Medical Cell Biology Commons^™

Uchl1 Is A Potential Molecular Indicator And Therapeutic Target For Neuroendocrine Carcinomas, Shiqin Liu, Timothy Chai, Fernando Garcia-Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Martin Shaw Toland, Abel Bermudez, Alifiani B Hartono, Christopher F Massey, Chung S Lee, Liwei Zheng, Maya Baron, Caden J Denning, Merve Aslan, Holly M Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian A Kunder, Brooke E Howitt, H Tom Soh, Irving L Weissman, Michael A Liss, Arnold I Chin, James D Brooks, Eva Corey, Sharon J Pitteri, Jiaoti Huang, Tanya Stoyanova

Faculty, Staff and Student Publications

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of …

I-Prf : A Smart Cell Scaffold, Dr.Lochini Suriya

Annual Research Symposium

In regenerative dentistry, platelet rich plasma (PRP) has been used as a supra-physiological concentration of autologous growth factors capable of encouraging tissue regeneration. Despite this, there have been concerns raised about the use of anticoagulants, which are known to impair wound healing. In this work, a liquid formulation of platelet rich fibrin (PRF) called injectable-PRF (I-PRF) was studied without the need of anti-coagulants .

The Novel Phosphatase Nudt5 Is A Critical Regulator Of Triple-Negative Breast Cancer Growth, Jing Qian, Yanxia Ma, William M Tahaney, Cassandra L Moyer, Amanda Lanier, Jamal Hill, Darian Coleman, Negar Koupaei, Susan G Hilsenbeck, Michelle I Savage, Brent D G Page, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target …

Genome-Wide P63-Target Gene Analyses Reveal Tap63/Nrf2-Dependent Oxidative Stress Responses, Marco Napoli, Avani A Deshpande, Deepavali Chakravarti, Kimal Rajapakshe, Preethi H Gunaratne, Cristian Coarfa, Elsa R Flores

Faculty, Staff and Students Publications

The p53 family member TP63 encodes two sets of N-terminal isoforms, TAp63 and ΔNp63 isoforms. They each regulate diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities have been extensively characterized, TAp63 prevents premature aging by regulating the quiescence and genomic stability of stem cells required for wound healing and hair regeneration, while ΔNp63 controls maintenance and terminal differentiation of epidermal basal cells. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical sequence for a DNA-binding domain. To understand the mechanisms of the transcriptional programs …

The Curious Case Of A Painful Leg Ulcer, Jay R Patel, Rubi Montejano, Christina Hopkins, Hanna Siatecka, Theodore Rosen

Faculty, Staff and Students Publications

Sickle cell disease is a condition that can involve numerous organ systems secondary to vascular occlusion. Herein, we present a case of a 21-year-old male with sickle cell disease requiring long-term hydroxyurea therapy. Upon migrating to the United States from Yemen, the patient developed a rapidly progressive, exquisitely painful ulcer on his right lower extremity. Given his country of origin, a broad differential, including select infectious diseases, was essential. Moreover, establishing the unequivocally correct diagnosis was crucial to determine proper and safe therapy. Ultimately, a lesional biopsy demonstrated numerous sickled red blood cells occluding blood vessels, leading to the diagnosis …

A Novel Erβ High Throughput Microscopy Platform For Testing Endocrine Disrupting Chemicals, Derek A Abbott, Maureen G Mancini, Michael J Bolt, Adam T Szafran, Kaley A Neugebauer, Fabio Stossi, Daniel A Gorelick, Michael A Mancini

Faculty, Staff and Students Publications

In this study we present an inducible biosensor model for the Estrogen Receptor Beta (ERβ), GFP-ERβ:PRL-HeLa, a single-cell-based high throughput (HT) in vitro assay that allows direct visualization and measurement of GFP-tagged ERβ binding to ER-specific DNA response elements (EREs), ERβ-induced chromatin remodeling, and monitor transcriptional alterations via mRNA fluorescence in situ hybridization for a prolactin (PRL)-dsRED2 reporter gene. The model was used to accurately (Z' = 0.58-0.8) differentiate ERβ-selective ligands from ERα ligands when treated with a panel of selective agonists and antagonists. Next, we tested an Environmental Protection Agency (EPA)-provided set of 45 estrogenic reference chemicals with known …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Kenneth A Wilson, Sudipta Bar, Eric B Dammer, Enrique M Carrera, Brian A Hodge, Tyler A U Hilsabeck, Joanna Bons, George W Brownridge, Jennifer N Beck, Jacob Rose, Melia Granath-Panelo, Christopher S Nelson, Grace Qi, Akos A Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B Brem, Philippe M Campeau, Hugo J Bellen, Birgit Schilling, Nicholas T Seyfried, Lisa M Ellerby, Pankaj Kapahi

Faculty, Staff and Students Publications

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function …

Integrative Computational Analyses Implicate Regulatory Genomic Elements Contributing To Spina Bifida, Paul Wolujewicz, Vanessa Aguiar-Pulido, Gaurav Thareja, Karsten Suhre, Olivier Elemento, Richard H Finnell, M Elizabeth Ross

Faculty, Staff and Students Publications

PURPOSE: Spina bifida (SB) arises from complex genetic interactions that converge to interfere with neural tube closure. Understanding the precise patterns conferring SB risk requires a deep exploration of the genomic networks and molecular pathways that govern neurulation. This study aims to delineate genome-wide regulatory signatures underlying SB pathophysiology.

METHODS: An untargeted, genome-wide approach was used to interrogate regulatory regions for rare single-nucleotide and copy-number variants (rSNVs and rCNVs, respectively) predicted to affect gene expression, comparing results from SB patients with healthy controls. Qualifying variants were subjected to a deep learning prioritization framework to identify the most functionally relevant variants, …

Folate Regulation Of Planar Cell Polarity Pathway And F-Actin Through Folate Receptor Alpha, Xiao Han, Xuanye Cao, Robert M Cabrera, Paula Andrea Pimienta Ramirez, Ying Linda Lin, Bogdan J Wlodarczyk, Cuilian Zhang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, Folic acid (FA) and 5-methyltetrahydrofolate(5mTHF), at concentration of 5uM, 500nM, 50nM and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages and cell proliferation and F-actin was monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and …

Mitochondrial-Related Hub Genes In Dermatomyositis: Muscle And Skin Datasets-Based Identification And In Vivo Validation, Shuo Wang, Yiping Tang, Xixi Chen, Siyuan Song, Xi Chen, Qiao Zhou, Li Zeng

Faculty, Staff and Students Publications

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of dermatomyositis (DM), a rare autoimmune disease affecting the skin and muscles. However, the genetic basis underlying dysfunctional mitochondria and the development of DM remains incomplete.

Methods: The datasets of DM muscle and skin tissues were retrieved from the Gene Expression Omnibus database. The mitochondrial related genes (MRGs) were retrieved from MitoCarta. DM-related modules in muscle and skin tissues were identified with the analysis of weighted gene co-expression network (WGCNA), and then compared with the MRGs to obtain the overlapping mitochondrial related module genes (mito-MGs). Subsequently, differential expression genes (DEGs) obtained …

Tim/Tam Receptors: A Potential Biomarker For Predicting Sensitivity To Zika Virus-Induced Oncolysis In Non-Small Cell Lung Cancers, Shankari Somasekar

Honors Undergraduate Theses

Non-small cell lung cancers (NSCLC) constitute 80-85% of lung cancers and are the leading cause of cancer-related deaths globally. The most common cause is prolonged smoking. Current treatment options for NSCLC include surgery, radiation, chemotherapy, targeted drug therapy, and immunotherapy. Although these medications are effective in the short term, patients often face issues of drug resistance and debilitating side effects with prolonged use. Currently, the use of Zika virus (ZIKV) is being researched as a possible alternative treatment for cancer, which minimizes side effects and the risk of drug resistance. TIM/TAM proteins are identified as the putative ZIKV receptors on …

The Kidney In Heart Failure: The Role Of Venous Congestion, Oluwaseun Adebayo Bamodu, Chen-Chih Chung, Thomas R Pisanic, Alexander T H Wu

Faculty, Staff and Student Publications

BACKGROUND: Cancer stem cells (CSCs) have emerged as pivotal players in tumorigenesis, disease progression, and resistance to therapies.

OBJECTIVE: This comprehensive review delves into the intricate relationship between CSCs and the cell-of-origin in diverse cancer types.

DESIGN: Comprehensive review of thematically-relevant literature.

METHODS: We explore the underlying molecular mechanisms that drive the conversion of normal cells into CSCs and the impact of the cell-of-origin on CSC properties, tumor initiation, and therapeutic responses. Moreover, we discuss potential therapeutic interventions targeting CSCs based on their distinct cell-of-origin characteristics.

RESULTS: Accruing evidence suggest that the cell-of-origin, the cell type from which the tumor …

Regulatory Elements In Sem1-Dlx5-Dlx6 (7q213) Locus Contribute To Genetic Control Of Coronal Nonsyndromic Craniosynostosis And Bone Density-Related Traits, Paola Nicoletti, Samreen Zafer, Lital Matok, Inbar Irron, Meidva Patrick, Rotem Haklai, John Erol Evangelista, Giacomo B Marino, Avi Ma'ayan, Anshuman Sewda, Greg Holmes, Sierra R Britton, Won Jun Lee, Meng Wu, Ying Ru, Eric Arnaud, Lorenzo Botto, Lawrence C Brody, Jo C Byren, Michele Caggana, Suzan L Carmichael, Deirdre Cilliers, Kristin Conway, Karen Crawford, Araceli Cuellar, Federico Di Rocco, Michael Engel, Jeffrey Fearon, Marcia L Feldkamp, Richard Finnell, Sarah Fisher, Christian Freudlsperger, Gemma Garcia-Fructuoso, Rhinda Hagge, Yann Heuzé, Raymond J Harshbarger, Charlotte Hobbs, Meredith Howley, Mary M Jenkins, David Johnson, Cristina M Justice, Alex Kane, Denise Kay, Arun Kumar Gosain, Peter Langlois, Laurence Legal-Mallet, Angela E Lin, James L Mills, Jenny E V Morton, Peter Noons, Andrew Olshan, John Persing, Julie M Phipps, Richard Redett, Jennita Reefhuis, Elias Rizk, Thomas D Samson, Gary M Shaw, Robert Sicko, Nataliya Smith, David Staffenberg, Joan Stoler, Elizabeth Sweeney, Peter J Taub, Andrew T Timberlake, Jolanta Topczewska, Steven A Wall, Alexander F Wilson, Louise C Wilson, Simeon A Boyadjiev, Andrew O M Wilkie, Joan T Richtsmeier, Ethylin Wang Jabs, Paul A Romitti, David Karasik, Ramon Y Birnbaum, Inga Peter

Faculty, Staff and Students Publications

PURPOSE: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown.

METHODS: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model.

RESULTS: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine …

Loss Of The Auxiliary Α 2Δ1 Voltage-Sensitive Calcium Channel Subunit Impairs Bone Formation And Anabolic Responses To Mechanical Loading, Madison M Kelly, Karan Sharma, Christian S Wright, Xin Yi, Perla C Reyes Fernandez, Aaron T Gegg, Taylor A Gorrell, Megan L Noonan, Ahmed Baghdady, Jacob A Sieger, Annette C Dolphin, Stuart J Warden, Padmini Deosthale, Lilian I Plotkin, Uma Sankar, Julia M Hum, Alexander G Robling, Mary C Farach-Carson, William R Thompson

Faculty, Staff and Student Publications

Voltage-sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual-energy X-ray absorptiometry and microcomputed tomography imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female …

Prospective Associations Of Psychedelic Treatment For Co-Occurring Alcohol Misuse And Posttraumatic Stress Symptoms Among United States Special Operations Forces Veterans, Stacey B Armstrong, Yitong Xin, Nathan D Sepeda, Martín Polanco, Lynnette A Averill, Alan K Davis

Faculty, Staff and Students Publications

This study evaluated prospective associations of ibogaine and 5-MeO-DMT treatment for risky alcohol use and post-traumatic stress disorder (PTSD) symptoms among United States (US) Special Operations Forces Veterans (SOFV). Data were collected during standard clinical operations at pre-treatment and 1-month (1 m), 3-months (3 m), and 6-months (6 m) post-treatment in an ibogaine and 5-MeO-DMT treatment program in Mexico. Of the 86 SOFV that completed treatment, 45 met criteria for risky alcohol use at pre-treatment (mean age = 44; male = 100%; White = 91%). There was a significant reduction in alcohol use from pre-treatment (M = 7.2, SD = …

Spatial Transcriptomics Resolve An Emphysema-Specific Lymphoid Follicle B Cell Signature In Chronic Obstructive Pulmonary Disease, Joselyn Rojas-Quintero, Scott A Ochsner, Felicia New, Prajan Divakar, Chen Xi Yang, Tianshi David Wu, Jerid Robinson, Darshan Shimoga Chandrashekar, Nicholas E Banovich, Ivan O Rosas, Maor Sauler, Farrah Kheradmand, Amit Gaggar, Camilla Margaroli, Raul San Jose Estepar, Neil J Mckenna, Francesca Polverino

Faculty, Staff and Students Publications

Rationale

Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component.

Objectives

To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema.

Methods

Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. …

Traf4-Mediated Nonproteolytic Ubiquitination Of Androgen Receptor Promotes Castration-Resistant Prostate Cancer, Yosi Gilad, Ortal Shimon, Sang Jun Han, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in …

Effects And Plasma Proteomic Analysis Of Glp-1ra Versus Cpa/Ee, In Combination With Metformin, On Overweight Pcos Women: A Randomized Controlled Trial, Mingyu Liao, Xing Li, Hao Zhang, Ling Zhou, Liu Shi, Weixin Li, Rufei Shen, Guiliang Peng, Huan Zhao, Jiaqing Shao, Xiujie Wang, Zheng Sun, Hongting Zheng, Min Long

Faculty, Staff and Students Publications

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS.

METHODS: In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-μg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. …

Triobp Modulates Β-Catenin Signaling By Regulation Of Mir-29b In Idiopathic Pulmonary Fibrosis, Lan Wang, Wenyu Zhao, Cong Xia, Shuaichen Ma, Zhongzheng Li, Ningdan Wang, Linke Ding, Yaxuan Wang, Lianhui Cheng, Huibing Liu, Juntang Yang, Yajun Li, Ivan Rosas, Guoying Yu

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited …

Drivers Of Chronic Pathology Following Ischemic Stroke: A Descriptive Review, Grant W Goodman, Trang H Do, Chunfeng Tan, Rodney M Ritzel

Faculty, Staff and Student Publications

Stroke is the third leading cause of death and long-term disability in the world. Considered largely a disease of aging, its global economic and healthcare burden is expected to rise as more people survive into advanced age. With recent advances in acute stroke management, including the expansion of time windows for treatment with intravenous thrombolysis and mechanical thrombectomy, we are likely to see an increase in survival rates. It is therefore critically important to understand the complete pathophysiology of ischemic stroke, both in the acute and subacute stages and during the chronic phase in the months and years following an …

A Literature Review On Thermogenesis As A Prospective Obesity Treatment, Kellyn Sheppard

Senior Honors Theses

The disease of obesity has quickly escalated from an epidemic to a worldwide pandemic in the last few decades, and viable treatment methods are being investigated with urgency. One such treatment method is increased induction of the thermogenesis pathway that is active in brown adipose tissue. This pathway is typically activated in mammals when they are exposed to cold temperatures for extended periods of time but can also be induced exogenously. Thermogenesis is a metabolically inefficient process that occurs in the mitochondria of a cell, meaning it uses substrate energy without generating ATP. The inefficiency of this process allows excess …

Cytogenetic Profile In Monoclonal Gammopathy Of Undetermined Significance, Smoldering And Symptomatic Multiple Myeloma: A Study Of 1087 Patients With Highly Purified Plasma Cells, Guilin Tang, Yilin Wu, Pei Lin, Gokce A Toruner, Shimin Hu, Shaoying Li, Muzaffar H Qazilbash, Robert Z Orlowski, Christine Ye, Jie Xu, Karen A Nahmod, L Jeffrey Medeiros, Zhenya Tang

Faculty, Staff and Student Publications

The aim of this study was to examine the cytogenetic profiles of plasma cell neoplasms (PCNs) at various disease stages, encompassing 1087 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (NDMM), and refractory/relapsed multiple myeloma (RRMM). Fluorescence in situ hybridization (FISH) analyses were conducted on highly purified plasma cell samples, revealing that 96% of patients exhibited at least one cytogenetic abnormality. The genomic complexity escalated from MGUS to SMM and further to NDMM and RRMM, largely driven by 1q gain, del(17p), MYC-rearrangement (MYC-R), del(1p), and tetraploidy. Elevated frequencies of …

Localization, Tissue Biology, And T Cell State — Implications For Cancer Immunotherapy, Jason M Schenkel, Kristen E Pauken

Faculty, Staff and Student Publications

Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this …

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 …

Gene Transcription Regulation By Er At The Single Cell And Allele Level, Fabio Stossi, Alejandra Rivera Tostado, Hannah L Johnson, Ragini M Mistry, Maureen G Mancini, Michael A Mancini

Faculty, Staff and Students Publications

In this short review we discuss the current view of how the estrogen receptor (ER), a pivotal member of the nuclear receptor superfamily of transcription factors, regulates gene transcription at the single cell and allele level, focusing on in vitro cell line models. We discuss central topics and new trends in molecular biology including phenotypic heterogeneity, single cell sequencing, nuclear phase separated condensates, single cell imaging, and image analysis methods, with particular focus on the methodologies and results that have been reported in the last few years using microscopy-based techniques. These observations augment the results from biochemical assays that lead …

Hematological Biomarkers Of Troponin, Neutrophil-To-Lymphocyte Ratio, And Monocyte-Tolymphocyte Ratio Serve As Effective Predictive Indicators Of High-Risk Mortality In Acute, Bryan Gervais De Liyis, Angela Faustine Ciaves, Marwa Humaira Intizam, Pierre Joshua Jusuf, I Made Junior Rina Artha

BioMedicine

Background: Assessing high-risk mortality in acute coronary syndrome (ACS) patients, encompassing ST-Elevation Myocardial Infarction (STEMI), Non-ST-Elevation Myocardial Infarction (NSTEMI), and Unstable Angina Pectoris (UAP), is crucial. However, the prognostic significance of hematological parameters in predicting high-risk mortality in ACS patients remains uncertain despite advancements in ACS research. Aim: The aim was to investigate prognostic significance of hematological parameters troponin, Creatine Kinase-MB (CKMB), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Monocyte-to-Lymphocyte Ratio (MLR), Basophil-to-Lymphocyte Ratio (BLR), and Eosinophil-to-Lymphocyte Ratio (ELR) levels in predicting high-risk mortality in ACS patients. Methods: In this retrospective observational study, data from medical records of 115 patients with …

Molecular Basis Of Retinal Remodeling In A Zebrafish Model Of Retinitis Pigmentosa, Abirami Santhanam, Eyad Shihabeddin, Haichao Wei, Jiaqian Wu, John O'Brien

Faculty, Staff and Student Publications

A hallmark of inherited retinal degenerative diseases such as retinitis pigmentosa (RP) is progressive structural and functional remodeling of the remaining retinal cells as photoreceptors degenerate. Extensive remodeling of the retina stands as a barrier for the successful implementation of strategies to restore vision. To understand the molecular basis of remodeling, we performed analyses of single-cell transcriptome data from adult zebrafish retina of wild type AB strain (WT) and a P23H mutant rhodopsin transgenic model of RP with continuous degeneration and regeneration. Retinas from both female and male fish were pooled to generate each library, combining data from both sexes. …

The Role Of Noncoding Rnas In Pancreatic Birth Defects, Ziyue Zoey Yang, Ronald J Parchem

Faculty, Staff and Students Publications

Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes …

Nad+ Rescues Aging-Induced Blood-Brain Barrier Damage Via The Cx43-Parp1 Axis, Rui Zhan, Xia Meng, Dongping Tian, Jie Xu, Hongtu Cui, Jialei Yang, Yangkai Xu, Mingming Shi, Jing Xue, Weiwei Yu, Gaofei Hu, Ke Li, Xiaoxiao Ge, Qi Zhang, Mingming Zhao, Jianyong Du, Xin Guo, Wenli Xu, Yang Gao, Changyu Yao, Fan Chen, Yue Chen, Wenxin Shan, Yujie Zhu, Liang Ji, Bing Pan, Yan Yu, Wenguang Li, Xuyang Zhao, Qihua He, Xiaohui Liu, Yue Huang, Shengyou Liao, Bin Zhou, Dehua Chui, Y Eugene Chen, Zheng Sun, Erdan Dong, Yongjun Wang, Lemin Zheng

Faculty, Staff and Students Publications

Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5

Circulating Tumor Dna Monitoring On Chemo-Immunotherapy For Risk Stratification In Advanced Non-Small Cell Lung Cancer, Bruna Pellini, Russell W Madison, Merrida A Childress, Shoshana T Miller, Ole Gjoerup, Jason Cheng, Richard S P Huang, Michael Krainock, Pratyush Gupta, Wei Zou, David S Shames, Solomon Moshkevich, Marcus Ballinger, Minetta C Liu, Amanda Young, Minu K Srivastava, Geoffrey R Oxnard, Mark A Socinski

Faculty, Staff and Student Publications

PURPOSE: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO.

EXPERIMENTAL DESIGN: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor …