Medical Specialties Commons^™

Sex Hormones Influence Ormdl3 Expression: Implications For Sex-Associated Asthma Phenotype, Elisabetta Granato, Ida Cerqua, Antonietta Rossi, Maria Antonietta Riemma, Maria Chiara Monti, Giusy Ferraro, Barbara Romano, Maria Francesca Nanì, Danilo D'Avino, Martina Simonelli, Joshua Malo, Francesca Polverino, Bruno D'Agostino, Giuseppe Cirino, Fiorentina Roviezzo

Faculty, Staff and Students Publications

Background: Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.

Objective: We investigated whether ORMDL3 contributes to sex differences in airway function and asthma-like features.

Methods: ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) after exposure to 17β-estradiol (E2), Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of …

Proteome-Wide Association Study Of Prostate Cancer Risk Across Populations, Hua Zhong, Jingjing Zhu, Shuai Liu, Chong Wu, Liang Wang, Seamus P Whelton, Catherine H Marshall, Michael J Blaha, Peter Durda, Xiuqing Guo, Craig W Johnson, Henry J Lin, Kent D Taylor, Russell P Tracy, Ronit I Yarden, Ani W Manichaikul, Stephen S Rich, Jerome I Rotter, Rajat Deo, Ruth F Dubin, Peter Ganz, Lang Wu

Faculty, Staff and Student Publications

There is insufficient understanding of the molecular basis of prostate cancer (PCa) across different populations. We perform a large-scale proteome-wide association study (PWAS) to identify proteins with genetically regulated expression in plasma to be associated with PCa risk across populations. We develop genetic prediction models for expression of 1578, 1993, 1218, and 1390 proteins for African (n = 450), European (n = 758), Asian (n = 289), and Hispanic/Latino (n = 474) males, respectively, and evaluate associations of genetically regulated protein expression with PCa risk in 19,391 PCa cases and 61,608 controls of African population, 122,188 cases and 604,640 controls …

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

A Comprehensive Study Of C-Kit-Expressing Amacrine Cells In The Mammalian Retina, Zheng Jiang, Wen Shen

Faculty, Staff and Students Publications

Amacrine cells assemble complex circuits in the inner retina, where they integrate, modulate, and relay spatial and temporal information to retinal ganglion cells. Nevertheless, their organization and functional diversity are still not fully understood. In this study, we identify a distinct group of amacrine cells that express the stem cell factor receptor-c-Kit. Using combined techniques of anti-CD117 (c-Kit) immunolabeling, confocal imaging, and computational algorithms, we characterize the morphological features and spatial distribution of the c-Kit-expressing amacrine cells. Our results show that c-Kit-expressing amacrine cells are GABA-positive neurons with medium to wide dendritic fields that stratify within the specific strata in …

Dinaciclib Improves Treatment Response In Chemoresistant Hepatoblastoma, Brian T Hickner, Andres F Espinoza, Rohit K Srivastava, Roma H Patel, Priyanka Rao, Nicholas A O'Brien, Kalyani R Patel, Andrew A Badachhape, Abhishek Kona, Dolores H López-Terrada, Sarah E Woodfield, Sanjeev A Vasudevan

Faculty, Staff and Students Publications

Chemoresistant hepatoblastoma (HB) is associated with poor outcomes. Cyclin-dependent kinases (CDKs) are potential therapeutic targets because of their critical role in cell growth and chemoresistance. To evaluate the efficacy of CDK inhibition, HB cell lines were treated with dinaciclib and evaluated with cytotoxic, cell-death reversal, and immunoblotting assays. A HB patient-derived xenograft (PDX) model was treated with placebo, vincristine + irinotecan (VI), dinaciclib, or VI + dinaciclib to evaluate tumor growth and response to therapy. We found that dinaciclib had a marked effect on HB cell viability, induced PARP cleavage, and decreased CDK9 protein expression in vitro. Overexpression of CDK9 …

Pitx2 Dosage-Dependent Changes In Pacemaker Cell State Underlie Sinus Node Dysfunction And Atrial Arrhythmias, Lieve E Van Der Maarel, M Ridwane Mungroo, Otto J Mulleners, Mathilde R Rivaud, Arie O Verkerk, Karel Van Duijvenboden, Freek H T Tiel Groenestege, Jeffrey D Steimle, Lianne Fokkert, Corrie De Gier-De Vries, Mischa Klerk, Arie R Boender, James F Martin, Bjarke Jensen, Gerard J J Boink, Harsha D Devalla, Vincent M Christoffels

Faculty, Staff and Students Publications

Physiologically relevant increases in transcription factor dosage and their role in development and disease remain largely unexplored. Genomic deletions upstream of the Paired-like homeodomain transcription factor gene (PITX2), identified in patients with sinus node dysfunction and atrial fibrillation and modeled in mice (delB), rewire the local epigenetic landscape, increasing PITX2 expression. Here, we demonstrate that pacemaker cardiomyocytes in the embryonic delB sinus node ectopically express PITX2 at physiological dosages in a heterogeneous pattern. The prenatal delB sinus node forms discrete subdomains showing PITX2 dosage-dependent mild or severe loss of pacemaker cardiomyocyte identity. Respective subdomain sizes and severity of sinus node …

Functional Vs Anatomical Cortico-Striatal Connectivity In The Macaque Brain, Wei Tang, Megan E Monko, Zoe Liu, Ana M G Manea, Fernando A Ortega, Damyan Hart, Jason Zhou, Jan Zimmermann, Sarah R Heilbronner

Faculty, Staff and Students Publications

The cerebral cortex provides the main input to the striatum, constituting the first step in cortico-basal ganglia loops. Decades of careful anatomical tract-tracing research have established the exquisite topography of each cortical region's projection to the striatum in nonhuman primates. In parallel, neuroimaging research has demonstrated the relationship between cortico-striatal resting-state functional connectivity and specific cognitive, behavioral, psychiatric, and neurological states in humans. However, still unclear is the extent to which functional connectivity recapitulates the specific topographies of cortico-striatal anatomical connectivity. Here, we combined datasets of cortico-striatal anatomical and functional connectivity in macaques to determine the degree of overlap between …

Racial And Ethnic Disparities In Neoadjuvant Chemotherapy Patterns And Outcomes In Early-Stage Her2-Positive Breast Cancer, Inimfon Jackson, Xiudong Lei, Hui Zhao, Rashmi Murthy, Sharon H Giordano, Mariana Chavez-Macgregor

Faculty, Staff and Student Publications

We examined neoadjuvant chemotherapy (NACT) use, pathological complete response (pCR) and the association with overall survival (OS) among patients with early-stage HER2-positive breast cancer (BC). Patients ≥18 years with stage I-III HER2-positive BC from 2010-2022 who had surgery and chemotherapy were identified. Of 195,023 patients treated with chemotherapy, 37.7% received NACT. NACT use increased from 18.6% in 2010 to 63.4% in 2022 (p <  0.001) and pCR rates rose from 21% to 47.6% (p <  0.001). Black patients were less likely to receive NACT (aOR = 0.96;95%CI 0.93-0.99) or achieve pCR (aOR = 0.86;95%CI 0.82-0.90) than White patients. pCR was associated with a reduction in the risk of death (aHR = 0.45;95%CI 0.42-0.48). 3-year OS increased from 91% in 2010 to 95% in 2019 for patients without a pCR (p <  0.001), and from 97% to 99% for patients with pCR (p = 0.002). Further research is needed to understand and address racial and ethnic disparities in treatment access and outcomes.

A Mouse Model Of Lipoatrophy Reveals Relationships Between Beige Fat Appearance And Female Fertility, Elizabeth S Anaya, William Dion, Pradip K Saha, Aaron R Cox, Evelyn De Groot, Avery A Ahmed, Jessica B Felix, Bokai Zhu, Stephanie A Pangas, Sean M Hartig

Faculty, Staff and Students Publications

White adipose tissue (WAT) performs vital metabolic and endocrine functions, but roles in female reproduction remain understudied and poorly understood. Here, we report that female mice experiencing progressive lipoatrophy after knockout of Ubc9 in adipocytes (Ubc9fKO) displayed disrupted estrous cycles, reduced ovarian reserve, and subfertility. During aging, female Ubc9fKO mice lose subcutaneous WAT more quickly than their male counterparts and weigh less than littermate controls. Subcutaneous WAT excised from female Ubc9fKO mice strongly enriched for thermogenesis genes generally associated with metabolic benefits. Female Ubc9fKO mice exhibited hypermetabolism and accumulated thermogenic, Uncoupling Protein 1-expressing beige fat cells in residual subcutaneous WAT …

Fgf13 Regulates Vgsc-Independent Cardiomyocyte Impulse Propagation Via Cx43 Trafficking, Lala Tanmoy Das, Mattia Malvezzi, Aravind R Gade, Maiko Matsui, Margaret Mckay, Eric Q Wei, Matea J Zelich, Keon Mazdisnian, Jared Kushner, Bi-Xing Chen, Isabella Distefano, Daniel Roybal, Lin Yang, Lisa Stoll, James C Lo, Marian Kalocsay, Fadi G Akar, Steven O Marx, Geoffrey S Pitt

Faculty, Staff and Student Publications

Background: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded.

Methods: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. …

Yap-Induced Glycolysis Drives Fibroinflammation And Disrupts Fibroblast Fidelity, Chang-Ru Tsai, Lin Liu, Yi Zhao, Jong H Kim, Paulo Czarnewski, Rich Gang Li, Fansen Meng, Mingjie Zheng, Jeffrey Steimle, Xiaolei Zhao, Francisco Grisanti, Zheng Sun, Jun Wang, Md Abul Hassan Samee, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Background: Separation of the pulmonic and systemic circulation is essential for terrestrial life, and mammals have evolved distinct cardiac chambers with specialized structures and functions. Transcriptomics profiling revealed cellular heterogeneity between heart chambers. However, the mechanisms underlying chamber-specific transcriptomic and metabolic differences-and their functional significance-remain poorly understood. The Hippo/YAP (yes-associated protein) pathway is a conserved signaling network that regulates diverse cellular processes. The Hippo kinases inhibit YAP in cardiac fibroblasts (CF) to restrict fibrosis and inflammation. Nonetheless, how YAP regulates the metabolic microenvironment during homeostasis and fibroinflammation remains unclear.

Methods: We investigated YAP and glycolysis activity in the 4 cardiac …

Revealing The Nervous System Requirements Of Alzheimer Disease Risk Genes In Drosophila, Jennifer M Deger, Shabab B Hannan, Mingxue Gu, Colleen E Strohlein, Lindsey D Goodman, Sasidhar Pasupuleti, Zahid Shaik, Liwen Ma, Yarong Li, Jiayang Li, Morgan C Stephens, Michal Tyrlík, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Chad A Shaw, Oguz Kanca, Hugo J Bellen, Joshua M Shulman

Faculty, Staff and Students Publications

Most Alzheimer disease (AD) susceptibility genes have poorly understood roles in the central nervous system (CNS). To address this gap, we systematically characterized 100 conserved candidate AD risk genes using a cross-species strategy in the fruit fly, Drosophila melanogaster. Genes were prioritized based primarily on human functional genomic evidence. We generated custom loss-of-function alleles for each of the conserved fly orthologs. Most of the genes are expressed in the adult brain, including 24 neuron- and 13 glia-specific expression patterns. Overall, we identify 50 candidate AD risk gene homologs with requirements for CNS structure or function, including 18 whose loss of …

Super-Fast, Super-Early: High-Frequency Oscillations May Be A Prelude To Alzheimer's Dementia In Down Syndrome, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. Methods: Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10–20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. Results: Fourteen individuals with DS and five age-matched euploid …

Acceptability Of Active And Sham Home-Based Transcranial Direct Current Stimulation In Major Depression: Mixed Methods Qualitative Analysis In A Randomised Controlled Trial, Peter J Lagerberg, Rachel D Woodham, Sudhakar Selvaraj, Nahed Lajmi, Harriet Hobday, Gabrielle Sheehan, Ali-Reza Ghazi-Noori, Maheen Rizvi, Sarah S Kwon, Paulette Orhii, Rodrigo Machado-Vieira, Jair C Soares, Allan H Young, António R Fidalgo, Hakimeh Rezaei, Cynthia H Y Fu

Faculty, Staff and Student Publications

Purpose: Transcranial direct current stimulation (tDCS) is a novel non-invasive brain stimulation therapy that is a potential treatment for major depressive disorder (MDD). Acceptability impacts patient preference, treatment adherence and outcomes, however, it has typically been assessed through measures of attrition, self-reported satisfaction levels, or adverse events. We sought to explore participant acceptability using structured questionnaires and individual interviews.

Methods: Acceptability was assessed in a fully remote, multisite, double-blind, placebo-controlled, randomized superiority trial of a 10-week course of home-based tDCS for MDD. Questionnaires were conducted at baseline and at the 10-week end of treatment. Participants were 174 adults (120 women) …

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …

A Distinct Pp2a Subunit Regulates Local Protein Phosphorylation At The Axon Initial Segment, Andrew P Anderson, Sanghyun Kim, Allison J Melton, Xiaoyun Ding, Wei Zhang, Alexander B Saltzman, Anna Malovannaya, Matthew N Rasband, Yudong Gao

Faculty, Staff and Students Publications

Protein phosphorylation plays a crucial role in regulating the cytoskeletal and membrane proteins at the axon initial segment (AIS). However, our knowledge of AIS-specific kinases and phosphatases is very limited. Here, we report the identification of a protein phosphatase 2A (PP2A) B55 regulatory subunit enriched at the AIS in mice: Ppp2r2c. Our results demonstrate that PP2A-B55 subunits exhibit substantial heterogeneity in their subcellular localization and function. Notably, the Ppp2r2c subunit is selectively concentrated at the AIS, and this enrichment is driven by its unique structure. Utilizing a microelectrode array system (MEA), we show that Ppp2r2c modulates neuronal activity during in …

The Perspectives And Experiences Of Prospective Parents Declining Diagnostic Prenatal Genome Sequencing In Continuing Pregnancies With Fetal Structural Anomalies, Lisa S Weingarten, Allison Rosenbaum, Jessica De Voest, Stephanie Galloway, Jessica L Giordano, Samantha Stover, Lauren E Westerfield, Grant Bonesteele, Kelly L Gilmore, Leandra Tolusso, Beatrix Wong, A Theresa Wittman, Daniel T Swarr, Nancy Leslie, Anthony Johnson, Ignatia B Van Den Veyver, Neeta L Vora, Rebecca G Clifton, Aaron B Caughey, Ronald J Wapner, Wendy K Chung

Duncan NRI Faculty and Staff Publications

Objective: This study evaluates an understudied perspective: the experiences of prospective parents who decline prenatal genome sequencing (pGS) for continuing pregnancies with fetal structural anomalies.

Method: We recruited a total cohort of 300 parents of 150 pregnancies who declined pGS, including 33 individuals who underwent an invasive procedure. These parents were invited to participate in a semi-structured interview between 1 and 15 months post-partum. We used Thematic Analysis to code and analyze interviews.

Results: We interviewed 22 parents of 16 pregnancies. Reasons for declining testing included risks of invasive procedures (n = 19, 86%), lack of prenatally actionable findings (n …

Long-Term Outcomes And Treatment Patterns In Waldenström Macroglobulinemia Patients Who Discontinue Bruton Tyrosine Kinase Inhibitor (Btki) Therapy, Karan L Chohan, Lorenzo Gensini, Sherif Seif, Xiaowen Sun, Lei Feng, Melody R Becnel, Mahmoud M Gaballa, Hans C Lee, Oren Pasvolsky, Krina K Patel, J Christine Ye, Donna M Weber, Robert Z Orlowski, Sheeba K Thomas

Faculty, Staff and Student Publications

No abstract provided.

Cdk2 Inhibition Enhances Cdk4/6 Inhibitor Antitumor Activity In Comprehensive Breast Cancer Pdx Model Screen, Nealia C House, Maxine M Chen, Sima Khazaei, Victoria Brown, Philip Ramsden, David H Peng, Sydney Moore, Liang Yuan, Rentian Wu, Fangyang Wang, Linjie Luo, Ningping Feng, Christopher A Bristow, Timothy A Yap, Khandan Keyomarsi, Joseph R Marszalek, Scott Ribich, Mikael L Rinne, Lakshmi B Muthuswamy, Kerrie L Faia

Faculty, Staff and Student Publications

Aberrant cyclin-dependent kinase 2 (CDK2) activity is implicated as a resistance mechanism to CDK4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Using preclinical patient-derived xenograft models, the CDK2i + CDK4/6i combination was active broadly across CDK4/6i-resistant and -naïve HR+ and triple-negative breast cancer models. A novel, weighted mRNA expression signature involving CCND1, CCNE1, RB1, and CDKN2A (p16) predicted response to combined inhibition of CDK2 and CDK4/6. Addition of endocrine therapy significantly enhanced antitumor activity in HR+ models, providing preclinical proof-of-concept for the broad antitumor activity of the triple combination. Early clinical data demonstrated …

Targeting Tet3 Suppresses Group 3 Medulloblastoma Stemness And Progression Via Impairing Hypomethylation Of Otx2 Super-Enhancer, Xuan Chen, Ziwei Wang, Yan Song, Yu Su, Yahui Zhao, Jiankang Li, Wei Wang, Jiao Zhang, Craig Daniels, Xiaochong Wu, Olivier Saulnier, Yanan Wang, Fei Liu, Kaiwen Deng, Dongming Han, Zijia Liu, Meiyu Li, Liam D Hendrikse, Alexandra Rasnitsyn, Evan Y Wang, Dongyang Wang, Zhaoyang Feng, Yanong Li, Zitong Zhao, Hongyu Yuan, Youliang Sun, Yifei Jiang, Yanfeng Shi, Tao Yang, Xueling Qi, Yong Hou, Chunde Li, Yong-Qiang Liu, Yu Tian, Shuaicheng Li, Xiaoguang Qiu, Michael D Taylor, Guo Liang Li, Tao Jiang, Hailong Liu

Faculty, Staff and Students Publications

Medulloblastoma (MB), particularly Group_3 (G3-MB), remains the most aggressive subgroup due to strong stemness and therapeutic resistance. Through genome-wide DNA methylation and transcriptomic analysis of human MB samples, we identify enhancer hypomethylation as a key feature sustaining G3-MB stemness and tumor progression. Notably, hypomethylation of the Otx2 super-enhancer (SE) is a prognostic marker and potential therapeutic target for G3-MB patients. We demonstrate that disrupting Otx2 SE activity effectively reduces tumor growth in vivo, highlighting its critical role in G3-MB maintenance. TET3, recruited by OTX2, demethylates the Otx2 SE, promoting chromatin opening and sustaining tumor proliferation and stemness. To translate these …

Multi-Omic Profiling Provides Insights Into The Heterogeneity, Microenvironmental Features, And Biomarker Landscape Of Small-Cell Lung Cancer, Mingchao Xie, Miljenka Vuko, Shashank Saran, Siyu Liu, Andrew G Chambers, Hana Baakza, Helen K Angell, Felicia Ng, Carl M Gay, Robert J Cardnell, Felix J Segerer, Alma Andoni, Jaime Rodriguez-Canales, Paul M Waring, Markus Schick, J Carl Barrett, Lauren A Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Background: Greater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.

Methods: We explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.

Results: Multi-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest …

Inhibition Of Clostridioides Difficile-Specific Dna Adenine Methyltransferase Cama By Analogs Of S‑Adenosyl‑L‑Methionine, Jujun Zhou, Youchao Deng, Dan Yu, Taraneh Hajian, Masoud Vedadi, Xing Zhang, Robert M Blumenthal, Rong Huang, Xiaodong Cheng

Faculty, Staff and Student Publications

Epigenetically targeted therapies, especially those inhibiting S-adenosyl-l-methionine (SAM)-dependent methylations of DNA, mRNA, and histones, have advanced rapidly in cancer treatment. However, these therapies remain underexplored for antibiotic development, despite the growing threat of antimicrobial resistance. Here, we screened a focused library of SAM analogs against the DNA adenine methyltransferase CamA specific to the enteric pathogen Clostridioides difficile. At the same time, we examined six other adenine methyltransferases, including two bacterial DNA methyltransferases and four human RNA methyltransferases having distinct RNA substrates. Compound 113 selectively inhibited CamA (IC50 = 0.15 μM). In addition, compound 67 inhibited Caulobacter crescentus CcrM …

Characterizing Circulating Rare Cells In Peripheral Blood For Detecting And Monitoring Multiple Myeloma And Precursor States, Stephanie N Shishido, Jeremy Mason, Mohamed Kamal, Sonia Maryam Setayesh, Amishi U Vora, David Berrios, Luz Yurany Moreno Rueda, Krina Patel, Elisabet E Manasanch, Robert Z Orlowski, Peter Kuhn

Faculty, Staff and Student Publications

Multiple myeloma (MM) arises from abnormal plasma cells (PCs) progressing from precursor states, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Understanding this transition and progression to overt MM requires improved non-invasive strategies. We employed a liquid biopsy approach to detect and characterize circulating PCs across disease states in 68 patients (MGUS = 11, SMM = 21, NDMM = 19, RRMM = 17) using multi-channel immunofluorescence staining and machine learning-assisted rare event detection. PCs were identified by CD138 and B-cell maturation antigen (BCMA) expressions, with distinct phenotypic subpopulations stratifying disease states. The D | CD138 | …

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …

Monte Carlo Simulations Of Geometric Deformation Of Harrison-Anderson-Mick Applicators Used In Intraoperative Radiation Therapy, Benjamin Insley, Brett Bocian, Sam Beddar, Reza Reiazi, Patrick James Jensen, Rachael M Martin-Paulpeter, Joshua Scott Niedzielski, David Flint, Gabriel Oliveira Sawakuchi, Luis Augusto Perles

Faculty, Staff and Student Publications

Background: The Harrison-Anderson-Mick (HAM) applicator is a high-dose-rate intraoperative radiotherapy (HDR-IORT) applicator used to position Ir-192 brachytherapy sources over surgically-accessed tumor volumes or post-resection tumor beds. Because of the lack of a 3D imaging system, dwell times are optimized pre-surgery by a TG-43-based treatment planning system (TPS) that assumes a perfectly flat applicator surface surrounded by an infinite water phantom. These assumed conditions are disparate from typical treatment conditions, especially in the pelvic regions, which often involve uneven patient surfaces and superficial irradiations with little to no backscatter material.

Purpose: Develop and validate a Monte Carlo (MC) model of HDR-IORT …

Fibroblasts Are The Primary Contributors To A Disrupted Micro-Environment In End-Stage Pediatric Hypertrophic Cardiomyopathy, Hanna J Tadros, Diwakar Turaga, Yi Zhao, Chang-Ru Tsai, Iki A Adachi, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Background: Hypertrophic cardiomyopathy (HCM) is a relatively rare but debilitating diagnosis in the pediatric population, and patients with end-stage HCM require heart transplantation. Here, we have examined the transcriptome in ventricular tissue from this patient group to identify cell states and underlying cellular processes unique to pediatric HCM.

Methods: We performed single-nucleus RNA sequencing (snRNA-seq) on explanted hearts at transplant in 3 pediatric patients with end-stage HCM and compared findings to pediatric control and adult HCM.

Results: We identified distinct underlying cellular processes in cardiomyocytes, fibroblasts, endothelial cells, and myeloid cells compared with controls. Pediatric HCM was enriched in cardiomyocytes …

Hes V20 Surpasses Galad For Hcc Detection: A Review Of Multi-Dimensional Biomarker Scores And Studies, Fouad Jaber, Hashem B El-Serag

Faculty, Staff and Students Publications

This was a narrative review of select studies published through September of 2024. We review the shift toward multi-dimensional scores such as HCC early detection screening (HES), GALAD, ASAP, and mt-HBT represents a significant advancement in biomarker research for hepatocellular carcinoma (HCC) detection. Unlike single biomarker approaches, these scores integrate various clinical and biochemical factors to enhance predictive accuracy by reflecting different complementary aspects of disease progression and HCC oncogenesis. Proper testing and validation of biomarker scores in phase 3 biomarker studies is essential before wide use can be recommended. We also review the comparative performance of biomarker scores in …

Characteristics Associated With Eurolupus Versus Modified National Institutes Of Health Cyclophosphamide Regimen Use In Children And Young Adults With Lupus Nephritis, Christine S Wang, Rebecca E Sadun, Wenru Zhou, Kristen R Miller, Stacy P Ardoin, Christine Bearer, Emily Hause, Joyce Hui-Yuen, Nicole Ling, Maria Pereira, Meredith Riebschleger, Kelly Rouster-Stevens, Aliese Sarkissian, Julia Shalen, William Daniel Soulsby, Marinka Twilt, Eveline Y Wu, Laura B Lewandowski, Scott E Wenderfer, Jennifer C Cooper

Faculty, Staff and Students Publications

Objective: To determine the demographic and clinical characteristics associated with use of the EuroLupus or modified National Institutes of Health (NIH) cyclophosphamide (CYC) regimen for treatment of lupus nephritis (LN) at North American pediatric centers.

Methods: A retrospective cohort study was conducted at 11 North American centers. Patients < 22 years of age with active LN treated with CYC using the EuroLupus or NIH regimen between July 2014 and June 2021 were included. Data were extracted via electronic medical record review. Demographic and clinical characteristics were compared at CYC initiation. A multivariable generalized estimating equation with logit link was fit to model EuroLupus use. An exchangeable correlation structure was used to account for correlation within centers. Independent variables were chosen using elastic net regression.

Results: The cohort consisted of 191 patients (85 EuroLupus, 106 NIH) with a median age of 15.3 years at CYC initiation. In multivariable analysis, characteristics significantly associated with EuroLupus regimen use (vs NIH regimen use) included more recent year of CYC initiation, longer disease duration, Hispanic ethnicity and Asian race (as compared …

Adrenomedullin Overexpression Protects Mice From Experimental Bronchopulmonary Dysplasia And Associated Pulmonary Hypertension, Shyam Thapa, Poonam Sarkar, M Waleed Gaber, Roberto Barrios, Madhulata Chauhan, Chandrasekhar Yallampalli, Binoy Shivanna

Faculty, Staff and Students Publications

Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) or BPD-PH is a lung disease of infants with significant morbidity. Adrenomedullin (Adm) is an angiogenic peptide that signals through calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2 (RAMP2). Adm deficiency potentiates hyperoxia-induced experimental BPD-PH in mice; however, whether Adm overexpression can mitigate this lung disease is unclear. Thus, we tested the hypothesis that Adm overexpression attenuates hyperoxia (HO)-induced murine experimental BPD-PH by using a novel transgenic mouse that overexpresses Adm globally (Admhi/hi mice). One-day-old Admhi/hi mice or their wild-type littermates (Adm+/+ mice) were exposed to …

Derivation Of Pluripotent Stem Cell Lines (Rfsci005-A, Rfsci006-A) From Siblings Harboring Identical High-Risk Complement Variants With Discordant Age-Related Macular Degeneration, Naresh Rajendran, Ajeet Singh, Wendy Runyon, Sam Hu, Ritu Kumar, Rinki Ratnapriya, Karl Csaky, Srinivasa R Sripathi

Faculty, Staff and Students Publications

Age-related macular degeneration (AMD) is a complex disease influenced by genetic and environmental factors. Variants in the complement pathway, especially in the CFH gene, increase AMD risk, yet disease severity can differ among individuals with identical high-risk genotypes. We generated induced pluripotent stem cell (iPSC) lines from siblings carrying identical high-risk complement variants but displaying discordant AMD phenotypes. These lines provide a unique platform to study epigenetic, transcriptomic, and environmental factors driving AMD heterogeneity. By comparing differentiated retinal cells, we aim to reveal mechanisms behind variable disease susceptibility and inform personalized therapies for AMD.