Medical Cell Biology Commons^™

Six-Month Report Assessing The Feasibility And Effectiveness Of Amniotic Membrane Injections In Patients With Short, Anterior, Urethral Strictures, Nicholas Pryde, Jack Vernocke, Aron Liaw, Michael Sessine, Nivedita Dhar

Medical Student Research Symposium

Introduction: Urethral stricture treatment has high recurrence rates and adjunct injectable agents have been explored. Amniotic membranes (AM) promote apoptosis of pro-inflammatory cells, prevent differentiation of pro-fibrotic cells, and decrease scar formation. These tissues generated interest in reconstructive urethral surgery. Thus, we performed urethral dilation combined with micronized AM injection in urethral scar tissue for treatment of urethral stricture.

Materials and Methods: Adult males with strictures ≤12Fr in diameter and ≤2 cm in length, International Prostate Symptom Score (IPSS) ≥11 and maximum flowrate <15 ml/s. Reconstituted 100mg micronized AM was injected at the time of urethral dilation. Primary study end point was anatomical success (≥14Fr by cystoscopy) at 6 months. Secondary end points were questionnaires, flow rate, and post void residual. Outcomes assessed at baseline, 5 days, 14 days, 3 months, and 6 months post-injection. Safety was analyzed.

Results: Ten men, mean age of 52 ± 15 years, were included. There were 7 patients with …

Wnt5b As A Therapeutic Target For Osteosarcoma Stemness, Metastasis, And Chemoresistance, Rachel S. Perkins

Alternative Theses and Dissertations (AETDs)

Osteosarcoma is a pediatric bone cancer that has no targeted therapy and has had no treatment advances for the last three decades. Osteosarcoma frequently metastasizes to the lungs and is highly chemotherapy resistant, reducing patient survival with metastatic disease to 20% after 5 years. New therapies targeted to metastasis and drug resistance in osteosarcoma are essential to improving patient outcomes.

Osteosarcoma is a pediatric bone cancer that has no targeted therapy and has had no treatment advances for the last three decades. Osteosarcoma frequently metastasizes to the lungs and is highly chemotherapy resistant, reducing patient survival with metastatic disease to …

Factors Associated With Late Diagnosis Of Cervical Cancer At Two National Referral Hospitals, Kenya 2017: A Case Control Study., Valerian Mwenda, Martin Mwangi, Gladwell Gathecha, Joseph Kibachio, Robert Too, Zeinab Gura, Marleen Temmerman

Obstetrics and Gynaecology, East Africa

Background: Cervical cancer is the leading cause of cancer mortality among women in Kenya. Two thirds of cervical cancer cases in Kenya are diagnosed in advanced stages. We aimed to identify factors associated with late diagnosis of cervical cancer, to guide policy interventions.

Methods: An unmatched case control study (ratio 1:2) was conducted among women aged ≥ 18 years with cervical cancer at Kenyatta National and Moi Teaching and Referral Hospitals. We defined a case as patients with International Federation of Gynecology and Obstetrics (FIGO) stage ≥ 2A and controls as those with stage ≤ 1B. A structured questionnaire was …

Autophagy Differentially Regulates Tissue Tolerance Of Distinct Target Organs In Graft-Versus-Host Disease Models, Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy

Faculty, Staff and Students Publications

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, …

Nadph Oxidase Overexpression And Mitochondrial Oxphos Impairment Are More Profound In Human Hearts Donated After Circulatory Death Than Brain Death, Nandan K Mondal, Shiyi Li, Abdussalam E Elsenousi, Aladdein Mattar, Katherine V Nordick, Harveen K Lamba, Camila Hochman-Mendez, Todd K Rosengart, Kenneth K Liao

Faculty, Staff and Students Publications

This study investigated cardiac stress and mitochondrial oxidative phosphorylation (OxPhos) in human donation after circulatory death (DCD) hearts regarding warm ischemic time (WIT) and subsequent cold storage and compared them with that of human brain death donor (DBD) hearts. A total of 24 human hearts were procured for the research study-6 in the DBD group and 18 in the DCD group. DCD group was divided into three groups (n = 6) based on different WITs (20, 40, and 60 min). All hearts received del Nido cardioplegia before being placed in normal saline cold storage for 6 h. Left ventricular …

Highlights Of How Single-Cell Analyses Are Illuminating Differentiation And Disease In The Gastric Corpus, Mahliyah Adkins-Threats, Yang-Zhe Huang, Jason C Mills

Faculty, Staff and Students Publications

Single-cell RNA-sequencing (scRNA-seq) has emerged as a powerful technique to identify novel cell markers, developmental trajectories, and transcriptional changes during cell differentiation and disease onset and progression. In this review, we highlight recent scRNA-seq studies of the gastric corpus in both human and murine systems that have provided insight into gastric organogenesis, identified novel markers for the various gastric lineages during development and in adults, and revealed transcriptional changes during regeneration and tumorigenesis. Overall, by elucidating transcriptional states and fluctuations at the cellular level in healthy and disease contexts, scRNA-seq may lead to better, more personalized clinical treatments for disease …

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 .

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Inter-Individual Variations In Circadian Misalignment-Induced Nafld Pathophysiology In Mice, Nobuya Koike, Yasuhiro Umemura, Hitoshi Inokawa, Isao Tokuda, Yoshiki Tsuchiya, Yuh Sasawaki, Atsushi Umemura, Naoko Masuzawa, Kazuya Yabumoto, Takashi Seya, Akira Sugimoto, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita

Faculty, Staff and Student Publications

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of …

A Mutation In F-Actin Polymerization Factor Suppresses The Distal Arthrogryposis Type 5 Piezo2 Pathogenic Variant In Caenorhabditis Elegans, Xiaofei Bai, Harold E Smith, Luis O Romero, Briar Bell, Valeria Vásquez, Andy Golden

Faculty, Staff and Student Publications

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a …

Assessing Adequacy: A Meta-Analysis Of Rapid Onsite Evaluation Of Thyroid Nodules, Peter P. Issa, Christina Mccarthy, Mohammad Hussein, Aaron L. Albuck, Essam Emad, Mohamed Shama, Krzysztof Moroz, Eman Toraih, Emad Kandil

School of Medicine Faculty Publications

Introduction: Fine-needle aspiration (FNA) is the standard form of preoperative evaluation of thyroid nodule cytological status. A significant number FNAs are classified as inadequate for interpretation, requiring a repeat FNA which is potentially avoidable, costly, and delays treatment. To address these concerns and maximize first-time FNA adequacy, rapid onsite evaluation (ROSE) of FNA specimens was introduced. Our study aims to determine the impact of ROSE on FNA adequacy. Methods: PubMed, Embase, and Web of Science were searched for primary articles assessing the adequacy of ROSE in thyroid nodules. Results: A total of 17 studies were included for a total of …

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 …

Ikaros Expression Drives The Aberrant Metabolic Phenotype Of Macrophages In Chronic Hiv Infection, Cecilia Vittori, Celeste Faia, Dorota Wyczechowska, Amber Trauth, Karlie Plaisance-Bonstaff, Mary Meyaski-Schluter, Krzysztof Reiss, Francesca Peruzzi

School of Medicine Faculty Publications

The increased risk for acquiring secondary illnesses in people living with HIV (PLWH) has been associated with immune dysfunction. We have previously found that circulating monocytes from PLWH display a trained phenotype. Here, we evaluated the metabolic profile of these cells and found increased mitochondrial respiration and glycolysis of monocyte-derived macrophages (MDMs) from PLWH. We additionally found that cART shifted the energy metabolism of MDMs from controls toward increased utilization of mitochondrial respiration. Importantly, both downregulation of IKAROS expression and inhibition of the mTOR pathway reversed the metabolic profile of MDMs from PLWH and cART-treated control-MDMs. Altogether, this study reveals …

Sex-Specific Negative Affect-Like Behaviour And Parabrachial Nucleus Activation Induced By Bnst Stimulation In Adult Mice With Adolescent Alcohol History, Lucas Albrechet-Souza, Chelsea R. Kasten, Natalia B. Bertagna, Tiffany A. Wills

School of Medicine Faculty Publications

Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for the onset of affective disorders, which can contribute to problematic drinking behaviours and relapse, particularly in females. Previous studies from our laboratory have shown that exposure to adolescent intermittent ethanol (AIE) vapour alters glutamatergic transmission in the bed nucleus of the stria terminalis (BNST) and, when combined with adult stress, elicits sex-specific changes in glutamatergic plasticity and negative affect-like behaviours in mice. Building on these findings, the current work investigated whether BNST stimulation could substitute …

Non-Canonical Hedgehog Signaling Mediates Profibrotic Hematopoiesis-Stroma Crosstalk In Myeloproliferative Neoplasms, Jessica E Pritchard, Juliette E Pearce, Inge A M Snoeren, Stijn N R Fuchs, Katrin Götz, Fabian Peisker, Silke Wagner, Adam Benabid, Niklas Lutterbach, Vanessa Klöker, James S Nagai, Monica T Hannani, Anna K Galyga, Ellen Sistemich, Bella Banjanin, Niclas Flosdorf, Eric Bindels, Kathrin Olschok, Katharina Biaesch, Nicolas Chatain, Neha Bhagwat, Andrew Dunbar, Rita Sarkis, Olaia Naveiras, Marie-Luise Berres, Steffen Koschmieder, Ross L Levine, Ivan G Costa, Hélène F E Gleitz, Rafael Kramann, Rebekka K Schneider

Faculty, Staff and Student Publications

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a …

Extracellular Carriers Control Lipid-Dependent Secretion, Delivery, And Activity Of Wnt Morphogens, Taciani De Almeida Magalhaes, Jingjing Liu, Charlene Chan, Kleiton Silva Borges, Jiuchun Zhang, Andrew J Kane, Bradley M Wierbowski, Yunhui Ge, Zhiwen Liu, Prabhath Mannam, Daniel Zeve, Ron Weiss, David T Breault, Pengxiang Huang, Adrian Salic

Faculty, Staff and Students Publications

WNT morphogens trigger signaling pathways fundamental for embryogenesis, regeneration, and cancer. WNTs are modified with palmitoleate, which is critical for binding Frizzled (FZD) receptors and activating signaling. However, it is unknown how WNTs are released and spread from cells, given their strong lipid-dependent membrane attachment. We demonstrate that secreted FZD-related proteins and WNT inhibitory factor 1 are WNT carriers, potently releasing lipidated WNTs and forming active soluble complexes. WNT release occurs by direct handoff from the membrane protein WNTLESS to the carriers. In turn, carriers donate WNTs to glypicans and FZDs involved in WNT reception and to the NOTUM hydrolase, …

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 …