Life Sciences Commons^™

Genetic Contributors Of Incident Stroke In 10,700 African Americans With Hypertension: A Meta-Analysis From The Genetics Of Hypertension Associated Treatments And Reasons For Geographic And Racial Differences In Stroke Studies, Nicole D. Armstrong, Vinodh Srinivasasainagendra, Amit Patki, Rikki M. Tanner, Bertha A. Hidalgo, Hemant K. Tiwari, Nita A. Limdi, Ethan M. Lange, Leslie A. Lange, Donna K. Arnett, Marguerite R. Irvin

Epidemiology and Environmental Health Faculty Publications

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals.

Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs …

Late-Life Exercise Mitigates Skeletal Muscle Epigenetic Aging, Kevin A. Murach, Andrea L. Dimet-Wiley, Yuan Wen, Camille R. Brightwell, Christine M. Latham, Cory M. Dungan, Christopher S. Fry, Stanley J. Watowich

Center for Muscle Biology Faculty Publications

There are functional benefits to exercise in muscle, even when performed late in life, but the contributions of epigenetic factors to late-life exercise adaptation are poorly defined. Using reduced representation bisulfite sequencing (RRBS), ribosomal DNA (rDNA) and mitochondrial-specific examination of methylation, targeted high-resolution methylation analysis, and DNAge™ epigenetic aging clock analysis with a translatable model of voluntary murine endurance/resistance exercise training (progressive weighted wheel running, PoWeR), we provide evidence that exercise may mitigate epigenetic aging in skeletal muscle. Late-life PoWeR from 22–24 months of age modestly but significantly attenuates an age-associated shift toward promoter hypermethylation. The epigenetic age of muscle …

Characterizing Long Covid: Deep Phenotype Of A Complex Condition, Rachel R. Deer, Madeline A. Rock, Nicole Vasilevsky, Leigh Carmody, Halie Rando, Alfred J. Anzalone, Marc D. Basson, Tellen D. Bennett, Timothy Bergquist, Eilis A. Boudreau, Carolyn T. Bramante, James Brian Byrd, Tiffany J. Callahan, Lauren E. Chan, Haitao Chu, Christopher G. Chute, Ben D. Coleman, Hannah E. Davis, Joel Gagnier, Casey S. Greene, Ramakanth Kavuluru

Institute for Biomedical Informatics Faculty Publications

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies.

METHODS: The Human Phenotype Ontology …

Adult Spiny Mice (Acomys) Exhibit Endogenous Cardiac Recovery In Response To Myocardial Infarction, Hsuan Peng, Kazuhiro Shindo, Renée R. Donahue, Erhe Gao, Brooke M. Ahern, Bryana M. Levitan, Himi Tripathi, David Powell, Ahmed Noor, Garrett A. Elmore, Jonathan Satin, Ashley W. Seifert, Ahmed K. Abdel-Latif

Physiology Faculty Publications

Complex tissue regeneration is extremely rare among adult mammals. An exception, however, is the superior tissue healing of multiple organs in spiny mice (Acomys). While Acomys species exhibit the remarkable ability to heal complex tissue with minimal scarring, little is known about their cardiac structure and response to cardiac injury. In this study, we first examined baseline Acomys cardiac anatomy and function in comparison with commonly used inbred and outbred laboratory Mus strains (C57BL6 and CFW). While our results demonstrated comparable cardiac anatomy and function between Acomys and Mus, Acomys exhibited a higher percentage of cardiomyocytes displaying …

Editorial: Perturbations In Metabolic Cues: Implications For Adverse Cardiac Function Leading To Sudden Cardiac Death, Brian P. Delisle, Ademuyiwa S. Aromolaran

Physiology Faculty Publications

No abstract provided.

Editorial For The Genetics Of Alzheimer’S Disease Special Issue: October 2021, Laura Ibanez, Justin B. Miller

Sanders-Brown Center on Aging Faculty Publications

No abstract provided.

Sedation And Acute Encephalopathy In A Pediatric Patient Following Ingestion Of Delta-8-Tetrahydrocannabinol Gummies, Peter Akpunonu, Regan A. Baum, Andrew Reckers, Blake Davidson, Ross Ellison, Matthew Riley, Jordan Trecki, Roy Gerona

Emergency Medicine Faculty Publications

BACKGROUND Delta-8 tetrahydrocannabinol (delta-8 THC) is an isomer of delta-9-tetrahydrocannabinol (delta-9 THC), the primary psychoactive cannabinoid in the marijuana plant. Typically found at lower concentrations in marijuana, delta-8 THC exhibits psychoactive properties similar to delta-9 THC. Products containing delta-8 THC are readily available across the US and currently there is a lack of available confirmatory testing specific to delta-8 THC as there is cross-reactivity to other naturally occurring cannabinoids in standard immunoassays. Pediatric exposures to this substance are on the rise.

CASE REPORT We present a case with laboratory confirmation of a previously healthy 2-year-old girl ingesting approximately 15 mg/kg …

Editorial: Recent Advances In Cardiotoxicity Testing, Tamer M. A. Mohamed, Javid Moslehi, Jonathan Satin

Physiology Faculty Publications

No abstract provided.

Untargeted Lipidomics Of Non-Small Cell Lung Carcinoma Demonstrates Differentially Abundant Lipid Classes In Cancer Vs. Non-Cancer Tissue, Joshua M. Mitchell, Robert M. Flight, Hunter N. B. Moseley

Molecular and Cellular Biochemistry Faculty Publications

Lung cancer remains the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. In this study, we utilized our untargeted assignment tool Small Molecule Isotope Resolved Formula Enumerator (SMIRFE) and ultra-high-resolution Fourier transform mass spectrometry to examine lipid profile differences between paired cancerous and non-cancerous lung tissue samples from 86 patients with suspected stage I or IIA primary NSCLC. Correlation and co-occurrence analysis revealed significant lipid profile differences between cancer and non-cancer samples. Further analysis of machine-learned lipid categories for the differentially abundant molecular formulas identified a high abundance sterol, …

Pairwise Correlation Analysis Of The Alzheimer’S Disease Neuroimaging Initiative (Adni) Dataset Reveals Significant Feature Correlation, Erik D. Huckvale, Matthew W. Hodgman, Brianna B. Greenwood, Devorah O. Stucki, Katrisa M. Ward, Mark T. W. Ebbert, John S. K. Kauwe, The Alzheimer’S Disease Neuroimaging Initiative, The Alzheimer’S Disease Metabolomics Consortium, Justin B. Miller

Sanders-Brown Center on Aging Faculty Publications

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) contains extensive patient measurements (e.g., magnetic resonance imaging [MRI], biometrics, RNA expression, etc.) from Alzheimer’s disease (AD) cases and controls that have recently been used by machine learning algorithms to evaluate AD onset and progression. While using a variety of biomarkers is essential to AD research, highly correlated input features can significantly decrease machine learning model generalizability and performance. Additionally, redundant features unnecessarily increase computational time and resources necessary to train predictive models. Therefore, we used 49,288 biomarkers and 793,600 extracted MRI features to assess feature correlation within the ADNI dataset to determine the …

Epigenetic Regulation And Post-Translational Modifications Of Snai1 In Cancer Metastasis, Bo Dong, Yadi Wu

Pharmacology and Nutritional Sciences Faculty Publications

SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelialmesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and posttranslational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help …

An Empirical Pipeline For Personalized Diagnosis Of Lafora Disease Mutations, M. Kathryn Brewer, Maria Machio-Castello, Rosa Viana, Jeremiah L. Wayne, Andrea Kuchtová, Zoe R. Simmons, Sarah Sternbach, Sheng Li, Maria Adelaida García-Gimeno, Jose M. Serratosa, Pascual Sanz, Craig W. Vander Kooi, Matthew S. Gentry

Molecular and Cellular Biochemistry Faculty Publications

Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed many EPM2A variants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutations in vitro using complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical …

Neurotensin Regulates Proliferation And Stem Cell Function In The Small Intestine In A Nutrient-Dependent Manner, Stephanie A. Rock, Kai Jiang, Yuanyuan Wu, Yajuan Liu, Jing Li, Heidi L. Weiss, Chi Wang, Jianhang Jia, Tianyan Gao, B. Mark Evers

Surgery Faculty Publications

BACKGROUND & AIMS: Intestinal stem cells (ISCs) are sensitive to dietary alterations and nutrient availability. Neurotensin (NT), a gut peptide localized predominantly to the small bowel and released by fat ingestion, stimulates the growth of intestinal mucosa under basal conditions and during periods of nutrient deprivation, suggesting a possible role for NT on ISC function.

METHODS: Leucine-rich repeat-containing G-protein coupled receptor 5-Enhanced Green Fluorescent Protein (Lgr5-EGFP) NT wild type (Nt^+/+) and Lgr5-EGFP NT knockout (Nt^-/-) mice were fed ad libitum or fasted for 48 hours. Small intestine tissue and crypts were examined by gene …

Real-World Evaluation Of Universal Germline Screening For Cancer Treatment-Relevant Pharmacogenes, Megan L. Hutchcraft, Nan Lin, Shulin Zhang, Catherine Sears, Kyle Zacholski, Elizabeth A. Belcher, Eric B. Durbin, John L. Villano, Michael J. Cavnar, Susanne M. Arnold, Frederick R. Ueland, Jill M. Kolesar

Pathology and Laboratory Medicine Faculty Publications

The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with …

Random Forest-Integrated Analysis In Ad And Late Brain Transcriptome-Wide Data To Identify Disease-Specific Gene Expression, Xinxing Wu, Chong Peng, Peter T. Nelson, Qiang Cheng

Sanders-Brown Center on Aging Faculty Publications

Alzheimer's disease (AD) is a complex neurodegenerative disorder that affects thinking, memory, and behavior. Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently identified common neurodegenerative disease that mimics the clinical symptoms of AD. The development of drugs to prevent or treat these neurodegenerative diseases has been slow, partly because the genes associated with these diseases are incompletely understood. A notable hindrance from data analysis perspective is that, usually, the clinical samples for patients and controls are highly imbalanced, thus rendering it challenging to apply most existing machine learning algorithms to directly analyze such datasets. Meeting this data analysis challenge is …

Bone Quality And Fractures In Women With Osteoporosis Treated With Bisphosphonates For 1 To 14 Years, Hartmut H. Malluche, Jin Chen, Florence Lima, Lucas J. Liu, Marie-Claude Monier-Faugere, David A. Pienkowski

Internal Medicine Faculty Publications

Oral bisphosphonates are the primary medication for osteoporosis, but concerns exist regarding potential bone-quality changes or low-energy fractures. This cross-sectional study used artificial intelligence methods to analyze relationships among bisphosphonate treatment duration, a wide variety of bone-quality parameters, and low-energy fractures. Fourier transform infrared spectroscopy and histomorphometry quantified bone-quality parameters in 67 osteoporotic women treated with oral bisphosphonates for 1 to 14 years. Artificial intelligence methods established two models relating bisphosphonate treatment duration to bone-quality changes and to low-energy clinical fractures. The model relating bisphosphonate treatment duration to bone quality demonstrated optimal performance when treatment durations of 1 to 8 …

Editorial: Roles Of Sleep Disruption And Circadian Rhythm Alterations On Neurodegeneration And Alzheimer's Disease, Marilyn J. Duncan, Sigrid C. Veasey, Phyllis Zee

Neuroscience Faculty Publications

No abstract provided.

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Physiology Faculty Publications

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

RESULTS: Single-cell …

Intravesical Cd74 And Cxcr4, Macrophage Migration Inhibitory Factor (Mif) Receptors, Mediate Bladder Pain, Shaojing Ye, Fei Ma, Dlovan F. D. Mahmood, Katherine L. Meyer-Siegler, Raymond E. Menard, David E. Hunt, Lin Leng, Richard Bucala, Pedro L. Vera

Physiology Faculty Publications

BACKGROUND: Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo.

METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary …

Innate Immune Activation By Checkpoint Inhibition In Human Patient-Derived Lung Cancer Tissues, Teresa W. M. Fan, Richard M. Higashi, Huan Song, Saeed Daneshmandi, Angela L. Mahan, Matthew S. Purdom, Therese J. Bocklage, Thomas A. Pittman, Daheng He, Chi Wang, Andrew N. Lane

Center for Environmental and Systems Biochemistry Faculty Publications

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with ¹³C₆-Glc/ …

White Matter Hyperintensity Volume And Location: Associations With Wm Microstructure, Brain Iron, And Cerebral Perfusion, Christopher E. Bauer, Valentinos Zachariou, Elayna R. Seago, Brian T. Gold

Neuroscience Faculty Publications

Cerebral white matter hyperintensities (WMHs) represent macrostructural brain damage associated with various etiologies. However, the relative contributions of various etiologies to WMH volume, as assessed via different neuroimaging measures, is not well-understood. Here, we explored associations between three potential early markers of white matter hyperintensity volume. Specifically, the unique variance in total and regional WMH volumes accounted for by white matter microstructure, brain iron concentration and cerebral blood flow (CBF) was assessed. Regional volumes explored were periventricular and deep regions. Eighty healthy older adults (ages 60–86) were scanned at 3 Tesla MRI using fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), …

Reduced Mitochondrial Dna And Oxphos Protein Content In Skeletal Muscle Of Children With Cerebral Palsy, Ferdinand Von Walden, Ivan J. Vechetti Jr., Davis A. Englund, Vandré C. Figueiredo, Rodrigo Fernandez-Gonzalo, Kevin A. Murach, Jessica Pingel, John J. Mccarthy, Per Stål, Eva Pontén

Physiology Faculty Publications

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP).

METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were …

Cardiomyocyte Deletion Of Bmal1 Exacerbates Qt- And Rr-Interval Prolongation In Scn5a+/Δkpq Mice, Elizabeth A. Schroder, Jennifer L. Wayland, Kaitlyn M. Samuels, Syed F. Shah, Don E. Burgess, Tanya S. Seward, Claude S. Elayi, Karyn A. Esser, Brian P. Delisle

Physiology Faculty Publications

Circadian rhythms are generated by cell autonomous circadian clocks that perform a ubiquitous cellular time-keeping function and cell type-specific functions important for normal physiology. Studies show inducing the deletion of the core circadian clock transcription factor Bmal1 in adult mouse cardiomyocytes disrupts cardiac circadian clock function, cardiac ion channel expression, slows heart rate, and prolongs the QT-interval at slow heart rates. This study determined how inducing the deletion of Bmal1 in adult cardiomyocytes impacted the in vivo electrophysiological phenotype of a knock-in mouse model for the arrhythmogenic long QT syndrome (Scn5a+/ΔKPQ). Electrocardiographic telemetry showed inducing the …

Healthy Dietary Intake Moderates The Effects Of Age On Brain Iron Concentration And Working Memory Performance, Valentinos Zachariou, Christopher E. Bauer, Elayna R. Seago, Georgia Panayiotou, Edward D. Hall, D. Allan Butterfield, Brian T. Gold

