Digital Commons Network^™

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

Improving Radiotherapy In Immunosuppressive Microenvironments By Targeting Complement Receptor C5ar1, Callum Beach, David Maclean, Dominika Majorova, Stavros Melemenidis, Dhanya K Nambiar, Ryan K Kim, Gabriel N Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily Vs Hillson, Ashley K Mcculloch, Ross K Mcmahon, Kathryn Pennel, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, Albert C Koong, Trent M Woodruff, Edward E Graves, Tim Maughan, Simon Ja Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J Leedham, Amato J Giaccia, Monica M Olcina

Faculty, Staff and Student Publications

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased …

Influenza Viral Infection Is A Risk Factor For Severe Illness In Covid-19 Patients: A Nationwide Population-Based Cohort Study, Jeong-Hwan Hwang, Yeon Seok You, Sang Woo Yeom, Min Gyu Lee, Jong-Hwan Lee, Min Gul Kim, Jong Seung Kim

Faculty, Staff and Student Publications

In order to prepare for the twindemic of influenza and SARS-CoV-2 infection, we investigated the association between influenza infection and subsequent severity of SARS-CoV-2 infection. A population-based nationwide cohort study was performed using data from the National Health Insurance Service (NHIS) in the Republic of Korea. This study included 274,126 individuals who underwent SARS-CoV-2 PCR testing between 20 January 2020 and 1 October 2020. Among these patients, 28,338 tested positive for SARS-CoV-2, and 4,003 of these individuals had a history of influenza. The control group was selected through 1:1 propensity score matching. In the group of 4,003 COVID-19-positive individuals with …

Effect Of Epithelial-Specific Myd88 Signaling Pathway On Airway Inflammatory Response To Organic Dust Exposure, Amber N Johnson, John Dickinson, Amy Nelson, Rohit Gaurav, Katrina Kudrna, Scott E Evans, Katherine Janike, Todd A Wyatt, Jill A Poole

Faculty, Staff and Student Publications

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, …

Sonographic Characteristics And Pathology Correlation Of Breast Imaging Reporting And Data System (Bi-Rads) Category 4 Lesions, Poonum Khan, Imrana Masroor, Muhammad S Alam, Abdus Salam, Yasir Ali, Muhammad Salman Khan

Faculty, Staff and Student Publications

Introduction: The Breast Imaging-Reporting and Database System (BI-RADS) category 4 is designated for breast lumps that do not display the typical features of malignancy but still raise enough suspicion to warrant a recommendation for a biopsy, as malignancy cannot be ruled out through imaging alone. The main objective of this study was to investigate the sonographic characteristics and pathology correlation of BI-RADS 4 breast lesions and determine the positive predictive rate of BI-RADS 4 lesions in diagnosing breast cancer, using histopathology as the gold standard.

Methods: This was a cross-sectional study conducted at the Department of Radiology, Aga Khan University …

Systematic Analysis Of Proximal Midgut- And Anorectal-Originating Contractions In Larval Zebrafish Using Event Feature Detection And Supervised Machine Learning Algorithms, Ryan M Cassidy, Erika M Flores, Anh K Trinh Nguyen, Sai S Cheruvu, Rosa A Uribe, Anne Marie Krachler, Max A Odem

Faculty, Staff and Student Publications

Background: Zebrafish larvae are translucent, allowing in vivo analysis of gut development and physiology, including gut motility. While recent progress has been made in measuring gut motility in larvae, challenges remain which can influence results, such as how data are interpreted, opportunities for technical user error, and inconsistencies in methods.

Methods: To overcome these challenges, we noninvasively introduced Nile Red fluorescent dye to fill the intraluminal gut space in zebrafish larvae and collected serial confocal microscopic images of gut fluorescence. We automated the detection of fluorescent-contrasted contraction events against the median-subtracted signal and compared it to manually annotated gut contraction …

Cbx4 Promotes Antitumor Immunity By Suppressing Pdcd1 Expression In T Cells, Liwei Ren, Ziyin Li, Yu Zhou, Jun Zhang, Ziheng Zhao, Zhaofei Wu, Ye Zhao, Yurong Ju, Xuewen Pang, Xiuyuan Sun, Wei Wang, Yu Zhang

Faculty, Staff and Student Publications

E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb-repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T-cell-mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from …

Radiation-Induced Innate Neutrophil Response In Tumor Is Mediated By The Cxcls/Cxcr2 Axis, Faya Zhang, Oscar Mulvaney, Erica Salcedo, Subrata Manna, James Z Zhu, Tao Wang, Chul Ahn, Laurentiu M Pop, Raquibul Hannan

Faculty, Staff and Student Publications

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24-48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration. CXCR2 blockade showed the same effects on RT-induced tumor inhibition and host survival as direct neutrophil depletion. Neutrophils highly and preferentially expressed CXCR2 compared to other immune …

An Ace2 Decamer Viral Trap As A Durable Intervention Solution For Current And Future Sars-Cov, Hailong Guo, Bomsoo Cho, Paul R Hinton, Sijia He, Yongjun Yu, Ashwin Kumar Ramesh, Jwala Priyadarsini Sivaccumar, Zhiqiang Ku, Kristen Campo, Sarah Holland, Sameer Sachdeva, Christopher Mensch, Mohamed Dawod, Annalis Whitaker, Philip Eisenhauer, Allison Falcone, Rebekah Honce, Jason W Botten, Stephen F Carroll, Bruce A Keyt, Andrew W Womack, William R Strohl, Kai Xu, Ningyan Zhang, Zhiqiang An, Sha Ha, John W Shiver, Tong-Ming Fu

Faculty, Staff and Student Publications

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by …

Enhanced Tp53 Reactivation Disrupts Myc Transcriptional Program And Overcomes Venetoclax Resistance In Acute Myeloid Leukemias, Yuki Nishida, Jo Ishizawa, Edward Ayoub, Rafael Heinz Montoya, Lauren B Ostermann, Muharrem Muftuoglu, Vivian R Ruvolo, Tallie Patsilevas, Darah A Scruggs, Shayaun Khazaei, Po Yee Mak, Wenjing Tao, Bing Z Carter, Steffen Boettcher, Benjamin L Ebert, Naval G Daver, Marina Konopleva, Takahiko Seki, Kensuke Kojima, Michael Andreeff

Faculty, Staff and Student Publications

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a …

Clinician Perspectives On Technology-Enhanced In Vivo Exposures During Prolonged Exposure Therapy For Ptsd, Delisa G Brown, Amber M Jarnecke, Tanya C Saraiya, Elizabeth Santa-Ana, Ron Acierno, Mclain Reese, Robert Adams, William Harley, Sudie E Back

Faculty, Staff and Student Publications

Objective: To investigate clinicians' perceptions regarding the use of mobile technology tools during prolonged exposure (PE) therapy to allow for monitoring and enhancing in-vivo exposures (IVEs).

Methods: Clinicians with training in PE therapy (N = 32; average of 9 years of practice) completed surveys asking about their perspectives on the utility of virtually attending IVEs with patients while simultaneously having access to real-time subjective and physiological data (i.e., heart rate, galvanic skin conductance) to guide exposure exercises and assure optimal stimulus engagement.

Results: Findings showed clinicians to have a favorable view of applying technology devices and systems to enhance IVEs …

Crispr-Cas9-Based Functional Interrogation Of Unconventional Translatome Reveals Human Cancer Dependency On Cryptic Non-Canonical Open Reading Frames, Caishang Zheng, Yanjun Wei, Peng Zhang, Kangyu Lin, Dandan He, Hongqi Teng, Ganiraju Manyam, Zhao Zhang, Wen Liu, Hye Rin Lindsay Lee, Ximing Tang, Wei He, Nelufa Islam, Antrix Jain, Yulun Chiu, Shaolong Cao, Yarui Diao, Sherita Meyer-Gauen, Magnus Höök, Anna Malovannaya, Wenbo Li, Ming Hu, Wenyi Wang, Han Xu, Scott Kopetz, Yiwen Chen

Faculty, Staff and Student Publications

Emerging evidence suggests that cryptic translation beyond the annotated translatome produces proteins with developmental or physiological functions. However, functions of cryptic non-canonical open reading frames (ORFs) in cancer remain largely unknown. To fill this gap and systematically identify colorectal cancer (CRC) dependency on non-canonical ORFs, we apply an integrative multiomic strategy, combining ribosome profiling and a CRISPR-Cas9 knockout screen with large-scale analysis of molecular and clinical data. Many such ORFs are upregulated in CRC compared to normal tissues and are associated with clinically relevant molecular subtypes. We confirm the in vivo tumor-promoting function of the microprotein SMIMP, encoded by a …

Whole-Genome Sequencing Uncovers Two Loci For Coronary Artery Calcification And Identifies Arse As A Regulator Of Vascular Calcification, Paul S De Vries, Matthew P Conomos, Kuldeep Singh, Christopher J Nicholson, Deepti Jain, Natalie R Hasbani, Wanlin Jiang, Sujin Lee, Christian L Lino Cardenas, Sharon M Lutz, Doris Wong, Xiuqing Guo, Jie Yao, Erica P Young, Catherine Tcheandjieu, Austin T Hilliard, Joshua C Bis, Lawrence F Bielak, Michael R Brown, Shaila Musharoff, Shoa L Clarke, James G Terry, Nicholette D Palmer, Lisa R Yanek, Huichun Xu, Nancy Heard-Costa, Jennifer Wessel, Margaret Sunitha Selvaraj, Rebecca H Li, Xiao Sun, Adam W Turner, Adrienne M Stilp, Alyna Khan, Anne B Newman, Asif Rasheed, Barry I Freedman, Brian G Kral, Caitlin P Mchugh, Chani Hodonsky, Danish Saleheen, David M Herrington, David R Jacobs, Deborah A Nickerson, Eric Boerwinkle, Fei Fei Wang, Gerardo Heiss, Goo Jun, Greg L Kinney, Haakon H Sigurslid, Harshavardhan Doddapaneni, Ira M Hall, Isabela M Bensenor, Jai Broome, James D Crapo, James G Wilson, Jennifer A Smith, John Blangero, Jose D Vargas, Jose Verdezoto Mosquera, Joshua D Smith, Karine A Viaud-Martinez, Kathleen A Ryan, Kendra A Young, Kent D Taylor, Leslie A Lange, Leslie S Emery, Marcio S Bittencourt, Matthew J Budoff, May E Montasser, Miao Yu, Michael C Mahaney, Mohammed S Mahamdeh, Myriam Fornage, Nora Franceschini, Paulo A Lotufo, Pradeep Natarajan, Quenna Wong, Rasika A Mathias, Richard A Gibbs, Ron Do, Roxana Mehran, Russell P Tracy, Ryan W Kim, Sarah C Nelson, Scott M Damrauer, Sharon L R Kardia, Stephen S Rich, Valentin Fuster, Valerio Napolioni, Wei Zhao, Wenjie Tian, Xianyong Yin, Yuan-I Min, Alisa K Manning, Gina Peloso, Tanika N Kelly, Christopher J O'Donnell, Alanna C Morrison, Joanne E Curran, Warren M Zapol, Donald W Bowden, Lewis C Becker, Adolfo Correa, Braxton D Mitchell, Bruce M Psaty, John Jeffrey Carr, Alexandre C Pereira, Themistocles L Assimes, Nathan O Stitziel, John E Hokanson, Cecelia A Laurie, Jerome I Rotter, Ramachandran S Vasan, Wendy S Post, Patricia A Peyser, Clint L Miller, Rajeev Malhotra

Faculty, Staff and Student Publications

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying …

Global Cardiovascular Research: Gaps And Opportunities, Maha Inam, Zainab Samad, Elizabeth M Vaughan, Aysha Almas, Bashir Hanif, Abdul Mannan Minhas, Zeerak Jarrar, Fatima Zohra Habib, Sana Sheikh, Dongshan Zhu, Salim S Virani

Faculty, Staff and Students Publications

Purpose of review: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. CVDs contribute to a large health and economic burden on a global scale. We aim to describe the current landscape of global cardiovascular research, highlight significant findings, and identify potential opportunities for further studies.

Recent findings: There has been remarkable research output regarding cardiovascular health in recent decades. Large-scale collaborative studies have made impactful strides in identifying modifiable risk factors and forming evidence-based guidelines to facilitate improved cardiovascular care and outcomes. However, there are significant CVD disparities between high- and low- income countries which require …

Development Of Thermosensitive Hydrogel Of Amphotericin-B And Lactoferrin Combination-Loaded Plga-Peg-Pei Nanoparticles For Potential Eradication Of Ocular Fungal Infections, Sammar Fathy Elhabal, Shrouk A Ghaffar, Raghda Hager, Nahla A Elzohairy, Mohamed Mansour Khalifa, Passant M Mohie, Rania A Gad, Nasreen N Omar, Mohammed H Elkomy, Mohammad Ahmad Khasawneh, Nashwa Abdelaal

Faculty, Staff and Students Publications

The most prevalent conditions among ocular surgery and COVID−19 patients are fungal eye infections, which may cause inflammation and dry eye, and may cause ocular morbidity. Amphotericin-B eye drops are commonly used in the treatment of ocular fungal infections. Lactoferrin is an iron-binding glycoprotein with broad-spectrum antimicrobial activity and is used for the treatment of dry eye, conjunctivitis, and ocular inflammation. However, poor aqueous stability and excessive nasolacrimal duct draining impede these agens' efficiency. The aim of this study was to examine the effect of Amphotericin-B, as an antifungal against Candida albicans, Fusarium, and Aspergillus flavus, and Lactoferrin, …

Development Of Canagliflozin Nanocrystals Sublingual Tablets In The Presence Of Sodium Caprate Permeability Enhancer: Formulation Optimization, Characterization, Sammar Fathy Elhabal, Mohamed A El-Nabarawi, Nashwa Abdelaal, Mohamed Fathi Mohamed Elrefai, Shrouk A Ghaffar, Mohamed Mansour Khalifa, Passant M Mohie, Dania S Waggas, Ahmed Mohsen Elsaid Hamdan, Samar Zuhair Alshawwa, Essa M Saied, Nahla A Elzohairy, Tayseer Elnawawy, Rania A Gad, Nehal Elfar, Hanaa Mohammed, Mohammad Ahmad Khasawneh

Faculty, Staff and Students Publications

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants …

Junctional Ectopic Tachycardia Caused By Junctophilin-2 Expression Silencing Is Selectively Sensitive To Ryanodine Receptor Blockade, Qixin Yang, Hanna J Tadros, Bo Sun, Minu-Tshyeto Bidzimou, Jordan E Ezekian, Feng Li, Andreas Ludwig, Xander H T Wehrens, Andrew P Landstrom

Faculty, Staff and Students Publications

Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)–mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a novel in vivo model of JET, Hcn4:shJph2 mice demonstrated rapid conversion of JET to sinus rhythm with infusion of EL20. Primary atrioventricular nodal cells demonstrated increased Ca2+ transient oscillation frequency and increased RyR2-mediated stored Ca2+ leak which was normalized by EL20. EL20 was found to be rapidly degraded in mouse and human plasma, making it a potential novel therapy for …

Microbial Products Linked To Steatohepatitis Are Reduced By Deletion Of Nuclear Hormone Receptor Shp In Mice, Ryan Mifflin, Jung Eun Park, Mikang Lee, Prasant Kumar Jena, Yu-Jui Yvonne Wan, Hazel A Barton, Mirjavid Aghayev, Takhar Kasumov, Li Lin, Xinwen Wang, Robert Novak, Feng Li, He Huang, Leah P Shriver, Yoon-Kwang Lee

Faculty, Staff and Students Publications

Deletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders. Since hepatic SHP is recognized as a critical regulator in BA synthesis, we assessed the involvement of gut microbiota in the antiobesity and anti-NASH phenotype of Shp−/− mice. Shp deletion significantly altered the levels of a few conjugated BAs. Sequencing the 16S …

Endometrial Tgfβ Signaling Fosters Early Pregnancy Development By Remodeling The Fetomaternal Interface, Sydney E Parks, Ting Geng, Diana Monsivais

Faculty, Staff and Students Publications

The endometrium is a unique and highly regenerative tissue with crucial roles during the reproductive lifespan of a woman. As the first site of contact between mother and embryo, the endometrium, and its critical processes of decidualization and immune cell recruitment, play a leading role in the establishment of pregnancy, embryonic development, and reproductive capacity. These integral processes are achieved by the concerted actions of steroid hormones and a myriad of growth factor signaling pathways. This review focuses on the roles of the transforming growth factor β (TGFβ) pathway in the endometrium during the earliest stages of pregnancy through the …

Microbial Stimulation Of Oxytocin Release From The Intestinal Epithelium Via Secretin Signaling, Heather A Danhof, Jihwan Lee, Aanchal Thapa, Robert A Britton, Sara C Di Rienzi

Faculty, Staff and Students Publications

Intestinal microbes impact the health of the intestine and organs distal to the gut. Limosilactobacillus reuteri is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for L. reuteri-mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, …

The Brd4-Nut Fusion Alone Drives Malignant Transformation Of Nut Carcinoma, R Taylor Durall, Julianna Huang, Luke Wojenski, Yeying Huang, Prafulla C Gokhale, Brittaney A Leeper, Joshua O Nash, Pedro L Ballester, Scott Davidson, Adam Shlien, Emmanuel Sotirakis, Fabien Bertaux, Vincent Dubus, Jia Luo, Catherine J Wu, Derin B Keskin, Kyle P Eagen, Geoffrey I Shapiro, Christopher A French

Faculty, Staff and Students Publications

NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4-NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous …

Biallelic Med27 Variants Lead To Variable Ponto-Cerebello-Lental Degeneration With Movement Disorders, Reza Maroofian, Rauan Kaiyrzhanov, Elisa Cali, Mina Zamani, Maha S Zaki, Matteo Ferla, Domenico Tortora, Saeid Sadeghian, Saadia Maryam Saadi, Uzma Abdullah, Ehsan Ghayoor Karimiani, Stephanie Efthymiou, Gözde Yeşil, Shahryar Alavi, Aisha M Al Shamsi, Homa Tajsharghi, Mohamed S Abdel-Hamid, Nebal Waill Saadi, Fuad Al Mutairi, Lama Alabdi, Christian Beetz, Zafar Ali, Mehran Beiraghi Toosi, Sabine Rudnik-Schöneborn, Meisam Babaei, Pirjo Isohanni, Jameel Muhammad, Sheraz Khan, Maha Al Shalan, Scott E Hickey, Daphna Marom, Emil Elhanan, Manju A Kurian, Dana Marafi, Alihossein Saberi, Mohammad Hamid, Robert Spaull, Linyan Meng, Seema Lalani, Shazia Maqbool, Fatima Rahman, Jürgen Seeger, Timothy Blake Palculict, Tracy Lau, David Murphy, Niccolo Emanuele Mencacci, Katharina Steindl, Anais Begemann, Anita Rauch, Sinan Akbas, Ayça Dilruba Aslanger, Vincenzo Salpietro, Hammad Yousaf, Shay Ben-Shachar, Katarina Ejeskär, Aida I Al Aqeel, Frances A High, Amy E Armstrong-Javors, Seyed Mohammadsaleh Zahraei, Tahereh Seifi, Jawaher Zeighami, Gholamreza Shariati, Alireza Sedaghat, Samaneh Noroozi Asl, Mohmmad Shahrooei, Giovanni Zifarelli, Lydie Burglen, Claudia Ravelli, Johannes Zschocke, Ulrich A Schatz, Maryam Ghavideldarestani, Walaa A Kamel, Hilde Van Esch, Annette Hackenberg, Jenny C Taylor, Lihadh Al-Gazali, Peter Bauer, Joseph J Gleeson, Fowzan Sami Alkuraya, James R Lupski, Hamid Galehdari, Reza Azizimalamiri, Wendy K Chung, Shahid Mahmood Baig, Henry Houlden, Mariasavina Severino

Faculty, Staff and Students Publications

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± …

Nonsense Variant Prdm16-Q187x Causes Impaired Myocardial Development And Tgf-Β Signaling Resulting In Noncompaction Cardiomyopathy In Humans And Mice, Bo Sun, Omid M T Rouzbehani, Ryan J Kramer, Rajeshwary Ghosh, Robin M Perelli, Sage Atkins, Amir Nima Fatahian, Kathryn Davis, Marta W Szulik, Michael A Goodman, Marissa A Hathaway, Ellenor Chi, Tarah A Word, Hari Tunuguntla, Susan W Denfield, Xander H T Wehrens, Kevin J Whitehead, Hala Y Abdelnasser, Junco S Warren, Mingfu Wu, Sarah Franklin, Sihem Boudina, Andrew P Landstrom

Faculty, Staff and Students Publications

BACKGROUND: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans.

METHODS: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR-mediated knock-in mouse model hosting the Prdm16Q187X allele was generated …

Exposure To Agent Orange And Hepatocellular Carcinoma Among Us Military Personnel, Jihane N Benhammou, Mei Leng, Shailja C Shah, George Cholankeril, Tien S Dong, Arpan A Patel, Myron J Tong

Faculty, Staff and Students Publications

IMPORTANCE: Hepatocellular carcinoma (HCC) and its mortality are on the rise. Viral hepatitis and alcohol are leading risk factors; however, other risk factors among veterans are less defined, including Agent Orange (AO), an herbicide linked to several cancers.

OBJECTIVE: To assess the association of AO exposure and HCC in a national cohort of Vietnam veterans.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included Vietnam veterans who served between 1966 and 1975, were male, were older than 18 years at the time of deployment, and had established follow-up in the Veterans Affairs (VA) between 2000 and 2019. Veterans with AO …

Steroid Receptor Coactivator-2 Drives Epithelial Reprogramming That Enables Murine Embryo Implantation, Vineet K Maurya, Maria M Szwarc, David M Lonard, Ramakrishna Kommagani, San Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon

Faculty, Staff and Students Publications

Although we have shown that steroid receptor coactivator-2 (SRC-2), a member of the p160/SRC family of transcriptional coregulators, is essential for decidualization of both human and murine endometrial stromal cells, SRC-2’s role in the earlier stages of the implantation process have not been adequately addressed. Using a conditional SRC-2 knockout mouse (SRC-2 ^d/d) in timed natural pregnancy studies, we show that endometrial SRC-2 is required for embryo attachment and adherence to the luminal epithelium. Implantation failure is associated with the persistent expression of Mucin 1 and E-cadherin on the apical surface and basolateral adherens junctions of the SRC-2 …

The 2023 Model Core Content Of Disaster Medicine, Bryan J Wexler, Carl Schultz, Paul D Biddinger, Gregory Ciottone, Angela Cornelius, Robert Fuller, Roxanna Lefort, Andrew Milsten, James Phillips, Ira Nemeth

Faculty, Staff and Students Publications

Introduction: Disaster Medicine (DM) is the clinical specialty whose expertise includes the care and management of patients and populations outside conventional care protocols. While traditional standards of care assume the availability of adequate resources, DM practitioners operate in situations where resources are not adequate, necessitating a modification in practice. While prior academic efforts have succeeded in developing a list of core disaster competencies for emergency medicine residency programs, international fellowships, and affiliated health care providers, no official standardized curriculum or consensus has yet been published to date for DM fellowship programs based in the United States.

Study objective: The objective …

Serum Biomarkers Of Nociceptive And Neuropathic Pain In Chronic Pancreatitis, Jami L Saloman, Yan Li, Kimberly Stello, Wenhao Li, Shuang Li, Anna Evans Phillips, Kristen Hall, Evan L Fogel, Santhi Swaroop Vege, Liang Li, Dana K Andersen, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Mark D Topazian, Stephen K Van Den Eeden, Jose Serrano, Darwin L Conwell, Dhiraj Yadav, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Students Publications

Debilitating abdominal pain is a common symptom affecting most patients with chronic pancreatitis (CP). There are multiple underlying mechanisms that contribute to CP-related pain, which makes successful treatment difficult. The identification of biomarkers for subtypes of pain could provide viable targets for nonopioid interventions and the development of mechanistic approaches to pain management in CP. Nineteen inflammation- and nociception-associated proteins were measured in serum collected from 358 subjects with definite CP enrolled in PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, a prospective observational study of pancreatitis in US adult subjects. First, serum levels of putative biomarkers were …

Nutrition Assessment And Mash Severity In Children Using The Healthy Eating Index, Ajay Kumar Jain, Paula Buchannan, Katherine P Yates, Patricia Belt, Jeffrey B Schwimmer, Philip Rosenthal, Karen F Murray, Jean P Molleston, Ann Scheimann, Stavra A Xanthakos, Cynthia A Behling, Paula Hertel, Jamie Nilson, Brent A Neuschwander-Tetri, James Tonascia, Miriam B Vos, Nonalcoholic Steatohepatitis Clinical Research Network (Nash Crn)

Faculty, Staff and Students Publications

BACKGROUND: Pediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD.

METHODS: Diet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components.

RESULTS: In all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index …

Ezh2 Cooperates With Brd4-Nut To Drive Nut Carcinoma Growth By Silencing Key Tumor Suppressor Genes, Yeying Huang, R Taylor Durall, Nhi M Luong, Hans J Hertzler, Julianna Huang, Prafulla C Gokhale, Brittaney A Leeper, Nicole S Persky, David E Root, Praju V Anekal, Paula D L M Montero Llopis, Clement N David, Jeffery L Kutok, Alejandra Raimondi, Karan Saluja, Jia Luo, Cynthia A Zahnow, Biniam Adane, Kimberly Stegmaier, Catherine E Hawkins, Christopher Ponne, Quan Le, Geoffrey I Shapiro, Madeleine E Lemieux, Kyle P Eagen, Christopher A French

Faculty, Staff and Student Publications

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NC that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy are limited. Here, we demonstrated that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple …

Clinical Exome Sequencing Efficacy And Phenotypic Expansions Involving Anomalous Pulmonary Venous Return, Emily A Huth, Xiaonan Zhao, Nichole Owen, Pamela N Luna, Ida Vogel, Inger L H Dorf, Shelagh Joss, Jill Clayton-Smith, Michael J Parker, Jacoba J Louw, Marc Gewillig, Jeroen Breckpot, Alison Kraus, Erina Sasaki, Usha Kini, Trent Burgess, Tiong Y Tan, Ruth Armstrong, Katherine Neas, Giovanni B Ferrero, Alfredo Brusco, Wihelmina S Kerstjens-Frederikse, Julia Rankin, Lindsey R Helvaty, Benjamin J Landis, Gabrielle C Geddes, Kim L Mcbride, Stephanie M Ware, Chad A Shaw, Seema R Lalani, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to …