Digital Commons Network^™

Oncolytic Virotherapies And Adjuvant Gut Microbiome Therapeutics To Enhance Efficacy Against Malignant Gliomas, Natalie M Meléndez-Vázquez, Candelaria Gomez-Manzano, Filipa Godoy-Vitorino

Faculty, Staff and Student Publications

Glioblastoma (GBM) is the most prevalent malignant brain tumor. Current standard-of-care treatments offer limited benefits for patient survival. Virotherapy is emerging as a novel strategy to use oncolytic viruses (OVs) for the treatment of GBM. These engineered and non-engineered viruses infect and lyse cancer cells, causing tumor destruction without harming healthy cells. Recent advances in genetic modifications to OVs have helped improve their targeting capabilities and introduce therapeutic genes, broadening the therapeutic window and minimizing potential side effects. The efficacy of oncolytic virotherapy can be enhanced by combining it with other treatments such as immunotherapy, chemotherapy, or radiation. Recent studies …

Evidence That Crispr-Cas9 Y537s-Mutant Expressing Breast Cancer Cells Activate Yes-Associated Protein 1 To Driving The Conversion Of Normal Fibroblasts Into Cancer-Associated Fibroblasts, Luca Gelsomino, Amanda Caruso, Emine Tasan, Adele Elisabetta Leonetti, Rocco Malivindi, Giuseppina Daniela Naimo, Francesca Giordano, Salvatore Panza, Guowei Gu, Benedetta Perrone, Cinzia Giordano, Loredana Mauro, Bruno Nardo, Gianfranco Filippelli, Daniela Bonofiglio, Ines Barone, Suzanne A W Fuqua, Stefania Catalano, Sebastiano Andò

Faculty, Staff and Students Publications

BACKGROUND: Endocrine therapy (ET) has improved the clinical outcomes of Estrogen receptor alpha-positive (ERɑ +) breast cancer (BC) patients, even though resistance to ET remains a clinical issue. Mutations in the hormone-binding domain of ERɑ represent an acquired intrinsic mechanism of ET resistance. However, the latter also depends on the multiple functional interactions between BC cells and the tumor microenvironment (TME). Here, we investigated how the most common Y537S-ERɑ mutation may influence the behavior of fibroblasts, the most prominent component of the TME.

METHODS: We conducted coculture experiments with normal human foreskin fibroblasts BJ1-hTERT (NFs), cancer-associated fibroblasts (CAFs), isolated from …

Bilateral Popliteal Entrapment Syndrome: A Rare And Challenging Case Report, Jose Burgos, Gabriela Llerena, Spencer Rheingold, Jorge De La Portilla

HCA-NSU MD Research Day

Bilateral Popliteal Entrapment Syndrome: A Rare and Challenging Case Report Burgos, Jose Julian, MD, MDIV, HCA Florida Kendall Department of Vascular Surgery Miami, Florida. Llerena, Gabriela2, OMSIV, Nova Southeastern University Dr. Kiran Patel College of Osteopathic Medicine. Rheingold, Spencer, MSIV, Nova Southeastern University Dr. Kiran Patel College of Allopathic Medicine. De La Portilla, Jorge MD, assistant professor, HCA Florida Kendall Department of Vascular Surgery Miami, Florida1 Objective: This case describes an atypical presentation of PES in an older male patient who presented with a sudden onset of symptoms without a history of claudication. Background: Popliteal entrapment syndrome (PES) is a …

Effects Of Sex And Estrous Cycle On Extended-Access Oxycodone Self-Administration And Cue-Induced Drug Seeking Behavior, Bhumiben P Patel, Jessica A Loweth

Rowan-Virtua School of Osteopathic Medicine Departmental Research

INTRODUCTION: Increasing evidence indicates that sex is a factor that impacts the abuse liability and relapse vulnerability of prescription opioids like oxycodone. However, while women are more likely than men to be prescribed and to use these drugs, the impact of sex and ovarian hormones on prescription opioid use and relapse vulnerability remains unclear. Accurately assessing these measures is complicated by the fact that chronic opioid exposure can lower ovarian hormone levels and cause cycle irregularities.

METHODS: Adult male and female Sprague-Dawley rats self-administered oxycodone (0.1 mg/kg/infusion) under extended-access conditions (6 h/day, 10 days) followed by forced abstinence. Separate groups …

Predictors Of Study Dropout In Cognitive-Behavioural Therapy With A Trauma Focus For Post-Traumatic Stress Disorder In Adults: An Individual Participant Data Meta-Analysis, Simonne Wright, Eirini Karyotaki, Pim Cuijpers, Jonathan Bisson, Davide Papola, Anke B Witteveen, Sudie E Back, Dana Bichescu-Burian, Liuva Capezzani, Marylene Cloitre, Grant J Devilly, Thomas Elbert, Marcelo Mello, Julian D Ford, Damion Grasso, Pedro Gamito, Richard Gray, Moira Haller, Nigel Hunt, Rolf J Kleber, Julia König, Claire Kullack, Jonathan Laugharne, Rachel Liebman, Christopher William Lee, Jeannette Lely, John C Markowitz, Candice Monson, Mirjam J Nijdam, Sonya B Norman, Miranda Olff, Tahereh Mina Orang, Luca Ostacoli, Nenad Paunovic, Eva Petkova, Patricia Resick, Rita Rosner, Maggie Schauer, Joy M Schmitz, Ulrich Schnyder, Brian N Smith, Anka A Vujanovic, Yinyin Zang, Érica Panzani Duran, Francisco Lotufo Neto, Soraya Seedat, Marit Sijbrandij

Faculty, Staff and Student Publications

Background: Available empirical evidence on participant-level factors associated with dropout from psychotherapies for post-traumatic stress disorder (PTSD) is both limited and inconclusive. More comprehensive understanding of the various factors that contribute to study dropout from cognitive-behavioural therapy with a trauma focus (CBT-TF) is crucial for enhancing treatment outcomes.

Objective: Using an individual participant data meta-analysis (IPD-MA) design, we examined participant-level predictors of study dropout from CBT-TF interventions for PTSD.

Methods: A comprehensive systematic literature search was undertaken to identify randomised controlled trials comparing CBT-TF with waitlist control, treatment-as-usual or another therapy. Academic databases were screened from conception until 11 January …

Ar (Cag)N Microsatellite And Apex1 C444t>G (Pasp148glu) Polymorphisms As Independent Prognostic Biomarkers In Prostate Cancer: Insights From An Argentinian Cohort, Gaston Pascual, Agustina Sabater, Juan Bizzotto, Rocio Seniuk, Pablo Sanchis, Sabrina Ledesma-Bazan, Estefania Labanca, Carlos Scorticati, Osvaldo Mazza, Elba Vazquez, Ayelen Toro, Federico Prada, Geraldine Gueron, Javier Cotignola

Faculty, Staff and Student Publications

Background/objectives: Prostate cancer (PCa) is the leading malignancy and the third most common cause of cancer-related death in Argentinian men. Predicting outcomes in localized PCa remains difficult due to tumor heterogeneity. In this study, we assessed the impact of AR (CAG)n and APEX1 c.444T>G polymorphisms on biochemical relapse in Argentine patients with localized PCa.

Methods: We genotyped blood samples from 123 PCa patients for AR (CAG)n and APEX1 p.Asp148Glu (c.444T>G) polymorphisms. Associations with clinicopathological parameters and biochemical relapse-free survival (BRFS) were assessed.

Results: AR (CAG)20-23 was associated with a family history of breast/ovarian cancer (p = 0.0469). …

The Il-1Β Inhibitor Canakinumab In Previously Treated Lower-Risk Myelodysplastic Syndromes: A Phase 2 Clinical Trial, Juan Jose Rodriguez-Sevilla, Vera Adema, Kelly S Chien, Sanam Loghavi, Feiyang Ma, Hui Yang, Guillermo Montalban-Bravo, Xuelin Huang, Xavier Calvo, Joby Joseph, Kristy Bodden, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells' (HSPCs') aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had …

Long-Read Sequencing Of An Advanced Cancer Cohort Resolves Rearrangements, Unravels Haplotypes, And Reveals Methylation Landscapes, Kieran O'Neill, Erin Pleasance, Jeremy Fan, Vahid Akbari, Glenn Chang, Katherine Dixon, Veronika Csizmok, Signe Maclennan, Vanessa Porter, Andrew Galbraith, Cameron J Grisdale, Luka Culibrk, John H Dupuis, Richard Corbett, James Hopkins, Reanne Bowlby, Pawan Pandoh, Duane E Smailus, Dean Cheng, Tina Wong, Connor Frey, Yaoqing Shen, Eleanor Lewis, Luis F Paulin, Fritz J Sedlazeck, Jessica M T Nelson, Eric Chuah, Karen L Mungall, Richard A Moore, Robin Coope, Andrew J Mungall, Melissa K Mcconechy, Laura M Williamson, Kasmintan A Schrader, Stephen Yip, Marco A Marra, Janessa Laskin, Steven J M Jones

Faculty, Staff and Students Publications

The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can …

Tumor-Promoted Changes In Pediatric Brain Histology Can Be Distinguished From Normal Parenchyma By Desorption Electrospray Ionization Mass Spectrometry Imaging, Ana L Seidinger, Felipe L T Silva, Mayara F Euzébio, Anna C Krieger, João Meidanis, Junier M Gutierrez, Thais M S Bezerra, Luciano Queiroz, Alex A Rosini Silva, Iva L Hoffmann, Camila M M Daiggi, Helder Tedeschi, Marcos N Eberlin, Livia S Eberlin, José A Yunes, Andreia M Porcari, Izilda A Cardinalli

Faculty, Staff and Students Publications

Background: Central nervous system (CNS) tumors are the second most frequent type of neoplasm in childhood and adolescence, after leukemia. Despite the incorporation of molecular classification and improvement of protocols combining chemotherapy, surgery, and radiotherapy, CNS tumors are still the most lethal neoplasm in this age group. Mass spectrometry imaging (MSI) is a powerful tool to map the distribution of molecular species in tissue sections. Among MSI techniques, desorption electrospray ionization (DESI-MSI) has been demonstrated to enable reliable agreement with the pathological evaluation of different adult cancer types, along with an acceptable time scale for intraoperative use.

Methods: In the …

Complete Genome Sequence Of Borrelia Miyamotoi Strain Mn18-0001, An Am-East-2 Strain Type Isolate Derived From An Ixodes Scapularis Tick (Minnesota), Alexander R Kneubehl, Lynn M Osikowicz, Christina M Parise, Taylor J Van Gundy, Adam J Replogle, Job E Lopez, Rebecca J Eisen, Andrias Hojgaard

Faculty, Staff and Students Publications

We report the genomic sequence of the hard tick relapsing fever spirochete Borrelia miyamotoi strain MN18-0001. B. miyamotoi causes human illness and is geographically widespread in Ixodes spp. (Acari: Ixodidae) ticks. This is a chromosome- and plasmid-resolved genome assembly of an Am-East-2 strain type isolate from the midwestern United States.

Intouch Week Of November 11, 2024, New York Medical College

InTouch

• More than $16,000 Raised by NYMC SOM Marathon Runners
• Department of Pediatrics Hosts Leonard Newman, M.D. ’70, Assistant Professor Research Symposium
• Jonathan Fisher, Ph.D., Presents at the Neighborhood Science Seminar Series
• NYMC Community Visits New York Historical Society Museum
• NYMC SNMA Brings Hope to Tampa Residents Impacted by Hurricanes
• NYMC Blood Drive Brings Community Together to Save Lives
• Health Literacy Club Hosts Educational Vegetable Stand
• Student Spotlight: SOM Student Takes Second Place in International Neurosurgery Innovation Competition
• Faculty Spotlight: From Pupil to Professor: Alumni Lighting the Way at NYMC

Addition Of Metastasis-Directed Therapy To Systemic Therapy For Oligometastatic Pancreatic Ductal Adenocarcinoma (Extend): A Multicenter, Randomized Phase Ii Trial, Ethan B Ludmir, Alexander D Sherry, Bryan M Fellman, Suyu Liu, Tharakeswara Bathala, Cara Haymaker, Marina N Medina-Rosales, Alexandre Reuben, Emma B Holliday, Grace L Smith, Sonal S Noticewala, Sarah Nicholas, Tracy R Price, Rachael M Martin-Paulpeter, Luis A Perles, Sunyoung S Lee, Michael S Lee, Brandon G Smaglo, Ryan W Huey, Jason Willis, Dan Zhao, Lorenzo Cohen, Cullen M Taniguchi, Eugene J Koay, Matthew H G Katz, Robert A Wolff, Prajnan Das, Shubham Pant, Albert C Koong, Chad Tang

Faculty, Staff and Student Publications

Purpose: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response …

Dna Methylation Classifier To Diagnose Pancreatic Ductal Adenocarcinoma Metastases From Different Anatomical Sites, Teodor G Calina, Eilís Perez, Elena Grafenhorst, Jamal Benhamida, Simon Schallenberg, Adrian Popescu, Ines Koch, Tobias Janik, Baoqing Chen, Jana Ihlow, Stephanie Roessler, Benjamin Goeppert, Bruno Sinn, Marcus Bahra, George A Calin, Eliane T Taube, Uwe Pelzer, Christopher C M Neumann, David Horst, Erik Knutsen, David Capper, Mihnea P Dragomir

Faculty, Staff and Student Publications

Background: We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites.

Methods: For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the …

The Rna Receptor Rig-I Binding Synthetic Oligodeoxynucleotide Promotes Pneumonia Survival, Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleóngarcía, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans

Faculty, Staff and Student Publications

Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in TLR9, the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, …

Unlocking Intracellular Oncology Targets: The Unique Role Of Antibody-Based T-Cell Receptor Mimic (Tcrm) Therapeutics In T-Cell Engagers (Tces) And Antibody-Drug Conjugates (Adcs), Jeffrey Molldrem, Dongxing Zha

Faculty, Staff and Student Publications

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This review focuses on the innovative use of T-cell receptor mimic (TCRm) antibodies within the therapeutic frameworks of T-cell engagers (TCE) and antibody-drug conjugates (ADCs). TCRm antibodies, designed to recognize peptide-MHC complexes rather than cell surface proteins, integrate the capacity of T-cells to reach intracellular targets with the unique strengths of antibodies. When incorporated into T-cell engaging therapeutics, …

Multi-Organ Gene Expression Analysis And Network Modeling Reveal Regulatory Control Cascades During The Development Of Hypertension In Female Spontaneously Hypertensive Rat, Eden Hornung, Sirisha Achanta, Alison Moss, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Hypertension is a multifactorial disease with stage-specific gene expression changes occurring in multiple organs over time. The temporal sequence and the extent of gene regulatory network changes occurring across organs during the development of hypertension remain unresolved. In this study, female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats were used to analyze expression patterns of 96 genes spanning inflammatory, metabolic, sympathetic, fibrotic, and renin-angiotensin (RAS) pathways in five organs, at five time points from the onset to established hypertension. We analyzed this multi-dimensional dataset containing ~15,000 data points and developed a data-driven dynamic network model that accounts for …

Ephb4-Rasa1 Inhibition Of Piezo1 Ras Activation Drives Lymphatic Valvulogenesis, Di Chen, Yipei Tang, Philip E Lapinski, David Wiggins, Eva M Sevick, Michael J Davis, Philip D King

Faculty, Staff and Student Publications

BACKGROUND: EPHB4 (ephrin receptor B4) and the RASA1 (p120 Ras GTPase-activating protein) are necessary for the development of lymphatic vessel (LV) valves. However, precisely how EPHB4 and RASA1 regulate LV valve development is unknown. In this study, we examine the mechanisms by which EPHB4 and RASA1 regulate the development of LV valves.

METHODS: We used LV-specific inducible EPHB4-deficient mice and EPHB4 knockin mice that express a form of EPHB4 that is unable to bind RASA1 yet retains protein tyrosine kinase activity (EPHB4 2YP) to study the role of EPHB4 and RASA1 in LV valve development in the embryo and LV …

Modeling Antisense Oligonucleotide Therapy In Mecp2 Duplication Syndrome Human Ipsc-Derived Neurons Reveals Gene Expression Programs Responsive To Mecp2 Levels, Sameer S Bajikar, Yehezkel Sztainberg, Alexander J Trostle, Harini P Tirumala, Ying-Wooi Wan, Caroline L Harrop, Jesse D Bengtsson, Claudia M B Carvalho, Davut Pehlivan, Bernhard Suter, Jeffrey L Neul, Zhandong Liu, Paymaan Jafar-Nejad, Frank Rigo, Huda Y Zoghbi

Faculty, Staff and Students Publications

Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human …

Tumor-Associated Edema In Children With Kaposi Sarcoma: 14 Years' Experience At Kamuzu Central Hospital, Lilongwe, Malawi, Fatsani Rose Manase, Allison Silverstein, William Kamiyango, Jimmy Villiera, Clement Dziwe, Claudia Wallrauch, Tom Heller, Mark Zobeck, Tamiwe Tomoka, Michael E Scheurer, Carl E Allen, Nmazuo Ozuah, Rizine Mzikamanda, Nader Kim El-Mallawany, Casey L Mcatee

Center for Medical Ethics and Health Policy Staff Publications

Background/objectives: Kaposi sarcoma (KS) is a common lymphatic endothelial cancer among children with and without HIV in central and eastern Africa. Despite its clinical heterogeneity, its various clinical phenotypes are often grouped together in staging and treatment algorithms. Patients with KS tumor-associated edema, referring to hard, non-pitting lesions which often lead to chronic disability, represent a unique, understudied subgroup of children with KS. To continue our work defining the distinct phenotypes of pediatric KS, this study aimed to assess the clinical progression and outcomes of KS edema in children.

Methods: A retrospective cohort study was conducted at Kamuzu Central Hospital …

Using A Rabbit Model To Understand The Impact Of Oral Versus Intravenous Transmission Of Epstein-Barr Virus, Meera Mohammed Al Ameri

Thesis/ Dissertation Defenses

The isolation of Epstein-Barr Virus (EBV) in 1964 from a case of Burkitt lymphoma prompted a surge in research on the biology of this oncogenic virus and its role in the pathogenesis of associated malignancies. Over half a century later, a number of pertinent questions on the dynamics of EBV and the cellular targets of primary infection remain poorly defined. One major obstacle in EBV research has been the lack of a suitable small animal model. EBV is a highly human tropic virus. We have recently established a novel rabbit model of EBV infection that appears to mimic natural infection …

Estimating The Number Of Polygenic Diseases Among Six Mutually Exclusive Entities Of Non-Tumors And Cancer, C I Edvard Smith, Jan A Burger, Rula Zain

Faculty, Staff and Student Publications

In the era of precision medicine with increasing amounts of sequenced cancer and non-cancer genomes of different ancestries, we here enumerate the resulting polygenic disease entities. Based on the cell number status, we first identified six fundamental types of polygenic illnesses, five of which are non-cancerous. Like complex, non-tumor disorders, neoplasms normally carry alterations in multiple genes, including in 'Drivers' and 'Passengers'. However, tumors also lack certain genetic alterations/epigenetic changes, recently named 'Goners', which are toxic for the neoplasm and potentially constitute therapeutic targets. Drivers are considered essential for malignant transformation, whereas environmental influences vary considerably among both types of …

Large-Scale Application Of Clingen-Insight Apc-Specific Acmg/Amp Variant Classification Criteria Leads To Substantial Reduction In Vus, Xiaoyu Yin, Marcy Richardson, Andreas Laner, Xuemei Shi, Elisabet Ognedal, Valeria Vasta, Thomas V O Hansen, Marta Pineda, Deborah Ritter, Johan De Dunnen, Emadeldin Hassanin, Wencong Lyman Lin, Ester Borras, Karl Krahn, Margareta Nordling, Alexandra Martins, Khalid Mahmood, Emily Nadeau, Victoria Beshay, Carli Tops, Maurizio Genuardi, Tina Pesaran, Ian M Frayling, Gabriel Capellá, Andrew Latchford, Sean V Tavtigian, Carlo Maj, Sharon E Plon, Marc S Greenblatt, Finlay A Macrae, Isabel Spier, Stefan Aretz

Faculty, Staff and Students Publications

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation …

Brain Metastases In Sarcomas: A Multicenter Retrospective Cohort Study, Ellen Zhang, Sheima Farag, Hilary Dietz, Daniel Wang, Angela Hirbe, Kristen Ganjoo, Brian Van Tine, Shane Zaid, Aisha Miah, Vicki Keedy, Elizabeth Davis, Nam Bui

Faculty, Staff and Students Publications

Purpose: Brain metastases (BM) in sarcomas occur rarely and are associated with poor prognosis. This study is a large retrospective cohort describing the demographic and clinical characteristics of these patients, treatment strategies, and survival outcomes.

Methods: In total, 81 patients with BM from sarcomas were identified across five sarcoma centers. Demographic data, clinical presentation, and treatment modalities were analyzed.

Results: The most common histologies were leiomyosarcoma (12.3%) and undifferentiated pleomorphic sarcoma (12.3%). The median time from sarcoma diagnosis to brain metastases was 1.9 years. Upon presentation, 88.9% of patients with BM from sarcomas were symptomatic with the most common presenting …

Homozygous Variants In Wdr83os Lead To A Neurodevelopmental Disorder With Hypercholanemia, Scott Barish, Sheng-Jia Lin, Reza Maroofian, Alper Gezdirici, Hamoud Alhebby, Aurélien Trimouille, Marta Biderman Waberski, Tadahiro Mitani, Ilka Huber, Kristian Tveten, Øystein L Holla, Øyvind L Busk, Henry Houlden, Ehsan Ghayoor Karimiani, Mehran Beiraghi Toosi, Reza Shervin Badv, Paria Najarzadeh Torbati, Fatemeh Eghbal, Javad Akhondian, Ayat Al Safar, Abdulrahman Alswaid, Giovanni Zifarelli, Peter Bauer, Dana Marafi, Jawid M Fatih, Kevin Huang, Cassidy Petree, Daniel G Calame, Charlotte Von Der Lippe, Fowzan S Alkuraya, Sami Wali, James R Lupski, Gaurav K Varshney, Jennifer E Posey, Davut Pehlivan

Faculty, Staff and Students Publications

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of …

Metallomic Approach To Mercury And Selenium In The Liver Tissue Of Psectrogaster Amazonica And Raphiodon Vulpinus From The Brazilian Amazon, Izabela Bataglioli, José Vieira, Joyce Da Siva, Luane Andrade, Victor Faria, Rebeca Corcoba, Ronaldo De Almeida, Luiz Zara, Marília Buzalaf, Jiri Adamec, Pedro Padilha

School of Medicine Faculty Publications

This paper reports the results of a mercury (Hg) and selenium (Se) metallomic study in the liver tissues of Psectrogaster amazonica and Raphiodon vulpinus from the Brazilian Amazon. Two-dimensional electrophoresis, graphite furnace atomic absorption spectrometry, and liquid chromatography-tandem mass spectrometry were performed. Hg and Se determinations allowed the calculation of Hg:Se and Se:Hg molar ratio and Se values for health benefits (Se HBVs). The Se:Hg values were >1 for both fish species, whereas the Se HBVs were >5 for P. amazonica and >10 for R. vulpinus, indicating that both possess Se reserves to control Hg toxicity. The metallomic data allowed …

High Incidence And Geographic Distribution Of Cleft Palate In Finland Are Associated With The Irf6 Gene, Fedik Rahimov, Pekka Nieminen, Priyanka Kumari, Emma Juuri, Tiit Nikopensius, Kitt Paraiso, Jakob German, Antti Karvanen, Mart Kals, Abdelrahman G Elnahas, Juha Karjalainen, Mitja Kurki, Aarno Palotie, Estonian Biobank Research Team, Finngen, Arja Heliövaara, Tõnu Esko, Sakari Jukarainen, Priit Palta, Andrea Ganna, Anjali P Patni, Daniel Mar, Karol Bomsztyk, Julie Mathieu, Hannele Ruohola-Baker, Axel Visel, Walid D Fakhouri, Brian C Schutte, Robert A Cornell, David P Rice

Faculty, Staff and Student Publications

In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10-34, OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10-5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence …

Skn-1 Activation During Infection Of Caenorhabditis Elegans Requires Cdc-48 And Endoplasmic Reticulum Proteostasis, Carolaing Gabaldón, Ozgur Karakuzu, Danielle A Garsin

Faculty, Staff and Student Publications

During challenge of Caenorhabditis elegans with human bacterial pathogens such as Pseudomonas aeruginosa and Enterococcus faecalis, the elicited host response can be damaging if not properly controlled. The activation of Nrf (nuclear factor erythroid-related factor)/CNC (Cap-n-collar) transcriptional regulators modulates the response by upregulating genes that neutralize damaging molecules and promote repair processes. Activation of the C. elegans Nrf ortholog, SKN-1, is tightly controlled by a myriad of regulatory mechanisms, but a central feature is an activating phosphorylation accomplished by the p38 mitogen-activated kinase (MAPK) cascade. In this work, loss of CDC-48, an AAA+ ATPase, was observed to severely compromise SKN-1 …

Automatically Extracting Social Determinants Of Health For Suicide: A Narrative Literature Review, Annika M Schoene, Suzanne Garverich, Iman Ibrahim, Sia Shah, Benjamin Irving, Clifford C Dacso

Faculty, Staff and Students Publications

Suicide is a complex phenomenon that is often not preceded by a diagnosed mental health condition, therefore making it difficult to study and mitigate. Artificial Intelligence has increasingly been used to better understand Social Determinants of Health factors that influence suicide outcomes. In this review we find that many studies use limited SDoH information and minority groups are often underrepresented, thereby omitting important factors that could influence risk of suicide.

Gene Discovery From Microbial Gene Libraries I: Protection Against Reactive Oxygen Species-Driven Dna Damage, John C Taylor, Carmen Gu Liu, James D Chang, Brianna E Thompson, Anthony W Maresso

Faculty, Staff and Students Publications

Reactive oxygen species (ROS) pose a lethal risk for all life forms by causing damage to cell processes, genome-wide DNA damage-driving mutation, replicative instability, and death. Thus, the development of mechanisms to resist or repair ROS-induced DNA damage is critical for the reliable replication of nucleic acids. DNA repair and protection mechanisms have been discovered in all forms of life. However, the vast array of microbes that may harbor novel repair or protection mechanisms, especially bacterial viruses, have not been adequately assessed. Here, we screened a microbial gene library composed primarily of phage open reading frames (ORFs) to uncover elements …

Activation Of A Gpcr, Orl1 Receptor: A Novel Therapy To Prevent Heart Failure Progression, Saliha S Pathan, Aarthi Pugazenthi, Beverly R E A Dixon, Theodore G Wensel, Todd K Rosengart, Megumi Mathison

Faculty, Staff and Students Publications

The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in rat hearts. We also found that Gata4 overexpression significantly increased the expression of a Pnoc gene, an endogenous ligand for the cell membrane receptor ORL1. We hypothesized that the activation of the ORL1 receptor would suppress HF in a rat ischemic heart model. Adult Sprague Dawley rats (8 weeks old, six males and six females) underwent left anterior descending coronary artery ligation. Three weeks …