Neuroscience Faculty Publications

Age-related brain iron accumulation is linked with oxidative stress, neurodegeneration and cognitive decline. Certain nutrients can reduce brain iron concentration in animal models, however, this association is not well established in humans. Moreover, it remains unknown if nutrition can moderate the effects of age on brain iron concentration and/or cognition. Here, we explored these issues in a sample of 73 healthy older adults (61-86 years old), while controlling for several factors such as age, gender, years of education, physical fitness and alcohol-intake. Quantitative susceptibility mapping was used for assessment of brain iron concentration and participants performed an N-Back paradigm to …

Analysis Of High-Risk Pedigrees Identifies 12 Candidate Variants For Alzheimer's Disease, Craig C. Teerlink, Justin B. Miller, Elizabeth L. Vance, Lyndsay A. Staley, Jeffrey Stevens, Justina P. Tavana, Matthew E. Cloward, Madeline L. Page, Louisa Dayton, Alzheimer's Disease Genetics Consortium, Lisa A. Cannon-Albright, John S. K. Kauwe

Institute for Biomedical Informatics Faculty Publications

INTRODUCTION: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants.

METHODS: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer's disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members.

RESULTS: AD-affected high-risk cousin pairs contained 564 shared rare variants. Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously …

Cd151 Drives Cancer Progression Depending On Integrin Α3Β1 Through Egfr Signaling In Non-Small Cell Lung Cancer, Jianjie Zhu, Tingting Cai, Jieqi Zhou, Wenwen Du, Yuanyuan Zeng, Ting Liu, Yulong Fu, Yue Li, Qian Qian, Xiuwei H. Yang, Qinglin Li, Jian-An Huang, Zeyi Liu

Pharmacology and Nutritional Sciences Faculty Publications

Background
Tetraspanins CD151, a transmembrane 4 superfamily protein, has been identified participating in the initiation of a variety of cancers. However, the precise function of CD151 in non-small cell lung cancer (NSCLC) remains unclear. Here, we addressed the pro-tumoral role of CD151 in NSCLC by targeting EGFR/ErbB2 which favors tumor proliferation, migration and invasion.

Methods
First, the mRNA expression levels of CD151 in NSCLC tissues and cell lines were measured by RT-PCR. Meanwhile, CD151 and its associated proteins were analyzed by western blotting. The expression levels of CD151 in NSCLC samples and its paired adjacent lung tissues were then verified …

Co-Targeting Plk1 And Dnmt3a In Advanced Prostate Cancer, Zhuangzhuang Zhang, Lijun Cheng, Qiongsi Zhang, Yifan Kong, Daheng He, Kunyu Li, Matthew Rea, Jianlin Wang, Ruixin Wang, Jinghui Liu, Zhiguo Li, Chongli Yuan, Enze Liu, Yvonne N. Fondufe-Mittendorf, Lang Li, Tao Han, Chi Wang, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 …

Inflammatory Regulation Of Cns Barriers After Traumatic Brain Injury: A Tale Directed By Interleukin-1, Colleen N. Bodnar, James B. Watson, Emma K. Higgins, Ning Quan, Adam D. Bachstetter

Neuroscience Faculty Publications

Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain’s health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during …

A Screen Of Fda-Approved Drugs Identifies Inhibitors Of Protein Tyrosine Phosphatase 4a3 (Ptp4a3 Or Prl-3), Dylan R. Rivas, Mark Vincent C. Dela Cerna, Caroline N. Smith, Shilpa Sampathi, Blaine G. Patty, Donghan Lee, Jessica S. Blackburn

Molecular and Cellular Biochemistry Faculty Publications

Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells …

The Context-Dependent Impact Of Integrin-Associated Cd151 And Other Tetraspanins On Cancer Development And Progression: A Class Of Versatile Mediators Of Cellular Function And Signaling, Tumorigenesis And Metastasis, Sonia F. Erfani, Hui Hua, Yueyin Pan, Binhua P. Zhou, Xiuwei H. Yang

Molecular and Cellular Biochemistry Faculty Publications

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition …