Digital Commons Network^™

The Utility Of Ultra-Deep Rna Sequencing In Mendelian Disorder Diagnostics, Sen Zhao, Jefferson C Sinson, Shenglan Li, Jill A Rosenfeld, Gladys Zapata, Kristina Macakova, Mezthly Pena, Becky Maywald, Kim C Worley, Lindsay C Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William Craigen, Lisa Emrick, Undiagnosed Diseases Network, Tyson Clark, Gila Yanai Lithwick, Zohar Shipony, Christine Eng, Brendan Lee, Pengfei Liu

Faculty, Staff and Students Publications

RNA sequencing (RNA-seq) has emerged as a powerful tool for resolving variants of uncertain significance (VUSs), particularly those affecting gene expression and splicing. However, most reference datasets and diagnostic protocols employ relatively modest sequencing depths (∼50-150 million reads), which may fail to detect low-abundance transcripts and rare splicing events critical for accurate diagnosis. We evaluated the diagnostic and translational utility of ultra-high-depth (up to ∼1 billion unique reads) RNA-seq in four clinically accessible tissues using the Ultima sequencing platform. After validating the performance of Ultima RNA-seq, we investigated how increasing sequencing depth affects gene and isoform detection, splicing variant discovery, …

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 …

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 …

Integrating Pathogenic Variants, Polygenic Risk Score, And Family History For Prostate Cancer Risk Estimation In Men Of African Ancestry, Fei Chen, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Wei Xiong, Loreall Pooler, Peggy Wan, Susan M Gundell, Godfrey Kigozi, Gertrude Nakigozi, Fred Nalugoda, Joseph Kagaayi, Grace Nalwoga Kigozi, Stephen Mugamba, Emmanuel Kyasanku, James Nkale, Vitalis Ofumbi Olwa, Alexander Lubwama, Alex Daama, Resty Nakajugo, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A Adjei, James Mensah, Pedro W Fernandez, Akindele Olupelumi Adebiyi, J Olufemi Ogunbiyi, Oseremen Inokhoife Aisuodionoe-Shadrach, Lindsay Petersen, Wenlong Carl Chen, Jo Mcbride, Jeannette T Bensen, James L Mohler, Jack A Taylor, Caroline Andrews, Mbaaga Kigongo, Amanya Colline, Vicky Kiddu, Juliet Namugambe, Shallot Owamaani, Kuteesa Job, Benon Joseph Masaba, Frank Asiimwe, Proscovia Muwanga, Joy Namulondo, Florence Nagawa, Charity Kayiraba, Martin Ogwang, Ronald Okidi, David Oweka, Elio Kitara, James Obonyo, Daniel Lajul, Paul Matovu, Precious Arinda Muheki, Johnson Natumanya, Emmanuel Agaba, Emmanuel Aculokin, Amos Twongyeirwe, George Mutema, Denis Bitamazire, Eboneé N Butler, Sue Ann Ingles, Benjamin A Rybicki, Janet L Stanford, Wei Zheng, Sonja I Berndt, Stephen J Chanock, Chad D Huff, Joseph Lachance, Luc Multigner, Burcu F Darst, Timothy R Rebbeck, Laurent Brureau, Stephen Watya, David V Conti, Christopher A Haiman

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVE: The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) remains understudied in large populations of African ancestry. This study aims to characterize the range of genetic risk of PCa and aggressive disease phenotypes in men of African ancestry.

METHODS: We analyzed 7176 PCa cases and 4873 controls from seven countries across North America and Africa to assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were used to estimate lifetime absolute risk based …

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 …

Global Trends And Forecast Of Cardiovascular Diseases, Cancer, And Shared Risk Factors: Insights From The Gbd 2021, Chieh Y Koo, Bryan Chong, Jayanth Jayabaskaran, Srinithy Nagarajan, Silingga M Jauhari, Yiming Chen, Li L Tan, Anurag Mehta, Muhammad S Khan, Mark Muthiah, Derek Hausenloy, A M Richards, Dennis T Ko, Christian D Mallen, Eric A Secemsky, Mark Y Chan, Paaladinesh Thavendiranathan, Nicholas W S Chew, Mamas A Mamas

Faculty, Staff and Students Publications

Background: Cardiovascular disease (CVD) and cancer share multiple risk factors and are the leading causes of morbidity and death worldwide. This study aims to examine historical and projected trends of the combined CVD-cancer global estimates and their shared risk factors.

Methods: Death and disability-adjusted life years (DALYs) associated with CVDs, cancers, and their risk factors were obtained from the GBD (Global Burden of Disease) 2021 study. Historical estimates from 1990 to 2021 and forecast data from 2025 to 2050 were examined across age groups, regions, sociodemographic index, and sex.

Results: In 2021, CVD-cancer resulted in age-standardized DALY rates of 8009 …

A Recurrent Acaa2 Variant Causes A Dominant Syndrome Of Lipodystrophy, Lipomatosis, Infantile Steatohepatitis And Hypoglycemia, Vinaya Simha, Mary Kate Lopiccolo, Anna Platt, Rebecca J Brown, Xandria Johnson, Deanna Alexis Carere, Colleen Donnelly, Matthew T Snyder, Chao Xing, Thomas P Mathews, Purva Gopal, Stephen C Ward, Diana R Tomchick, Anil K Agarwal, Ralph J Deberardinis, Abhimanyu Garg

Faculty, Staff and Student Publications

No abstract provided.

Optimising Drowning Prevention Counselling Through A Physician Maintenance Of Certification (Moc) Quality Improvement (Qi) Initiative, Tracy E Mccallin, Anthony R Arredondo, Elizabeth A Camp, Shabana Yusuf

Faculty, Staff and Students Publications

Drowning is the leading cause of death in children 1–4 years old in the USA. Paediatricians play an important role in giving anticipatory guidance on drowning prevention. This quality improvement initiative aimed to increase the rate of drowning prevention counselling with provision of educational materials to caregivers of children aged 0–10 years during clinical encounters in an outpatient setting.

We refined a previously published Texas state educational programme that included evidence-based counselling strategies across three Plan Do Study Act (PDSA) cycles, with the addition of preintervention baseline counselling phase during expansion of the programme nationally to 17 and 21 states …

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 …

Disparate Leukemia Mutations Converge On Nuclear Phase-Separated Condensates, Gandhar K Datar, Elmira Khabusheva, Archish Anand, Joshua Beale, Marwa Sadek, Chun-Wei Chen, Evdokiia Potolitsyna, Nayara Alcantara-Contessoto, Guangyuan Liu, Josephine De La Fuente, Christina Dollinger, Anna Guzman, Alejandra Martell, Katharina Wohlan, Abhishek Maiti, Nicholas J Short, S Stephen Yi, Vibeke Andresen, Bjørn Tore Gjertsen, Brunangelo Falini, Rachel E Rau, Lorenzo Brunetti, Nidhi Sahni, Margaret A Goodell, Joshua A Riback

Faculty, Staff and Students Publications

During cancer development, mutations promote changes in gene expression that cause transformation. Leukemia associated with aberrant HOXA expression is driven by translocations of nucleoporin genes or KMT2A as well as mutations in NPM1. The mechanistic convergence of these disparate mutations remains elusive. Here, we demonstrate that mutant nucleophosmin 1 (NPM1c) forms nuclear condensates in human cell lines, mouse models, and primary patient samples. We show NPM1c phase separation is necessary and sufficient to recruit NUP98 and KMT2A to condensates. Through extensive mutagenesis and pharmacological destabilization of phase separation, we find that NPM1c condensates are necessary for regulating gene expression, promoting …

Accidental Daily Dosing: Severe Methotrexate Toxicity In A Patient With Rheumatoid Arthritis, Sidra Memon, Kavitha Vemuri, Syed Uzair Mahmood, Darshit Patel

Advances in Clinical Medical Research and Healthcare Delivery

This case highlights a crucial complication of oral methotrexate therapy: toxicity due to dosing errors. A patient’s daily dosing regimen, instead of the intended weekly schedule, led to a significantly excessive cumulative dose of methotrexate over a short period, resulting in severe hematologic and mucosal toxicity. This underscores the importance of clear patient education and vigilant prescription practices to prevent such errors.

Plasmacytoma As The Initial Presentation Of Multiple Myeloma: A Case Report, Chantelle Martin, Sidra Memon, Austin Kim, Saleha Asghar

Advances in Clinical Medical Research and Healthcare Delivery

We report an unusual case of a woman who presented with nonspecific symptoms of unilateral facial mass and bleeding from her lower lip over several weeks. The mass was found to be relatively fixed and irregular with destruction of facial bone as evidenced by imaging. Initial investigations indicated the possibility of multiple myeloma, which was later confirmed with serum protein electrophoresis and bone marrow biopsy. Cervical lymph node biopsy confirmed presence of plasmacytoid cells positive for CD 20.

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 …

National Alliance Of Sickle Cell Centers Consensus Recommendations On Sickle Cell Disease Health Maintenance: A Consensus Statement, Seethal A. Jacob, Melissa Frei-Jones, Sana Saif-Ur-Rehman, Monica L. Hulbert, Andrew R. W. O'Brien, Crawford Strunk, Anthony Villella, Ravi Talati, Amma Owusu-Ansah, Francis Coyne, Patrick T. Mcgann, Parul Rai, Robin Miller, Angeli Rampersad, Vishwas Sakhalkar, Neha Bhasin, Deepa Manwani, Sophie Lanzkron, Julie Kanter

Cardeza Foundation for Hematologic Research

IMPORTANCE: The most common inherited blood disorder in the world, sickle cell disease (SCD) is a known global health concern. While survival of children into adulthood has improved significantly over the last few decades in high-resource countries, substantial gaps in care standards and limited practice harmonization persist.

OBJECTIVE: To provide up-to-date recommendations for preventive care and treatment of all people living with SCD and its related comorbidities.

EVIDENCE REVIEW: As part of the National Alliance of Sickle Cell Centers (NASCC), 41 pediatric and adult sickle cell disease experts developed consensus standards and recommendations based on available evidence and expert consensus …

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 …

Condition-Specific Growth Charts For Children With Alagille Syndrome., Koen Huysentruyt, Shannon M. Vandriel, Mathieu Roelants, David A. Piccoli, Kathleen M. Loomes, Elizabeth B. Rand, Noelle H. Ebel, Jeffrey A. Feinstein, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz-Miedzinska, Emmanuel M. Gonzales, Emmanuel Jacquemin, Jérôme Bouligand, Saul J. Karpen, Rene Romero, Henry C. Lin, Björn Fischler, Henrik Arnell, Li-Ting Li, Jian-She Wang, Rima Fawaz, Silvia Nastasio, Kyung Mo Kim, Seak Hee Oh, Lorenzo D'Antiga, Emanuele Nicastro, Ryan T. Fischer, Susan M. Siew, Michael Stormon, Chatmanee Lertudomphonwanit, Winita Hardikar, Sahana Shankar, James E. Squires, Shikha S. Sundaram, Catherine Larson-Nath, Deirdre A. Kelly, Jane Hartley, Pinar Bulut, M Kyle Jensen, Catalina Jaramillo, Amin J. Roberts, Helen M. Evans, Étienne M. Sokal, Tanguy Demaret, Henkjan J. Verkade, Richard J. Thompson, Bettina E. Hansen, Tim J. Cole, Binita M. Kamath, Dominique Debray, Florence Lacaille, Jernej Brecelj, Nehal M. El-Koofy, Mohamed A. Elmonem, Way Seah Lee, Maria Camila Sanchez, Maria Lorena Cavalieri, Christina Hajinicolaou, Kathleen B. Schwarz, Elisa Carvalho, Nathalie Rock, Wikrom Karnsakul, Ruben E. Quiros-Tejeira, Seema Alam, Gabriella Nebbia, Yael Mozer-Glassberg, Pamela L. Valentino, Ermelinda Santos-Silva, Zerrin Önal, Antal Dezsofi-Gottl, Melina Melere, María Legarda Tamara, John Eshun, Aglaia Zellos, Giuseppe Indolfi, Maria Rogalidou, Niviann Blondet, Pier Luigi Calvo, Marisa Beretta, Andréanne N. Zizzo, Cigdem Arikan, Mureo Kasahara, Nanda Kerkar, Amal A. Aqul, Victorien M. Wolters, Raquel Borges Pinto, Jesus Quintero Bernabeu, Jennifer Garcia, Sabina Wiecek, Christos Tzivinikos, Quais Mujawar, Carolina Jimenez-Rivera, Cristina Molera Busoms, Cristina Gonçalves, Luis Bujanda, Global Alagille Alliance (Gala) Study Group

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Different degrees of growth delay have been reported in children with Alagille syndrome (ALGS), yet these patients are routinely evaluated using standard growth charts.

OBJECTIVE: To develop condition-specific growth charts for ALGS using modern statistical approaches.

DESIGN, SETTING, AND PARTICIPANTS: This case series used data from the international, multicenter Global Alagille Alliance (GALA) study accrued between May 14, 2018, and March 20, 2023. Children born at full term between January 1, 1997, and August 31, 2019, with a clinically and/or genetically confirmed ALGS diagnosis and their native liver were included. Data from children with a known history of prematurity …

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 …

Genetic Contribution To Treatment-Related Dyslipidemia In Adult Survivors Of Childhood Cancer: Findings From The Ccss, Sjlife, And Dccss-Later Cohorts, Melissa Bolier, Vincent G Pluimakers, Linda Broer, Sebastian J C M M Neggers, Demi T C De Winter, Fan Wang, Jessica L Baedke, André G Uitterlinden, Kateryna Petrykey, Leontien C M Kremer, Jacqueline J Loonen, Marloes Louwerens, Heleen J Van Der Pal, E Lieke A M Feijen, Kevin C Oeffinger, Rebecca M Howell, Eric J Chow, Wendy M Leisenring, Maria Monica M Gramatges, Lindsay M Morton, Leslie L Robison, Melissa M Hudson, Kirsten K Ness, Yadav Sapkota, Gregory T Armstrong, Smita Bhatia, Yutaka Yasui, Marry M Van Den Heuvel-Eibrink

Faculty, Staff and Student Publications

Background: Dyslipidemia can occur as a long-term side effect of childhood cancer treatment. The difference in prevalence among children receiving comparable treatment suggests a role for genetic variation. We conducted the first genome-wide association study on dyslipidemia in a large childhood cancer survivor cohort, using three additional cohorts for replication.

Methods: Discovery analysis was performed in the original Childhood Cancer Survivor Study (CCSS) cohort (N = 4,332). Replication analyses were carried out in the CCSS expansion (N = 2,212), St. Jude Lifetime (N = 2,829), and Dutch Childhood Cancer Survivor Study (DCCSS-LATER) (N = 1,814) cohorts. In the CCSS cohorts, …

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 …

Orphan Nuclear Receptor 4a1 (Nr4a1) And Nr4a2 Are Endogenous Regulators Of Cd71 And Their Ligands Induce Ferroptosis In Breast Cancer, Arafat Rahman Oany, Srijana Upadhyay, Wai Ning Tiffany Tsui, Amanuel Hailemariam, Sarah Latka, John D Landua, Sandra D Scherer, Alana L Welm, Hugo Villanueva, Michael T Lewis, Stephen Safe

Faculty, Staff and Students Publications

Ferroptosis is an iron-dependent cell death pathway that involves multiple genes, including the transferrin receptor (TFRC/CD71), glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11). This study is based on the hypothesis that orphan nuclear receptor 4A1 (NR4A1) and NR4A2 maintain low levels of ferroptosis in triple negative breast cancer (TNBC) cells and bis-indole derived (CDIM) compounds act as NR4A1/2 ligands that induce ferroptosis by enhancing CD71 expression. 1,1-Bis(3'-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) analogs were investigated for their cytotoxicity and effects on NR4A1 and NR4A2 regulated genes and induction of ferroptosis. Several assays also determined enhanced lipoperoxidation, reactive oxygen species and malondialdehyde formation in …

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 …

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 …

Acute Myeloid Leukemia Drives Atrial Fibrillation Through Tnfα Signaling Activation, Ninad Oak, Jose Alberto Navarro-Garcia, Minhua Li, Mara R Turkieltaub Paredes, Satadru K Lahiri, Bharat K Kantharia, Daisuke Nakada, Xander H T Wehrens, Mohit M Hulsurkar

Faculty, Staff and Students Publications

No abstract provided.

A Multiomics Recovery Factor Predicts Long Covid In The Impacc Study, Gisela Gabernet, Jessica Maciuch, Jeremy P Gygi, John F Moore, Annmarie Hoch, Caitlin Syphurs, Tianyi Chu, Naresh Doni Jayavelu, David B Corry, Farrah Kheradmand, Lindsey R Baden, Rafick-Pierre Sekaly, Grace A Mccomsey, Elias K Haddad, Charles B Cairns, Nadine Rouphael, Ana Fernandez-Sesma, Viviana Simon, Jordan P Metcalf, Nelson I Agudelo Higuita, Catherine L Hough, William B Messer, Mark M Davis, Kari C Nadeau, Bali Pulendran, Monica Kraft, Chris Bime, Elaine F Reed, Joanna Schaenman, David J Erle, Carolyn S Calfee, Mark A Atkinson, Scott C Brakenridge, Esther Melamed, Albert C Shaw, David A Hafler, Alison D Augustine, Patrice M Becker, Al Ozonoff, Steven E Bosinger, Walter Eckalbar, Holden T Maecker, Seunghee Kim-Schulze, Hanno Steen, Florian Krammer, Kerstin Westendorf, Bjoern Peters, Slim Fourati, Matthew C Altman, Ofer Levy, Kinga K Smolen, Ruth R Montgomery, Joann Diray-Arce, Steven H Kleinstein, Leying Guan, Lauren Ir Ehrlich

Faculty, Staff and Students Publications

Background: Following SARS-CoV-2 infection, approximately 10%–35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.

Methods: We utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics “recovery factor,” trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor …

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 …

Gut Bacterial Dysbiosis In Pediatric Severe Malaria Associates With Post-Discharge Mortality, Olivia Bednarski, Sawyer Lehman, David Mzinza, Caroline Kazinga, Ruth Namazzi, Robert Opoka, Jie Ren, Tuan Tran, Terrie Taylor, Karl Seydel

Paediatrics and Child Health, East Africa

Gut microbiota have been implicated in severe malaria in murine models, but their contribution to the pathogenesis of severe malaria in children is unknown. Here we show through analysis of gut bacteria in stool samples from two separate African studies enrolling children with severe malaria, and children from local communities, that children with severe malaria have gut bacteria dysbiosis. Among children with severe malaria, there is increased abundance of Enterobacteriaceae that associates with multiple clinical complications of severe malaria. Moreover, increased abundance of Escherichia coli was a predictor of post-discharge mortality. Metagenome analysis identify elevated metabolic pathways and genes supporting …

Oesophageal Cancer And Its Associated Factors Among Patients Attending Surgical And Oncology Clinics At Garissa County Referral Hospital, Kenya: A Case-Control Study, Abdi Bashir, Moses Ngari, Berrick Otieno, Makorani Y’Dhidha-A-Mjidho, Osman Abdullahi, Symon Kariuki

Institute for Human Development, East Africa

Background Oesophageal cancer (EC) is a common cause of cancer mortality. Evidence on the burden, risk factors and treatment outcomes is limited in low-income and middle-income countries. This study aimed to describe the features of EC cases and determine associated factors among patients attending surgical and oncology clinics in Garissa County Referral Hospital (GCRH).

Methods We conducted a case–control study in which cases were patients with EC and positive histological confirmation and controls were patients admitted to GCRH for other diseases. Data on exposures were extracted from patient files. Data on tobacco and alcohol use were based on current or …

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 …

Associations Of Estrogen With Modifiable And Non-Modifiable Risk Factors For Dementia: A Narrative Review, Sarah Gregory, Katie Bridgeman, Hannah Darwin, Mariapaola Barbato, Laura Booi, Anna Serrat, Antonella Chadha, Francesca Farina, Natalie Jenkins, Beverly Cheserem

Brain and Mind Institute

Female sex is associated with higher incidence and risk of dementia. Estrogen may rep-resent one important mechanism contributing to the increase in incidence rates. In thisreview, we synthesize narratively the evidence for associations between estrogen—across the life course from menarche to menopause, estrogen-containing hormonalcontraception and hormone replacement therapies, and pregnancy—with potentialmodifiable risk factors for dementia. These include education, hearing loss, traumaticbrain injury, hypertension, alcohol use, obesity, smoking, depression, physical inactiv-ity, diabetes, low-density lipoprotein (LDL) cholesterol, social isolation, air pollution,and untreated visual loss, as well as apolipoprotein E ε4. In addition, evidence is sum-marized for associations with sleep, diet, and stress. …