Genetics and Genomics Commons^™

Pulmonary Microrna Profiles Identify Involvement Of Creb1 And Sec14l3 In Bronchial Epithelial Changes In Allergic Asthma., Sabine Bartel, Nikola Schulz, Francesca Alessandrini, Andrea C Schamberger, Philipp Pagel, Fabian J Theis, Katrin Milger, Elfriede Noessner, Stephen M Stick, Anthony Kicic, Oliver Eickelberg, Robert J Freishtat, Susanne Krauss-Etschmann

Medicine Faculty Publications

Asthma is highly prevalent, but current therapies cannot influence the chronic course of the disease. It is thus important to understand underlying early molecular events. In this study, we aimed to use microRNAs (miRNAs) - which are critical regulators of signaling cascades - to identify so far uncharacterized asthma pathogenesis pathways. Therefore, deregulation of miRNAs was assessed in whole lungs from mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI). In silico predicted target genes were confirmed in reporter assays and in house-dust-mite (HDM) induced AAI and primary human bronchial epithelial cells (NHBE) cultured at the air-liquid interface. We identified and …

Molecular Evolution Of App Gene In Alzheimer's Disease, Mary E. Husk

Student Research Conference Select Presentations

The purpose of my study is to examine the role of the APP gene in Alzheimer's Disease. Also this study intends to explore the interactions between the APP, PSEN1, and PSEN2 genes in the molecular pathways related to the Alzheimer's disease . My central theme of research is to decipher the molecular evolution of the APP gene and utilize the phylogenetic analyses to examine specific molecular domains involved in the molecular pathways related to Alzheimer's disease . Current research indicates the role of several types of mutations discovered in the APP gene related to disease. My study intends to look …

Development Of An Interleukin-4-Inducing Principle From Schistosoma Mansoni Eggs (Ipse)-Specific Pcr Assay As A Quantitative Predictor Of Schistosomiasis-Associated Morbidity, Dannah Farah, Evaristis Mbanefo, Michael H. Hsieh

GW Research Days 2016 - 2020

Schistosomiasis is a neglected tropical disease affecting between 200-500 million people worldwide. The two species causing most human cases of schistosomiasis are Schistosoma mansoni and Schistosoma haematobium. The gold standard for diagnosis is parasitological detection of parasite eggs in stool using the Kato-Katz method. Counting eggs shed in stool is labor-intensive and inaccurate. Interleukin-4- inducing principle from Schistosoma mansoni eggs (IPSE) is the most abundant secreted protein from schistosome eggs. We hypothesized that the mRNA transcripts of the IPSE protein may be found in the liver tissue and stool of experimentally infected animals, and that these transcripts can be specifically …

Differential Mrna Expression In Ectopic Germinal Centers Of Myasthenia Gravis Thymus, Manjistha Sengupta, Bi-Dar Wang, Norman H. Lee, Gary Cutter, Linda L. Kusner, Henry J. Kaminski

GW Research Days 2016 - 2020

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder resulting in weakness of voluntary muscles. It is caused by antibodies directed against proteins present at the post-synaptic surface of neuromuscular junction (NMJ). A characteristic pathology of patients with early onset MG is thymic hyperplasia with ectopic germinal centers (GC). However, mechanisms that trigger and maintain thymic hyperplasia are poorly characterized.

In order to determine the central mechanisms involved in the pathology, thymus samples from MG patients were assessed by histology and grouped based on appearance of GC compared to samples without them. We assessed the differential mRNA expression profiles between the …

Csf Protein Changes Associated With Hippocampal Sclerosis Risk Gene Variants Highlight Impact Of Grn/Pgrn, David W. Fardo, Yuriko Katsumata, John S. K. Kauwe, Yuetiva Deming, Oscar Harari, Carlos Cruchaga, Alzheimer’S Disease Neuroimaging Initiative, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk …

Overcoming Hurdles To Development Of A Vaccine Against Pneumocystis Jirovecii, Beth A. Garvy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Development of Pneumocystis pneumonia (PCP) is a common problem among immunosuppressed individuals. There are windows of opportunity in which vaccination would be beneficial, but to date, no vaccines have made it to clinical trials. Significant hurdles to vaccine development include host range specificity, making it difficult to translate from animal models to humans. Discovery of cross-reactive epitopes is critical to moving vaccine candidates from preclinical animal studies to clinical trials.

