Digital Commons Network^™

Modeling The Influence Of Early Skin-To-Skin Contact On Exclusive Breastfeeding In A Sample Of Hispanic Immigrant Women, Ana Maria Linares, Karen Wambach, Mary Kay Rayens, Amanda Wiggins, Elizabeth Coleman, Mark B. Dignan

Nursing Faculty Publications

Using data from a longitudinal study of breastfeeding in Hispanics, this study evaluated the influence of early skin-to-skin contact (SSC) on initiation and sustained exclusive breastfeeding (EBF) at 1 month postpartum. Two-thirds of the women in the sample participated in early SSC. At discharge, over half of the women were EBF; this proportion decreased to one-third at 1 month postpartum. Controlling for demographic and clinical variables in the model, participation in early SSC was associated with a greater than sevenfold increase in the odds of EBF at discharge (p = .005) but was not predictive of EBF at 1 …

Sleeper Cells: The Stringent Response And Persistence In The Borreliella (Borrelia) Burgdorferi Enzootic Cycle, Felipe C. Cabello, Henry Godfrey, J Bugrysheva, Stuart A. Newman

NYMC Faculty Publications

Infections with tick-transmitted Borreliella (Borrelia) burgdorferi, the cause of Lyme disease, represent an increasingly large public health problem in North America and Europe. The ability of these spirochetes to maintain themselves for extended periods of time in their tick vectors and vertebrate reservoirs is crucial for continuance of the enzootic cycle as well as for the increasing exposure of humans to them. The stringent response mediated by the alarmone (p)ppGpp has been determined to be a master regulator in B. burgdorferi. It modulates the expression of identified and unidentified open reading frames needed to deal with and overcome the many …

Mutsβ Abundance And Msh3 Atp Hydrolysis Activity Are Important Drivers Of Ctg•Cag Repeat Expansions, Norma Keogh, Kara Y. Chan, Guo-Min Li, Robert S. Lahue

Toxicology and Cancer Biology Faculty Publications

CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutSβ (Msh2-Msh3 heterodimer). To evaluate properties of MutSβ that drive expansions, previous studies have tested under-expression, ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems. Additionally, some variants destabilize MutSβ, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutSβ. Msh3^−/− cells are severely defective for CTG•CAG repeat expansions but show full activity on contractions. Msh3^−/− cells provide a single, isogenic system …

Decorin-Evoked Paternally Expressed Gene 3 (Peg3) Is An Upstream Regulator Of The Transcription Factor Eb (Tfeb) In Endothelial Cell Autophagy., Thomas Neill, Catherine Sharpe, Rick T. Owens, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Macroautophagy is a fundamental and evolutionarily conserved catabolic process that eradicates damaged and aging macromolecules and organelles in eukaryotic cells. Decorin, an archetypical small leucine-rich proteoglycan, initiates a protracted autophagic program downstream of VEGF receptor 2 (VEGFR2) signaling that requires paternally expressed gene 3 (PEG3). We have discovered that PEG3 is an upstream transcriptional regulator of transcription factor EB (TFEB), a master transcription factor of lysosomal biogenesis, for decorin-evoked endothelial cell autophagy. We found a functional requirement of PEG3 for TFEB transcriptional induction and nuclear translocation in human umbilical vein endothelial and PAER2 cells. Mechanistically, inhibiting VEGFR2 or AMP-activated protein …

A Type Of Human Skin Dendritic Cell Marked By Cd5 Is Associated With The Development Of Inflammatory Skin Disease, Daniel Korenfeld, Laurent Gorvel, Adiel Munk, Joshua Man, Andras Schaffer, Thomas Tung, Caroline Mann, Eynav Klechevsky

Open Access Publications

Dendritic cells (DCs) are important in regulating immunity and tolerance and consist of functionally distinct subsets that differentially regulate T lymphocyte function. The underlying basis for this subset specificity is lacking, particularly in humans, where the classification of tissue DCs is currently incomplete. Examination of healthy human epidermal Langerhans cells and dermal skin cells revealed a tissue CD5-expressing DC subtype. The CD5+ DCs were potent inducers of cytotoxic T cells and Th22 cells. The products of these T cells, IL-22 and IFN-γ, play a key role in the pathogenesis of psoriasis. Remarkably, CD5+ DCs were significantly enriched in lesional psoriatic …

Monocyte Dysregulation And Systemic Inflammation During Pediatric Falciparum Malaria, Katherine R. Dobbs, Paula Embury, John Vulule, Peter S. Odada, Bruce A. Rosa, Makedonka Mitreva, James W. Kazura, Arlene E. Dent

Open Access Publications

BACKGROUND: Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood.

METHODS: We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community.

RESULTS: Acute malaria was marked by elevated levels of …

Loss Of Fructose-1,6-Bisphosphatase Induces Glycolysis And Promotes Apoptosis Resistance Of Cancer Stem-Like Cells: An Important Role In Hexavalent Chromium-Induced Carcinogenesis, Jin Dai, Yanli Ji, Wei Wang, Donghern Kim, Leonard Yenwong Fai, Lei Wang, Jia Luo, Zhuo Zhang

Toxicology and Cancer Biology Faculty Publications

Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI)-transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance. BEAS-2B-Cr-CSC are metabolic inactive as evidenced by reductions in oxygen consumption, glucose uptake, ATP production, and lactate …

Gucy2c Signaling Opposes The Acute Radiation-Induced Gi Syndrome., Peng Li, Evan Wuthrick, Jeff A. Rappaport, Crystal Kraft, Jieru E. Lin, Glen Marszalowicz, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. …

Posttranscriptional Regulation Of Parg Mrna By Hur Facilitates Dna Repair And Resistance To Parp Inhibitors, Saswati N. Chand, Mahsa Zarei, M. J. Schiewer, Akshay R. Sanan, Carmella Romeo, Shruti Lal, Joseph A. Cozzitorto, Avinoam Nevler, Laura Scolaro, Eric R. Londin, Wei Jiang, Nicole Meisner-Kober, Michael J. Pishvaian, Karen E. Knudsen, Charles Yeo, John M Pascal, Jordan M. Winter, Jonathan R. Brody

Department of Surgery Faculty Papers

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3⁰ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to …

Neurosyphilis Increases Human Immunodeficiency Virus (Hiv)-Associated Central Nervous System Inflammation But Does Not Explain Cognitive Impairment In Hiv-Infected Individuals With Syphilis., Emily L Ho, Clare L Maxwell, Shelia B Dunaway, Sharon K Sahi, Lauren C Tantalo, Sheila A Lukehart, Christina M Marra

Articles, Abstracts, and Reports

Background: Individuals infected with human immunodeficiency virus (HIV) who have previously had syphilis may have cognitive impairment. We tested the hypothesis that neurosyphilis causes cognitive impairment in HIV by amplifying HIV-related central nervous system (CNS) inflammation.

Methods: HIV-infected participants enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis underwent the mental alternation test (MAT), venipuncture, and lumbar puncture. CSF concentrations of chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and neurofilament light (NFL) were determined by commercial assays. The proportion of peripheral blood mononuclear cells (PBMCs) and of CSF white blood cells (WBCs) that …

A Global Staphylococcus Aureus Proteome Resource Applied To The In Vivo Characterization Of Host-Pathogen Interactions., Stephan Michalik, Maren Depke, Annette Murr, Manuela Gesell Salazar, Ulrike Kusebauch, Zhi Sun, Tanja C Meyer, Kristin Surmann, Henrike Pförtner, Petra Hildebrandt, Stefan Weiss, Laura Marcela Palma Medina, Melanie Gutjahr, Elke Hammer, Dörte Becher, Thomas Pribyl, Sven Hammerschmidt, Eric W Deutsch, Samuel L Bader, Michael Hecker, Robert L Moritz, Ulrike Mäder, Uwe Völker, Frank Schmidt

Articles, Abstracts, and Reports

Data-independent acquisition mass spectrometry promises higher performance in terms of quantification and reproducibility compared to data-dependent acquisition mass spectrometry methods. To enable high-accuracy quantification of Staphylococcus aureus proteins, we have developed a global ion library for data-independent acquisition approaches employing high-resolution time of flight or Orbitrap instruments for this human pathogen. We applied this ion library resource to investigate the time-resolved adaptation of S. aureus to the intracellular niche in human bronchial epithelial cells and in a murine pneumonia model. In epithelial cells, abundance changes for more than 400 S. aureus proteins were quantified, revealing, e.g., the precise temporal regulation …

Silver Oxide Coatings With High Silver-Ion Elution Rates And Characterization Of Bactericidal Activity., Sarah S Goderecci, Eric Kaiser, Michael Yanakas, Zachary Norris, Jeffrey Scaturro, Robert Oszust, Clarence D Medina, Fallon Waechter, Min Heon, Robert R Krchnavek, Lei Yu, Samuel E Lofland, Renee M Demarest, Gregory A Caputo, Jeffrey D Hettinger

Rowan-Virtua School of Osteopathic Medicine Departmental Research

This paper reports the synthesis and characterization of silver oxide films for use as bactericidal coatings. Synthesis parameters, dissolution/elution rate, and bactericidal efficacy are reported. Synthesis conditions were developed to create AgO, Ag₂O, or mixtures of AgO and Ag₂O on surfaces by reactive magnetron sputtering. The coatings demonstrate strong adhesion to many substrate materials and impede the growth of all bacterial strains tested. The coatings are effective in killing Escherichia coli and Staphylococcus aureus, demonstrating a clear zone-of-inhibition against bacteria growing on solid media and the ability to rapidly inhibit bacterial growth in planktonic culture. Additionally, the coatings exhibit very …

Long-Term Impact Of Changing Childhood Malnutrition On Rotavirus Diarrhoea: Two Decades Of Adjusted Association With Climate And Socio-Demographic Factors From Urban Bangladesh, Sumon Kumar Das, Mohammod Jobayer Chisti, Mohammad Habibur Rahman Sarker, Jui Das, Shawnawaz Ahmed, K. M. Shahunja, Shamsun Nahar, Nora Gibbons, Tahmeed Ahmed, Abu Syed Golam Faruque, Mustafizur Rahman, George J. Fuchs Iii, Abdullah Al Mamun, Peter John Baker

Pediatrics Faculty Publications

Background

There is strong association between childhood rotavirus, diarrhoea, climate factors and malnutrition. Conversely, a significant nutritional transition (reduced under-nutrition) with a concurrent increasing trend of rotavirus infection in last decade was also observed among under 5 children, especially in developing countries including Bangladesh. Considering the pathophysiology of rotavirus, there might be an interaction of this nutrition transition which plays a pivotal role in increasing rotavirus infection in addition to climate and other man-made factors in urban areas such as Dhaka, Bangladesh.

Methods

Relevant monthly data from 1993–2012 were extracted from the archive of the Diarrhoeal Disease Surveillance System of …

Amlexanox Enhances Premature Termination Codon Read-Through In Col7a1 And Expression Of Full Length Type Vii Collagen: Potential Therapy For Recessive Dystrophic Epidermolysis Bullosa., Velina S. Atanasova, Qiujie Jiang, Marco Prisco, Christina Gruber, Josefina Piñón Hofbauer, Mei Chen, Cristina Has, Leena Bruckner-Tuderman, John A. Mcgrath, Jouni Uitto, Andrew P. South

Department of Dermatology and Cutaneous Biology Faculty Papers

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare monogenic blistering disorder caused by the lack of functional type VII collagen, leading to skin fragility and subsequent trauma-induced separation of the epidermis from the underlying dermis. A total of 46% of patients with RDEB harbor at least one premature termination codon (PTC) mutation in COL7A1, and previous studies have shown that aminoglycosides are able to overcome RDEB PTC mutations by inducing "read-through" and incorporation of an amino acid at the PTC site. However, aminoglycoside toxicity will likely prevent widespread clinical application. Here the FDA-approved drug amlexanox was tested for its ability …

Probing The Metabolic Phenotype Of Breast Cancer Cells By Multiple Tracer Stable Isotope Resolved Metabolomics, Andrew N. Lane, Julie Tan, Yali Wang, Jun Yan, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using ¹³C₆-glucose, ¹³C-1+2-glucose, ¹³C₅,¹⁵N₂-Gln, ¹³C₃-glycerol, and ¹³C₈-octanoate as tracers. These tracers were designed to probe the central energy producing …

Healthcare Contact And Treatment Uptake Following Hepatitis C Virus Screening And Counseling Among Rural Appalachian People Who Use Drugs, Dustin B. Stephens, April M. Young, Jennifer R. Havens

Behavioral Science Faculty Publications

Background—Hepatitis C virus (HCV) remains a major contributor to morbidity and mortality worldwide. Since 2009, Kentucky has led the United States in cases of acute HCV, driven largely by injection drug use in rural areas. Improved treatment regimens hold promise of mitigating the impact and transmission of HCV, but numerous barriers obstruct people who inject drugs (PWID) from receiving care, particularly in medically underserved settings.

Methods—503 rural people who use drugs were recruited using respondent-driven sampling and received HCV screening and post-test counseling. Presence of HCV antibodies was assessed using enzyme immunoassay of dried blood samples. Sociodemographic and …

A Longitudinal Study Of The Reciprocal Relationship Between Ever Smoking And Urgency In Early Adolescence, Jessica L. Burris, Elizabeth N. Riley, Gabriella E. Puleo, Gregory T. Smith

Psychology Faculty Publications

Background—Among early adolescents in the United States (U.S.), the prevalence of cigarette smoking is at its lowest level in recent decades. Nonetheless, given the risks of smoking in early development, it remains critically important to study both risk factors for smoking and risks from smoking. This longitudinal study with U.S. early adolescents examines smoking initiation and tests a model of reciprocal prediction between ever smoking and the personality trait of urgency (i.e., mood-based impulsivity), a trait that increases risk for multiple forms of dysfunction.

Methods—Participants (n=1906; 90% 10–11 years old, 50% female, 39% racial minorities at …

Thiamine Deficiency And Neurodegeneration: The Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, And Autophagy, Dexiang Liu, Zunji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Thiamine (vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since it is synthesized only in bacteria, fungi, and plants. Thiamine deficiency (TD) can result from inadequate intake, increased requirement, excessive deletion, and chronic alcohol consumption. TD affects multiple organ systems, including the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems. In the brain, TD causes a cascade of events including mild impairment of oxidative metabolism, neuroinflammation, and neurodegeneration, which are commonly observed in …

Tailoring A Nicu-Based Tobacco Treatment Program For Mothers Who Are Dependent On Opioids, Amanda Fallin-Bennett, Kristin Ashford

Nursing Faculty Publications

Objective—To collect formative information to design a tailored tobacco treatment intervention for women with newborns treated or evaluated for neonatal abstinence syndrome and to explore current tobacco use behaviors and facilitators and barriers to smoking cessation.

Design—Qualitative descriptive study.

Setting—An academic medical center in the southern United States.

Participants—Mothers of newborns who were treated or evaluated for neonatal abstinence syndrome at birth within the preceding three months. Women were recruited who were older than 18 and reported opioid dependence and smoking during pregnancy.

Methods—Participants took part in semi-structured individual interviews that lasted approximately one hour. …

Extended-Spectrum Antiprotozoal Bumped Kinase Inhibitors: A Review, Wesley C. Van Voorhis, J. Stone Doggett, Marilyn Parsons, Matthew A. Hulverson, Ryan Choi, Samuel L. M. Arnold, Michael W. Riggs, Andrew Hemphill, Daniel K. Howe, Robert H. Mealey, Audrey O. T. Lau, Ethan A. Merritt, Dustin J. Maly, Erkang Fan, Kayode K. Ojo

Veterinary Science Faculty Publications

Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites’ survival and proliferation. In this review, we review efficacy against the kinase target, the parasite growth in vitro, and in animal infection models, as well …

Advertising Exposure And Use Of E-Cigarettes Among Female Current And Former Tobacco Users Of Childbearing Age, Kristin Ashford, Emily Rayens, Amanda T. Wiggins, Mary Kay Rayens, Amanda Fallin-Bennett, Molly Malany Sayre

Nursing Faculty Publications

Objective: The study examined the relationship between exposure to e‐cigarette advertising and e‐cigarette use by pregnancy status, including use of flavored e‐cigarette products, among women of childbearing age.

Design: A cross‐sectional, correlational design was used.

Subjects: Female current or former tobacco users in Central and Eastern Kentucky, 18–45 years old (N = 194, 52% pregnant).

Measures: Demographics, pregnancy status, cigarette and e‐cigarette use, and exposure to e‐cigarette advertising.

Results: Younger age, white non‐Hispanic race, and greater exposure to e‐cigarette advertising were associated with a higher likelihood of ever using e‐cigarettes (p < .05 for each variable). Pregnancy was not associated with ever use (p = .11). Younger age was associated …

Tia1 Mutations In Amyotrophic Lateral Sclerosis And Frontotemporal Dementia Promote Phase Separation And Alter Stress Granule Dynamics., Ian R. Mackenzie, Alexandra M. Nicholson, Mohona Sarkar, James Messing, Maria D. Purice, Cyril Pottier, Kavya Annu, Matt Baker, Ralph B. Perkerson, Aishe Kurti, Billie J. Matchett, Tanja Mittag, Jamshid Temirov, Ging-Yuek R. Hsiung, Charles Krieger, Melissa E. Murray, Masato Kato, John D. Fryer, Leonard Petrucelli, Lorne Zinman, Sandra Weintraub, Marsel Mesulam, Julia Keith, Sasha A. Zivkovic, Veronica Hirsch-Reinshagen, Raymond P. Roos, Stephan Züchner, Neill R. Graff-Radford, Ronald C. Petersen, Richard J. Caselli, Zbigniew K. Wszolek, Elizabeth Finger, Carol Lippa, David Lacomis, Heather Stewart, Dennis W. Dickson, Hong Joo Kim, Ekaterina Rogaeva, Eileen Bigio, Kevin B. Boylan, J. Paul Taylor, Rosa Rademakers

Department of Neurology Faculty Papers

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10

Interleukin-6 (Il-6) Rs1800796 And Cyclin Dependent Kinase Inhibitor (Cdkn2a/Cdkn2b) Rs2383207 Are Associated With Ischemic Stroke In Indigenous West African Men, Rufus Akinyemi, Donna K. Arnett, Hemant K. Tiwari, Bruce Ovbiagele, Fred Sarfo, Vinodh Srinivasasainagendra, Marguerite Ryan Irvin, Abiodun Adeoye, Rodney T. Perry, Albert Akpalu, Carolyn Jenkins, Lukman Owolabi, Reginald Obiako, Kolawole Wahab, Emmanuel Sanya, Morenikeji Komolafe, Michael Fawale, Philip Adebayo, Godwin Osaigbovo, Taofiki Sunmonu, Paul Olowoyo, Innocent Chukwuonye, Yahaya Obiabo, Onoja Akpa, Sylvia Melikam, Raelle Saulson, Raj Kalaria, Adesola Ogunniyi, Mayowa Owolabi

Epidemiology and Environmental Health Faculty Publications

Background—Inherited genetic variations offer a possible explanation for the observed peculiarities of stroke in sub – Saharan African populations. Interleukin–6 polymorphisms have been previously associated with ischemic stroke in some non-African populations.

Aim—Herein we investigated, for the first time, the association of genetic polymorphisms of IL-6 and CDKN2A- CDKN2B and other genes with ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study.

Methods—Twenty-three previously identified single nucleotide polymorphisms (SNPs) in 14 genes of relevance to the neurobiology of ischemic stroke were investigated. Logistic regression models adjusting for known …

Posttranscriptional Upregulation Of Idh1 By Hur Establishes A Powerful Survival Phenotype In Pancreatic Cancer Cells., Mahsa Zarei, Shruti Lal, Seth J. Parker, Avinoam Nevler, Ali Vaziri-Gohar, Katerina Dukleska, Nicole C. Mambelli-Lisboa, Cynthia Moffat, Fernando F Blanco, Saswati N. Chand, Masaya Jimbo, Joseph A. Cozzitorto, Wei Jiang, Charles J. Yeo, Eric R. Londin, Erin L. Seifert, Christian M. Metallo, Jonathan R. Brody, Jordan M. Winter

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal …

Integrative Analysis Identifies Four Molecular And Clinical Subsets In Uveal Melanoma., A Gordon Robertson, Juliann Shih, Christina Yau, Ewan A Gibb, Junna Oba, Karen L Mungall, Julian M Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M Lichtenberg, Melanie Kucherlapati, Patrick K Kimes, Ming Tang, Alexander Penson, Ozgun Babur, Rehan Akbani, Christopher A Bristow, Katherine A Hoadley, Lisa Iype, Matthew T Chang, Andrew D Cherniack, Christopher Benz, Gordon B Mills, Roel G W Verhaak, Klaus G Griewank, Ina Felau, Jean C Zenklusen, Jeffrey E Gershenwald, Lynn Schoenfield, Alexander J Lazar, Mohamed H Abdel-Rahman, Sergio Roman-Roman, Marc-Henri Stern, Colleen M Cebulla, Michelle D Williams, Martine J Jager, Sarah E Coupland, Bita Esmaeli, Cyriac Kandoth, Scott E Woodman

Articles, Abstracts, and Reports

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

Abl Kinase Regulation By Braf/Erk And Cooperation With Akt In Melanoma, Aditi Jain, Rakshamani Tripathi, Courtney P. Turpin, Chi Wang, Rina Plattner

Pharmacology and Nutritional Sciences Faculty Publications

The melanoma incidence continues to increase, and the disease remains incurable for many due to its metastatic nature and high rate of therapeutic resistance. In particular, melanomas harboring BRAF^V600E and PTEN mutations often are resistant to current therapies, including BRAF inhibitors (BRAFi) and immune checkpoint inhibitors. Abl kinases (Abl/Arg) are activated in melanomas and drive progression; however, their mechanism of activation has not been established. Here we elucidate a novel link between BRAF^V600E/ERK signaling and Abl kinases. We demonstrate that BRAF^V600E/ERK play a critical role in binding, phosphorylating and regulating Abl localization and Abl/Arg activation …

Polymer Nanoassemblies With Hydrophobic Pendant Groups In The Core Induce False Positive Sirna Transfection In Luciferase Reporter Assays, Steven Rheiner, Derek Alexander Reichel, Piotr G. Rychahou, Tadahide Izumi, Hsin-Sheng Yang, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Poly(ethylene glycol)-conjugated polyethylenimine (PEG-PEI) is a widely studied cationic polymer used to develop non-viral vectors for siRNA therapy of genetic disorders including cancer. Cell lines stably expressing luciferase reporter protein typically evaluate the transfection efficacy of siRNA/PEG-PEI complexes, however recent findings revealed that PEG-PEI can reduce luciferase expression independent of siRNA. This study elucidates a cause of the false positive effect in luciferase assays by using polymer nanoassemblies (PNAs) made from PEG, PEI, poly-(L-lysine) (PLL), palmitate (PAL), and deoxycholate (DOC): PEG-PEI (2P), PEG-PEI-PAL (3P), PEG-PLL (2P′), PEG-PLL-PAL (3P′), and PEG-PEI-DOC (2PD). In vitro transfection and western blot assays of luciferase …

Substance Use Disorders, Violence, Mental Health, And Hiv: Differentiating A Syndemic Factor By Gender And Sexuality, Kiyomi Tsuyuki, Eileen V. Pitpitan, Maria A. Levi-Minzi, Lianne A. Urada, Steven P. Kurtz, Jamila K. Stockman, Hilary L. Surratt

Center for Health Services Research Faculty Publications

This paper measures syndemic substance use disorder, violence, and mental health and compares the syndemic among HIV-infected heterosexual men, heterosexual women, and men who have sex with men (MSM). Data were from a sample of high needs substance-using, HIV-infected people in South Florida between 2010 and 2012 (n = 481). We used confirmatory factor analysis to measure a syndemic latent variable and applied measurement invariance models to identify group differences in the data structure of syndemic co-morbidities among heterosexual men, heterosexual women, and MSM. We found that variables used to measure the syndemic fit each sub-group, supporting that substance use …

A Randomized Placebo-Controlled Trial Of N-Acetylcysteine For Cannabis Use Disorder In Adults, Kevin M. Gray, Susan C. Sonne, Erin A. Mcclure, Udi E. Ghitza, Abigail G. Matthews, Aimee L. Mcrae-Clark, Kathleen M. Carroll, Jennifer S. Potter, Katharina Wiest, Larissa J. Mooney, Albert Hasson, Sharon L. Walsh, Michelle R. Lofwall, Shanna Babalonis, Robert W. Lindblad, Steven Sparenborg, Aimee Wahle, Jacqueline S. King, Nathaniel L. Baker, Rachel L. Tomko, Louise F. Haynes, Ryan G. Vandrey, Frances R. Levin

Behavioral Science Faculty Publications

Background—Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults.

Methods—In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18–50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200 mg (n=153) or placebo (n=149) twice daily. All …

Using Neonatal Skin To Study The Developmental Programming Of Aging, Leryn J. Reynolds, Brett J. Dickens, Benjamin B. Green, Carmen J. Marsit, Kevin J. Pearson

Pharmacology and Nutritional Sciences Faculty Publications

Numerous studies have examined how both negative and positive maternal exposures (environmental contaminants, nutrition, exercise, etc.) impact offspring risk for age-associated diseases such as obesity, type 2 diabetes, hypertension, and others. The purpose of this study was to introduce the foreskin as a novel model to examine developmental programming in human neonates, particularly in regard to adipogenesis and insulin receptor signaling, major contributors to age-associated diseases such as obesity and diabetes. Neonatal foreskin was collected following circumcision and primary dermal fibroblasts were isolated to perform adipocyte differentiation and insulin stimulation experiments. Human neonatal foreskin primary fibroblasts take up lipid when …