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Dnmt3a Haploinsufficiency Provokes Hematologic Malignancy Of B-Lymphoid, T-Lymphoid, And Myeloid Lineage In Mice, Garland Michael Upchurch

Theses & Dissertations

DNA methyltransferase 3A (DNMT3A) is a master epigenetic regulator of benign and malignant hematopoiesis. To dissect the biological consequences of homozygous and heterozygous Dnmt3a inactivation in malignant hematopoiesis, we generated Dnmt3a homozygous null (Dnmt3a^Δ/Δ) and Dnmt3a heterozygous (Dnmt3a^+/–) mice and compared the presentations of hematologic malignancies between cohorts. Bi-allelic inactivation of Dnmt3a results in the presentation of mature lymphoid neoplasms resembling chronic lymphocytic leukemia (CLL; B220⁺CD19⁺CD5⁺; 88% penetrance (37/42)) and CD8+ peripheral T-cell lymphoma (PTCL; TCRβ⁺CD3⁺CD8⁺CD4^—; 40% penetrance (17/42)). …

Sensitive Droplet Digital Pcr Method For Detection Of Tert Promoter Mutations In Cell Free Dna From Patients With Metastatic Melanoma, Ashleigh C. Mcevoy, Leslie Calapre, Michelle Pereira, Tindaro M. Giardina, Cleo Robinson, Muhammad A. Khattak, Tarek M. Meniawy, Antonia L. Pritchard, Nicholas K. Hayward, Benhur Amanuel, Michael J. Millward, Mel R. Ziman Dr, Elin S. Gray

Research outputs 2014 to 2021

Background:

Currently mainly BRAF mutant circulating tumor DNA (ctDNA) is utilized to monitor patients with melanoma. TERT promoter mutations are common in various cancers and found in up to 70 % of melanomas, including half of BRAF wildtype cases. Therefore, a sensitive method for detection of TERT promoter mutations would increase the number of patients that could be monitored through ctDNA analysis.

Methods:

A droplet digital PCR (ddPCR) assay was designed for the concurrent detection of chr5:1,295,228 C > T and chr5:1,295,250 C > T TERT promoter mutations. The assay was validated using 39 melanoma cell lines and 22 matched plasma and …

Inflammation And Bone Mineral Density: A Mendelian Randomization Study, Jian V. Huang, C. Mary Schooling

Publications and Research

Osteoporosis is a common age-related disorder leading to an increase in osteoporotic fractures and resulting in significant suffering and disability. Inflammation may contribute to osteoporosis, as it does to many other chronic diseases. We examined whether inflammation is etiologically relevant to osteoporosis, assessed from bone mineral density (BMD), as a new potential target of intervention, or whether it is a symptom/biomarker of osteoporosis. We obtained genetic predictors of inflammatory markers from genome-wide association studies and applied them to a large genome wide association study of BMD. Using two-sample Mendelian randomization, we obtained unconfounded estimates of the effect of high-sensitivity C-reactive …

Cabazitaxel In The Treatment Of Metastatic Castration-Resistant Prostate Cancer: Patient Selection And Special Considerations., Sheel Patel, Jean Hoffman-Censits

Department of Medical Oncology Faculty Papers

Cabazitaxel is an effective chemotherapeutic agent used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel. With the advent of new antiandrogen therapies, immune-based treatments, and radioactive-targeted therapy, there are now multiple effective and approved agents for this disease state. The optimal sequencing of these agents is unclear as there are no large-scale head-to-head comparisons. Clinicians must familiarize themselves with the most recent studies as well as drug toxicities to determine the best treatment option for their patients. In this review, we focus on the development of cabazitaxel for mCRPC, evaluate its efficacy, and highlight key strategies …

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

Autoantibodies As Diagnostic Biomarkers For The Detection And Subtyping Of Multiple Sclerosis, Cassandra Demarshall, Eric Goldwaser, Abhirup Sarkar, George Godsey, Nimish Acharya, Umashanger Thayasivam, Benjamin Belinka, Robert Nagele

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The goal of this preliminary proof-of-concept study was to use human protein microarrays to identify blood-based autoantibody biomarkers capable of diagnosing multiple sclerosis (MS). Using sera from 112 subjects, including 51 MS subjects, autoantibody biomarkers effectively differentiated MS subjects from age- and gender-matched normal and breast cancer controls with 95.0% and 100% overall accuracy, but not from subjects with Parkinson's disease. Autoantibody biomarkers were also useful in distinguishing subjects with the relapsing-remitting form of MS from those with the secondary progressive subtype. These results demonstrate that autoantibodies can be used as noninvasive blood-based biomarkers for the detection and subtyping of …

Racial And Socioeconomic Disparities Are More Pronounced In Inflammatory Breast Cancer Than Other Breast Cancers, Ryan A. Denu, John M. Hampton, Adam Currey, Roger T. Anderson, Rosemary D. Cress, Steven T. Fleming, Joseph Lipscomb, Xiao-Cheng Wu, J. Frank Wilson, Amy Trentham-Dietz

Epidemiology and Environmental Health Faculty Publications

Inflammatory breast cancer (IBC) is a rare yet aggressive form of breast cancer. We examined differences in patient demographics and outcomes in IBC compared to locally advanced breast cancer (LABC) and all other breast cancer patients from the Breast and Prostate Cancer Data Quality and Patterns of Care Study (POC-BP), containing information from cancer registries in seven states. Out of 7,624 cases of invasive carcinoma, IBC and LABC accounted for 2.2% (N = 170) and 4.9% (N = 375), respectively. IBC patients were more likely to have a higher number (P = 0.03) and severity (P …

Pharmacologic Or Genetic Targeting Of Glutamine Synthetase Skews Macrophages Toward An M1-Like Phenotype And Inhibits Tumor Metastasis., Erika M. Palmieri, Alessio Menga, Rosa Martín-Pérez, Annamaria Quinto, Carla Riera-Domingo, Giacoma De Tullio, D Craig Hooper, Wouter H. Lamers, Bart Ghesquière, Daniel W. Mcvicar, Attilio Guarini, Massimiliano Mazzone, Alessandra Castegna

Department of Cancer Biology Faculty Papers

Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial …

Epigenetic Regulation Of Kpc1 Ubiquitin Ligase Affects The Nf-Κb Pathway In Melanoma., Yuuki Iida, Aaron Ciechanover, Diego M Marzese, Keisuke Hata, Matias Bustos, Shigeshi Ono, Jinhua Wang, Matthew P Salomon, Kevin Tran, Stella Lam, Sandy Hsu, Nellie Nelson, Yelena Kravtsova-Ivantsiv, Gordon B Mills, Michael A Davies, Dave S B Hoon

Articles, Abstracts, and Reports

Purpose: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA …

Prognostic Value Of Routine Laboratory Variables In Prediction Of Breast Cancer Recurrence., Zhu Zhu, Ling Li, Zhong Ye, Tong Fu, Ye Du, Aiping Shi, Di Wu, Ke Li, Yifan Zhu, Chun Wang, Zhimin Fan

Department of Medical Oncology Faculty Papers

The prognostic value of routine laboratory variables in breast cancer has been largely overlooked. Based on laboratory tests commonly performed in clinical practice, we aimed to develop a new model to predict disease free survival (DFS) after surgical removal of primary breast cancer. In a cohort of 1,596 breast cancer patients, we analyzed the associations of 33 laboratory variables with patient DFS. Based on 3 significant laboratory variables (hemoglobin, alkaline phosphatase, and international normalized ratio), together with important demographic and clinical variables, we developed a prognostic model, achieving the area under the curve of 0.79. We categorized patients into 3 …

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.

Novel Influences Of Il-10 On Cns Inflammation Revealed By Integrated Analyses Of Cytokine Networks And Microglial Morphology., Warren D. Anderson, Andrew D. Greenhalgh, Aditya Takwale, Samuel David, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Coordinated interactions between cytokine signaling and morphological dynamics of microglial cells regulate neuroinflammation in CNS injury and disease. We found that pro-inflammatory cytokine gene expression in vivo showed a pronounced recovery following systemic LPS. We performed a novel multivariate analysis of microglial morphology and identified changes in specific morphological properties of microglia that matched the expression dynamics of pro-inflammatory cytokine TNFα. The adaptive recovery kinetics of TNFα expression and microglial soma size showed comparable profiles and dependence on anti-inflammatory cytokine IL-10 expression. The recovery of cytokine variations and microglial morphology responses to inflammation were negatively regulated by IL-10. Our novel …

The Role Of The Clinical Nurse Leader In Reintroducing And Sustaining A Successful Cancer Risk Assessment Program In A Community Hospital Setting, Tiffany Gishizky

Master's Projects and Capstones

Abstract

The goal of implementing a comprehensive cancer risk assessment (CRA) program prompted the evaluation of a community-based breast center microsystem and previous CRA program for feasibility and sustainability. The development of a value proposition by the Clinical Nurse Leader student highlights the role in the advancement of the nursing profession as an interdisciplinary leader. Review of current literature facilitated development of program structure and identification of downstream revenue sources. Data analysis includes historical patient volume, screening and procedural reimbursement rates, population statistics and organization market share, and program financial impacts. Data synthesis reveals a CRA program demonstrates potential revenue …

Linking Kindling To Increased Glutamate Release In The Dentate Gyrus Of The Hippocampus Through The Stxbp5/Tomosyn-1 Gene, Seth R. Batten, Elena A. Matveeva, Sidney W. Whiteheart, Thomas C. Vanaman, Greg A. Gerhardt, John T. Slevin

Psychology Faculty Publications

Introduction: In kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn-1, in kindling.

Methods: Stimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild-type and STXBP5/tomosyn-1^−/− (Tom^−/−) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate-selective microelectrode array (MEA).

Results: Naïve Tom^−/− mice had significant increases in KCl-evoked glutamate release compared to naïve wild type as …

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 …

Accurate Cytogenetic Biodosimetry Through Automated Dicentric Chromosome Curation And Metaphase Cell Selection, Jin Liu, Yanxin Li, Ruth Wilkins, Canadian Nuclear Laboratories, Joan H. Knoll, Peter Rogan

Biochemistry Publications

Accurate digital image analysis of abnormal microscopic structures relies on high quality images and on minimizing the rates of false positive (FP) and negative objects in images. Cytogenetic biodosimetry detects dicentric chromosomes (DCs) that arise from exposure to ionizing radiation, and determines radiation dose received based on DC frequency. Improvements in automated DC recognition increase the accuracy of dose estimates by reclassifying FP DCs as monocentric chromosomes or chromosome fragments. We also present image segmentation methods to rank high quality digital metaphase images and eliminate suboptimal metaphase cells. A set of chromosome morphology segmentation methods selectively filtered out FP DCs …

Body Size Predicts Cardiac And Vascular Resistance Effects On Men's And Women's Blood Pressure, Joyce M. Evans, Siqi Wang, Christopher Greb, Vladimir Kostas, Charles F. Knapp, Qingguang Zhang, Eric S. Roemmele, Michael B. Stenger, David C. Randall

Biomedical Engineering Faculty Publications

Key Points Summary

• We report how blood pressure, cardiac output and vascular resistance are related to height, weight, body surface area (BSA), and body mass index (BMI) in healthy young adults at supine rest and standing.
• Much inter-subject variability in young adult's blood pressure, currently attributed to health status, may actually result from inter-individual body size differences.
• Each cardiovascular variable is linearly related to height, weight and/or BSA (more than to BMI).
• When supine, cardiac output is positively related, while vascular resistance is negatively related, to body size. Upon standing, the change in vascular resistance is positively related to size. …

Targeting Hepatic Heparin-Binding Egf-Like Growth Factor (Hb-Egf) Induces Anti-Hyperlipidemia Leading To Reduction Of Angiotensin Ii-Induced Aneurysm Development, Seonwook Kim, Lihua Yang, Seongu Kim, Richard G. Lee, Mark J. Graham, Judith A. Berliner, Aldons J. Lusis, Lei Cai, Ryan E. Temel, Debra L. Rateri, Sangderk Lee

Saha Cardiovascular Research Center Faculty Publications

Objective

The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model.

Approach and results

Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin …

The Oral Microbiome And Adverse Pregnancy Outcomes., Charles M. Cobb, Patricia J. Kelly, Karen B. Williams, Shilpa Babbar, Mubashir Angolkar, Richard J. Derman

Department of Obstetrics and Gynecology Faculty Papers

Significant evidence supports an association between periodontal pathogenic bacteria and preterm birth and preeclampsia. The virulence properties assigned to specific oral pathogenic bacteria, for example, Fusobacterium nucleatum, Porphyromonas gingivalis, Filifactor alocis, Campylobacter rectus, and others, render them as potential collaborators in adverse outcomes of pregnancy. Several pathways have been suggested for this association: 1) hematogenous spread (bacteremia) of periodontal pathogens; 2) hematogenous spread of multiple mediators of inflammation that are generated by the host and/or fetal immune response to pathogenic bacteria; and 3) the possibility of oral microbial pathogen transmission, with subsequent colonization, in the vaginal microbiome resulting from sexual …

A Life Course Examination Of The Physical Environmental Determinants Of Physical Activity Behaviour: A “Determinants Of Diet And Physical Activity” (Dedipac) Umbrella Systematic Literature Review, Angela Carlin, Camille Perchoux, Anna Puggina, Katina Aleksovska, Christoph Buck, Con Burns, Greet Cardon, Simon Chantal, Donatella Ciarapica, Giancarlo Condello, Tara Coppinger, Cristina Cortis, Sara D’Haese, Marieke De Craemer, Andrea Di Blasio, Sylvia Hansen, Licia Iacoviello, Johann Issartel, Pascal Izzicupo, Lina Jaeschke, Martina Kanning, Aileen Kennedy, Jeroen Lakerveld, Fiona Chun Man Ling, Agnes Luzak, Giorgio Napolitano, Julie Anne Nazare, Tobias Pischon, Angela Polito, Alessandra Sannella, Holger Schulz, Rhoda Sohun

Publications

Background: Participation in regular physical activity is associated with a multitude of health benefits across the life course. However, many people fail to meet PA recommendations. Despite a plethora of studies, the evidence regarding the environmental (physical) determinants of physical activity remains inconclusive. Objective: To identify the physical environmental determinants that influence PA across the life course. Methods: An online systematic literature search was conducted using MEDLINE, ISI Web of Science, Scopus and SPORTDiscus. The search was limited to studies published in English (January 2004 to April 2016). Only systematic literature reviews (SLRs) and meta-analyses (MAs) of observational studies, that …

Stromal Cyclin D1 Promotes Heterotypic Immune Signaling And Breast Cancer Growth, Timothy G. Pestell, Xuanmao Jiao, Mukesh Kumar, Amy R. Peck, Marco Prisco, Shengqiong Deng, Zhiping Li, Adam Ertel, Matthew C. Casimiro, Xiaoming Ju, Agnese Di Rocco, Gabriele Di Sante, Sanjay Katiyar, Alison Shupp, Michael P. Lisanti, Pooja Jain, Kongming Wu, Hallgeir Rui, Douglas Craig Hooper, Zuoren Yu, Aaron R. Goldman, David W. Speicher, Lisa Laury-Kleintop, Richard G. Pestell

Department of Cancer Biology Faculty Papers

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased > 30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1^Stroma) in vivo, enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1^Stroma had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80⁺ and CD11b⁺ macrophages and increasing …

Relative Contribution Of Porcine Reproductive And Respiratory Syndrome Virus Open Reading Frames 2–4 To The Induction Of Protective Immunity, Katherine Kimpston-Burkgren, Ignacio Correas, Fernando A. Osorio, David Steffen, Asit K. Pattnaik, Ying Fang, Hiep L. X. Vu

Nebraska Center for Virology: Faculty Publications

The minor glycoproteins (GPs) of PRRSV, GP2, GP3, and GP4, form a heterotrimer that is required for viral infectivity, presumably due to its interaction with the key cellular receptor CD163. These 3 GPs are encoded by open reading frames (ORFs) 2a, 3, and 4 (herein referred to as ORFs 2–4), respectively. The goal of this study was to investigate the immunogenicity of the PRRSV-2 minor GPs. Through the use of reverse genetics, a chimeric virus (designated SDFL24) was constructed by replacing ORFs 2–4 of the PRRSV-1 strain SD01-08 with the corresponding genes of the PRRSV-2 strain FL12. While the parental …

Endothelial Function Is Associated With White Matter Microstructure And Executive Function In Older Adults, Nathan F. Johnson, Brian T. Gold, Christopher A. Brown, Emily F. Anggelis, Alison L. Bailey, Jody L. Clasey, David K. Powell

Physical Therapy Faculty Publications

Age-related declines in endothelial function can lead to cognitive decline. However, little is known about the relationships between endothelial function and specific neurocognitive functions. This study explored the relationship between measures of endothelial function (reactive hyperemia index; RHI), white matter (WM) health (fractional anisotropy, FA, and WM hyperintensity volume, WMH), and executive function (Trail Making Test (TMT); Trail B - Trail A). Participants were 36 older adults between the ages of 59 and 69 (mean age = 63.89 years, SD = 2.94). WMH volume showed no relationship with RHI or executive function. However, there was a positive relationship between RHI …

Structure-Based Design Of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses To A Conserved Epitope, Brian G. Pierce, Elisabeth N. Boucher, Kurt H. Piepenbrink, Monir Ejemal, Chelsea A. Rapp, William D. Thomas Jr, Eric J. Sundberg, Zhiping Weng, Yang Wang

Food for Health: Publications

Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, as …

Functionally Pathogenic Ears2 Variants In Vitro May Not Manifest A Phenotype In Vivo, Nathan Mcneill, Alessia Nasca, Aurelio Reyes, Benjamin Lemoine, Brandi Cantarel, Adeline Vanderver, Raphael Schiffmann, Daniele Ghezzi

Neurology Faculty Publications

Objective: To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC).

Methods: Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional testing to determine pathogenicity.

Results: Whole-exome sequencing uncovered compound heterozygous mutations in EARS2, c.328G>A (p.G110S), and c.1045G>A (p.E349K). This gene has previously been implicated in the autosomal recessive leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The p.G110S mutation has been found in multiple patients with LTBL. In silico analysis supported pathogenicity …

Proximal Femur Locking Plate For Sub-Trochanteric Femur Fractures: Factors Associated With Failure, Akbar Zubairi, Rizwan Haroon Rashid, Marij Zahid, Pervaiz Mahmood Hashmi, Shahryar Noordin

Section of Orthopaedic Surgery

Introduction: Proximal femur locking compression plates (PF-LCP) have gained popularity since their inception due to superior biomechanical stability and durability but clinical experience has shown conflicting results including implant failure.
Objective: To study the incidence of implant failure in patients with sub-trochanteric fractures managed with proximal femoral locking compression plate and identify potential risk factors associated with the failure.
Materials & Methods: Fifty patients with sub-trochanteric fractures, operated upon with titanium PF-LCP were included in the study from January 2012 to December 2014. These plates were of two designs including one five 5.0 mm proximal locking screws (implant A) and …

Clinical And Experimental Studies Of A Novel P525r Fus Mutation In Amyotrophic Lateral Sclerosis, Lisha Kuang, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Objective: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.

Methods: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same …

Brain Microvascular Injury And White Matter Disease Provoked By Diabetes-Associated Hyperamylinemia, Han Ly, Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.

METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses …

A Naturally Generated Decoy Of The Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance In Tumors, Nikhil Hebbar, Ravshan Burikhanov, Nidhi Shukla, Shirley Qiu, Yanming Zhao, Kojo S. J. Elenitoba-Johnson, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA …