Digital Commons Network^™

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Development Of A Targeted Bioprotac Degrader Selective For Misfolded Sod1, Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke Mcalary, Jeremy S Lum, Justin J Yerbury

Faculty, Staff and Student Publications

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we …

Hyperoxia During Neonatal Cardiopulmonary Bypass Is Associated With Worse Clinical Outcomes: A Multi-Institutional Study, Asaad G Beshish, David M Kwiatkowski, Nathaniel Sznycer-Taub, John M Costello, Andrew Jergel, Scott Gillespie, Katherine Cashen, Ahmed Asfari, Maria Batsis, Jason R Buckley, Meghan M Chlebowski, Saul Flores, Nimrod Goldshtrom, Karl Migally, Kimberly I Mills, Monique R Radman, Chetana Reddy, Brittany Shutes, Christine M Riley, Sukumar Suguna Narasimhulu, Dana Mueller, Venugopal Amula, Raji Venkitachalam, Brian F Joy, Karan B Karki, Scott M Leopold, Jennifer E Schramm, Christine A Capone, Scott I Aydin, Adnan M Bakar, Kieran Leong, Agnieszka Kulikowska, Sarah Wing, Christopher W Mastropietro, Collaborative Research From The Pediatric Intensive Care Society (Core‐Pcics) Investigators

Faculty, Staff and Students Publications

Background: Exposure to supraphysiologic oxygen concentrations, or hyperoxia, during neonatal cardiopulmonary bypass (CPB) has been associated with worse outcomes in single-center studies. We aimed to describe variation in oxygen exposure during CPB and determine if hyperoxia is associated with worse outcomes in a multicenter cohort of neonates undergoing cardiac surgery.

Methods: We conducted a retrospective study of neonates who underwent surgery with CPB between January 2021 and December 2022 at 29 centers. Primary outcomes were operative mortality and major adverse cardiovascular events (MACE), which included CPR, extracorporeal support, stroke, and mortality. Logistic regression assessed the associations between median PaO2 during …

Standardizing And Scaffolding Health Care Ai-Chatbot Evaluation: Systematic Review., Yining Hua, Winna Xia, David Bates, George Hartstein, Hyungjin Tom Kim, Michael Li, Benjamin Nelson, Charles Stromeyer Iv, Darlene King, Jina Suh, Li Zhou, John Torous

Department of Psychiatry and Human Behavior Faculty Papers

BACKGROUND: Health care chatbots are rapidly proliferating, while generative artificial intelligence (AI) outpaces existing evaluation standards.

OBJECTIVE: We aimed to develop a structured, stakeholder-informed framework to standardize evaluation of health care chatbots.

METHODS: PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses)-guided searches across multiple databases identified 266 records; 152 were screened, 21 full texts were assessed, and 11 frameworks were included. We extracted 356 questions (refined to 271 by deduplication and relevance review), mapped items to Coalition for Health AI constructs, and organized them with iterative input from clinicians, patients, developers, epidemiologists, and policymakers.

RESULTS: We developed the Health …

Pathways And Challenges In The Clinical Translational Of Radiopharmaceuticals For Pediatric Investigations, Erik Stauff, Hanieh Karimi, Heidi H. Kecskemethy, Thomas H. Shaffer, Reza Vali, Lauren W. Averill, Xuyi Yue

Department of Radiology Faculty Papers

Radiopharmaceutical development and clinical translation face numerous scientific, ethical, and regulatory challenges, particularly within the pediatric population. Although molecular imaging holds significant promise for improving diagnosis and treatment across a spectrum of diseases, including pediatric-specific conditions like Kawasaki disease, autism spectrum disorders, attention-deficit/hyperactivity disorder, and neuroblastoma, the path from discovery to clinical application remains problematic. The U.S. Food and Drug Administration (FDA) provides three primary pathways-traditional Investigational New Drug (IND) applications, exploratory Investigational New Drug application (eIND), and the Radioactive Drug Research Committee (RDRC) mechanism-to facilitate clinical translation of radiotracers. However, these frameworks are not specifically tailored to pediatric needs. …

Her3 Promotes Triple-Negative Breast Cancer Progression By Upregulating Phf8 Via Mir-34b-5p-Dependent Mechanism, Hui Lyu, Cong Cong Tan, Yakun Wu, Margaret E. Larsen, Qingzhao Yu, Guobin Kang, Charles Wood, Shou Ching Tang, Bolin Liu

School of Graduate Studies Faculty Publications

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with limited targeted treatment options and poor clinical outcomes. HER3 has recently emerged as a promising therapeutic target, with HER3-directed antibody–drug conjugates advancing to Phase III clinical trials for non-small cell lung cancer. However, the downstream molecular mechanisms by which HER3 promotes TNBC progression remain poorly defined. In this study, we uncovered a previously unrecognized HER3/miR-34b-5p/PHF8 signaling axis that drives TNBC cell proliferation and tumor growth. Mechanistically, HER3 activation suppresses the tumor-suppressive microRNA miR-34b-5p, resulting in the upregulation of the histone demethylase PHF8 (KDM7B), which in …

Menin Inhibitor Ds-1594b Drives Differentiation And Induces Synergistic Lethality In Combination With Venetoclax In Acute Myeloid Leukemia Cells With Rearranged Mixed-Lineage Leukemia And Mutated Nucleophosmin-1, Valerio Ciaurro, Vassilena Sharlandjieva, Anna Skwarska, Catherine Chahrour, Natalia Baran, Zhihong Zeng, Cassandra Ramage, Naval Daver, Bing Z Carter, Sovira Chaundhry, Palaniraja Thandapani, Maria Paola Martelli, Thomas A Milne, Marina Konopleva

Faculty, Staff and Student Publications

Mixed-lineage leukemia (MLL) rearrangements and Nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the antiapoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLL-rearranged and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLL rearrangements, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS- 1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, Western blotting, and …

Survival Analysis Of Breast Cancer Patients In Texas Using Classical And Machine Learning Methods, Sidketa Fofana, Tamer Oraby, Salique H. Shaham, Everardo Cobos, Manish K. Tripathi

School of Medicine Publications

Background

Breast cancer is considered one of the most common cancers in women worldwide. In this study, we used an 11-year cohort of malignant breast cancer survival data in Texas to investigate the factors that might explain why some breast cancer patients live longer than others.

Methods

We performed standard survival analyses, including generating Kaplan‒Meier survival curves, using the log-rank test, and applying Cox proportional hazards regression to identify the unique features of breast cancer patients and determine the main factors influencing long-term survival. We also conducted a Random Survival Forest analysis for classification and prediction. Finally, we used Mahalanobis …

Development Of A Clinically Relevant Rabbit Model Of Acute Laryngeal Injury, Ryan Stepp, Naushin Ali, Areli A. Rodriguez, Ethan Nicklow, Noah Thornton, Adithya Reddy, Hannah L. Kenny, Patrick S. Cottler, Donald R. Griffin, James J. Daniero

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVES: Acute laryngeal injury (ALgI) is created as a result of endotracheal tube pressure ulcer formation leading to fibrosis and inflammation. This condition often leads to airway obstruction and voice and swallowing dysfunction. This study demonstrates a reliable animal model of ALgI to reproduce the acute wound process seen clinically, to explore the pathophysiology of this disease process, and to serve as a reproducible injury suitable for the evaluation of therapeutic interventions.

METHODS: An ALgI model was developed in New Zealand White rabbits using precise mucosal stripping of the posterior larynx, followed by intubation with an oversized 4.0 endotracheal tube …

Mutant P53 Variants Differentially Impact Replication Initiation And Activate Cgas-Sting To Affect Immune Checkpoint Inhibition, Kang Liu, Lidija A Wilhelms Garan, Fang-Tsyr Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

Prior research shows that Akt-dependent phosphorylation of TopBP1 in S phase results in the switch of TopBP1/Treslin binding to TopBP1/E2F1 binding, which is important to prevent replication re-initiation in late S and G2 phases. Here, we demonstrate that contact, but not conformational, mutant p53 can override this switch by binding to both TopBP1 and Treslin, thereby facilitating persistent TopBP1/Treslin interaction in late S and G2 phases, which ultimately leads to over-firing of replication initiation. This increases micronuclei formation, which is further enhanced by genotoxic stressors such as doxorubicin, PARP inhibitors, or ATR inhibitors. Consequently, contact mutant p53 increases the sensitivity …

Cofilin Inhibition Ameliorates Piezo2 And Ampa Dysfunction In A Mouse Model Of Angelman Syndrome, Luis O Romero, Manisha Bade, Elisa Carrillo, Sonia Paz-López, Syed A M Hasan, William James Antonisamy, Vasanthi Jayaraman, Zahoor A Shah, Valeria Vásquez, Julio F Cordero-Morales

Faculty, Staff and Student Publications

Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous (F-)actin, a decrease we also reported in dorsal root ganglia (DRG) neurons, along with impaired mechanosensitive ion channel activity. Currently, there are no pharmacological targets to prevent the decrease of F-actin in AS. Here, we utilize a first-in-class selective cofilin inhibitor (SZ-3) to restore PIEZO2 function in DRG neurons and glutamate-evoked currents in hippocampal neurons from AS mice. Using atomic force microscopy, we demonstrate that inhibiting cofilin, an actin-severing protein, with SZ-3 increases cellular stiffness by stabilizing the actin …

Roux-En-Y Gastric Bypass Is Associated With Increased Intestinal Glucose Uptake In Humans, Florina Corpodean, Maryam Naseri, Michael Kachmar, Julia St Amant, Denis P. Blondin, Owen T. Carmichael, Vance L. Albaugh

School of Medicine Faculty Publications

CONTEXT: In animal models, Roux-en-Y gastric bypass (RYGB) is associated with increased Roux limb intestinal glucose uptake that may contribute to early metabolic benefits, though prospective clinical studies are lacking. OBJECTIVE: The present study aimed to test the hypothesis that Roux limb glucose uptake would increase relative to baseline in a cohort of patients undergoing RYGB. METHODS: RYGB patients underwent preoperative baseline, and 3- and 6-month positron emission tomography/computed tomography postoperative imaging. Maximum and mean standardized uptake values (SUV) were measured from the following predefined regions of interest: cecum, hepatic flexure, splenic flexure, sigmoid colon, duodenal bulb, Roux limb, and …

Pregnancy Outcomes In Women With Heritable Thoracic Aortic Disease: Data From The Eorp Esc Registry Of Pregnancy And Cardiac Disease (Ropac) Iii, Puck N J Peters, Johanna A Van Der Zande, Julie De Backer, Guillaume Jondeau, Osama Ahmad, Marjorie Richardson, Francesca M Comoglio, Heleen Van Der Zwaan, Siddharth K Prakash, Christina Christersson, Karishma P Ramlakhan, Roger Hall, Mark R Johnson, Jolien W Roos-Hesselink, Ropac Investigators

Faculty, Staff and Student Publications

Aims: The risk of pregnancy in women with heritable thoracic aortic disease (HTAD) is estimated to be high, but supporting data are scarce. The aim of this study is to prospectively investigate pregnancy outcomes to improve patient management and care.

Methods and results: The Registry of Pregnancy and Cardiac disease (ROPAC) III is a prospective global registry including pregnant women with known aortic pathology between 2018 and 2023. Cardiac, obstetric and fetal outcomes, beta-blocker use, and the impact of breastfeeding were investigated. Additionally, changes in aortic diameters were assessed. In total, 176 pregnancies in 170 women (mean age 32 years, …

Effects Of Combining Traditional East Asian And Conventional Western Medicine On Acute Stroke Outcomes, Dong-Seok Gwak, Jong-Sik Lee, Dawid Schellingerhout, Jinyong Chung, Hyerin Oh, Sang-Wuk Jeong, Ji Sung Lee, Hee-Joon Bae, Mikyung Kim, Dong-Jun Choi, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Traditional East Asian medicine (TM) is widely used in Korea and other East Asian countries. However, the effects of TM treatment on acute ischemic stroke (AIS) outcomes remain unclear, as previous studies lacked a sufficient sample size, a consecutive series design, or a prospective outcome capture approach. We aimed to investigate whether combining TM with conventional Western medicine (CM) treatments (C+TM) leads to better outcomes after AIS, relative to CM treatment alone.

Methods: We retrospectively analyzed 2157 consecutive patients with AIS from a prospectively collected registry (2011-2021) at our center and compared the CM and C+TM groups in terms …

Serum Response Factor Is Essential For Endometrial Function And Prevention Of Inflammatory Fibrosis, Ryan M Marquardt, Sara A Grimm, San-Pin Wu, Peter F Lais, Shu-Yun Li, Xin Xu, Erin Smithberger, David Cunefare, Charan Ganta, David Olson, Eunhee M Jeong, Jae-Wook Jeong, Bruce A Lessey, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

Pregnancy requires a supportive uterine environment facilitated by steroid hormone–regulated differentiation of endometrial stromal fibroblasts into decidual cells and tight control of inflammation. Serum response factor (SRF) is a widely expressed transcription factor essential for mesenchymal cell growth and differentiation with noted roles in hormonal regulation of muscle tissues but little characterization in reproductive organs. Here, we reveal that endometrial SRF is dysregulated in human endometriosis and is critical for female reproductive success in mice through regulation of endometrial stromal and epithelial cells. Immunohistochemical analysis identified decreased endometrial SRF expression in infertile endometriosis patient tissues. RNAi-based SRF knockdown in human …

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 …

Integrative Proteogenomics And Forward Genetics Reveal A Novel Mitotic Vulnerability In Triple-Negative Breast Cancer, Nicholas J Neill, Shankha Satpathy, Karsten Krug, Jitendra K Meena, Nivetha Ramesh Babu, Cheyenne Calderon, Desmon Reed, Marcus J Weber, Lacey E Dobrolecki, Alaina Lewis, Christina Sallas, Meenakshi Anurag, Kimberly R Holloway, Chen Huang, Suhas Vasaikar, Maria F Cardenas, Beom-Jun Kim, Doug W Chan, Shayan C Avanessian, Siddhartha Tyagi, Mayra Orellana, Sufeng Mao, Heyuan Li, Fade Gong, Sarah J Kurley, Kristen L Meerbrey, Calla M Olson, Amritha Nair, Tingting Sun, Hsiang-Ching Chung, Elizabeth A Bowling, Jarey H Wang, Pengju Zhang, Peng Xiao, Duxiao Yang, Fabio Stossi, Mei-Yin C Polley, Alexander B Saltzman, Filip Mundt, D R Mani, Michael A Gillette, Susan G Hilsenbeck, George Miles, Carolina Gutierrez, C Kent Osborne, Charles Y Lin, Nathanael S Gray, Jinpeng Sun, David A Wheeler, Charles M Perou, Anna Malovannaya, Michael T Lewis, Bing Zhang, Matthew J Ellis, Steven A Carr, Thomas F Westbrook

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent …

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 …

An Annotated Biobank Of Triple-Negative Breast Cancer Patient-Derived Xenografts Features Treatment-Naïve And Longitudinal Samples During Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Baameur Hancock, Sabrina L Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443), including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT treatment and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of the PDX models were capable of metastasizing …

Therapeutic Radiation Drives Leptomeningeal Dissemination Of Medulloblastoma Through An Innate Immune Process, Carolina Nör, Kaitlin Kharas, Alex Rasnitsyn, Maria C Vladoiu, Nam Woo Cho, Jacob S Young, Felipe Nör, Ncedile Mankahla, Joonas Haapasalo, Kristiina Nordfors, Sara Rapic, Patryk Skowron, Raúl A Suárez, Alexander T Bahcheli, Oliver Ocsenas, Xin Chen, Shahrzad Bahrampour, Ali Momin, Lakshmikirupa Sundaresan, Winnie Ong, Liam D Hendrikse, Namal Abeysundara, Kyle Juraschka, Michelle Ly, Jonelle G Pallota, Tajana Douglas, Ning Huang, Hao Wang, Esta Mak, Lei Qin, Jessica Liu, Lily Shen, Betty Luu, Alex Manno, Sachin A Kumar, Laura K Donovan, Vernon Fong, Cory Richman, Craig Daniels, Livia Garzia, Jeremy N Rich, Cynthia Hawkins, Xiaochong Wu, Ralph Dacosta, Jüri Reimand, Xi Huang, Vijay Ramaswamy, David R Raleigh, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives …

Avasopasem Manganese Treatment For Severe Oral Mucositis From Chemoradiotherapy For Locally Advanced Head And Neck Cancer: Phase 3 Randomized Controlled Trial (Roman), Carryn Anderson, Christopher M. Lee, Joseph Randall Kelley, Gary V. Walker, Neal E. Dunlap, Voichita Bar-Ad, Douglas A. Miller, Vernon J. King, Abhinand V. Peddada, Douglas F. Ciuba, Francois Vincent, Brian C. Muzyka, Amanda Lynn Gillespie-Twardy, Stephen T. Sonis, Jon Holmlund, Robert A Beardsley, Eugene P Kennedy, Deborah Saunders

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: Of patients who receive standard concomitant chemoradiation (CRT; intensity-modulated radiation therapy [IMRT] plus cisplatin) for locally advanced head and neck cancer (HNC), approximately two-thirds will develop severe oral mucositis (SOM), limiting their ability to eat solids (WHO grade 3) or drink liquids (WHO grade 4). In a randomized, double-blind phase 2b trial, avasopasem manganese substantially reduced duration and incidence of SOM versus placebo. This phase 3 trial further assessed avasopasem's reduction of SOM due to CRT.

METHODS: In this double-blind, placebo-controlled trial (Clinicaltrials.gov: NCT03689712), patients receiving 60-72 Gy IMRT (>50 Gy to ≥2 oral mucosal sites) plus cisplatin …

The Epidemiology Of Us Upper Extremity Amputations: An Analysis Of The Global Burden Of Disease Database (1990-2019)., Ambrose Loc T Ngo, Cameron J Sabet, Gabrielle Dykhouse, Ayah Ibrahim, Taylor J Manes, Arsalaan Sayyed, Shaheryar Asad, Benjamin C Taylor

Surgery Articles

Background Upper extremity amputations (UEAs) are medically, psychologically, and functionally devastating. This study aimed to evaluate region- and sex-specific differences in unilateral and bilateral upper extremity amputations in the United States (US) from 1990 to 2019. Methods The Global Burden of Disease (GBD) database was used to analyze years lived with disability (YLDs), prevalence, and incidence rates per 100,000 people for upper extremity amputations in the US from 1990 to 2019. Data were stratified into four US Census Bureau-defined regions: Northeast, Midwest, South, and West. Differences between regions and sexes were assessed, with statistical significance defined as p< 0.05. Results Between 1990 and 2019, unilateral upper extremity amputations in the US showed a 34.51% decrease in YLDs, 34.34% in prevalence, and 37.38% in incidence. Bilateral amputations decreased by 51.32%, 48.94%, and 56.80%, respectively. Men consistently had higher YLDs, prevalence, and incidence rates for unilateral amputations (p< 0.001). Regionally, the Northeast had the highest mean YLDs, prevalence, and incidence, while the South had the lowest. Men also experienced significantly higher rates of both unilateral and bilateral amputations across all regions compared to women (p< 0.05). Conclusions From 1990 to 2019, the US experienced declines in YLDs, prevalence, and incidence of upper extremity amputations. Men had higher rates than women across all regions. The Northeast exhibited the highest rates, while the South had the lowest. These findings underscore notable gender and regional disparities in upper extremity amputation trends.

Identifying Sex- And Gender-Specific Endocrinological, Lifestyle, Psychosocial, And Socio-Cultural Targets For Alzheimer's Disease Prevention In Africans: The Female Brain Health And Endocrine Research In Africa (Fember-Africa) Project, Chinedu Momoh, Benard Aliwa, Lukoye Atwoli, Karen Blackmon, Edna Bosire, Samuel Gitau, Harrison Kaleli, Ciru Kamanda, Linda Khakali, Rachel Maina, Peter Mativo, Sylvia Mbugua, Zul Merali, Kendi Muchungi, Anne Njogu, Douglas Nyankira, Alice Ondieki, Catherine Onyancha, Stanely Onyango, Jasmit Shah, Sheena Shah, Cynthia Smith, Dilraj Sokhi, Sheila Waa, Thomas Thesen

Brain and Mind Institute

Dementia rates are rising globally, with the burden increasing most rapidly in low- tomiddle-income countries. Despite this, research into Alzheimer’s disease and relateddementias (ADRD) among African populations remains limited, with existing modelsbased on Western cohorts that overlook sex-, gender-, and ancestry-specific factors.The Female Brain Health and Endocrine Research in Africa (FemBER-Africa) project,hosted at the Brain and Mind Institute, Aga Khan University, Kenya, will establish adeeply phenotyped cohort of 250 African individuals across the ADRD spectrum. Itwill assess sex-specific risk factors linked to ethnicity, lifestyle, and endocrinologicalvariables using fluid-based biomarkers (blood and saliva), neuroimaging (magneticresonance imaging and positron emission tomography), and …

Prevalence And Determinants Of Nomophobia Among Healthcare Workers In Nepal: A Cross-Sectional Study, Prakash Banjade, Asmita Itani, Munish Sharma, Reena Shah, Jasmit Shah, Aakansha Singh, Rahul Kashyap, Salim Surani

Brain and Mind Institute

Introduction: Nomophobia, the fear of being without a mobile phone, has become a significant concern in the current digital age. Healthcare professionals rely heavily on mobile devices for communication and information access. This cross-sectional study aimed to assess the prevalence and determinants of nomophobia among healthcare workers in Nepal.

Methods: A modified Nomophobia Questionnaire (NMP-Q) was used to determine nomophobia scores. Demographic characteristics such as age, gender, race, type of smartphone, hours spent on a smartphone, and type of medical specialty were considered to evaluate nomophobia in diverse groups of healthcare workers. Summary statistics were presented as frequencies …

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 …

Pathogenic Xpo1 Variants Cause A Dominant Neurodevelopmental Disorder, Amber S E Van Oirsouw, Pavla Nedbalova, Miroslava Hancarova, Jan Prchal, Darina Prchalova, Marketa Vlckova, Sarka Bendova, Kristin G Monaghan, Lisa M Dyer, Yanmin Chen, Deanna Alexis Carere, Emma A M Te Bogt, Heather Fisher, Angela E Scheuerle, Stephanie Riley, Mahim Jain, Weiyi Mu, Joann N Bodurtha, Albertien M Van Eerde, Marijn F Stokman, Nicola Longo, Meena Balasubramanian, Michael Spiller, Gregory Costain, Charlotte Von Der Lippe, Kristian Tveten, Marianne Jortveit, Øystein L Holla, Bertrand Isidor, Benjamin Cogné, Kevin E Glinton, Blake Vuocolo, Roberta Ann Sierra, Brad Angle, Kelly Bontempo, Klaas Koop, Rachel Rabin, John Pappas, David A Staffenberg, Pascal Joset, Peter Miny, Isabel Filges, Abdulrazak Alali, Kara Vitalone, Jill A Rosenfeld, Weimin Bi, Samuel Bradbrook, Renee Perrier, Subhadra Ramanathan, June-Anne Gold, María Palomares Bralo, María Ángeles Gómez-Cano, Ann Haskins Olney, Shelly Nielsen, Alban Ziegler, Dominique Bonneau, Clément Prouteau, Ange-Line Bruel, Charlotte Caille-Benigni, Laëtitia Lambert, Andrea C Yu, Nathaniel H Robin, Dana Goodloe, Jan Fischer, Joseph Porrmann, Yvonne D Hennig, Rami Abou Jamra, Isabella Herman, Ivy R Johnson, Lucas Hérissant, Guillaume Jouret, Koen L I Van Gassen, Ellen Van Binsbergen, Bert Van Der Zwaag, Alwin Kamermans, Renske Oegema, Zdenek Sedlacek, Michaela Fenckova, Richard H Van Jaarsveld

Faculty, Staff and Students Publications

Purpose: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date.

Methods: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used Drosophila to study XPO1 function in development and habituation learning.

Results: A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We …

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 …

Redefining Central Nervous System Multiple Myeloma: From Rare Phenomenon To Emerging Entity, Ian Landry, Adam F. Binder, Marc Yorker, Sarah Ramirez

Department of Medical Oncology Faculty Papers

BACKGROUND: Central nervous system involvement in multiple myeloma (CNS-MM) is considered a rare but devastating manifestation of extra-medullary disease (EMD) associated with aggressive biology and dismal outcomes. Treatment advances over the past few decades have improved survival in patients with MM, however, it has not translated into a similar survival benefit for those with CNS-MM. Early recognition and targeted management of CNS-MM remain major clinical challenges.

OBJECTIVE: This literature review summarizes the current literature on epidemiology, risk factors, clinical features, diagnostic modalities, and therapeutic approaches to CNS-MM. It focuses on emerging biomarkers and new treatment options that may affect the …

Who Classification Of Skin Tumours: Key Updates In The Fifth Edition, Gabrielle Goldman-Lévy, Raymond Barnhill, Boris Bastian, Werner Kempf, David Elder, Pedram Gerami, Wayne Grayson, Dmitry Kazakov, Daniela Massi, Shahin Sayed

Pathology, East Africa

The 5th edition of the World Health Organization Classification of Tumours (WCT) serves as a foundation for global diagnostic standards in tumour pathology. Similar to other volumes in this series, the Skin Tumours (Skin5) edition follows a standardized approach. This edition introduces two new chapters: ‘Tumours of the nail unit’ and ‘Metastases to skin’, along with new entities across relevant chapters. This review article provides an overview of the updates in Skin5 based on currently published evidence, with emphasis on newly introduced chapters and newly described entities that involve the skin, in particular, epidermal, melanocytic and appendageal tumours.

A Tour Of Leukemia Progress In 2025, Viewed Through The Md Anderson Leukemia Research Lens, Hagop M Kantarjian, Gautam Borthakur, Naval Daver, Courtney Dinardo, Guillermo Garcia-Manero, Ghayas Issa, Elias Jabbour, Nitin Jain, Tapan Kadia, Sanam Loghavi, Farhad Ravandi, Guilin Tang, Mary Alma Welch, William Wierda

Faculty, Staff and Student Publications

Advances in the prognostication, monitoring, and treatment of both the acute and chronic leukemias have led to drastically improved outcomes over the past 2 decades. With the advent of targeted therapies, including antibodies such as blinatumomab and inotuzumab and small molecule inhibitors, such as the BCR::ABL1 tyrosine kinase inhibitors, Bruton tyrosine kinase inhibitors, and venetoclax, the treatment landscape of leukemia has drastically changed, improving survival outcomes while relying less on overall chemotherapy intensity in many leukemia types. This progress has allowed the categorization of more leukemia types as favorable (i.e., chronic lymphocytic leukemia, younger acute lymphoblastic leukemia [patients younger than …