Digital Commons Network^™

Health Systems Responsiveness In Low And Middle-Income Countries (L&Mics): Revisiting Its Scope, Meesha Iqbal, Robert Morgan, Cici Bauer, Cecilia Ganduglia Cazaban, Sameen Siddiqi

Faculty, Staff and Student Publications

Introduction: Health systems responsiveness (HSR) addresses the legitimate non-health expectations of the population and plays a vital role in strengthening health systems and enhancing population health. Identifying specific constructs or domains within HSR is particularly important in the context of low and middle-income countries (L&MICs) to facilitate targeted improvement. Following a comprehensive systematic review of the literature, we developed a conceptual framework for HSR. This study was designed to validate our proposed framework through a Delphi process.

Methods: Global HSR experts were contacted via email to participate in the study, and a copy of the proposed framework (12 domains, 53 …

Infectious Prions In Brains And Muscles Of Domestic Pigs Experimentally Challenged With The Bse, Scrapie, And Cwd Agents, Francisca Bravo-Risi, Fraser Brydon, Angela Chong, Kane Spicker, Justin J Greenlee, Glenn Telling, Claudio Soto, Sandra Pritzkow, Marcelo A Barria, Rodrigo Morales

Faculty, Staff and Student Publications

Experimental studies suggest that animal species not previously described as naturally infected by prions are susceptible to prion diseases affecting sheep, cattle, and deer. These interspecies transmissions may generate prions with unknown host ranges. Pigs are susceptible to prions from different origins, including deer chronic wasting disease (CWD), sheep scrapie, and bovine spongiform encephalopathy (BSE). Here, we studied prions in brains and muscles from pigs previously infected with these different prion sources. Specifically, we measured the total prion protein (PrP) and PK-resistant PrP by western blot. Seeding activity in these tissues was evaluated using the protein misfolding cyclic amplification (PMCA) …

Computationally Resolved Neuroprogenitor Cell Biomarkers Associate With Human Disorders, Gerarda Cappuccio, William T Choi, Fatih Semerci, Jill A Rosenfeld, Toni Claire Tacorda, Guantong Qi, Anthony W Zoghbi, Yi Zhong, Hu Chen, Pengfei Liu, Zhandong Liu, Mirjana Maletić-Savatić

Duncan NRI Faculty and Staff Publications

Adult hippocampal neurogenesis, the process of generating new neurons, relies on a rare population of neural stem and progenitor cells (NPCs) within the dentate gyrus complex microenvironment. Discovering the specific genes that define these cells is vital yet challenging due to overlapping expression patterns, limiting detection of rare cell populations using traditional approaches. By employing the computational digital sorting algorithm (DSA) that deconvolves complex gene expression data based on pattern recognition, we identified 129 genes enriched in murine NPCs. We validated these genes against published single-cell RNA sequencing (scRNA-seq) data and discovered that 25 human orthologs were known to cause …

Integrative Analysis Of Lung Adenocarcinoma Across Diverse Ethnicities And Exposures, Shankha Satpathy, Natalie M Clark, Yi-Ju Chen, Noshad Hosseini, Ya-Hsuan Chang, Yi Hsiao, Jonathan T Lei, Francesca Petralia, Jin-Shing Chen, Yifat Geffen, David I Heiman, Indranil Paul, Hanbyul Cho, Michelle Hollenberg, Giacomo B Marino, Kuen-Tyng Lin, Rahul Mannan, C Jackson White, Joe Allen, Shayan C Avanessian, M Harry Kane, Ashley Wolfe, Miloni Kinarivala, Wenke Liu, Shankara Anand, Mong-Wei Lin, Moe Haines, Erik J Bergstrom, Grant Hussey, Ginny Xiaohe Li, Deepak C Mani, Hao Fang, Eric J Jaehnig, Hasmik Keshishian, Brecca Miller, Kang-Yi Su, Yi-Jing Hsiao, Hsao-Hsun Hsu, Min-Shu Hsieh, Kuo-Hsuan Hsu, Alexi Monovoukas, Simone Gohsman, John R Thorup, Yamei Deng, Yo Akiyama, Eden Deng, Eric Sheng-Wen Chen, Azra Krek, Rodrigo Espinoza, Weiping Ma, Daniel Charytonowicz, Robert Sebra, Jyun-Hong Lin, Yan-Si Chen, Yin-Chen Hsu, Ze-Shiang Lin, Kun-Chieh Chen, Chang-Wei Yeh, Yu-Tai Wang, Alexander J Lazar, Mehdi Mesri, Eunkyung An, Xu Zhang, Karl R Clauser, David Fenyö, Arul M Chinnaiyan, Bing Zhang, Li Ding, Kelly Ruggles, Chelsea Newton, Hui Zhang, Pei Wang, Galen Hostetter, Gilbert S Omenn, Chandan Kumar-Sinha, Mathangi Thiagarajan, Ramaswamy Govindan, Paul Paik, Abhijit Parolia, Qing K Li, Avi Ma'ayan, Gad A Getz, Saravana M Dhanasekaran, Ana I Robles, Gee-Chen Chang, Pan-Chyr Yang, Sung-Liang Yu, Hsuan-Yu Chen, Alexey I Nesvizhskii, Steven A Carr, D R Mani, Marcin P Cieslik, Yu-Ju Chen, Michael A Gillette, Taiwan Cancer Moonshot Program, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Lung adenocarcinomas (LUAD) are a pressing global health problem with enduring lethality and rapidly shifting epidemiology. Proteogenomic studies integrating proteomics and post-translational modifications with genomics can identify clinical strata and oncogenic mechanisms, but have been underpowered to examine effects of ethnicity, smoking and environmental exposures, or sex on this heterogeneous disease. This comprehensive proteogenomic analysis of LUAD tumors and matched normal adjacent tissues from 406 patients across diverse geographic and demographic backgrounds explores the impact of understudied driver mutations, prognostic role of chromosomal instability, patterns of immune signaling, differential and sex-specific effects of endogenous mutagens and environmental carcinogens, and pathobiology …

Human Papillomavirus Integration Induces Oncogenic Host Gene Fusions In Oropharyngeal Cancers, Nusrat Khan, Keiko Akagi, Shiming Jiang, Joe Dan Dunn, Bo Jiang, Weihong Xiao, Madison P O'Hara, Li Shen, Qi Wang, Vakul Mohanty, Jing Wang, Sara Goodwin, Jamie L Hutchins, Kevin R Coombes, Jagannadha K Sastry, David E Symer, Maura L Gillison

Faculty, Staff and Student Publications

HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host fusion genes, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of …

Neoadjuvant Bms-813160, Nivolumab, Gemcitabine, And Nab-Paclitaxel For Patients With Pancreatic Cancer, Patrick M Grierson, Crystal Wolf, Rama Suresh, Andrea Wang-Gillam, Benjamin R Tan, Lee Ratner, Peter Oppelt, Olivia Aranha, Ashley Frith, Katrina S Pedersen, Jennifer Spann, Nicholas Boice, Amberly Brown, John M Baer, Emily G Butka, Faiz Ahmad, Yifei Xu, Jingxia Liu, David G Denardo, Kian-Huat Lim

2020-Current year OA Pubs

PURPOSE: Targeting tumor-associated macrophages through C-C chemokine receptor type 2 (CCR) in pancreatic ductal adenocarcinoma (PDAC) improves the efficacy of chemotherapy and restores T-cell immunity in preclinical models.

PATIENTS AND METHODS: We conducted a phase I/II single-institution study (NCT03496662) combining chemotherapy gemcitabine and nab-paclitaxel (GnP), CCR2/5 inhibitor BMS-813160, and nivolumab for four 28-day cycles for patients with borderline resectable (BR) or locally advanced (LA) PDAC. The recommended phase II dose of BMS-813160 was established in the 3 + 3 design. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included resection rate, median progression-free survival, and median overall …

Unplanned Hospitalization Among Advanced Prostate Cancer Patients By Diabetes Status: A Population-Based Study, Amy L. Shaver, Krupa Gandhi, Scott W. Keith, Nikita Nikita, Christopher C. Yang, Felix J. Kim, Hushan Yang, William K. Kelly, Stephen J. Freedland, Grace Lu-Yao

Kimmel Cancer Center Faculty Papers

BACKGROUND: Older adults with advanced prostate cancer and type 2 diabetes mellitus are underrepresented in trials of androgen receptor pathway inhibitors. This study examined changes in unplanned hospitalization rates in patients receiving androgen receptor pathway inhibitors by type 2 diabetes mellitus status and assessed if unplanned hospitalization varies according to androgen receptor pathway inhibitors.

METHODS: This population-based study of advanced prostate cancer patients aged older than 66 years used Surveillance, Epidemiology, and End Results-Medicare data. Prepost androgen receptor pathway inhibitor initiation changes and androgen receptor pathway inhibitor differences in unplanned hospitalization rates were estimated by adjusted incidence rate ratio with …

Immune Impacts Of Fire Smoke Exposure, Mary M Johnson, Abhinav Kaushik, Olivia A Kline, Eric M Smith, Xiaoying Zhou, Yagiz Pat, Laura Buergi, Juan Aguilera, Shifaa Alkotob, Elisabeth M Simonin, Alberto Favaro, Miguel Couto, Oscar Bennett, R Sharon Chinthrajah, Ella Parsons, Mohamed Shamji, Marshall Burke, Melissa Bondy, Mubeccel Akdis, Cezmi A Akdis, Kari C Nadeau

Faculty, Staff and Student Publications

Fire smoke exposure has become a global health concern and is associated with increased morbidity and mortality. There is a lack of understanding of the specific immune mechanisms involved in smoke exposure with preventative and targeted interventions needed. After exposure to fire smoke, which includes PM2.5, toxic metals and per- and polyfluoroalkyl substances (PFAS), epidemiology-based studies demonstrate increases in respiratory (e.g. asthma exacerbations), cardiac (e.g. myocardial infarctions, arrhythmias), neurologic (e.g. stroke) and pregnancy-related (e.g. low birthweight, premature births) outcomes. However, mechanistic studies exploring how smoke exposure disrupts cellular homeostasis are lacking. Therefore, we collected blood from smoke-exposed individuals (n …

Beyond Frequency Of Use: Exploring Additional Metrics For Quantifying Cocaine Use And Their Relation To Life Functioning And Treatment Outcome, Samantha Ellis, Rachel Sun, Angela Heads, Jin Ho Yoon, Heather Webber, Joy Schmitz, Margaret Wardle

Faculty, Staff and Student Publications

Background: Frequency of use - the number of days of use - is the most common metric for quantifying cocaine use and the most common target of treatment. However, frequency may not capture all important aspects of cocaine use. This study examined how other aspects of cocaine use (typical amount spent, variability etc.) relate to life functioning and cocaine use disorder (CUD) treatment outcomes.

Method: This is a secondary analysis of 3 clinical trials for CUD, N = 207 for the life functioning analysis and N = 173 for the outcomes analysis. Eight metrics of use were calculated from baseline …

Computational Analysis Of Dna Methylation From Long-Read Sequencing, Yilei Fu, Winston Timp, Fritz J Sedlazeck

Faculty, Staff and Students Publications

DNA methylation is a critical epigenetic mechanism in numerous biological processes, including gene regulation, development, ageing and the onset of various diseases such as cancer. Studies of methylation are increasingly using single-molecule long-read sequencing technologies to simultaneously measure epigenetic states such as DNA methylation with genomic variation. These long-read data sets have spurred the continuous development of advanced computational methods to gain insights into the roles of methylation in regulating chromatin structure and gene regulation. In this Review, we discuss the computational methods for calling methylation signals, contrasting methylation between samples, analysing cell-type diversity and gaining additional genomic insights, and …

Acute Loss Of Tactile Input Leads To General Compensatory Changes In Eye-Hand Coordination During Object Manipulation, Kevin Ung, John F Magnotti, Brandon Kim, Jeffrey M Yau, Per F Nordmark

Faculty, Staff and Students Publications

Current models of motor control emphasize the critical role of sensory feedback, as demonstrated by movement coordination deficits following sensory impairment. When both vision and touch are available for object-oriented manual behaviors, they serve distinct roles; vision guides the execution of planned movements, while touch provides more direct feedback on hand-object interactions. The impact of losing somatosensory feedback on eye-hand coordination during dexterous object manipulation tasks has not been thoroughly studied. Conceivably, vision is recruited to compensate for the feedback lost when touch is abolished based on the dexterity demands of the behavior. To investigate this, we tested healthy participants …

Unravelling The Global Tapestry Of Genetic Ataxias: Epidemiology And Genetic Testing Approaches, Malco Rossi, Christopher D Stephen, Joana Damásio, José Luiz Pedroso, Sheng-Han Kuo, Chi-Ying R Lin, Oluwadamilola Ojo, Shaimaa El-Jaafary, Woong-Woo Lee, Harutyun Madoev, Orlando G P Barsottini, Achal Kumar Srivastava, Christine Klein, Bart P Van De Warrenburg

Faculty, Staff and Students Publications

The landscape of genetic ataxias is influenced by migration, population genetics, consanguinity, and founder effects, resulting in significant regional variation. Within the expanding domain of genetic ataxias, knowledge of regional epidemiology is scarce, particularly outside of North America and Europe. Understanding the epidemiology of genetic ataxias, together with deep phenotyping and knowledge of the appropriate ancillary studies, is crucial for the development and deployment of diagnostic testing strategies. This review offers a comprehensive, data-driven overview of 2932 articles with regional epidemiological estimates and the occurrence and prevalence of 548 genes associated with ataxia across 122 countries. Regional differences in epidemiology …

A Consensus Guide To Preclinical Indirect Calorimetry Experiments, Alexander S Banks, David B Allison, Thierry Alquier, Ansarullah, Steven N Austad, Johan Auwerx, Julio E Ayala, Joseph A Baur, Stefania Carobbio, Gary A Churchill, Morten Dall, Rafael De Cabo, Jose Donato, Nathalia R V Dragano, Carol F Elias, Anthony W Ferrante, Brian N Finck, Jose E Galgani, Zachary Gerhart-Hines, Laurie J Goodyear, Justin L Grobe, Rana K Gupta, Kirk M Habegger, Sean M Hartig, Andrea L Hevener, Steven B Heymsfield, Corey D Holman, Martin Hrabě De Angelis, David E James, Lawrence Kazak, Jae Bum Kim, Martin Klingenspor, Xingxing Kong, Sander Kooijman, Louise Lantier, K C Kent Lloyd, James C Lo, Irfan J Lodhi, Paul S Maclean, Owen P Mcguinness, Gema Medina-Gómez, Raghavendra G Mirmira, Christopher D Morrison, Gregory J Morton, Timo D Müller, Yoshihiro Ogawa, David Pajuelo-Reguera, Matthew J Potthoff, Nathan Qi, Marc L Reitman, Patrick C N Rensen, Jan Rozman, Jennifer M Rutkowsky, Kei Sakamoto, Philipp E Scherer, Gary J Schwartz, Radislav Sedlacek, Mohammed Selloum, Saame Raza Shaikh, Shuai Chen, Gerald I Shulman, Vojtěch Škop, Alexander A Soukas, John R Speakman, Bruce M Spiegelman, Gregory R Steinberg, Katrin J Svensson, John P Thyfault, Tony Tiganis, Paul M Titchenell, Nigel Turner, Licio A Velloso, Antonio Vidal-Puig, Christopher S Ward, Ashley S Williams, Christian Wolfrum, Allison W Xu, Ying Xu, Juleen R Zierath, International Indirect Calorimetry Consensus Committee (Iiccc)

Children’s Nutrition Research Center Staff Publications

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data …

Mechanisms Underlying Treatment-Resistant Depression: Exploring Sex-Based Biological Differences, Francisco E R Da Silva, Atakan Yucel, Antonio P M Menezes, Ana C Ruiz, Marcela C Carbajal Tamez, Tatiana Barichello, Giselli Scaini, Joao Quevedo

Faculty, Staff and Student Publications

Treatment-resistant depression (TRD) represents a severe and complex subtype of major depressive disorder (MDD), affecting approximately 30% of patients who fail to respond adequately to multiple standard antidepressant therapies. While the pathophysiology of TRD remains incompletely understood, emerging evidence suggests that sex-based biological differences might influence its onset, progression, and treatment response. Women are disproportionately affected by depression and are more likely to experience residual symptoms and treatment resistance, potentially due to hormonal fluctuations, immune system differences, and variations in brain circuitry and neuroplasticity. This narrative explores the current literature on the mechanisms underlying TRD, with a particular emphasis on …

Mechanisms Underlying Treatment-Resistant Depression: Exploring Sex-Based Biological Differences, Francisco E R Da Silva, Atakan Yucel, Antonio P M Menezes, Ana C Ruiz, Marcela C Carbajal Tamez, Tatiana Barichello, Giselli Scaini, Joao Quevedo

Faculty, Staff and Student Publications

Treatment-resistant depression (TRD) represents a severe and complex subtype of major depressive disorder (MDD), affecting approximately 30% of patients who fail to respond adequately to multiple standard antidepressant therapies. While the pathophysiology of TRD remains incompletely understood, emerging evidence suggests that sex-based biological differences might influence its onset, progression, and treatment response. Women are disproportionately affected by depression and are more likely to experience residual symptoms and treatment resistance, potentially due to hormonal fluctuations, immune system differences, and variations in brain circuitry and neuroplasticity. This narrative explores the current literature on the mechanisms underlying TRD, with a particular emphasis on …

Leveraging Existing Cohort Studies Of Mexican Women To Better Understand Hispanic Health And Cancer Risk, Dalia Stern, Liliana Gomez-Flores-Ramos, Britton Trabert, V Wendy Setiawan, Loïc Le Marchand, Henry Gomez, Paul A Scheet, Humberto Parada, Amber Pirzada, Martin Lajous, Leslie V Farland

Faculty, Staff and Student Publications

Background: Hispanics have been historically underrepresented in epidemiologic cancer research. Existing cohort studies focused on recruiting Hispanic participants have been relatively small, making studying cancer outcomes challenging. Therefore, we aimed to compare the distribution of cancer risk factors among Hispanic women of Mexican heritage (HWMH) participating in existing cohorts to explore the possibility of future data pooling efforts.

Methods: We used baseline data of HWMH from three US-based studies, the Mexican American Cohort (MAC; n = 19,797; 2001-2017), the Multiethnic Cohort (MEC; n = 18,007; 1993-1996), and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n = 4,022; 2008-2011), and …

Current Controversies In Prenatal Diagnosis 2: Conventional Postmortem Examination Remains The Gold Standard For The Anatomical Examination Of Fetal Loss, J Ciaran Hutchinson, Lorraine Potocki, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

A comprehensive postmortem examination is an essential component of a work-up after stillbirth. Its findings can support accurate counseling of parents about causes and risk of recurrence. It also supports providers' decisions about most appropriate testing and management plans for future pregnancy to prevent recurrence. Informing parents about fetal autopsy and obtaining their consent is challenging, and conducting a fetal autopsy requires expertise that is, not universally available. Newer non-invasive or minimally invasive methods such as postmortem MRI and targeted biopsies can replace or supplement autopsies, but one must recognize that expertise in these methods is likewise not broadly available. …

Prenatal Genetic Consultation And Testing, Sarah Araji, Lauren Westerfield, Roni Zemet, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

The evolution of prenatal genetic testing has transformed prenatal diagnosis into a more precise and individualized approach. Advanced tools such as chromosomal microarray analysis and exome sequencing have enabled the prenatal diagnosis of more genetic conditions, including anomalies and disorders eligible for fetal therapy. When in utero therapy is considered, accurate genetic diagnosis is essential for guiding providers' and patients' decisions regarding management and outcomes. This chapter reviews available prenatal genetic screens and tests, their indications, and counseling strategies. It also explores genetic abnormalities associated with fetal structural anomalies and their implications for decision-making in fetal interventions.

Machine Learning Feasibility In Cochlear Implant Speech Perception Outcomes-Moving Beyond Single Biomarkers For Cochlear Implant Performance Prediction, Matthew A. Shew, Cole Pavelchek, Andrew Michelson, Amanda Ortmann, Shannon Lefler, Amit Walia, Nedim Durakovic, Alisa Phillips, Ayna Rejepova, Jacques A. Herzog, Phillip Payne, Jay F. Piccirillo, Craig A. Buchman

2020-Current year OA Pubs

OBJECTIVES: Machine learning (ML) is an emerging discipline centered around complex pattern matching and large data-based prediction modeling and can improve precision medicine healthcare. Cochlear implants (CI) are highly effective, however, outcomes vary widely, and accurately predicting speech perception performance outcomes between patients remains a challenge. This study aims to evaluate the ability of ML to predict speech perception performance among CI recipients at 6-month post-implantation using only preoperative variables on one of the largest CI datasets to date, with an emphasis placed on identification of poor performers.

DESIGN: All patients enrolled in the national CI outcome tracking database, HERMES, …

S1pr1 Regulates Lymphatic Valve Development And Tertiary Lymphoid Organ Formation In The Ileum, Xin Geng, Gwendalyn J Randolph, Et Al.

2020-Current year OA Pubs

Efficient lymph flow is ensured by lymphatic valves (LVs). The mechanisms that regulate LV development are incompletely understood. Here, we show that the deletion of the GPCR sphingosine 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs) results in fewer LVs. Interestingly, LVs that remained in the terminal ileum-draining lymphatic vessels were specifically dysfunctional. Furthermore, tertiary lymphoid organs (TLOs) formed in the terminal ileum of the mutant mice. TLOs in this location are associated with ileitis in humans and mice. However, mice lacking S1PR1 did not develop obvious characteristics of ileitis. Mechanistically, S1PR1 regulates shear stress signaling and the expression of …

Minimally Invasive, Bioadaptive Multimodal Sensor Probe With Safe Deployment For Real-Time Acute Compartment Syndrome Diagnosis, Seung Gi Seo, Amanda M Westman, William Moritz, Joseph Ribaudo, Mitchell A Pet, Et Al.

2020-Current year OA Pubs

Acute Compartment Syndrome (ACS) is a serious medical condition that arises from increased pressure within osteofascial compartments, leading to impaired blood flow and potential tissue damage. Early and accurate diagnosis is critical for preventing permanent damage. Current methods rely largely on qualitative assessments with limited accuracy, and those that exploit invasive pressure measurements often prove inadequate. Herein, a soft materials-based multimodal sensor probe is introduced, as well as the mechanical and thermal influences to monitor intra-compartmental pressure, tissue oxygen saturation (StO

Auprc: A Metric For Evaluating The Performance Of In-Silico Perturbation Methods In Identifying Differentially Expressed Genes, Hongxu Zhu, Amir Asiaee, Leila Azinfar, Jun Li, Han Liang, Ehsan Irajizad, Kim-Anh Do, James P Long

Faculty, Staff and Student Publications

In silico perturbation models, computational methods that can predict cellular responses to perturbations, present an opportunity to reduce the need for costly and time-intensive in vitro experiments. Many recently proposed models predict high-dimensional cellular responses, such as gene or protein expression to perturbations such as gene knockout or drugs. However, evaluating in silico performance has largely relied on metrics such as $R^{2}$, which assess overall prediction accuracy but fail to capture biologically significant outcomes like the identification of differentially expressed (DE) genes. In this study, we present a novel evaluation framework that introduces the AUPRC metric to assess the precision …

Expression Graph Network Framework For Biomarker Discovery, Yang Liu, Jason Huse, Kasthuri Kannan

Faculty, Staff and Student Publications

Biomarker discovery for complex diseases, such as cancer, hinges on uncovering molecular signatures that capture intricate, interconnected relationships within biological data-a challenge that traditional statistical and machine learning methods often fail to meet due to the complexity of high-dimensional gene expression profiles. To overcome this, we introduce the expression graph network framework (EGNF). This cutting-edge graph-based approach integrates graph neural networks with network-based feature engineering to enhance the predictive identification of biomarkers. EGNF constructs biologically informed networks by combining gene expression data and clinical attributes within a graph database, utilizing hierarchical clustering to generate dynamic, patient-specific representations of molecular interactions. …

Ras-Membrane Interaction And Oligomerization: There Is More Than Meets The Eye, Abraham C Sianoya, Vijay K Bhardwaj, Alemayehu A Gorfe

Faculty, Staff and Student Publications

Membrane association is fundamental to Rat sarcoma (RAS) function, driving both its physiologic signaling and oncogenic transformation. This review consolidates recent advances in the study of RAS-membrane interactions, emphasizing the molecular mechanisms underlying its membrane engagement and oligomerization. We first discuss the roles of RAS lipid modification and conformational diversity of its intrinsically disordered C-terminus in these processes, and we then examine the debate surrounding RAS dimerization and its potential role in the formation of higher-order oligomers. By integrating emerging insights into these issues, we offer our own perspectives on the driving forces of RAS oligomerization and propose potential new …

Optimizing Pharmacologic Treatment For Neonatal Opioid Withdrawal Syndrome (Optimize Now): A Symptom-Based Dosing Approach Study Protocol For A Multi-Center, Cluster Crossover Design Randomized Controlled Trial, Leslie W. Young, Denise C. Babineau, Abhik Das, Sara Demauro, Walter K. Kraft, Scott Lorch, Michele C. Walsh, Stephanie Merhar, Lori A. Devlin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

BACKGROUND: Opioid use and misuse during pregnancy rose from 1.5 to 6.5 per 1000 deliveries between 1999 and 2014 and continues as a significant public health concern. A fivefold increase in neonatal opioid withdrawal syndrome (NOWS) has accompanied the increase in opioid use. The Eating, Sleeping, Consoling care approach (ESC) has been shown to improve outcomes for infants with NOWS and is quickly becoming the standard of care for infants affected by opioid use disorder. Quality improvement initiatives following the implementation of ESC provide some evidence to suggest that symptom-based (i.e., as needed, PRN, just in time) dosing of opioid …

Pfkfb3 Activates Cad To Enhance De Novo Pyrimidine Synthesis For Cell Growth, Qingen Da, Yongfeng Cai, Qian Ma, Qiuhua Yang, Yapeng Cao, Yaqi Zhou, Dingwei Zhao, Zhiping Liu, Jiean Xu, Junming Quan, Liang Zhang, Rui Wang, Xuejun Jiang, Xiao Liu, Kunfu Ouyang, Zhen Han, Jikui Liu, Tao Wang, Chunxiang Zhang, Neal L Weintraub, David J R Fulton, Jun Zhao, Mei Hong, Zigang Li, Yuqing Huo

Faculty, Staff and Students Publications

Aerobic glycolysis, termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. Research on the direct interactions between glycolysis and other metabolic pathways is an emerging field that has garnered significant interest. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three …

Cathartocytosis: Jettisoning Of Cellular Material During Reprogramming Of Differentiated Cells, Jeffrey W Brown, Xiaobo Lin, Gabriel Anthony Nicolazzi, Xuemei Liu, Thanh Nguyen, Megan D Radyk, Joseph Burclaff, Jason C Mills

Faculty, Staff and Students Publications

Injury causes differentiated cells to undergo massive reprogramming to become proliferative and repair tissue via paligenosis. Gastric chief cells use paligenosis to reprogram into progenitor-like spasmolytic-polypeptide-expressing metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we notice that sulfated glycoproteins are not only digested during paligenosis but also excreted into the gland. Various genetic and pharmacological approaches show that endoplasmic reticulum membranes and secretory granule cargo are also excreted and that the process proceeds in parallel with but is mechanistically independent of autophagy. Three-dimensional light and electron microscopy demonstrated …

Hepcidin, Incident Heart Failure, And Cardiac Dysfunction In Older Adults: The Aric Study, Iman A F Aboelsaad, Brian L Claggett, Victoria Lamberson, Pranav Dorbala, Kunihiro Matsushita, Pamela Lutsey, Bing Yu, Brandon W Lennep, Youssef M K Farag, Amil M Shah, Leo F Buckley

Faculty, Staff and Student Publications

Aims: Hepcidin regulates plasma and tissue iron levels. We studied the association of hepcidin levels with the risk of incident heart failure (HF) and cardiac dysfunction in older adults.

Methods and results: We included adults from the ongoing, longitudinal Atherosclerosis Risk in Communities (ARIC) study, who were free from prevalent anaemia and HF at Visit 5 (2011-13) and had available hepcidin and covariate data. Associations of plasma hepcidin levels with overall adjudicated incident HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF) were assessed using multivariable Cox proportional hazards regression models. Cross-sectional associations of hepcidin …

Β-Catenin Functions As A Molecular Adapter For Disordered Cbaf Interactions, Yuen San Chan, Qinyu Gao, Sarah A Robinson, Wenzhi Wang, Ruzena Filandrova, Lisa-Maria Weinhold, Mario Loeza Cabrera, Miao Zhang, Chandra Shekar R Ambati, Antonio M Lerario, Nagireddy Putluri, Katja Kiseljak-Vassiliades, Margaret E Wierman, Mouhammed Amir Habra, Gary D Hammer, Vaclav Veverka, Katerina Cermakova, H Courtney Hodges

Faculty, Staff and Students Publications

BAF (SWI/SNF) chromatin remodelers engage binding partners to generate site-specific DNA accessibility. However, the basis for interaction between BAF and divergent binding partners has remained unclear. Here, we tested the hypothesis that scaffold proteins augment BAF's binding repertoire by examining β-catenin (CTNNB1) and steroidogenic factor 1 (SF-1, NR5A1), a transcription factor central to steroid production in human cells. BAF inhibition rapidly opposed SF-1/β-catenin enhancer occupancy, impairing SF-1 target activation and SF-1/β-catenin autoregulation. These effects arise due to β-catenin's role as a molecular adapter between SF-1 and an intrinsically disordered region (IDR) of the canonical BAF (cBAF) subunit ARID1A. In contrast …

Causes Of Symptoms And Symptom Persistence In Long Covid And Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Anthony L Komaroff, Robert Dantzer

Faculty, Staff and Student Publications

Debilitating symptoms for many years can follow acute COVID-19 ("long COVID"), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms. In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural …