Genetic Phenomena Commons^™

Spatiotemporal Microrna-Gene Expression Network Related To Orofacial Clefts, F Yan, L M Simon, A Suzuki, C Iwaya, P Jia, J Iwata, Z Zhao

Faculty, Staff and Student Publications

Craniofacial structures change dynamically in morphology during development through the coordinated regulation of various cellular molecules. However, it remains unclear how these complex mechanisms are regulated in a spatiotemporal manner. Here we applied natural cubic splines to model gene and microRNA (miRNA) expression from embryonic day (E) 10.5 to E14.5 in the proximal and distal regions of the maxillary processes to identify spatiotemporal patterns of gene and miRNA expression, followed by constructing corresponding regulatory networks. Three major groups of differentially expressed genes (DEGs) were identified, including 3,927 temporal, 314 spatial, and 494 spatiotemporal DEGs. Unsupervised clustering further resolved these spatiotemporal …

A Retrospective Analysis Of Ebv-Dna Status With The Prognosis Of Lymphoma, Lihua Qiu, Junqi Si, Junnan Kang, Zehui Chen, Rexidan Nuermaimaiti, Zhengzi Qian, Lanfang Li, Shiyong Zhou, Mingjian James You, Huilai Zhang, Chen Tian

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV-DNA status after treatment and prognosis. In this study, real-time polymerase chain reaction (PCR) was used for quantitative detection of EBV-DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV-DNA and 102 randomly selected patients with negative EBV-DNA. We found that the average rate of EBV-DNA positivity in lymphomas was 0.376%, and EBV-DNA-positive patients presented higher risk with elevated lactate …

Lurbinectedin, A Selective Inhibitor Of Oncogenic Transcription, In Patients With Pretreated Germline Brca1/2 Metastatic Breast Cancer: Results From A Phase Ii Basket Study, V Boni, B Pistilli, I Braña, G I Shapiro, J Trigo, V Moreno, D Castellano, C Fernández, C Kahatt, V Alfaro, M Siguero, A Zeaiter, F Longo, K Zaman, A Antón, A Paredes, G Huidobro, V Subbiah

Faculty, Staff and Student Publications

Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer.

Patients and methods: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival …

The Circular Rna Edis Regulates Neurodevelopment And Innate Immunity, Xiao-Peng Xiong, Weihong Liang, Wei Liu, Shiyu Xu, Jian-Liang Li, Antonio Tito, Julia Situ, Daniel Martinez, Chunlai Wu, Ranjan J Perera, Sheng Zhang, Rui Zhou

Faculty, Staff and Student Publications

Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset has been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis (circ_Ect4) causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotor activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective …

Stat3 Inhibits Autocrine Ifn Signaling In Type I Conventional Dendritic Cells, Taylor T Chrisikos, Yifan Zhou, Laura M Kahn, Bhakti Patel, Nina L Denne, Athena Brooks, Li Shen, Jing Wang, Stephanie S Watowich

Faculty, Staff and Student Publications

Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli regulate cDC1 function remain unclear. We previously demonstrated that the cytokine-responsive transcriptional regulator STAT3 inhibits polyinosinic:polycytidylic acid [poly(I:C)]-induced cDC1 maturation and cDC1-mediated antitumor immunity in murine breast cancer, indicating an intrinsic, suppressive role for STAT3 in cDC1s. To probe transcriptional mechanisms regulating cDC1 function, we generated novel RNA sequencing datasets representing poly(I:C)-, IL-10-, and STAT3-mediated gene expression responses in murine cDC1s. Bioinformatics analyses …

Comprehensive Multiplexed Immune Profiling Of The Ductal Carcinoma In Situ Immune Microenvironment Regarding Subsequent Ipsilateral Invasive Breast Cancer Risk, Mathilde M Almekinders, Tycho Bismeijer, Tapsi Kumar, Fei Yang, Bram Thijssen, Rianne Van Der Linden, Charlotte Van Rooijen, Shiva Vonk, Baohua Sun, Edwin R Parra Cuentas, Ignacio I Wistuba, Savitri Krishnamurthy, Lindy L Visser, Iris M Seignette, Ingrid Hofland, Joyce Sanders, Annegien Broeks, Jason K Love, Brian Menegaz, Lodewyk Wessels, Alastair M Thompson, Karin E De Visser, Erik Hooijberg, Esther Lips, Andrew Futreal, Jelle Wesseling

Faculty, Staff and Student Publications

Background: Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.

Methods: Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8- T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with …

Handling Informative Premature Treatment Or Study Discontinuation For Assessing Between-Group Differences In A Comparative Oncology Trial, Bo Huang, Ryan Sun, Brian Claggett, Lu Tian, Ethan B Ludmir, Lee-Jen Wei

Faculty, Staff and Student Publications

This decision analytical model study examines premature treatment discontinuation in clinical trials for patients with advanced renal cell carcinoma.

