Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Targeting The Pro-Survival Protein Bcl-2 To Prevent Breast Cancer, Adelaide Young, Wen Bu, Weiyu Jiang, Amy Ku, Jyoti Kapali, Sagar Dhamne, Lan Qin, Susan G Hilsenbeck, Yi-Chieh Nancy Du, Yi Li

Faculty, Staff and Students Publications

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone …

Identification Of Serum Mirna Signature And Establishment Of A Nomogram For Risk Stratification In Patients With Pancreatic Ductal Adenocarcinoma, Raju Kandimalla, Tadanobu Shimura, Saurav Mallik, Fuminori Sonohara, Susan Tsai, Douglas B Evans, Song Cheol Kim, Hideo Baba, Yasuhiro Kodera, Daniel Von Hoff, Xi Chen, Ajay Goel

Faculty, Staff and Students Publications

OBJECTIVE: The aim of the study was to perform mRNA-miRNA regulatory network analyses to identify a miRNA panel for molecular subtype identification and stratification of high-risk patients with pancreatic ductal adenocarcinoma (PDAC).

BACKGROUND: Recent transcriptional profiling effort in PDAC has led to the identification of molecular subtypes that associate with poor survival; however, their clinical significance for risk stratification in patients with PDAC has been challenging.

METHODS: By performing a systematic analysis in The Cancer Genome Atlas and International Cancer Genome Consortium cohorts, we discovered a panel of miRNAs that associated with squamous and other poor molecular subtypes in PDAC. …

Nuclear Progesterone Receptor Expressed By The Cortical Thymic Epithelial Cells Dictates Thymus Involution In Murine Pregnancy, Soo Hyun Ahn, Sean L Nguyen, Tae Hoon Kim, Jae-Wook Jeong, Ripla Arora, John P Lydon, Margaret G Petroff

Faculty, Staff and Students Publications

Progesterone is a gonadal pro-gestational hormone that is absolutely necessary for the success of pregnancy. Most notable actions of progesterone are observed in the female reproductive organs, the uterus and the ovary. Acting through the nuclear progesterone receptor (PGR), progesterone prepares the endometrium for implantation of the embryo. Interestingly, the maternal thymus also is a known expressor of Pgr; its absence is associated with murine pregnancy complications. However, the localization of its expression and its functional importance were not known. Here, we used a transgenic dual fluorescent reporter mouse model and genetic deletion of Pgr in Foxn1+ thymic epithelial …

Case Report: Molecular Diagnosis Of Cystoisospora Belli In A Severely Immunocompromised Patient With Hiv And Kaposi Sarcoma, Roumen Borilov Iordanov, Lauren M Leining, Meng Wu, Galant Chan, Andrew R Dinardo, Rojelio Mejia

Faculty, Staff and Students Publications

Diarrhea in an immunocompromised patient has a broad infectious differential. Diagnosis is difficult despite advances in diagnostic modalities. We report a case of a 45-year-old Nigerian woman who immigrated to the United States 2 years ago. She presented to the hospital with gastrointestinal bleeding, newly diagnosed HIV, and disseminated Kaposi sarcoma. During hospitalization, the patient had an onset of watery diarrhea and high eosinophilia. Subsequent stool analysis using multi-parallel real-time quantitative polymerase chain reaction for 13 parasites was positive for Cystoisospora belli. The patient was treated with trimethoprim-sulfamethoxazole, but had relapsed disease when her antibiotics were stopped prematurely. After restarting …

Invariant Natural Killer T-Cell Subsets Have Diverse Graft-Versus-Host-Disease-Preventing And Antitumor Effects, Kristina Maas-Bauer, Juliane K Lohmeyer, Toshihito Hirai, Teresa Lopes Ramos, Furqan M Fazal, Ulrike M Litzenburger, Kathryn E Yost, Jessica V Ribado, Neeraja Kambham, Arielle S Wenokur, Po-Yu Lin, Maite Alvarez, Melissa Mavers, Jeanette Baker, Ami S Bhatt, Howard Y Chang, Federico Simonetta, Robert S Negrin

Faculty, Staff and Students Publications

Invariant natural killer T (iNKT) cells are a T-cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic graft-versus-host-disease (GVHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2, and iNKT17 sublineages, which differ transcriptomically and epigenomically and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GVHD is currently unknown. In this work, we generated highly purified murine iNKT sublineages, characterized their transcriptomic and epigenomic landscape, …

Exogenous Inter-Α Inhibitor Proteins Prevent Cell Death And Improve Ischemic Stroke Outcomes In Mice, Louise D Mccullough, Meaghan Roy-O'Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C Kraushaar, Anjali Chauhan, Lauren H Sansing, Barbara S Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna

Faculty, Staff and Students Publications

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when …

Soluble Angiotensin-Converting Enzyme 2, Cardiac Biomarkers, Structure, And Function, And Cardiovascular Events (From The Atherosclerosis Risk In Communities Study), Aliza Hussain, Olive Tang, Caroline Sun, Xiaoming Jia, Elizabeth Selvin, Vijay Nambi, Aaron Folsom, Gerardo Heiss, Faiez Zannad, Thomas Mosley, Salim S Virani, Josef Coresh, Eric Boerwinkle, Bing Yu, Jonathan W Cunningham, Amil M Shah, Scott D Solomon, James A De Lemos, Ron C Hoogeveen, Christie M Ballantyne

Faculty, Staff and Students Publications

Membrane-bound angiotensin-converting enzyme 2 is important in regulation of the renin-angiotensin-aldosterone system, but the association of cleaved soluble ACE2 (sACE2) with cardiovascular disease (CVD) is unclear. We evaluated the association of sACE2 with cardiac biomarkers, structure, and function and cardiovascular events in the Atherosclerosis Risk in Communities Study. sACE2 was measured in a subset of 497 participants (mean age 78±5.4 years, 53% men, 27% black); Cox regression analyses assessed prospective associations of sACE2 with time to first CVD event at median 6.1-year follow-up. sACE2 was higher in men, blacks, and participants with prevalent CVD, diabetes, or hypertension. Higher sACE2 levels …

Functional Interpretation Of Atad3a Variants In Neuro-Mitochondrial Phenotypes, Zheng Yie Yap, Yo Han Park, Saskia B Wortmann, Adam C Gunning, Shlomit Ezer, Sukyeong Lee, Lita Duraine, Ekkehard Wilichowski, Kate Wilson, Johannes A Mayr, Matias Wagner, Hong Li, Usha Kini, Emily Davis Black, Kristin G Monaghan, James R Lupski, Sian Ellard, Dominik S Westphal, Tamar Harel, Wan Hee Yoon

Faculty, Staff and Students Publications

BACKGROUND: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.

METHODS: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 …

Rapid Induction Of The Unfolded Protein Response And Apoptosis By Estrogen Mimic Ttc-352 For The Treatment Of Endocrine-Resistant Breast Cancer, Balkees Abderrahman, Philipp Y Maximov, Ramona F Curpan, Sean W Fanning, Jay S Hanspal, Ping Fan, Charles E Foulds, Yue Chen, Anna Malovannaya, Antrix Jain, Rui Xiong, Geoffrey L Greene, Debra A Tonetti, Gregory R J Thatcher, V Craig Jordan

Faculty, Staff and Students Publications

Patients with long-term estrogen-deprived breast cancer (BC), after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen’s anti-tumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecological and non-gynecological adverse events thus the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEMs) BMI-135 and TTC-352, and the naturally-occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared to 17β-estradiol (E2), for the treatment of endocrine-resistant BC. TTC-352 and E4 are being evaluated in BC clinical trials. …

Age Of Acquisition Impacts The Brain Differently Depending On Neuroanatomical Metric, Hannah Claussenius-Kalman, Kelly A Vaughn, Pilar Archila-Suerte, Arturo E Hernandez

Faculty, Staff and Student Publications

Although researchers generally agree that a certain set of brain areas underlie bilingual language processing, there is discrepancy regarding what effect timing of language acquisition has on these regions. We aimed to investigate the neuroanatomical correlates of age of acquisition (AoA), which has been examined previously, but with inconsistent results, likely influenced by methodological differences across studies. We analyzed gray matter density, volume, and thickness using whole-brain linear models in 334 bilinguals and monolinguals. Neuroanatomical correlates of AoA differed depending on gray matter metric. Relative to early bilinguals, late bilinguals had thicker cortex in language processing and cognitive control regions, …

The Zinc Transporter Zipt-7.1 Regulates Sperm Activation In Nematodes, Yanmei Zhao, Chieh-Hsiang Tan, Amber Krauchunas, Andrea Scharf, Nicholas Dietrich, Kurt Warnhoff, Zhiheng Yuan, Marina Druzhinina, Sam Guoping Gu, Long Miao, Andrew Singson, Ronald E Ellis, Kerry Kornfeld

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a leading model for studies of sperm activation, the mechanisms by which signaling pathways induce this transformation remain poorly characterized. Here we show that a conserved transmembrane zinc transporter, ZIPT-7.1, regulates the induction of sperm activation in Caenorhabditis nematodes. The zipt-7.1 mutant hermaphrodites cannot self-fertilize, and males reproduce poorly, because mutant spermatids are defective in responding to activating …

Mdm2 Is Required For Survival And Growth Of P53-Deficient Cancer Cells., Kyle P Feeley, Clare M. Adams, Ramkrishna Mitra, Christine M. Eischen

Department of Cancer Biology Faculty Papers

p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of Mdm2 in T-cell lymphomas or sarcomas lacking p53 induced apoptosis and G₂ cell-cycle arrest, prolonging survival of mice with these tumors. p53^-/- fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to pre-malignant cells. Mdm2 deletion in p53^-/- cells upregulated p53 transcriptional target genes that induce apoptosis and cell-cycle arrest. Mdm2 deletion also increased levels of …

Mitochondrial Akt Regulation Of Hypoxic Tumor Reprogramming., Young Chan Chae, Valentina Vaira, M. Cecilia Caino, Hsin-Yao Tang, Jae Ho Seo, Andrew V. Kossenkov, Luisa Ottobrini, Cristina Martelli, Giovanni Lucignani, Irene Bertolini, Marco Locatelli, Kelly G. Bryant, Jagadish C. Ghosh, Sofia Lisanti, Bonsu Ku, Silvano Bosari, Lucia R. Languino, David W. Speicher, Dario C. Altieri

Department of Cancer Biology Faculty Papers

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer.