Digital Commons Network^™

Targeting Dendritic Cell Dysfunction To Circumvent Anti-Pd1 Resistance In Head And Neck Cancer, Shin Saito, Michihisa Kono, Hoang C B Nguyen, Ann Marie Egloff, Cameron Messier, Patrick Lizotte, Cloud Paweletz, Douglas Adkins, Ravindra Uppaluri

2020-Current year OA Pubs

PURPOSE: Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed, but further insights into the mechanisms underlying resistance and approaches to improve responses are needed.

EXPERIMENTAL DESIGN: We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-sequencing data to explore the mechanism of aPD1 resistance. Tumors and tumor-draining lymph nodes (DLN) from MOC models were analyzed for antigen-specific priming. CCL5 expression was enforced in an aPD1-resistant model.

RESULTS: An aPD1-resistant mouse model showed poor priming in the tumor DLN due …

Impact Of Sustained Calorie Restriction And Weight Cycling On Body Composition In High-Fat Diet-Fed Male And Female C57bl/6j Mice, Daniel L Smith, Yongbin Yang, Luis M Mestre, Beate Henschel, Erik Parker, Stephanie Dickinson, Amit Patki, David B Allison, Tim R Nagy

Children’s Nutrition Research Center Staff Publications

Objective: The objective of this study was to investigate body composition changes with weight cycling (WC) among adult C57BL/6J mice with diet-induced obesity.

Methods: A total of 555 single-housed mice were fed a high-fat diet ad libitum (AL) from 8 to 43 weeks of age. The 200 heaviest mice of each sex were randomized to the following four groups: ever obese (EO, continued AL feeding); obese weight loser (OWL, calorie-restricted); obese weight loser moderate (OWLM, body weight halfway between EO and OWL); and WC (diet restricted to OWL followed by AL refeeding cycles). Body weight and composition data were collected. …

Fungi In Cancer, Jessica Galloway-Peña, Iliyan D Iliev, Florencia Mcallister

Faculty, Staff and Student Publications

Both the gut and the tumour microbiome are now established as crucial regulators of cancer phenotypes and have been implicated in cancer initiation, progression and therapy response. Although the role of bacteria in these processes is beginning to be unravelled, the relevance of fungi is only just emerging. In this Viewpoint, we asked experts to discuss the current knowledge on the mycobiome–cancer connection and share their opinion on how to best solve open questions.

Programming A Ferroptosis-To-Apoptosis Transition Landscape Revealed Ferroptosis Biomarkers And Repressors For Cancer Therapy, Yaron Vinik, Avi Maimon, Vinay Dubey, Harsha Raj, Ifat Abramovitch, Sergey Malitsky, Maxim Itkin, Avi Ma'ayan, Frank Westermann, Eyal Gottlieb, Eytan Ruppin, Sima Lev

Faculty, Staff and Student Publications

Ferroptosis and apoptosis are key cell-death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron-dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis-to-apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of …

Jak2v617f Reversible Activation Shows Its Essential Requirement In Myeloproliferative Neoplasms, Andrew J Dunbar, Robert L Bowman, Young C Park, Kavi O'Connor, Franco Izzo, Robert M Myers, Abdul Karzai, Zachary Zaroogian, Won Jun Kim, Inés Fernández-Maestre, Michael R Waarts, Abbas Nazir, Wenbin Xiao, Tamara Codilupi, Max Brodsky, Mirko Farina, Louise Cai, Sheng F Cai, Benjamin Wang, Wenbin An, Julie L Yang, Shoron Mowla, Shira E Eisman, Amritha Varshini Hanasoge Somasundara, Jacob L Glass, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R Martinez Benitez, Aaron D Viny, Richard P Koche, Sara C Meyer, Dan A Landau, Ross L Levine

Faculty, Staff and Student Publications

Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic …

Co-Clinical Trial Of Novel Bispecific Anti-Her2 Antibody Zanidatamab In Patient-Derived Xenografts, Timothy P Diperi, Kurt W Evans, Bailiang Wang, Ming Zhao, Argun Akcakanat, Maria Gabriela Raso, Yasmeen Q Rizvi, Xiaofeng Zheng, Anil Korkut, Kaushik Varadarajan, Burak Uzunparmak, Ecaterina E Dumbrava, Shubham Pant, Jaffer A Ajani, Paula R Pohlmann, V Behrana Jensen, Milind Javle, Jordi Rodon, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We …

Synthetic Cationic Helical Polypeptides For The Stimulation Of Antitumour Innate Immune Pathways In Antigen-Presenting Cells, Daeyong Lee, Kristin Huntoon, Yifan Wang, Minjeong Kang, Yifei Lu, Seong Dong Jeong, Todd M Link, Thomas D Gallup, Yaqing Qie, Xuefeng Li, Shiyan Dong, Benjamin R Schrank, Adam J Grippin, Abin Antony, Jonghoon Ha, Mengyu Chang, Yi An, Liang Wang, Dadi Jiang, Jing Li, Albert C Koong, John A Tainer, Wen Jiang, Betty Y S Kim

Faculty, Staff and Student Publications

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) …

Mapping Genotypes To Chromatin Accessibility Profiles In Single Cells, Franco Izzo, Robert M Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Tamara Prieto, Elliot O Eton, Theo Botella, Andrew J Dunbar, Robert L Bowman, Jesus Sotelo, Catherine Potenski, Eleni P Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, Joann Arandela, Ramya Raviram, Daniel C Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M Ghobrial, Joseph M Scandura, Bridget Marcellino, Ross L Levine, Dan A Landau

Faculty, Staff and Student Publications

In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. …

Stat3 Protects Hematopoietic Stem Cells By Preventing Activation Of A Deleterious Autocrine Type-I Interferon Response, Bhakti Patel, Yifan Zhou, Rachel L Babcock, Feiyang Ma, M Anna Zal, Dhiraj Kumar, Yusra B Medik, Laura M Kahn, Josué E Pineda, Elizabeth M Park, Sarah M Schneider, Ximing Tang, Maria Gabriela Raso, Collene R Jeter, Tomasz Zal, Karen Clise-Dwyer, Khandan Keyomarsi, Filippo G Giancotti, Simona Colla, Stephanie S Watowich

Faculty, Staff and Student Publications

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, …

Head-To-Head Comparison Of Relevant Cell Sources Of Small Extracellular Vesicles For Cardiac Repair: Superiority Of Embryonic Stem Cells, Hernán González-King, Patricia G Rodrigues, Tamsin Albery, Benyapa Tangruksa, Ramya Gurrapu, Andreia M Silva, Gentian Musa, Dominika Kardasz, Kai Liu, Bengt Kull, Karin Åvall, Katarina Rydén-Markinhuhta, Tania Incitti, Nitin Sharma, Cecilia Graneli, Hadi Valadi, Kasparas Petkevicius, Miguel Carracedo, Sandra Tejedor, Alena Ivanova, Sepideh Heydarkhan-Hagvall, Phillipe Menasché, Jane Synnergren, Niek Dekker, Qing-Dong Wang, Karin Jennbacken

Faculty, Staff and Student Publications

Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM-MSC), human immortalized MSC (hTERT-MSC), human embryonic stem cells (ESC), ESC-derived cardiac progenitor cells (CPC), human ESC-derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC-derived sEV (ESC-sEV) …

Dynamics Of Karyotype Evolution, Elena Kuzmin, Toby M Baker, Peter Van Loo, Leon Glass

Faculty, Staff and Student Publications

In the evolution of species, the karyotype changes with a timescale of tens to hundreds of thousand years. In the development of cancer, the karyotype often is modified in cancerous cells over the lifetime of an individual. Characterizing these changes and understanding the mechanisms leading to them has been of interest in a broad range of disciplines including evolution, cytogenetics, and cancer genetics. A central issue relates to the relative roles of random vs deterministic mechanisms in shaping the changes. Although it is possible that all changes result from random events followed by selection, many results point to other non-random …

A Novel Sik2 Inhibitor Sic-19 Exhibits Synthetic Lethality With Parp Inhibitors In Ovarian Cancer, Fang Wang, Xuejiao Yu, Jun Qian, Yumin Cao, Shunli Dong, Shenghua Zhan, Zhen Lu, Robert C Bast, Qingxia Song, Youguo Chen, Yi Zhang, Jinhua Zhou

Faculty, Staff and Student Publications

Purpose: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer.

Methods: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, …

Modulation Of Host Immunity By Sensory Neurons, Telma Saraiva-Santos, Tiago H Zaninelli, Felipe A Pinho-Ribeiro

2020-Current year OA Pubs

Recent studies have uncovered a new role for sensory neurons in influencing mammalian host immunity, challenging conventional notions of the nervous and immune systems as separate entities. In this review we delve into this groundbreaking paradigm of neuroimmunology and discuss recent scientific evidence for the impact of sensory neurons on host responses against a wide range of pathogens and diseases, encompassing microbial infections and cancers. These valuable insights enhance our understanding of the interactions between the nervous and immune systems, and also pave the way for developing candidate innovative therapeutic interventions in immune-mediated diseases highlighting the importance of this interdisciplinary …

Computationally Restoring The Potency Of A Clinical Antibody Against Omicron, Thomas A Desautels, Suzanne M Scheaffer, Bradley Whitener, James B Case, Larissa B Thackray, Michael S Diamond, Et Al.

2020-Current year OA Pubs

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs

Tabernanthalog And Ibogainalog Inhibit The Α7 And Α9Α10 Nicotinic Acetylcholine Receptors Via Different Mechanisms And With Higher Potency Than The Gabaa Receptor And Cav2.2 Channel, Han-Shen Tae, Marcelo O Ortells, Arsalan Yousuf, Sophia Q Xu, Gustav Akk, David J Adams, Hugo R Arias

2020-Current year OA Pubs

In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ibogainalog (IBG) at heterologously-expressed rat (r) and human (h) nicotinic acetylcholine receptors (nAChRs), the rα1β2γ2L γ-aminobutyric acid type A receptor (GABA

Sialic Acid-Siglec-E Interactions Regulate The Response Of Neonatal Macrophages To Group B Streptococcus, Sean J Lund, Pamela G B Del Rosario, Asami Honda, Kaitlin J Caoili, Marten A Hoeksema, Victor Nizet, Kathryn A Patras, Lawrence S Prince

Faculty, Staff and Students Publications

The mammalian Siglec receptor sialoadhesin (Siglec1, CD169) confers innate immunity against the encapsulated pathogen group B Streptococcus (GBS). Newborn lung macrophages have lower expression levels of sialoadhesin at birth compared with the postnatal period, increasing their susceptibility to GBS infection. In this study, we investigate the mechanisms regulating sialoadhesin expression in the newborn mouse lung. In both neonatal and adult mice, GBS lung infection reduced Siglec1 expression, potentially delaying acquisition of immunity in neonates. Suppression of Siglec1 expression required interactions between sialic acid on the GBS capsule and the inhibitory host receptor Siglec-E. The Siglec1 gene contains multiple STAT binding …

Cardiac Conduction Diseases: Understanding The Molecular Mechanisms To Uncover Targets For Future Treatments, Tingting Li, Qussay Marashly, Jitae A Kim, Na Li, Mihail G Chelu

Faculty, Staff and Students Publications

Introduction: The cardiac conduction system (CCS) is crucial for maintaining adequate cardiac frequency at rest and modulation during exercise. Furthermore, the atrioventricular node and His-Purkinje system are essential for maintaining atrioventricular and interventricular synchrony and consequently maintaining an adequate cardiac output.

Areas covered: In this review article, we examine the anatomy, physiology, and pathophysiology of the CCS. We then discuss in detail the most common genetic mutations and the molecular mechanisms of cardiac conduction disease (CCD) and provide our perspectives on future research and therapeutic opportunities in this field.

Expert opinion: Significant advancement has been made in understanding the molecular …

Piezo1 Regulates Meningeal Lymphatic Vessel Drainage And Alleviates Excessive Csf Accumulation, Dongwon Choi, Eunkyung Park, Joshua Choi, Renhao Lu, Jin Suh Yu, Chiyoon Kim, Luping Zhao, James Yu, Brandon Nakashima, Sunju Lee, Dhruv Singhal, Joshua P Scallan, Bin Zhou, Chester J Koh, Esak Lee, Young-Kwon Hong

Faculty, Staff and Students Publications

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of …

Selective Cdk7 Inhibition Suppresses Cell Cycle Progression And Myc Signaling While Enhancing Apoptosis In Therapy-Resistant Estrogen Receptor-Positive Breast Cancer, Cristina Guarducci, Agostina Nardone, Douglas Russo, Zsuzsanna Nagy, Capucine Heraud, Albert Grinshpun, Qi Zhang, Allegra Freelander, Mathew Joseph Leventhal, Avery Feit, Gabriella Cohen Feit, Ariel Feiglin, Weihan Liu, Francisco Hermida-Prado, Nikolas Kesten, Wen Ma, Carmine De Angelis, Antonio Morlando, Madison O'Donnell, Sergey Naumenko, Shixia Huang, Quang-Dé Nguyen, Ying Huang, Luca Malorni, Johann S Bergholz, Jean J Zhao, Ernest Fraenkel, Elgene Lim, Rachel Schiff, Geoffrey I Shapiro, Rinath Jeselsohn

Faculty, Staff and Students Publications

Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.

Experimental design: We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide …

Engineering Small-Molecule And Protein Drugs For Targeting Bone Tumors, Yixian Wang, Chenhang Wang, Meng Xia, Zeru Tian, Joseph Zhou, Julian Meyer Berger, Xiang H-F Zhang, Han Xiao

Faculty, Staff and Students Publications

Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and death. Currently, treatments such as chemotherapy, hormone therapy, and radiation therapy are used to treat bone cancer, but they often only shrink or slow tumor growth and do not eliminate cancer completely. The bone microenvironment contributes unique signals that influence cancer growth, immunogenicity, and metastasis. Traditional cancer therapies have limited effectiveness due to off-target effects and poor distribution on bones. As a result, therapies with improved specificity and efficacy for treating bone tumors are highly needed. …

Mechanisms Driving Fasting-Induced Protection From Genotoxic Injury In The Small Intestine, Kali Deans-Fielder, Timothy Wu, Thanh Nguyen, Sarah To, Yang-Zhe Huang, Steven J Bark, Jason C Mills, Noah F Shroyer

Faculty, Staff and Students Publications

Genotoxic agents such as doxorubicin (DXR) can cause damage to the intestines that can be ameliorated by fasting. How fasting is protective and the optimal timing of fasting and refeeding remain unclear. Here, our analysis of fasting/refeeding-induced global intestinal transcriptional changes revealed metabolic shifts and implicated the cellular energetic hub mechanistic target of rapamycin complex 1 (mTORC1) in protecting from DXR-induced DNA damage. Our analysis of specific transcripts and proteins in intestinal tissue and tissue extracts showed that fasting followed by refeeding at the time of DXR administration reduced damage and caused a spike in mTORC1 activity. However, continued fasting …

Use Of Topical Methylene Blue To Image Nuclear Morphometry With A Low-Cost Scanning Darkfield Microendoscope, Huayu Hou, Jennifer Carns, Richard A Schwarz, Ann M Gillenwater, Sharmila Anandasabapathy, Rebecca R Richards-Kortum

Faculty, Staff and Students Publications

SIGNIFICANCE: Fiber-optic microendoscopy is a promising approach to noninvasively visualize epithelial nuclear morphometry for early cancer and precancer detection. However, the broader clinical application of this approach is limited by a lack of topical contrast agents available for

AIM: The aim of this study was to evaluate the ability to image nuclear morphometry in vivo with a novel fiber-optic microendoscope used together with topical application of methylene blue (MB), a dye with FDA approval for use in chromoendoscopy in the gastrointestinal tract.

APPROACH: The low-cost, high-resolution microendoscope implements scanning darkfield imaging without complex optomechanical components by leveraging programmable illumination and …

Altered Myocardial Lipid Regulation In Junctophilin-2-Associated Familial Cardiomyopathies, Satadru K Lahiri, Feng Jin, Yue Zhou, Ann P Quick, Carlos F Kramm, Meng C Wang, Xander Ht Wehrens

Faculty, Staff and Students Publications

Myocardial lipid metabolism is critical to normal heart function, whereas altered lipid regulation has been linked to cardiac diseases including cardiomyopathies. Genetic variants in the JPH2 gene can cause hypertrophic cardiomyopathy (HCM) and, in some cases, dilated cardiomyopathy (DCM). In this study, we tested the hypothesis that JPH2 variants identified in patients with HCM and DCM, respectively, cause distinct alterations in myocardial lipid profiles. Echocardiography revealed clinically significant cardiac dysfunction in both knock-in mouse models of cardiomyopathy. Unbiased myocardial lipidomic analysis demonstrated significantly reduced levels of total unsaturated fatty acids, ceramides, and various phospholipids in both mice with HCM and …

Caenorhabditis Elegans Endorse Bacterial Nanocellulose Fibers As Functional Dietary Fiber Reducing Lipid Markers, Amanda Muñoz-Juan, Adrien Assié, Anna Esteve-Codina, Marta Gut, Núria Benseny-Cases, Buck S Samuel, Esther Dalfó, Anna Laromaine

Faculty, Staff and Students Publications

Bacterial nanocellulose (BNC) is a promising dietary fiber with potential as a functional food additive. We evaluated BNC fibers (BNCf) in the Caenorhabditis elegans model to obtain insight into the BNCf's biointeraction with its gastrointestinal tract while reducing the variables of higher complex animals. BNCf were uptaken and excreted by worms without crossing the intestinal barrier, confirming its biosafety regarding survival rate, reproduction, and aging for concentrations up to 34 μg/ml BNCf. However, a slight decrease in the worms' length was detected. A possible nutrient shortage or stress produced by BNCf was discarded by measuring stress and chemotactic response pathways. …

Bmp4 And Grem1 Are Targets Of Shh Signaling And Downstream Regulators Of Collagen In The Penis, Jiangping Deng, Timothy Searl, Samuel Ohlander, Danuta Dynda, Daniel A Harrington, Kevin T Mcvary, Carol A Podlasek

Faculty, Staff and Student Publications

Background: Cavernous nerve (CN) injury, caused by prostatectomy and diabetes, initiates a remodeling process (smooth muscle apoptosis and increased collagen) in the corpora cavernosa of the penis of patients and animal models that is an underlying cause of erectile dysfunction (ED), and the Sonic hedgehog (SHH) pathway plays an essential role in the response of the penis to denervation, as collagen increases with SHH inhibition and decreases with SHH treatment.

Aim: We examined if part of the mechanism of how SHH prevents penile remodeling and increased collagen with CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1) and …

Decorin Suppresses Tumor Lymphangiogenesis: A Mechanism To Curtail Cancer Progression, Dipon K. Mondal, Christopher Xie, Gabriel J. Pascal, Simone Buraschi, Renato V. Iozzo

Kimmel Cancer Center Faculty Papers

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, …

Quorum-Sensing Agr System Of Staphylococcus Aureus Primes Gene Expression For Protection From Lethal Oxidative Stress, Magdalena Podkowik, Andrew I Perault, Gregory Putzel, Andrew Pountain, Jisun Kim, Ashley L Dumont, Erin E Zwack, Robert J Ulrich, Theodora K Karagounis, Chunyi Zhou, Andreas F Haag, Julia Shenderovich, Gregory A Wasserman, Junbeom Kwon, John Chen, Anthony R Richardson, Jeffrey N Weiser, Carla R Nowosad, Desmond S Lun, Dane Parker, Alejandro Pironti, Xilin Zhao, Karl Drlica, Itai Yanai, Victor J Torres, Bo Shopsin

Faculty, Staff and Student Publications

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic …

Pml::Rara And Gata2 Proteins Interact Via Dna Templates To Induce Aberrant Self-Renewal In Mouse And Human Hematopoietic Cells, Casey D S Katerndahl, Olivia R S Rogers, Ryan B Day, Ziheng Xu, Nichole M Helton, Sai Mukund Ramakrishnan, Christopher A Miller, Timothy J Ley

2020-Current year OA Pubs

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies …

Shh Regulates Penile Morphology And Smooth Muscle Through A Mechanism Involving Bmp4 And Grem1, Jiangping Deng, Sarah Martin, Timothy Searl, Samuel Ohlander, Daniel A Harrington, Kevin T Mcvary, Carol A Podlasek

Faculty, Staff and Student Publications

Background: The cavernous nerve (CN) is frequently damaged in prostatectomy and diabetic patients with erectile dysfunction (ED), initiating changes in penile morphology including an acute and intense phase of apoptosis in penile smooth muscle and increased collagen, which alter penile architecture and make corpora cavernosa smooth muscle less able to relax in response to neurotransmitters, resulting in ED.

Aim: Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and SHH treatment suppresses penile remodeling after CN injury through an unknown mechanism; we examine if part of the mechanism of how SHH preserves smooth muscle after CN injury involves …

Quorum-Sensing Agr System Of Staphylococcus Aureus Primes Gene Expression For Protection From Lethal Oxidative Stress, Magdalena Podkowik, Andrew I Perault, Gregory Putzel, Andrew Pountain, Jisun Kim, Ashley L Dumont, Erin E Zwack, Robert J Ulrich, Theodora K Karagounis, Chunyi Zhou, Andreas F Haag, Julia Shenderovich, Gregory A Wasserman, Junbeom Kwon, John Chen, Anthony R Richardson, Jeffrey N Weiser, Carla R Nowosad, Desmond S Lun, Dane Parker, Alejandro Pironti, Xilin Zhao, Karl Drlica, Itai Yanai, Victor J Torres, Bo Shopsin

Faculty, Staff and Student Publications

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic …