Digital Commons Network^™

Human Kallikrein 2: A Novel Lineage-Specific Surface Target In Prostate Cancer, Fei Shen, Ryan Smith, Theresa Mcdevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer Mccann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake

Kimmel Cancer Center Faculty Papers

PURPOSE: Targeted therapies for metastatic prostate cancer are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer …

Genomic Profiling Of Intraocular Leiomyomas Reveals Recurrent Copy Number Alterations, Vivian Tang, Yubai Chou, Cuyan Demirkesen, Michele M. Bloomer, Joseph B. Crawford, Ahmet M. Sarici, Carol L. Shields, Ralph C. Eagle Jr., Codrin E. Iacob, Walter P. Devine, Tatyana Milman, Melike Pekmezci

Wills Eye Hospital Papers

PURPOSE: Leiomyomas are benign smooth muscle tumors that commonly present in the uterus, soft tissue, skin, and gastrointestinal tract but in rare cases can also arise within the eye. Notably, intraocular leiomyomas often show slightly different histopathologic and immunohistochemical features, referred to as mesectodermal morphology, given their presumed neural crest origin. Genetic and cytogenetic alterations of intraocular leiomyomas, as well as their association with various clinical and histopathologic features, have not been previously studied.

METHODS: We identified eight patients diagnosed with intraocular leiomyoma and performed targeted next-generation sequencing, whole transcriptome RNA sequencing, and chromosomal copy number analysis on those with …

Developing Optogenetic Approaches To Study Ca2+ Signaling Processes, Tatsuki Nonomura, Xiaoxuan Liu, Megan Chiu, Zhi Tan, Tien-Hung Lan, Yubin Zhou

Faculty, Staff and Students Publications

Calcium ions (Ca2+) are essential second messengers intimately implicated in a variety of biological processes, ranging from short-term events such as muscle contraction to long-term effects like gene expression. Dysregulated Ca2+ signaling can disrupt cellular function and contribute to the development of various human diseases, including developmental, neurological, immunoinflammatory, metabolic, and cardiovascular disorders. To study the mechanisms and biological consequences of Ca2+ signaling, optogenetic approaches have proven invaluable, as they offer exceptional spatiotemporal resolution compared to traditional methods. Recent progress in non-opsin-based optogenetics, particularly those engineered from Ca2+ release–activated Ca2+ (CRAC) channels, has substantially advanced our understanding of Ca2+ signaling …

A Clinical Practice Guideline For The Management Of Pregnancy Alloimmunized To Red Blood Cell Antigens\, Kenneth J Moise, Kara B Markham, Philip C Spinella, Molly R Sherwood, Karen A Robinson, Lisa M Wilson, Jay Malone, Jimmy Espinoza, Donna Dizon-Townson, Laura Mercer, Russell Miller, Leonardo Pereira, Anthony Sciscione, Alireza A Shamshirsaz, Kathryn Shanahan, Saul Snowise, Thomas Trevett, Juan M González Vélez, Bethany Weathersby

Faculty, Staff and Student Publications

Importance: Red blood cell alloimmunization is typically associated with the transplacental transfer of incompatible fetal red blood cells into maternal circulation. Subsequent pregnancies can be affected by fetal anemia, hydrops fetalis, and perinatal death. Most cases of Rhesus D (RhD) alloimmunization due to pregnancy can be prevented by the proper administration of Rhesus immune globulin. However, an emerging practice of using low-titer, O, RhD-positive whole blood (LTOWB) in cases of life-threatening hemorrhage has the potential to increase the exposure of the female population to a new source of incompatible red blood cells.

Objective: To establish recommendations for the management of …

A Multi-National Cross-Sectional Exploration Of Rehabilitation Services For Children And Young People Following Brain Injury In Low And Middle Income Countries, Mark A Linden, Leigh Schrieff-Brown, Linda Ewing-Cobbs, R A Leonard, Rajendra Prasad, Juan Carlos Arango-Lasprilla, Sandra Strazzer, Lucia Braga, Consuelo Reyes Payeras, Kim C Davis, Lisa Kalungwana-Mambwe, Flavia Dorrego, Mathilde Chevignard

Faculty, Staff and Student Publications

Background: Brain injury (BI) is the largest cause of mortality and morbidity among children and can lead to significant cognitive, social, emotional and behavioural deficits. There has been an absence of research examining the availability of rehabilitation services for affected children and young people in low and middle income countries (LMICs). This study therefore investigated current rehabilitation provision in LMICs for children and young people with BI.

Methods: An online survey was developed which collected data on funding support for rehabilitation, causes of BI and access to services. The survey was distributed to healthcare professionals known to members of the …

Preclinical Fluorescence-Guided Imaging Leveraging Surrounding Sentinel Tumor Microenvironment Identifies High-Risk Premalignant Pancreatic Lesions, Shilpa Sharma, Xiaoxia Wen, Jianbo Wang, Beibei Huang, Denise A Hernandez, Cong-Dat Pham, Zhiwen Liu, Susanne Je-Han Lin, Aiko Yamaguchi, Dimitra K Georgiou, Ryan P Coll, H Charles Manning

Faculty, Staff and Student Publications

Purpose: Because surgery is the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often evade detection by palpation or white-light visualization, increasing the risk of recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment as a sentinel of local disease and, thus, enhance surgery outcomes.

Experimental design: Fluorescence-guided surgery was performed on genetically engineered mice [Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox (KSC)] at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein …

Early Ctdna Dynamics Inform First-Line Therapy In Patients With Extensive-Stage Small Cell Lung Cancer, Carmela Ciardullo, Luis Tobalina, T Hedley Carr, Philip Szekeres, Silvija Kraljevic, Lauren Averett Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis despite initial treatment responses. This study evaluates ctDNA for monitoring disease and assessing the efficacy of first-line therapy in patients with extensive-stage SCLC (1L ES-SCLC).

Experimental design: In the TAZMAN trial, 31 patients with 1L ES-SCLC received standard treatment with durvalumab and etoposide plus carboplatin or cisplatin. We analyzed 228 plasma samples from 27 of 31 patients using a liquid biopsy approach to detect somatic mutations and copy-number aberrations, while also accounting for clonal hematopoiesis mutations.

Results: Baseline ctDNA analysis detected somatic alterations in 96.3% of …

Proteomic Perspectives On Kras-Driven Cancers And Emerging Therapeutic Approaches, Ramesh Karki, Ru Chen, Sheng Pan

Faculty, Staff and Student Publications

KRAS mutations are implicated in approximately 23% of all human malignancies, with particularly high prevalence in pancreatic ductal adenocarcinoma (PDAC) (~92%), colorectal cancer (CRC) (~49%), and non-small cell lung cancer (NSCLC) (~35%). The recent approval of the KRASG12C-specific inhibitors for NSCLC represents a pivotal advancement in KRAS-targeted therapy. Nevertheless, the emergence of intrinsic and acquired resistance to KRAS-targeted therapies poses a significant clinical obstacle to targeting KRAS, which necessitates a deeper understanding of the resistance mechanisms. Recent progress in proteomic studies has enabled comprehensive profiling of the proteomic alterations driven by KRAS mutations, offering valuable insights into the disrupted KRAS …

Risk Score Roulette: A Cautionary Tale Of Polygenic Risk Score Reliability, Diane Xue, Elizabeth E Blue, Alexis C Wood, Jerome I Rotter, Alison E Fohner

Children’s Nutrition Research Center Staff Publications

Genetic risk prediction for Alzheimer's disease (AD) has high potential impact, yet few studies have assessed the reliability of various polygenic risk score (PRS) methods at the individual level. Here, we evaluated the reliability of AD PRS estimates among 6338 participants from the Multi-Ethnic Study of Atherosclerosis. We compared four PRS models that have been previously associated with dementia risk. Despite similar population-level performance metrics, inter-model reliability of individual-level risk assessment was low, even among individuals classified in the top and bottom deciles. These findings raise serious concerns about the downstream application of PRS for guiding interventions for AD.

Sensory-Selective Peripheral And Neuraxial Nerve Blockade With 2',6'-Pipecoloxylidide, Claire A Ostertag-Hill, Shuanglong Chen, Tianrui Xue, Rachelle Shao, Matthew Torre, Bin Feng, Zahra Vahedi, Longtu Chen, Steven J Staffa, Yueqin Zheng, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Background: Safe sensory-selective local anesthetics would be a major advance in the management of acute and chronic pain. This articles describes the sensory-selective local anesthetic properties and the toxicity profile of a known metabolite of amino-amide local anesthetics, 2',6'-pipecoloxylidide (PPX).

Methods: PPX was synthesized and made into its hydrochloride salt. PPX or ropivacaine (ROP) were injected at the sciatic nerve or intrathecally in rats, who then underwent modified hotplate (sensory) testing and weight-bearing (motor) testing. Rats injected with PPX or ROP were assessed for clinical toxicity endpoints. Conduction blockade was studied with single-unit recordings in mice. Biocompatibility was assessed histologically. …

Using Artificial Intelligence For Text Screening In A Systematic Review Of Cardiotoxicity, Steven E Canfield, Moez Karim Aziz, Muhammad Imran Omar, James N'Dow, Bob J A Schijvenaars, Jennifer Ghith, Kausar Riaz Ahmed, Donald Molony, Arnulf Stenzl

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVE: Artificial intelligence (AI), capable of analyzing vast volume of data rapidly, presents a promising solution to optimize literature screening for systematic reviews (SRs). Using the INSIDE (artificial INtelligence to Support Informed DEcision making) platform, we compared the performance of AI against the "gold standard" traditional SR method in the context of prostate cancer (PC) to assess whether AI could potentially improve efficiency and quality of screening.

METHODS: Publications from traditional screening of four SRs (focused on PC therapies and potential cardiotoxicity) were compared with the AI-based approach. Publications were ranked based on relevance scores. Work saved over …

Predictors Of Response To Emergent Therapies In Paediatric Immune Thrombocytopenia, Candelaria O'Farrell, Taylor M Luckie, Matthew J Willis, Susan E Kirk, Brandon R Lucari, Michael E Scheurer, Xiaotian Gao, Amanda B Grimes

Faculty, Staff and Students Publications

Emergent therapies (ET), which include intravenous immunoglobulin (IVIG), corticosteroids and intravenous anti‐Rho(D) immunoglobulin, are used to treat acute episodes of bleeding in children with immune thrombocytopenia (ITP). There are currently no known biomarkers or clinical features predictive of treatment response to any specific ET. Thus, the treatment of ITP remains largely trial and error, exposing patients to potentially ineffective medications, which are often expensive and associated with adverse effects. We therefore sought to identify the predictors of treatment response through comparison of clinical characteristics in paediatric patients with ITP responsive to ET versus those non‐responsive to ET. We identified high …

Low Socioeconomic Status Adversely Influences Outcomes After Coronary Artery Bypass Grafting, Paige E Brlecic, Christopher B Sylvester, Katie J Hogan, Qianzi Zhang, Joseph S Coselli, Marc R Moon, Todd K Rosengart, Subhasis Chatterjee, Ravi K Ghanta

Faculty, Staff and Students Publications

Objectives: Although socioeconomic status (SES) is believed to affect patient outcomes after coronary artery bypass grafting (CABG), readmission data are sparse. In a national cohort, we analyzed the influence of SES on readmission, resource utilization, and mortality after CABG.

Methods: We queried the Nationwide Readmissions Database to identify patients who underwent isolated CABG from January 2016 through December 2018. We derived low, middle, and high SES from International Classification of Diseases, 10th Revision, Clinical Modification codes, patient demographics, and neighborhood-level factors. The effect of SES on risk-adjusted outcomes was assessed with multivariable analysis.

Results: Of 523,042 patients who underwent CABG, …

Early Outcomes Of Endovascular Repair Of Aortic Arch Lesions In Zone 0/1 With A Thoracic Branched Endoprosthesis, Matthew P Sweet, Ali Azizzadeh, Gustavo S Oderich, William Brinkman, Jon S Matsumura, Takao Ohki, Sara Zettervall, Shinji Miyamoto, Himanshu J Patel, Michael D Dake

Faculty, Staff and Students Publications

Objective: The pivotal trial 30-day outcomes of the GORE TAG Thoracic Branch Endoprosthesis in patients with endovascular repair of the aortic arch or descending thoracic aorta using a zone 0 or 1 landing zone were evaluated.

Methods: In this nonrandomized, multicenter, prospective study, the primary, clinically driven outcome was a composite of the following through 1 month: technical success (successful device deployment with maintenance of side-branch patency and the absence of aortic rupture), lesion-related mortality, disabling stroke, permanent paraplegia or paraparesis, new onset renal failure requiring permanent dialysis, and protocol-defined unanticipated reintervention.

Results: The 77 study patients enrolled had aneurysm …

Empowering Community Health Workers In Dementia Care In South Texas, Stephanie Santiago-Mejias, Shanae L. Rhodes, Fayron R. Epps, Robin C. Hilsabeck, Noe Garza, Sudha Seshadri, Neela K. Patel

School of Medicine Publications

Alzheimer's disease and related dementias disproportionately affect minority racial and ethnic communities. Community health workers are essential in addressing these disparities. We evaluated the impact of an educational workshop focusing on improving knowledge and preparedness in dementia care. Sixty-one CHWs attended in-person sessions in Texas and completed surveys to measure confidence and plans to apply the knowledge gained. Results revealed a significant increase in confidence in providing dementia care post-training (p < 0.001). Qualitative analysis identified five primary roles of CHWs. These findings demonstrate the potential of training interventions to improve knowledge gaps and empower CHWs to address dementia in underserved communities.

Real-World Effectiveness And Safety Of Upadacitinib In Crohn's Disease: A Multicenter Study, Jalpa Devi, Anthony Xu, Molly Stone, Anish Patel, Abdul Khan, Nikhil Reddy, Jeremy Klein, Navreet Chowla, Caroline Benson, Bryan Christopher Luu, Katherine Huang, Fnu Jaiprada, Marc Fenster, Ryan Ungaro, Joel Pekow, Amanda M Johnson, Andres J Yarur, Richa Shukla, Julia Huecker, Shrinivas Bishu, Reboot Ibd Consortium, Parakkal Deepak

Faculty, Staff and Students Publications

Background & aims: We aimed to describe the real-world effectiveness and safety of upadacitinib (UPA), an oral Janus kinase 1 inhibitor, in patients with Crohn's disease (CD).

Methods: A retrospective analysis was conducted across 9 centers in the United States, focusing on adults with CD treated with UPA, 45 mg, as induction therapy for active luminal disease. The coprimary end points were clinical remission at 12 weeks (Harvey Bradshaw Index ≤4 or absence of symptoms on physician's global assessment) and endoscopic remission at 6 months (Simplified Endoscopic Mucosal Assessment for Crohn's Disease score of 0-1 or absence of ulcers). Secondary …

Foreword: Addressing Diagnostic Error: The First 10 Years, Mark L Graber, Edward P Hoffer, Hardeep Singh

Faculty, Staff and Students Publications

No abstract provided.

Using Video Ethnography And Stimulated Recall Interviews To Describe The Diagnostic Process In The Emergency Department, Milisa Manojlovich, Caitlin Cassady, Sarah J Parker, Ellie Davis, Charlotte Ahr, David Ryamukuru, Anna Wang, Kalyan Pasupathy, Hardeep Singh, Prashant Mahajan

Faculty, Staff and Students Publications

Objectives: Understanding how physicians make diagnoses is challenging because cognitive processes are unobservable and partly unconscious, making it difficult for physicians to describe how they arrived at a diagnosis. Physicians who work in emergency departments (EDs) are especially vulnerable to making diagnostic errors because the ED is a fast-paced, dynamic setting where complex decision-making occurs under severe time, information, and resource constraints. The purpose of our study was to describe how the diagnostic process evolves for ED clinicians in both pediatric and adult ED settings.

Methods: We used a qualitative, video ethnography study design to capture in situ, real-time ED …

Parental Psychosocial Outcomes After A Positive Newborn Screen For A Lysosomal Storage Disorder., Courtney D. Berrios, Randi N. Gadea, Meghan Strenk, Twisha Nadella, Jennifer L. Gannon, Janelle R. Noel-Macdonnell Phd

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: This study explores the psychosocial impact of a positive newborn screen (NBS) result for four lysosomal storage disorders (LSDs) (Fabry disease, Krabbe disease, Mucopolysaccharidosis Type I, Pompe disease) across confirmatory results.

METHODS: Parents whose child who had a positive NBS for one of the included LSDs were recruited for a retrospective cohort (n = 80) or prospective, longitudinal cohorts (n = 50). Surveys assessed uncertainty, anxiety, intrusive or avoidant thoughts, and perceived vulnerability of their child's health. In-depth interviews explored the NBS experience and psychosocial response.

RESULTS: Participants experienced uncertainty and anxiety during confirmatory testing that improved as parents …

Centrally Inserted Central Catheter Placement Using A Novel, Handheld, Image-Guided, Robotic Device: Results Of Initial Feasibility Trial In Patients, James P Herlihy, William E Cohn, Adrian Ebner

Faculty, Staff and Students Publications

Background: Central venous access devices (CVADs) are an essential and widely used tool for the treatment of the critically ill, patients undergoing major surgery, and for many patients requiring hemodialysis. Automation of centrally inserted central catheters (CICCs) could potentially make CVAD placement safer, more effective, and more accessible. A new device that uses ultrasound image-guided, robotic needle placement, in addition to traditional Seldinger technique, to place a CICC is described.

Objective: The device was used in a small, first-in-human, trial for placing non-tunneled hemodialysis catheters (NTHDCs), in order to determine feasibility of clinical use.

Methods: Consecutive patients requiring a NTHDC, …

Dysregulated Mitochondrial Energy Metabolism Drives The Progression Of Mucosal Field Effects To Invasive Bladder Cancer, Sangkyou Lee, Sung Yun Jung, Pawel Kuś, Jolanta Bondaruk, June Goo Lee, Roman Jaksik, Nagireddy Putluri, Khanh N Dinh, David Cogdell, Huiqin Chen, Yishan Wang, Jiansong Chen, Neema Navai, Colin Dinney, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Charles C Guo, Peng Wei, Marek Kimmel, Bogdan Czerniak

Faculty, Staff and Students Publications

Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from field effects. Analysis of the mutational landscape identified three types of mutations, referred to as α, β, and γ. Time modeling of the mutations revealed that carcinogenesis may span 30 years and can be divided into dormant and progressive phases. The α mutations developed in the dormant phase. The progressive phase lasted 5 years and was signified by expanding β mutations, but it was driven to invasive cancer by γ mutations. …

Glycerol-3-Phosphate Activates Chrebp, Fgf21 Transcription And Lipogenesis In Citrin Deficiency, Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner

Faculty, Staff and Students Publications

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms …

Molecular Mechanisms In Masld/Mash-Related Hcc, Xiaobo Wang, Liang Zhang, Bingning Dong

Faculty, Staff and Students Publications

Liver cancer is the third leading cause of cancer-related deaths and ranks as the sixth most prevalent cancer type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, and its more severe manifestation, NASH or metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% of the population. The increased prevalence of metabolic dysfunction-associated steatotic liver disease and MASH is parallel to the increasing rates of obesity-associated metabolic diseases, including type 2 diabetes, insulin resistance, and fatty liver diseases. MASH can progress to MASH-related HCC (MASH-HCC) in about 2% of cases each year, influenced by various factors such …

Chemical Modulation Of Gut Bacterial Metabolism Induces Colanic Acid And Extends The Lifespan Of Nematode And Mammalian Hosts, Guo Hu, Marzia Savini, Matthew Brandon Cooke, Xin Wei, Dinghuan Deng, Shihong M Gao, Ruyue Alps Xia, Youchen Guan, Alice X Wen, Xin Yu, Jin Wang, Chao Jiang, Christophe Herman, Jiefu Li, Meng C Wang

Faculty, Staff and Students Publications

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored. Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that wild-type Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased life span in the host organism Caenorhabditis elegans. In the mouse gut, …

Restricting Metabolic Plasticity Enhances Stress Adaptation Through The Modulation Of Pdh And Hif1a In Trap1-Depleted Colon Cancer, Hong-Yuan Tsai, Miao-Hsueh Chen, Jihye Yun, Lisa A Lai, John F Valentine, Mary P Bronner, Teresa A Brentnall, Sheng Pan, Ru Chen

Faculty, Staff and Student Publications

Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. …

Apol2 Stabilizes Ku80 To Confer Nhej-Mediated Radioresistance In Gastric Cancer, Dan Zu, Qimei Bao, Hanyi He, Yuke Zhong, Mingcong Deng, Yangchan Hu, Chunkai Zhang, Chen Liang, Yixing Huang, Haidong Liu, Xiao Li, Yanhua He, Guoyan Luo, Weixin Wu, Fenghui Guan, Shengfeng Xu, Min Liu, Albino Bacolla, Ji Jing, Yian Du, John A Tainer, Yin Shi, Zu Ye, Xiangdong Cheng

Faculty, Staff and Student Publications

Radiotherapy is one of the most important adjuvant treatment methods for gastric cancer (GC). However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair and enhancing radioresistance in GC. Bioinformatics and clinical data revealed that high APOL2 expression is correlated with poor prognosis in GC patients. Functional experiments showed that APOL2 overexpression enhances genomic stability by accelerating DSB repair via the NHEJ pathway, while APOL2 knockout impairs repair capacity. Mechanistically, APOL2 binds to and stabilizes Ku80 by enhancing USP7-mediated deubiquitylation, thereby increasing Ku80 …

A Historical Cohort Comparison After Inpatient Admission For Adolescents With Anorexia Nervosa: Feasibility Of Virtual Group Therapy, Elizabeth V Franklin, Margaret Mathias, Rachel Wolfe, Duc T Nguyen, Drusilla M Rosales, Sofia Pedroza, Albert C Hergenroeder, Constance M Wiemann

Center for Medical Ethics and Health Policy Staff Publications

Objective: Access to follow-up care after a medical admission for adolescents with anorexia nervosa (AN) is important; yet access can be delayed or unavailable. This study assessed the feasibility and acceptability of a supplemental virtual 8-week outpatient group therapy program following inpatient care. A secondary aim explored the outpatient program's impact on self-reported anxiety, disordered eating, and depression symptoms, and readmission rates.

Method: A retrospective chart review study compared 68 adolescents (aged 11-18) with AN enrolled in an 8-week group therapy program (Recovery and Prevention Program [RAPP]) to 64 adolescents who were not enrolled in RAPP (historical cohort). "RAPP completers" …

Information Theory Analysis Of Ctx Shows Consistent Clinical Presentation, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Cerebrotendinous xanthomatosis (CTX) is a rare, metabolic disorder caused by pathogenic variants in CYP27A1. The classic clinical presentation includes infantile-onset chronic diarrhea, juvenile-onset bilateral cataracts, with development of tendon xanthomas and progressive neurological dysfunction. These multisystem clinical features typically appear in different decades of life often confounding diagnosis of CTX. Further complicating diagnosis is the generally held belief that the clinical presentation of CTX varies highly between individuals and even within families. We applied information theory analyses to CTX patient data to quantitatively assess clinical variability in CTX. We conducted a systematic review of the literature to identify all CTX …

Mutations In The Key Autophagy Tethering Factor Epg5 Link Neurodevelopmental And Neurodegenerative Disorders Including Early-Onset Parkinsonism, Hormos Salimi Dafsari, Celine Deneubourg, Kritarth Singh, Reza Maroofian, Zita Suprenant, Ay Lin Kho, Neil J Ingham, Karen P Steel, Preethi Sheshadri, Franciska Baur, Lea Hentrich, Birgit Gerisch, Mina Zamani, Cesar Alves, Ata Siddiqui, Haidar S Dafsari, Mehri Salari, Anthony E Lang, Michael Harris, Alice Abdelaleem, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Gholamreza Shariati, Alireza Sedaghat, Jawaher Zeighami, Daniel Calame, Dana Marafi, Ruizhi Duan, Adrian Boehnke, Gary D Clark, Jill A Rosenfeld, Carrie A Mohila, Dora Steel, Saurabh Chopra, Suvasini Sharma, Nicolai Kohlschmidt, Steffi Patzer, Afshin Saffari, Darius Ebrahimi-Fakhari, Büşra Eser Çavdartepe, Irene J Chang, Erika Beckman, Renate Peters, Andrew Paul Fennell, Bernice Lo, Luisa Averdunk, Felix Distelmaier, Martina Baethmann, Frances Elmslie, Kairit Joost, Sheela Nampoothiri, Dhanya Yesodharan, Hanna Mandel, Amy Kimball, Antonie D Kline, Cyril Mignot, Boris Keren, Vincent Laugel, Katrin Õunap, Kalpana Devadathan, Frederique M C Van Berkestijn, Arpana Silwal, Saskia Koene, Sumit Verma, Mohammed Yousuf Karim, Chahynez Boubidi, Majid Aziz, Gehad Elghazali, Lauren Mattas, Mohammad Miryounesi, Farzad Hashemi-Gorji, Shahryar Alavi, Nayereh Nouri, Mehrdad Noruzinia, Saeideh Kavousi, Arveen Kamath, Sandeep Jayawant, Russell Saneto, Nourelhoda A Haridy, Pinar Ozkan Kart, Ali Cansu, Madeleine Joubert, Claire Beneteau, Kyra E Stuurman, Martina Wilke, Tahsin Stefan Barakat, Homa Tajsharghi, Annarita Scardamaglia, Sadeq Vallian, Semra Hız, Ali Shoeibi, Reza Boostani, Narges Hashemi, Meisam Babaei, Norah Saleh Alsaleh, Julie Porter, Tania Attié-Bitach, Pauline Marzin, Dorota Wicher, Jessica I Gold, Elisabeth Schuler, Amna Kashgari, Rakan F Alanazi, Wafaa Eyaid, Marc Engelen, Mirjam Langeveld, Burkhard Stüve, Yun Li, Gökhan Yigit, Bernd Wollnik, Mariana H G Monje, Dimitri Krainc, Niccolò E Mencacci, Somayeh Bakhtiari, Michael Kruer, Emanuela Argilli, Elliott Sherr, Yalda Jamshidi, Ehsan Ghayoor Karimiani, Yiu Wing Sunny Cheung, Ivan Karin, Giovanni Zifarelli, Peter Bauer, Wendy K Chung, James R Lupski, Manju A Kurian, Jörg Dötsch, Jürgen-Christoph Von Kleist-Retzow, Thomas Klopstock, Matias Wagner, Calvin Yip, Andreas Roos, Rita Carsetti, Carlo Dionisi-Vici, Mathias Gautel, Michael R Duchen, Adam Antebi, Henry Houlden, Manolis Fanto, Heinz Jungbluth

Faculty, Staff and Students Publications

Objective: Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.

Methods: We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.

Results: Through worldwide collaboration, we identified 211 patients, 97 …

Pleiotropy And The Increasing Complexity Of Parkinson's Disease Genetics, Jonggeol Kim, Joshua M Shulman

Faculty, Staff and Students Publications

No abstract provided.