Digital Commons Network^™

Protocol For Unlocking Alternative Polyadenylation Insights From Bulk Rna-Seq Data With Polyaminer-Bulk, Venkata Jonnakuti, Sriya Jonnakuti, Hari Krishna Yalamanchili

Duncan NRI Faculty and Staff Publications

PolyAMiner-Bulk, a deep-learning-based algorithm to decode alternative polyadenylation (APA) dynamics from bulk RNA sequencing (RNA-seq) data, enables scientists to identify and quantify APA events from processed bulk RNA-seq data. The protocol allows researchers to explore differential APA usage between two conditions and gain a better understanding of post-transcriptional regulatory mechanisms. The major steps involve input data preparation, executing PolyAMiner-Bulk, and interpreting the results. A basic familiarity with pre-processing bulk RNA-seq data and command-line tools is suggested.

For complete details on the use and execution of this protocol, please refer to Jonnakuti et al.¹

Longitudinal Changes In Aerodigestive Responses To Varying Nipple Properties In Infant Pigs, François D H Gould, Christopher Mayerl, Khaled Adjerid, Jessica Reibel, Nichole Charles, Chloe Edmonds, Rebecca Z German

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Coordination of respiration and swallowing is critical for survival in infant mammals and changes throughout infant maturation. Infants show sensorimotor feeding responses to changes in physical properties of nipples. Commercial nipples are promoted as improving aerodigestive coordination. However, it is unknown how nipple properties influence coordination of respiration and swallowing. Furthermore, how infant-nipple interactions change throughout maturation is not well understood. We designed and manufactured four silicone nipples of the same shape that varied in two parameters: nipple opening diameter and nipple stiffness. We used our validated infant pig model to test the impact of nipple parameters on aerodigestive coordination …

Using The 5ms Framework To Advance Aging-Responsive Care For Heart Failure With Reduced Ejection Fraction, Abigail Latimer, Debra K. Moser, Jia-Rong Wu, Kim K. Birtcher, Malachy J. Clancy, Jennifer D. Portz, Joanna Paladino, Daniel D. Matlock, Christopher E. Knoepke

Department of Occupational Therapy Faculty Papers

Complexity of care is the inevitable consequence of an aging population and is particularly true in instances where patients are managing chronic conditions such as heart failure with reduced ejection fraction (HFrEF). HFrEF itself is complex, with an undulating course of illness, increased risk of sudden cardiac death, and myriad accompanying treatment considerations. Generalist management of HFrEF among older patients is further complicated by competing comorbidities, potential for financial toxicity, potential for mental health symptoms, and risk of care with does not align with goals and preferences. The 5Ms (multicomplexity, mind, mobility, medications, and matters most) is a holistic conceptualization …

Adipose Progenitor Cell-Derived Extracellular Vesicles Suppress Macrophage M1 Program To Alleviate Midlife Obesity, Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu, Yanjun Liu, Cong-Yi Wang

Children’s Nutrition Research Center Staff Publications

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs …

Deciphering The Dark Cancer Phosphoproteome Using Machine-Learned Co-Regulation Of Phosphosites, Wen Jiang, Eric J Jaehnig, Yuxing Liao, Zhiao Shi, Tomer M Yaron-Barir, Jared L Johnson, Lewis C Cantley, Bing Zhang

Faculty, Staff and Students Publications

Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, yet our limited knowledge about the regulation and function of most phosphosites hampers the extraction of meaningful biological insights. To address this challenge, we integrate machine learning with phosphoproteomic data from 1195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network that maps the co-regulation of 26,280 phosphosites. By incorporating network features from CoPheeMap into a second machine learning model, namely CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA uncovers 24,015 associations between 9399 phosphosites and 104 serine/threonine kinases, shedding light on many unannotated phosphosites and …

Perceptions Of Cardiac Surgeons Regarding The Integration Of Artificial Intelligence In Cardiac Surgery, Nada Alguizzani, Fareed Khouqeer, Rasha Alorini, Imtenan Oberi

Journal of the Saudi Heart Association

Background: After the surge of artificial intelligence in late 2022, researchers started exploring the idea of using artificial intelligence in the medical field. Considering the endless possibilities of artificial intelligence, there is still some hesitation toward its use in the medical field. This study aims to explore the attitudes of cardiac surgeons toward involving artificial intelligence in diagnosing cardiac conditions and planning cardiac operations.

Methodology: This study surveyed cardiac surgeons on AI integration in their field using a cross-sectional design and purposive sampling. Data were collected via a structured questionnaire and analyzed in IBM SPSS 29.0.

Results: Our study included …

Severe Maternal Morbidity In Twin Pregnancies: The Impact Of Body Mass Index And Gestational Weight Gain, Nathan A. Keller, Frank Ian Jackson, Insaf Kouba, Luis A. Bracero, Matthew J. Blitz

Specialty Medicine Faculty Publications

Objectives: The objective of this study was to determine whether body mass index (BMI) and gestational weight gain (GWG) are associated with severe maternal morbidity (SMM) in twin gestations.
Methods: This was a retrospective cohort of all twin pregnancies delivered at seven hospitals in New York from 2019 to 2023. Multivariable logistic regression modeled the probability of SMM as a function of BMI group, adjusting for excessive GWG, race-ethnicity, and obstetric comorbidity index. A total of 1,976 twin gestations were included.
Results: The SMM rate was 14.0 % (n=276).
Conclusions: Neither pre-pregnancy BMI nor GWG was associated with SMM, both …

Guanine Nucleotide Biosynthesis Blockade Impairs Mll Complex Formation And Sensitizes Leukemias To Menin Inhibition, Xiangguo Shi, Minhua Li, Zian Liu, Jonathan Tiessen, Yuan Li, Jing Zhou, Yudan Zhu, Swetha Mahesula, Qing Ding, Lin Tan, Mengdie Feng, Yuki Kageyama, Yusuke Hara, Jacob J Tao, Xuan Luo, Kathryn A Patras, Philip L Lorenzi, Suming Huang, Alexandra M Stevens, Koichi Takahashi, Ghayas C Issa, Md Abul Hassan Samee, Michalis Agathocleous, Daisuke Nakada

Faculty, Staff and Student Publications

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding …

Using Ehr Reminders To Control Hypertension, Umme Kulsoom Ghous, Logan Mcculley, Danielle C. Hall, Linda Katherine Lambert, Laura Reed Dnp, Aprn, Fnp-Bc, Cne

Doctor of Nursing Practice Projects

Purpose/Background

Hypertension is a significant risk factor for cardiovascular and kidney diseases but is often under-diagnosed and poorly managed. Electronic Health Records (EHR) can help by providing automated reminders to recheck elevated blood pressure (BP) readings, ensuring accurate measurements, and guiding clinical interventions. This study aims to determine if EHR-based reminders improve BP control in adult patients aged 21 and older, focusing on hypertension diagnosis accuracy and timely management.

Methods

After a literature review, the study took place in a primary care clinic and only included patients with an existing diagnosis of hypertension. Thirty patients were included in the study. …

Diverse Ancestral Representation Improves Genetic Intolerance Metrics, Alexander L Han, Chloe F Sands, Dorota Matelska, Jessica C Butts, Vida Ravanmehr, Fengyuan Hu, Esmeralda Villavicencio Gonzalez, Nicholas Katsanis, Carlos D Bustamante, Quanli Wang, Slavé Petrovski, Dimitrios Vitsios, Ryan S Dhindsa

Duncan NRI Faculty and Staff Publications

The unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant to variation—regions often implicated in disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple ancestries to test several key intolerance metrics, including the Residual Variance Intolerance Score (RVIS), Missense Tolerance Ratio (MTR), and Loss-of-Function Observed/Expected ratio (LOF O/E). We demonstrate that increasing ancestral representation, rather than sample size alone, critically drives their performance. Scores trained on variation observed in African and Admixed …

Exploring Profiles Of Fathers Integrating Food And Physical Activity Parenting Practices, John A Jimenez-Garcia, Louise C Mâsse, Robert L Newton, Salma M Musaad, Alicia Beltran, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

Objective: This study aims to identify fathers' profiles integrating food parenting practices (FPP) and physical activity parenting practices (PAPP).

Design: We analysed cross-sectional data. The fathers completed the reduced FPP and PAPP item banks and socio-demographic and family dynamics (co-parenting and household responsibility) questionnaires. We identified fathers' profiles via latent profile analysis. We explored the influence of social determinants, child characteristics and family dynamics on fathers' profiles using multinomial logistic regression.

Setting: Online survey in the USA.

Participants: Fathers of 5-11-year-old children.

Results: We analysed data from 606 fathers (age = 38 ± 8·0; Hispanic = 37·5 %). Most fathers …

Dengue Cases In Hanoi, Vietnam: Unseasonal Surge Foreshadows Increased Incidence That Demands Organized Preventive Action, Andrew W. Taylor-Robinson

Chulalongkorn Medical Journal

Letter to the Editor - Abstract not required.

Effect Of Testosterone Treatment During Puberty In Boys With Klinefelter Syndrome (The Tipy Study): Protocol For A Nationwide Randomised, Double-Blinded, Placebo-Controlled Study, Ida Dyhr Caspersen, Andrés Felipe Østergaard Fritzbøger, Jørgen Holm Petersen, Niels Birkebæk, Ann-Margrethe Rønholt Christensen, Anders Jørgen Schou, Kurt Kristensen, Judith L. Ross, Shanlee Davis, Gary Butler, Sophie Van Rijn, Anders Juul, Lise Aksglaede

Department of Pediatrics Faculty Papers

INTRODUCTION: Klinefelter syndrome (KS) is a genetic condition characterised by the presence of an extra X chromosome in males (47,XXY). KS is associated with various phenotypic characteristics in adult life, including infertility, hypogonadism and increased risk of type II diabetes, cardiovascular disease and osteoporosis. Additionally, individuals with KS often experience mental health challenges and functional impairments that significantly impact their quality of life. Currently, testosterone replacement therapy (TRT) in adolescence is considered the first-line treatment by some physicians for patients with KS and biochemical signs of hypogonadism. However, comprehensive evidence on its effectiveness in preventing typical phenotypic traits associated with …

Inflammation And Gut Barrier Function-Related Genes And Colorectal Cancer Risk In Western European Populations, Hannah B Mandle, Mazda Jenab, Marc J Gunter, Anne Tjønneland, Anja Olsen, Christina C Dahm, Jie Zhang, Pierre-Emmanuel Sugier, Joseph Rothwell, Gianluca Severi, Rudolf Kaaks, Verena A Katzke, Matthias B Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Carlotta Sacerdote, Catalina Bonet, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Marcela Guevara, Richard Palmqvist, Thyra Löwenmark, Aurora Perez-Cornago, Elisabete Weiderpass, Alicia K Heath, Amanda J Cross, Paolo Vineis, David J Hughes, Veronika Fedirko

Faculty, Staff and Student Publications

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N = 1374; colon = 871, rectum = 503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set …

Investigation Of Dynamic Regulation Of Tfeb Nuclear Shuttling By Microfluidics And Quantitative Modelling, Iacopo Ruolo, Sara Napolitano, Lorena Postiglione, Gennaro Napolitano, Andrea Ballabio, Diego Di Bernardo

Duncan NRI Faculty and Staff Publications

Transcription Factor EB (TFEB) controls lysosomal biogenesis and autophagy in response to nutritional status and other stress factors. Although its regulation by nuclear translocation is known to involve a complex network of well-studied regulatory processes, the precise contribution of each of these mechanisms is unclear. Using microfluidics technology and real-time imaging coupled with mathematical modelling, we explored the dynamic regulation of TFEB under different conditions. We found that TFEB nuclear translocation upon nutrient deprivation happens in two phases: a fast one characterised by a transient boost in TFEB dephosphorylation dependent on transient calcium release mediated by mucolipin 1 (MCOLN1) followed …

Parent Feedback On The Reducing Emotional Distress For Childhood Hypoglycemia In Parents (Redchip) Intervention: A Qualitative Analysis., Nicole A. Kahhan, Maryjane S. Campbell, Mark A. Clements, Kimberly A. Driscoll, Amy I. Milkes, Holly K. O'Donnell, Susana R. Patton

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVES: Severe hypoglycemia is more common among young children with type 1 diabetes mellitus (T1DM) than older youth, and parents report significant hypoglycemia fear (HF). Parents experiencing HF describe constant and extreme worry about the occurrence of hypoglycemia and may engage in potentially risky behaviors to avoid hypoglycemia. Our team developed and tested a behavioral intervention, Reducing Emotional Distress for Childhood Hypoglycemia in Parents (REDCHiP), to decrease HF in parents of young children with T1DM. Here, we qualitatively analyzed parent feedback to refine and optimize future intervention iterations.

METHODS: The randomized pilot study included parents (n = 73) of …

Precision Phenotyping For Curating Research Cohorts Of Patients With Unexplained Post-Acute Sequelae Of Covid-19, Alaleh Azhir, Jonas Hügel, Jiazi Tian, Jingya Cheng, Ingrid V Bassett, Douglas S Bell, Elmer V Bernstam, Maha R Farhat, Darren W Henderson, Emily S Lau, Michele Morris, Yevgeniy R Semenov, Virginia A Triant, Shyam Visweswaran, Zachary H Strasser, Jeffrey G Klann, Shawn N Murphy, Hossein Estiri

Faculty, Staff and Student Publications

BACKGROUND: Scalable identification of patients with post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms, which has led to suboptimal accuracy, demographic biases, and underestimation of the PASC.

METHODS: In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying cohorts of patients with PASC. We used longitudinal electronic health records data from over 295,000 patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to simultaneously exclude sequelae that prior conditions can explain and include infection-associated chronic conditions. We performed independent chart reviews …

Tunneling Nanotube-Like Structures Regulate Distant Cellular Interactions During Heart Formation, Lianjie Miao, Yangyang Lu, Anika Nusrat, Guizhen Fan, Shaohua Zhang, Luqi Zhao, Chia-Ling Wu, Hongyan Guo, Trang Le Nu Huyen, Yi Zheng, Zhen-Chuan Fan, Weinian Shou, Robert J Schwartz, Yu Liu, Ashok Kumar, Haixin Sui, Irina I Serysheva, Alan R Burns, Leo Q Wan, Bin Zhou, Sylvia M Evans, Mingfu Wu

Faculty, Staff and Student Publications

In the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube-like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and …

The Supporting Role Of Physical Exercise In The Prevention And Treatment Of Neurodegenerative And Mental Diseases, Celestyna Grzywniak

Baltic Journal of Health and Physical Activity

The aim of the article is to draw attention to the possibility of using physical exercises in treating neurodegenerative diseases such as Parkinson’s, Alzheimer’s, multiple sclerosis, dementia as well as mental disorders, particularly depression. This article emphasizes the significance of physical exercise in stimulating the nervous system, including the glial cells, as well as their role in the production of proteins called myokines and myostatins belonging to cytokines. It briefly characterizes the most common neurotrophins in the human body including the BDNF and their role in stabilizing and treating neurodegenerative and mental diseases. It presents the secretory functions of skeletal …

Exploration Of Working Memory Retrieval Stage For Mild Cognitive Impairment: Time-Varying Causality Analysis Of Electroencephalogram Based On Dynamic Brain Networks, Yi Jiang, Zhiwei Guo, Xiaobo Zhou, Ning Jiang, Jiayuan He

Faculty, Staff and Student Publications

Background: Mild Cognitive Impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and Alzheimer's disease (AD). Its management is crucial for it helps intervene and slow the progression of cognitive decline to AD. However, the understanding of the MCI mechanism is not completely clear. As working memory (WM) damage is a common symptom of MCI, this study focused on the core stage of WM, i.e., the memory retrieval stage, to investigate information processing and the causality relationships among brain regions based on electroencephalogram (EEG) signals.

Method: 21 MCI and 20 normal cognitive control (NC) participants …

Understanding The Coping Mechanisms Used By Older Formerly Incarcerated Persons During Reentry, Sayla Victores

USF Tampa Graduate Theses and Dissertations

The current study investigated the coping mechanisms employed by older formerly incarcerated individuals during reentry. While there is research on the reentry experiences of older formerly incarcerated individuals, less is known about how they cope with the strains of reentry. As such, this study fills this gap in the literature by exploring both adaptive and maladaptive coping mechanisms employed by this population during reentry. Using in-depth interviews with 20 older, formerly incarcerated individuals, I found that older formerly incarcerated persons experienced challenges related to securing stable housing, finding employment and economic security, community supervision, stigma and judgment, and overall reintegration. …

Protocol And Design Of The Repose Study: A Double-Blinded, Randomised, Placebo-Controlled Trial To Evaluate The Efficacy Of Suvorexant To Improve Postoperative Sleep And Reduce Delirium Severity In Older Patients Undergoing Non-Cardiac Surgery, John Michael Fallon, Mona Hashemaghaie, Christy E. Peterson, Dieplinh Tran, Sophie R. Wu, Jonathan M. Valdes, Nicole M. Pedicini, Melissa E. Adams, Marjorie Soltis, Wissam Mansour, Mary Cooter Wright, Karthik Raghunathan, Miriam M. Treggiari, Cina Sasannejad, Michael J. Devinney

School of Medicine Faculty Publications

INTRODUCTION: Postoperative delirium occurs in up to 40% of older surgical patients and has been associated with prolonged hospital stays, long-term cognitive impairment and increased 1-year postoperative mortality. Postoperative sleep disturbances may increase the risk of delirium, but studies investigating pharmacotherapies to improve postoperative sleep to prevent delirium remain limited. Suvorexant is a selective antagonist of orexin 1 and 2 receptors and is approved for insomnia pharmacotherapy by the Food and Drug Administration. It has the potential to improve postoperative sleep and reduce postoperative delirium rates, but randomised controlled trials (RCTs) are needed to determine the efficacy of postoperative suvorexant …

Cranial Radiation Disrupts Dopaminergic Signaling And Connectivity In The Mammalian Brain, Die Zhang, Riya Thomas, Thanh Thai Lam, Ines Veselinovic, David R Grosshans

Faculty, Staff and Student Publications

Cognitive impairment is a common and challenging side effect of cranial radiation therapy for brain tumors, though its precise mechanisms remain unclear. The mesocortical dopaminergic pathway, known to play a key role in cognitive function, is implicated in several neuropsychiatric disorders, yet its involvement in radiation-induced cognitive dysfunction is unexplored. Here, with using in vivo multi-electrode array recordings of both anesthetized and free-moving rats to monitor the firing activities of dopamine neurons in the ventral tegmental area (VTA) and local field potentials in both the prefrontal cortex (PFC) and VTA, as well as the immunofluorescence assays and western blotting, we …

Access To Outreach Athletic Trainers Improves Orthopedic Specialty Appointment Adherence, Katie Sniffen, Katie Smith, Michael Rozier, Katherine Stamatakis, Paula Buchanan, Leslie Hinyard

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Background: Adolescent sports participation carries an inherent risk of musculoskeletal injury, with an estimated 2 million injuries occurring annually among high school athletes. Navigating the healthcare system to receive appropriate care can be challenging, potentially leading to delayed treatment and poorer outcomes. Athletic trainers (ATs) may play a crucial role in facilitating timely access to specialized care. The objective of this study was to assess the relationship between referral pathways (outreach athletic trainers (OATs), non-outreach athletic trainers (ATs), urgent care (UC), and emergency department (ED)) and appointment adherence while controlling for predisposing, enabling, and need factors. Methods: Using electronic medical …

The Role Of Electrophysiologic Study In Device Selection For Leadless Atrial Pacing, Joshua R Hirsch, Jordan M Gales, Irakli Giorgberidze, Hamid Afshar

The Texas Heart Institute Journal

The AVEIR DR (Abbott Medical) was the first dual-chamber leadless pacing system approved by the US Food and Drug Administration. Many patients with sinus node dysfunction have physiologically normal atrioventricular conduction, so an atrial-only pacing system may be appropriate for them. Three patients with symptomatic sinus node dysfunction underwent device implantation with electrophysiologic study, including incremental atrial pacing until loss of 1:1 atrioventricular conduction (atrioventricular Wenckebach cycle length) and His-ventricular interval measurement. If the atrioventricular Wenckebach cycle length was no more than 400 milliseconds and the His-ventricular interval measurement was no more than 55 milliseconds, single-chamber atrial implantation was deemed …

Vdac2 And Bak Scarcity In Liver Mitochondria Enables Targeting Hepatocarcinoma While Sparing Hepatocytes, Shamim Naghdi, Piyush Mishra, Soumya S. Roy, David Weaver, Ludivine Walter, Erika Davies, Anil N. Antony, Xuena Lin, Gisela Moehren, Mark A. Feitelson, Christopher A. Reed, Tullia Lindsten, Craig B. Thompson, Hien T. Dang, Jan B. Hoek, Erik S. Knudsen, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins …

Avasimibe Abolishes The Efficacy Of Fluvastatin For The Prevention Of Cancer In A Spontaneous Mouse Model Of Breast Cancer, Anjana Bhardwaj, Alexander Koh, Rhea Bhala, Janvi Sandhu, Zhenlin Ju, Leslie Faye Cando, Jing Wang, Isabelle Bedrosian

Faculty, Staff and Student Publications

The cholesterol biosynthesis pathway is upregulated during breast cancer development and progression. Inhibition of the aberrantly upregulated cholesterol pathway by statins reduces breast tumor incidence and burden by 50% in SV40 C3(1) TAg mice, a mouse model of triple negative breast cancer. We hypothesized that fluvastatin's preventive efficacy could be further enhanced by co-targeting the statin-induced restorative feedback pathways that tightly control the cholesterol pathway and are involved in resistance to statins. Acyl-coenzyme A: cholesterol acyltransferase (

Two-Year Follow-Up Of Additive Manufactured, Fully 3d Printed Humeral Prosthesis, Jie Jonathan Yao, Andrew Jawa, J Michael Wiater, Anand M. Murthi, Matthew J. Smith, Derek J. Cuff, Samantha Anne Riebesell, Dennis Debernardis, Luke Stanford Austin

Conference Presentation Abstracts

INTRODUCTION: A fully 3D printed prosthetic may offer numerous potential advantages including improved pore precision, overall porosity, topology optimization, spatial variability in stiffness, communication between pores, and strut size. However, there are numerous theoretical concerns surrounding inferior mechanical performance with fully 3D printed implants (e.g. potentially higher rates of fatigue, increased in vivo particle release, etc.) compared to conventionally fabricated ones. We are aware of no reports on the clinical performance of fully 3D printed, off-the-shelf, humeral prostheses. To validate fully 3D printed humeral designs, the purpose of this study was to provide minimum 2-year postoperative clinical outcomes and survivorship …

Suppression Of Stress Granule Formation Is A Vulnerability Imposed By Mutant P53., Elizabeth A. Thoenen, Atul Ranjan, Alejandro Parrales, Shigeto Nishikawa, Dan A. Dixon, Sugako Oka, Tomoo Iwakuma

Manuscripts, Articles, Book Chapters and Other Papers

Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53^null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 …

Molecular Model Of Tfiih Recruitment To The Transcription-Coupled Repair Machinery, Tanmoy Paul, Chunli Yan, Jina Yu, Susan E Tsutakawa, John A Tainer, Dong Wang, Ivaylo Ivanov

Faculty, Staff and Student Publications

Transcription-coupled repair (TCR) is a vital nucleotide excision repair sub-pathway that removes DNA lesions from actively transcribed DNA strands. Binding of CSB to lesion-stalled RNA Polymerase II (Pol II) initiates TCR by triggering the recruitment of downstream repair factors. Yet it remains unknown how transcription factor IIH (TFIIH) is recruited to the intact TCR complex. Combining existing structural data with AlphaFold predictions, we build an integrative model of the initial TFIIH-bound TCR complex. We show how TFIIH can be first recruited in an open repair-inhibited conformation, which requires subsequent CAK module removal and conformational closure to process damaged DNA. In …