Hla-B*57:01 Allele Prevalence In Hiv-Infected North American Subjects And The Impact Of Allele Testing On The Incidence Of Abacavir-Associated Hypersensitivity Reaction In Hla-B*57:01-Negative Subjects, Catherine Small, D Margolis, M Shaefer, L Ross

NYMC Faculty Publications

BACKGROUND: The presence of the HLA-B*57:01 allele in HIV-infected subjects is associated with a higher risk of abacavir-associated hypersensitivity reaction (ABC HSR). HLA-B*57:01 allele prevalence varies in different populations, but HLA-B*57:01 testing with immunological confirmation has had a negative predictive value for ABC HSR between 97 and 100%. METHODS: In the ASSURE study (EPZ113734), the HLA-B*57:01 prevalence in virologically suppressed, antiretroviral treatment-experienced, HIV-infected subjects from the United States, including Puerto Rico, was assessed. RESULTS: Three hundred eighty-five subjects were screened; 13 were HLA-B*57:01 positive and 372 were negative. Only HLA-B*57:01-negative, abacavir-naive subjects were eligible to enroll into the ASSURE trial. …

Gene 33/Mig6 Regulates Apoptosis And The Dna Damage Response Through Independent Mechanisms, Cen Li, Soyoung Park, Leonard M. Eisenberg, Hong Zhao, Zbigniew Darzynkiewicz, Dazhong Xu

NYMC Faculty Posters

Gene 33 (Mig6, ERRFI1) is an inducible adaptor/scaffold protein whose expression can be induced by both stress and mitogenic signals. It contains multiple domains for protein-protein interaction and is involved in a broad spectrum of cellular functions. Gene 33 promotes apoptosis in a cell type-dependent manner. A recent study has linked Gene 33 to the DNA damage response (DDR) induced by hexavalent chromium [Cr(VI)]. Here we show that Gene 33 induces apoptosis via both c-Abl/p73 and EGFR/AKT-dependent pathways in lung epithelial and lung carcinoma cells. Ectopic expression of Gene 33 also triggers DDR in an ATM-dependent fashion and through pathways …

A Novel Multi-Network Approach Reveals Tissue-Specific Cellular Modulators Of Fibrosis In Systemic Sclerosis, Jaclyn N. Taroni, Casey S. Greene, Viktor Martyanov, Tammara A. Wood

Dartmouth Scholarship

Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology.We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast …

Mirnas Associated With Prostate Cancer Risk And Progression, Hung N. Luu, Hui-Yi Lin, Karina Dalsgaard Sorensen, Olorunseun O. Ogunwobi, Nagi Kumar, Ganna Chornokur, Catherine Phelan, Dominique Jones, Lacreis Kidd, Jyotsna Batra, Kosj Yamoah, Anders Berglund, Robert J. Rounbehler, Mihi Yang, Sang Haak Lee, Nahyeon Kang, Seung Joon Kim, Jong Y. Park, Giuliano Di Pietro

Publications and Research

Prostate cancer is the most common malignancy among men in the US. Though considerable improvement in the diagnosis of prostate cancer has been achieved in the past decade, predicting disease outcome remains a major clinical challenge. Recent expression profiling studies in prostate cancer suggest microRNAs (miRNAs) may serve as potential biomarkers for prostate cancer risk and disease progression. miRNAs comprise a large family of about 22-nucleotide-long non-protein coding RNAs, regulate gene expression post-transcriptionally and participate in the regulation of numerous cellular processes. In this review, we discuss the current status of miRNA in studies evaluating the disease progression of prostate …

Coccolithoviruses: A Review Of Cross-Kingdom Genomic Thievery And Metabolic Thuggery, Jozef I. Nissimov, António Pagarete, Fangrui Ma, Sean Cody, David D. Dunigan, Susan A. Kimmance, Michael J. Allen

Nebraska Center for Virology: Faculty Publications

Coccolithoviruses (Phycodnaviridae) infect and lyse the most ubiquitous and successful coccolithophorid in modern oceans, Emiliania huxleyi. So far, the genomes of 13 of these giant lytic viruses (i.e., Emiliania huxleyi viruses—EhVs) have been sequenced, assembled, and annotated. Here, we performed an in-depth comparison of their genomes to try and contextualize the ecological and evolutionary traits of these viruses. The genomes of these EhVs have from 444 to 548 coding sequences (CDSs). Presence/absence analysis of CDSs identified putative genes with particular ecological significance, namely sialidase, phosphate permease, and sphingolipid biosynthesis. The viruses clustered into distinct clades, based on their DNA polymerase …

Latexin Inactivation Enhances Survival And Long-Term Engraftment Of Hematopoietic Stem Cells And Expands The Entire Hematopoietic System In Mice, Yi Liu, Cuiping Zhang, Zhenyu Li, Chi Wang, Jianhang Jia, Tianyan Gao, Gerhard C. Hildebrandt, Daohong Zhou, Subbarao Bondada, Peng Ji, Daret K. St. Clair, Jinze Liu, Chang-Guo Zhan, Hartmut Geiger, Shuxia Wang, Ying Liang

Toxicology and Cancer Biology Faculty Publications

Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1 …

Draft Genome Sequence Of Cercospora Sojina Isolate S9, A Fungus Causing Frogeye Leaf Spot (Fls) Disease Of Soybean, Fanchang Zeng, Chaofan Wang, Guirong Zhang, Junmei Wei, Carl A. Bradley, Ray Ming

Plant Pathology Faculty Publications

Fungi are the causal agents of many of the world's most serious plant diseases causing disastrous consequences for large-scale agricultural production. Pathogenicity genomic basis is complex in fungi as multicellular eukaryotic pathogens. The fungus Cercospora sojina is a plant pathogen that threatens global soybean supplies. Here, we report the genome sequence of C. sojina strain S9 and detect genome features and predicted genomic elements. The genome sequence of C. sojina is a valuable resource with potential in studying the fungal pathogenicity and soybean host resistance to frogeye leaf spot (FLS), which is caused by C. sojina. …

Apolipoprotein E4 And Insulin Resistance Interact To Impair Cognition And Alter The Epigenome And Metabolome, Lance A. Johnson, Eileen Ruth S. Torres, Soren Impey, Jan F. Stevens, Jacob Raber

Physiology Faculty Publications

Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in …

Cpt1a Methylation Is Associated With Plasma Adiponectin, S. Aslibekyan, A. N. Do, H. Xu, S. Li, M. R. Irvin, D Zhi, H. K. Tiwari, D. M. Absher, A. R. Shuldiner, T. Zhang, W. Chen, K. Tanner, C. Hong, B. D. Mitchell, G. Berenson, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background and Aims—Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood.

Methods and Results—We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression …

Diagnosis Of Lchad/Tfp Deficiency In An At Risk Newborn Using Umbilical Cord Blood Acylcarnitine Analysis, Donna Raval, Kristina Cusmano-Ozog, Omar Ayyub, Callie Jenevein, Laura Kofman, Brendan Lanpher, Natalie Hauser, Debra Regier

Pathology Faculty Publications

Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates.

We present a 4 week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started …

Micrornas, Heart Failure, And Aging: Potential Interactions With Skeletal Muscle, Kevin A. Murach, John J. Mccarthy

Center for Muscle Biology Faculty Publications

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting mRNAs for degradation or translational repression. MiRNAs can be expressed tissue specifically and are altered in response to various physiological conditions. It has recently been shown that miRNAs are released into the circulation, potentially for the purpose of communicating with distant tissues. This manuscript discusses miRNA alterations in cardiac muscle and the circulation during heart failure, a prevalent and costly public health issue. A potential mechanism for how skeletal muscle maladaptations during heart failure could be mediated by myocardium-derived miRNAs released to the circulation is presented. An overview …

Epigenomic Reprogramming In Inorganic Arsenic-Mediated Gene Expression Patterns During Carcinogenesis, Meredith Eckstein, Rebekah Eleazer, Matthew Rea, Yvonne N. Fondufe-Mittendorf

Molecular and Cellular Biochemistry Faculty Publications

Arsenic is a ubiquitous metalloid that is not mutagenic but is carcinogenic. The mechanism(s) by which arsenic causes cancer remain unknown. To date, several mechanisms have been proposed, including the arsenic-induced generation of reactive oxygen species (ROS). However, it is also becoming evident that inorganic arsenic (iAs) may exert its carcinogenic effects by changing the epigenome, and thereby modifying chromatin structure and dynamics. These epigenetic changes alter the accessibility of gene regulatory factors to DNA, resulting in specific changes in gene expression both at the levels of transcription initiation and gene splicing. In this review, we discuss recent literature reports …

Effect Of Cigarette Smoke Exposure And Mutant Kras Overexpression On Pancreatic Cell Proliferation, Howard P. Glauert, R. Scott Elliott, Sung Gu Han, Mark Athey, Eun Young Lee, C. Gary Gairola

Pharmacology and Nutritional Sciences Faculty Publications

Pancreatic cancer is the fourth leading cause of cancer‑associated mortality. The major risk factor for pancreatic cancer is cigarette smoking. Kras mutations are commonly observed in human pancreatic cancers. The present study examined the hypothesis that exposure to cigarette smoke and overexpression of a mutant Kras gene in the pancreas affects pancreatic cell proliferation in mice. Mice overexpressing the mutant Kras gene (KRas^G12D) in the pancreas as well as wild‑type mice were exposed to environmental tobacco smoke for 2 weeks. Overexpression of mutant Kras increased cell proliferation in pancreatic ductal, acinar and islet cells. Notably, cigarette smoke exposure …

High Resolution Time-Course Mapping Of Early Transcriptomic, Molecular And Cellular Phenotypes In Huntington's Disease Cag Knock-In Mice Across Multiple Genetic Backgrounds., Seth A Ament, Jocelynn R Pearl, Andrea Grindeland, Jason St Claire, John C Earls, Marina Kovalenko, Tammy Gillis, Jayalakshmi Mysore, James F Gusella, Jong-Min Lee, Seung Kwak, David Howland, Min Young Lee, David Baxter, Kelsey Scherler, Kai Wang, Donald Geman, Jeffrey B Carroll, Marcy E Macdonald, George Carlson, Vanessa C Wheeler, Nathan D Price, Leroy Hood

Articles, Abstracts, and Reports

Huntington's disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, …

A Systematic Study Of Dysregulated Microrna In Type 2 Diabetes Mellitus., Yuqing He, Yuanlin Ding, Biyu Liang, Juanjuan Lin, Taek-Kyun Kim, Haibing Yu, Hanwei Hang, Kai Wang

Articles, Abstracts, and Reports

MicroRNAs (miRNAs) are small noncoding RNAs that modulate the cellular transcriptome at the post-transcriptional level. miRNA plays important roles in different disease manifestation, including type 2 diabetes mellitus (T2DM). Many studies have characterized the changes of miRNAs in T2DM, a complex systematic disease; however, few studies have integrated these findings and explored the functional effects of the dysregulated miRNAs identified. To investigate the involvement of miRNAs in T2DM, we obtained and analyzed all relevant studies published prior to 18 October 2016 from various literature databases. From 59 independent studies that met the inclusion criteria, we identified 158 dysregulated miRNAs in …

A Blueprint To Evaluate One Health, Simon R. Rüegg, Barry J. Mcmahon, Barbara Häsler, Roberto Esposito, Helen O'Shea, Et Al

Department of Biological Sciences Publications

One Health (OH) positions health professionals as agents for change and provides a platform to manage determinants of health that are often not comprehensively captured in medicine or public health alone. However, due to the organization of societies and disciplines, and the sectoral allocation of resources, the development of transdisciplinary approaches requires effort and perseverance. Therefore, there is a need to provide evidence on the added value of OH for governments, researchers, funding bodies, and stakeholders. This paper outlines a conceptual framework of what OH approaches can encompass and the added values they can provide. The framework was developed during …

Sumo Regulates The Activity Of Smoothened And Costal-2 In Drosophila Hedgehog Signaling, Jie Zhang, Yajuan Liu, Kai Jiang, Jianhang Jia

Markey Cancer Center Faculty Publications

In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing. We further show that Hh-induced-sumoylation stabilizes Smo, whereas desumoylation by Ulp1 …

Hypoxia Inducible Factor 1: A Urinary Biomarker Of Kidney Disease., S Movafagh, Dominic Raj, M Sanaei-Ardekani, D Bhatia, K Vo, M Mahmoudieh, R Rahman, E H Kim, Arthur F Harralson

Medicine Faculty Publications

Identifying noninvasive biomarkers of kidney disease is valuable for diagnostic and therapeutic purposes. Hypoxia inducible factor 1 (HIF-1) expression is known to be elevated in the kidneys in several renal disease pathologies. We hypothesized that the urinary HIF-1a mRNA level may be a suitable biomarker for expression of this protein in chronic kidney disease (CKD). We compared HIF-1a mRNA levels from urine pellets of CKD and healthy subjects. To ensure that urinary HIF-1a mRNA is of kidney origin, we examined colocalization of HIF-1a mRNA with two kidney specific markers in urine cells. We found that HIF-1a mRNA is readily quantifiable …

The Molecular Basis Of Talin2'S High Affinity Toward Β1-Integrin, Yaxia Yuan, Liqing Li, Yanyan Zhu, Lei Qi, Latifeh Azizi, Vesa P. Hytönen, Chang-Guo Zhan, Cai Huang

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β–integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with …

Genome-Wide Dna Methylation Reprogramming In Response To Inorganic Arsenic Links Inhibition Of Ctcf Binding, Dnmt Expression And Cellular Transformation, Matthew Rea, Meredith Eckstein, Rebekah Eleazer, Caroline Smith, Yvonne N. Fondufe-Mittendorf

Molecular and Cellular Biochemistry Faculty Publications

Chronic low dose inorganic arsenic (iAs) exposure leads to changes in gene expression and epithelial-to-mesenchymal transformation. During this transformation, cells adopt a fibroblast-like phenotype accompanied by profound gene expression changes. While many mechanisms have been implicated in this transformation, studies that focus on the role of epigenetic alterations in this process are just emerging. DNA methylation controls gene expression in physiologic and pathologic states. Several studies show alterations in DNA methylation patterns in iAs-mediated pathogenesis, but these studies focused on single genes. We present a comprehensive genome-wide DNA methylation analysis using methyl-sequencing to measure changes between normal and iAs-transformed cells. …

Estimating The Probability Of Clonal Relatedness Of Pairs Of Tumors In Cancer Patients, Audrey Mauguen, Venkatraman E. Seshan, Irina Ostrovnaya, Colin B. Begg

Memorial Sloan-Kettering Cancer Center, Dept. of Epidemiology & Biostatistics Working Paper Series

Next generation sequencing panels are being used increasingly in cancer research to study tumor evolution. A specific statistical challenge is to compare the mutational profiles in different tumors from a patient to determine the strength of evidence that the tumors are clonally related, i.e. derived from a single, founder clonal cell. The presence of identical mutations in each tumor provides evidence of clonal relatedness, although the strength of evidence from a match is related to how commonly the mutation is seen in the tumor type under investigation. This evidence must be weighed against the evidence in favor of independent tumors …

Pcsk9 Genetic Variants And Risk Of Type 2 Diabetes: A Mendelian Randomisation Study, A. Schmidt, D. Swerdlow, M. Holmes, R. Patel, Z. Fairhurst-Hunter, Cara L. Carty, +Several Additional Authors

Pediatrics Faculty Publications

BACKGROUND:

Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.

METHODS:

In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and …

Pneumocystis Infection Alters The Activation State Of Pulmonary Macrophages, Jessica M. Deckman, Cathryn J. Kurkjian, Joseph P. Mcgillis, Theodore J. Cory, Susan E. Birket, Linda M. Schutzman, Brian S. Murphy, Beth A. Garvy, David J. Feola

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Recent studies show a substantial incidence of Pneumocystis jirovecii colonization and infection in patients with chronic inflammatory lung conditions. However, little is known about the impact of Pneumocystis upon the regulation of pulmonary immunity. We demonstrate here that Pneumocystis polarizes macrophages towards an alternatively activated macrophage-like phenotype. Genetically engineered mice that lack the ability to signal through IL-4 and IL-13 were used to show that Pneumocystis alternative macrophage activation is dependent upon signaling through these cytokines. To determine whether Pneumocystis-induced macrophage polarization would impact subsequent immune responses, we infected mice with Pneumocystis and then challenged them with Pseudomonas aeruginosa 14 …

Inhibition Of The Integrin/Fak Signaling Axis And C-Myc Synergistically Disrupts Ovarian Cancer Malignancy, B. Xu, Jason R. Lefringhouse, Z. Liu, D. West, Lauren A. Baldwin, C. Ou, L. Chen, Dana L. Napier, Luksana Chaiswing, Lawrence D. Brewer, Daret K. St Clair, Olivier Thibault, John R. Van Nagell, Binhua P. Zhou, R. Drapkin, J.-A. Huang, M. L. Lu, Frederick R. Ueland, X. H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 …