Digital Commons Network^™

Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images, Zhuoyu Wen, Yu-Hsuan Lin, Shidan Wang, Naoto Fujiwara, Ruichen Rong, Kevin W Jin, Donghan M Yang, Bo Yao, Shengjie Yang, Tao Wang, Yang Xie, Yujin Hoshida, Hao Zhu, Guanghua Xiao

Faculty, Staff and Student Publications

Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in clinical settings due to high financial and time costs. To improve accessibility for clinical samples, we developed a computational algorithm to quantify hepatic ploidy using hematoxylin-eosin (H&E) histopathology images, which are commonly obtained during routine clinical practice. Our algorithm uses a deep learning model to first segment and classify different types of cell nuclei in H&E images. …

The Potential Regulation Of A-To-I Rna Editing On Genes In Parkinson's Disease, Sijia Wu, Qiuping Xue, Xinyu Qin, Xiaoming Wu, Pora Kim, Jacqueline Chyr, Xiaobo Zhou, Liyu Huang

Faculty, Staff and Student Publications

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD's transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) …

Can Local Vibration Alter The Contribution Of Persistent Inward Currents To Human Motoneuron Firing?, T. Lapole, Ricardo N. O. Mesquita, S. Baudry, R. Souron, C. G. Brownstein, V. Rozand

Research outputs 2022 to 2026

The response of spinal motoneurons to synaptic input greatly depends on the activation of persistent inward currents (PICs), which in turn are enhanced by the neuromodulators serotonin and noradrenaline. Local vibration (LV) induces excitatory Ia input onto motoneurons and may alter neuromodulatory inputs. Therefore, we investigated whether LV influences the contribution of PICs to motoneuron firing. This was assessed in voluntary contractions with concurrent, ongoing LV, as well as after a bout of prolonged LV. High-density surface electromyograms (HD-EMG) of the tibialis anterior were recorded with a 64-electrode matrix. Twenty males performed isometric, triangular, dorsiflexion contractions to 20% and 50% …

Anthracycline-Containing And Taxane-Containing Chemotherapy For Early-Stage Operable Breast Cancer: A Patient-Level Meta-Analysis Of 100 000 Women From 86 Randomised Trials, Early Breast Cancer Trialists’ Collaborative Group (Ebctcg)

Faculty, Staff and Student Publications

BACKGROUND: Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens.

METHODS: We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including …

Nuclear Export Signal Mutation Of Epidermal Growth Factor Receptor Enhances Malignant Phenotypes Of Cancer Cells, Lei Nie, Ying-Nai Wang, Jung-Mao Hsu, Junwei Hou, Yu-Yi Chu, Li-Chuan Chan, Longfei Huo, Yongkun Wei, Rong Deng, Jun Tang, Yi-Hsin Hsu, How-Wen Ko, Seung-Oe Lim, Kebin Huang, Mei-Kuang Chen, Tai-Jan Chiu, Chien-Chia Cheng, Yueh-Fu Fang, Chia-Wei Li, Aarthi Goverdhan, Hsing-Ju Wu, Cheng-Chung Lee, Wen-Ling Wang, Jennifer Hsu, Paul Chiao, Shao-Chun Wang, Mien-Chie Hung

Faculty, Staff and Student Publications

Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) …

Molecular Disparity Of Hla-Dpb1 Is Associated With The Development Of Subsequent Solid Cancer After Allogeneic Hematopoietic Stem Cell Transplantation, Jun Zou, Piyanuch Kongtim, Betül Oran, Samer A Srour, Uri Greenbaum, Yudith Carmazzi, Gabriela Rondon, Stefan O Ciurea, Qing Ma, Elizabeth J Shpall, Richard E Champlin, Kai Cao

Faculty, Staff and Student Publications

Background: An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) …

Ethnic Disparities In Childhood Leukemia Survival By Border Residence: A Texas Population-Based Analysis, Maria I Castellanos, Abiodun O Oluyomi, Tiffany M Chambers, Maria M Gramatges, Lena E Winestone, Philip J Lupo, Michael E Scheurer

Faculty, Staff and Students Publications

Background: The US-Mexico border is a medically underserved region where survival disparities have been observed in adults diagnosed and treated for various malignancies. Studies examining survival disparities among children living in this region and diagnosed with cancer are lacking. The objective of this study was to evaluate the impact of border residence on survival among children with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and living near the Texas-Mexico border at the time of their diagnosis. The authors hypothesized that this group experiences inferior survival compared with patients with childhood leukemia living in nonborder areas.

Methods: The authors conducted …

Ethnic-Specific Predictors Of Neurotoxicity Among Patients With Pediatric Acute Lymphoblastic Leukemia After High-Dose Methotrexate, Rachel D Harris, Melanie Brooke Bernhardt, Mark C Zobeck, Olga A Taylor, Maria Monica Gramatges, Eric S Schafer, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Faculty, Staff and Students Publications

High-dose methotrexate (HD-MTX; 5,000 mg/m2) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity which may disproportionately affect Latino children. Thus, we evaluated risk factors for neurotoxicity in an ethnically diverse population of 351 patients (58.1% Latino) who received 1,183 HD-MTX infusions. Overall, thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, we found that serum creatinine elevations ≥50% of baseline were associated with a 3-fold increased odds (OR = 3.32, 95% CI: 0.98-11.21, p=0.05) for …

Update On The Role Of Feno In Asthma Management, Neveda Murugesan, Damini Saxena, Arundhati Dileep, Muhammad Adrish, Nicola A Hanania

Faculty, Staff and Students Publications

Asthma is a heterogenous disorder characterized by presence of different phenotypes and endotypes. Up to 10% of the individuals suffer from severe asthma and are at increased risk of morbidity and mortality. Fractional exhaled nitric oxide (FeNO) is a cost-effective, point of care biomarker that is used to detect type 2 airway inflammation. Guidelines have proposed to measure FeNO as an adjunct to diagnostic evaluation in individuals with suspected asthma and to monitor airway inflammation. FeNO has lower sensitivity, suggesting that it may not be a good biomarker to rule out asthma. FeNO may also be used to predict response …

Mechanisms Of Chromosomal Instability (Cin) Tolerance In Aggressive Tumors: Surviving The Genomic Chaos, Brittiny Dhital, Veronica Rodriguez-Bravo

Student Papers, Posters & Projects

Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles' heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the …

Bayesian Adaptive Model Selection Design For Optimal Biological Dose Finding In Phase I/Ii Clinical Trials, Ruitao Lin, Guosheng Yin, Haolun Shi

Faculty, Staff and Student Publications

Identification of the optimal dose presents a major challenge in drug development with molecularly targeted agents, immunotherapy, as well as chimeric antigen receptor T-cell treatments. By casting dose finding as a Bayesian model selection problem, we propose an adaptive design by simultaneously incorporating the toxicity and efficacy outcomes to select the optimal biological dose (OBD) in phase I/II clinical trials. Without imposing any parametric assumption or shape constraint on the underlying dose-response curves, we specify curve-free models for both the toxicity and efficacy endpoints to determine the OBD. By integrating the observed data across all dose levels, the proposed design …

The Abscopal Effect In Patients With Cancer Receiving Immunotherapy, Blessie Elizabeth Nelson, Jacob J Adashek, Steven H Lin, Vivek Subbiah

Faculty, Staff and Student Publications

Interest in the abscopal effect has been rekindled over the past decade with the advent of immunotherapy. Although purportedly elusive, this phenomenon is being increasingly reported. Venturing further using a multimodality approach with an array of systemic agents and unconventional modalities is direly needed. In this perspective, we describe the fundamentals of abscopal responses (ARs), explore combinations with systemic therapies that hold promise in eliciting ARs, and reconnoiter unconventional modalities that may induce ARs. Finally, we scrutinize prospective agents and modalities that exhibit preclinical ability to elicit ARs and discuss prognostic biomarkers, their limitations, and pathways of abscopal resistance for …

Serinc5 Restricts Hiv Membrane Fusion By Altering Lipid Order And Heterogeneity In The Viral Membrane, Amanda E Ward, Daria Sokovikova, Melvin Neal Waxham, Frederick A Heberle, Ilya Levental, Kandice R Levental, Volker Kiessling, Judith M White, Lukas K Tamm

Faculty, Staff and Student Publications

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, …

Feature Selection For Support Vector Regression Using A Genetic Algorithm, Shannon B Mckearnan, David M Vock, G Elisabeta Marai, Guadalupe Canahuate, Clifton D Fuller, Julian Wolfson

Faculty, Staff and Student Publications

Support vector regression (SVR) is particularly beneficial when the outcome and predictors are nonlinearly related. However, when many covariates are available, the method's flexibility can lead to overfitting and an overall loss in predictive accuracy. To overcome this drawback, we develop a feature selection method for SVR based on a genetic algorithm that iteratively searches across potential subsets of covariates to find those that yield the best performance according to a user-defined fitness function. We evaluate the performance of our feature selection method for SVR, comparing it to alternate methods including LASSO and random forest, in a simulation study. We …

Mmp9 Clears The Way For Metastatic Cell Penetration Across The Blood-Brain Barrier, Joseph H Mccarty

Faculty, Staff and Student Publications

Although brain metastases are 10-fold more prevalent than primary brain cancers, relatively little is understood about the genes and pathways that promote metastatic cell entry, growth, and survival in the brain. Hence, determining how metastatic tumors colonize the brain and thrive within the neural microenvironment is a topic of both fundamental importance and direct clinical relevance. In this issue, a report by Karreman and colleagues explores pathways that are exploited by metastatic tumor cells to arrest in the circulation, cross the endothelial blood-brain barrier (BBB), and thrive in the brain microenvironment. The authors used elegant imaging tools including intravital fluorescence …

Pertuzumab, Trastuzumab, And An Aromatase Inhibitor For Her2-Positive And Hormone Receptor-Positive Metastatic Or Locally Advanced Breast Cancer: Pertain Final Analysis, Grazia Arpino, Juan De La Haba Rodríguez, Jean-Marc Ferrero, Sabino De Placido, C Kent Osborne, Dirk Klingbiel, Valentine Revelant, Christine Wohlfarth, Raf Poppe, Mothaffar F Rimawi

Faculty, Staff and Students Publications

PURPOSE: In PERTAIN's primary analysis (31 months' median follow-up), adding pertuzumab to trastuzumab and an aromatase inhibitor (AI) with/without chemotherapy significantly improved progression-free survival (PFS) in patients with previously untreated HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (M/LABC). A potentially enhanced treatment effect was observed in patients with no induction chemotherapy. We present the final analysis (>6 years' median follow-up).

PATIENTS AND METHODS: Patients (N = 258) were randomized 1:1 to pertuzumab (loading/maintenance: 840/420 mg) plus trastuzumab (loading/maintenance: 8/6 mg/kg) every 3 weeks and an AI (1 mg anastrozole or 2.5 mg letrozole daily; Arm A), …

Second Annual Research Symposium Program With Abstracts, Office Of Research Affairs, Boonshoft School Of Medicine

Boonshoft School of Medicine Research Symposium

The program booklet is a compilation of abstracts from oral and poster presentations at Wright State University's First Annual Boonshoft School of Medicine Medical Research Symposium held on April 13, 2023.

Basal Expression Of Nuclear Transcription Factor, Nr4a1, Is Lower In Triple Negative Breast Cancer Compared To Other Breast Cancer Subsets, Manu Khosla, Hassan Yousefi, Celeste Wagner, Arian Lahiji, Suresh Alahari

School of Graduate Studies Faculty Publications

DiscoverBMB, March 25 - 28, 2023, Seattle, WA

Cancer Neuroscience: State Of The Field, Emerging Directions, Frank Winkler, Humsa S Venkatesh, Moran Amit, Tracy Batchelor, Ihsan Ekin Demir, Benjamin Deneen, David H Gutmann, Shawn Hervey-Jumper, Thomas Kuner, Donald Mabbott, Michael Platten, Asya Rolls, Erica K Sloan, Timothy C Wang, Wolfgang Wick, Varun Venkataramani, Michelle Monje

Faculty, Staff and Student Publications

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new …

Spdef Modulates Transcriptional Output To Regulate Multiple Pathways: Immune And Inflammatory Pathways As Potential Hubs Targeted By Spdef In Rcc 7/T Cells, A Line Of Prostate Cancer Cells Of African American Origin, Mousa Vatanmakanian, Sweaty Koul, Hari Koul

School of Graduate Studies Faculty Publications

DiscoverBMB, March 25 - 28, 2023, Seattle, WA

Pancreatic Cancer: Advances And Challenges, Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca Di Magliano, Anirban Maitra

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant …

Targeting Of Epigenetic Co-Dependencies Enhances Anti-Aml Efficacy Of Menin Inhibitor In Aml With Mll1-R Or Mutant Npm1, Warren Fiskus, Christopher P Mill, Christine Birdwell, John A Davis, Kaberi Das, Steffen Boettcher, Tapan M Kadia, Courtney D Dinardo, Koichi Takahashi, Sanam Loghavi, Michael J Soth, Tim Heffernan, Gerard M Mcgeehan, Xinjia Ruan, Xiaoping Su, Christopher R Vakoc, Naval Daver, Kapil N Bhalla

Faculty, Staff and Student Publications

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A …

A Reduced Pancreatic Polypeptide Response Is Associated With New-Onset Pancreatogenic Diabetes Versus Type 2 Diabetes, Phil A Hart, Yogish C Kudva, Dhiraj Yadav, Dana K Andersen, Yisheng Li, Frederico G S Toledo, Fuchenchu Wang, Melena D Bellin, David Bradley, Randall E Brand, Kenneth Cusi, William Fisher, Kieren Mather, Walter G Park, Zeb Saeed, Robert V Considine, Sarah C Graham, Jo Ann Rinaudo, Jose Serrano, Mark O Goodarzi

Faculty, Staff and Student Publications

PURPOSE: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM).

METHODS: Subjects with new-onset DM (<3 >years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of …

Targeting Mirnas And Other Non-Coding Rnas As A Therapeutic Approach: An Update, Emine Bayraktar, Recep Bayraktar, Hulya Oztatlici, Gabriel Lopez-Berestein, Paola Amero, Cristian Rodriguez-Aguayo

Faculty, Staff and Student Publications

Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression, and because miRNAs act as tumor suppressors or oncogenes (oncomiRs), they have emerged as attractive tools and, more importantly, as a new class of targets for drug development in cancer therapeutics. With the use of miRNA mimics or molecules targeting miRNAs (i.e., small-molecule inhibitors such …

The Role Of Extracellular Vesicles In Cancer, Raghu Kalluri, Kathleen M Mcandrews

Faculty, Staff and Student Publications

Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics.

Mechanisms Of Response And Resistance To Combined Decitabine And Ipilimumab For Advanced Myeloid Disease, Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M Cullen, Kathleen L Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen X Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S Neuberg, F Stephen Hodi, Matthew S Davids, Sacha Gnjatic, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

Faculty, Staff and Student Publications

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were …

Immune Checkpoint Therapy-Current Perspectives And Future Directions, Padmanee Sharma, Sangeeta Goswami, Deblina Raychaudhuri, Bilal A Siddiqui, Pratishtha Singh, Ashwat Nagarajan, Jielin Liu, Sumit K Subudhi, Candice Poon, Kristal L Gant, Shelley M Herbrich, Swetha Anandhan, Shajedul Islam, Moran Amit, Gayathri Anandappa, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

Low And Differential Polygenic Score Generalizability Among African Populations Due Largely To Genetic Diversity, Lerato Majara, Allan Kalungi, Nastassja Koen, Kristin Tsuo, Ying Wang, Rahul Gupta, Lethukuthula L Nkambule, Heather Zar, Dan J Stein, Eugene Kinyanda, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across …

One Population, Multiple Lifestyles: Commensalism And Pathogenesis In The Human Mycobiome, Diana M Proctor, Rebecca A Drummond, Michail S Lionakis, Julia A Segre

Faculty, Staff and Student Publications

Candida auris and Candida albicans can result in invasive fungal diseases. And yet, these species can stably and asymptomatically colonize human skin and gastrointestinal tracts. To consider these disparate microbial lifestyles, we first review factors shown to influence the underlying microbiome. Structured by the damage response framework, we then consider the molecular mechanisms deployed by C. albicans to switch between commensal and pathogenic lifestyles. Next, we explore this framework with C. auris to highlight how host physiology, immunity, and/or antibiotic receipt are associated with progression from colonization to infection. While treatment with antibiotics increases the risk an individual will succumb …

Quantitative Proteomic Screening Uncovers Candidate Diagnostic And Monitoring Serum Biomarkers Of Ankylosing Spondylitis, Mark Hwang, Shervin Assassi, Jim Zheng, Jessica Castillo, Reyna Chavez, Kamala Vanarsa, Chandra Mohan, John Reveille

Faculty, Staff and Student Publications

BACKGROUND: We sought to discover serum biomarkers of ankylosing spondylitis (AS) for diagnosis and monitoring disease activity.

METHODS: We studied biologic-treatment-naïve AS and healthy control (HC) patients' sera. Eighty samples matched by age, gender, and race (1:1:1 ratio) for AS patients with active disease, inactive disease, and HC were analyzed with SOMAscan™, an aptamer-based discovery platform. T-tests tests were performed for high/low-disease activity AS patients versus HCs (diagnosis) and high versus low disease activity (Monitoring) in a 2:1 and 1:1 ratio, respectively, to identify differentially expressed proteins (DEPs). We used the Cytoscape Molecular Complex Detection (MCODE) plugin to find clusters …