor and clinically beneficial effects in non-small cell lung cancer (NSCLC). However, crizotinib's effects on cancer cell energy metabolism, which is linked with tumor proliferation and migration, in NSCLC are unclear. Therefore, the present study focused on crizotinib's effect on NSCLC glucose metabolism. Crizotinib's effects on glucose metabolism, proliferation, migration and apoptosis in A549 cells were explored. Several other inhibitors, including 2-DG, rotenone and MG132, were used to define the mechanism of action in further detail. Data showed that crizotinib treatment reduced A549 cell viability, increased glucose consumption and lactate production, while decreased mitochondrial transmembrane potential (Δψm) and ATP production. Crizotinib treatment, combined with rotenone and MG132 treatment, further inhibited ATP production and Δψm and increased reactive oxygen species content. However, crizotinib did not suppress cell proliferation, migration, ATP production, Δψm or mitochondrial-related apoptosis signals further following 2-DG-mediated inhibition of glycolysis. These results indicated that crizotinib induced low mitochondrial function and compensatory high anaerobic metabolism, but failed to maintain sufficient ATP levels. The alternation of metabolic pattern and insufficient ATP supply may serve important roles in the metabolic antitumor mechanism of crizotinib in A549 cells.
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http://dx.doi.org/10.3892/ol.2020.12323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709560PMC
January 2021

Evolution of regulatory signatures in primate cortical neurons at cell-type resolution.

Proc Natl Acad Sci U S A 2020 11 27;117(45):28422-28432. Epub 2020 Oct 27.

Research & Development, James J. Peters VA Medical Center, Bronx, NY 10468;

The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell-type-specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee, and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype-specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder, and drug addiction. We observe preferential evolutionary divergence in neuron subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergoes subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type-dependent gene-expression programs, and provides a resource for further exploration of human brain evolution and function.
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http://dx.doi.org/10.1073/pnas.2011884117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668098PMC
November 2020

Genetic architecture of cardiometabolic risks in people living with HIV.

BMC Med 2020 10 28;18(1):288. Epub 2020 Oct 28.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, United States of America.

Background: Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown.

Methods: We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH.

Results: We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI.

Conclusions: Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.
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http://dx.doi.org/10.1186/s12916-020-01762-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592520PMC
October 2020
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