Detecting Förster Resonance Energy Transfer In Living Cells By Conventional And Spectral Flow Cytometry, Jared Henderson, Ondrej Havranek, Man Chun John Ma, Vaclav Herman, Kristyna Kupcova, Tereza Chrbolkova, Mariana Pacheco-Blanco, Zhiqiang Wang, Justin M Comer, Tomasz Zal, Richard Eric Davis

Faculty, Staff and Student Publications

Assays based on Förster resonance energy transfer (FRET) can be used to study many processes in cell biology. Although this is most often done with microscopy for fluorescence detection, we report two ways to measure FRET in living cells by flow cytometry. Using a conventional flow cytometer and the "3-cube method" for intensity-based calculation of FRET efficiency, we measured the enzymatic activity of specific kinases in cells expressing a genetically-encoded reporter. For both AKT and protein kinase A, the method measured kinase activity in time-course, dose-response, and kinetic assays. Using the Cytek Aurora spectral flow cytometer, which applies linear unmixing …

Discovery Of An Orally Active Benzoxaborole Prodrug Effective In The Treatment Of Chagas Disease In Non-Human Primates, Angel M Padilla, Wei Wang, Tsutomu Akama, David S Carter, Eric Easom, Yvonne Freund, Jason S Halladay, Yang Liu, Sarah A Hamer, Carolyn L Hodo, Gregory K Wilkerson, Dylan Orr, Brooke White, Arlene George, Huifeng Shen, Yiru Jin, Michael Zhuo Wang, Susanna Tse, Robert T Jacobs, Rick L Tarleton

Faculty, Staff and Student Publications

Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA …

Mismatch Repair And Microsatellite Instability Testing For Immune Checkpoint Inhibitor Therapy: Guideline From The College Of American Pathologists In Collaboration With The Association For Molecular Pathology And Fight Colorectal Cancer, Angela N Bartley, Anne M Mills, Eric Konnick, Michael Overman, Christina B Ventura, Lesley Souter, Carol Colasacco, Zsofia K Stadler, Sarah Kerr, Brooke E Howitt, Heather Hampel, Sarah F Adams, Wenora Johnson, Cristina Magi-Galluzzi, Antonia R Sepulveda, Russell R Broaddus

Faculty, Staff and Student Publications

Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.

Objective.—: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.

Design.—: The College of American Pathologists convened an expert panel to perform a systematic review …

Semi-Parametric Bayes Regression With Network-Valued Covariates, Xin Ma, Suprateek Kundu, Jennifer Stevens

Faculty, Staff and Student Publications

Although there has been an explosive rise in network data in a variety of disciplines, there is very limited development of regression modeling approaches based on high-dimensional networks. The scarce literature in this area typically assume linear relationships between the outcome and the high-dimensional network edges that results in an inflated model plagued by the curse of dimensionality and these models are unable to accommodate non-linear relationships or higher order interactions. In order to overcome these limitations, we develop a novel two-stage Bayesian non-parametric regression modeling framework using high-dimensional networks as covariates, which first finds a lower dimensional node-specific representation …

Gpu Accelerated Estimation Of A Shared Random Effect Joint Model For Dynamic Prediction, Shikun Wang, Zhao Li, Lan Lan, Jieyi Zhao, W Jim Zheng, Liang Li

Faculty, Staff and Student Publications

In longitudinal cohort studies, it is often of interest to predict the risk of a terminal clinical event using longitudinal predictor data among subjects at risk by the time of the prediction. The at-risk population changes over time; so does the association between predictors and the outcome, as well as the accumulating longitudinal predictor history. The dynamic nature of this prediction problem has received increasing interest in the literature, but computation often poses a challenge. The widely used joint model of longitudinal and survival data often comes with intensive computation and excessive model fitting time, due to numerical optimization and …

T1 Signal Intensity Ratio Of The Pancreas As An Imaging Biomarker For The Staging Of Chronic Pancreatitis, Temel Tirkes, Anil K Dasyam, Zarine K Shah, Evan L Fogel, Santhi Swaroop Vege, Liang Li, Shuang Li, Stephanie T Chang, Carlos A Farinas, Joseph R Grajo, Kareem Mawad, Naoki Takahashi, Sudhakar K Venkatesh, Ashley Wachsman, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Stephen K Van Den Eeden, Yunlong Yang, Mark Topazian, Dana K Andersen, Jose Serrano, Darwin L Conwell, Dhiraj Yadav, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Purpose: Our purpose was to validate the T1 SIR (T1 score) as an imaging biomarker for the staging of CP in a large, multi-institutional, prospective study.

Methods: The prospective study population included 820 participants enrolled in the PROCEED study from nine clinical centers between June 2017 and December 2021. A radiologist at each institution used a standardized method to measure the T1 signal intensity of the pancreas and the reference organs (spleen, paraspinal muscle, liver), which was used to derive respective T1 scores. Participants were stratified according to the seven mechanistic stages of chronic pancreatitis (MSCP 0-6) based on their …

Brequinar And Dipyridamole In Combination Exhibits Synergistic Antiviral Activity Against Sars-Cov-2 In Vitro: Rationale For A Host-Acting Antiviral Treatment Strategy For Covid-19, James F Demarest, Maryline Kienle, Ruthmabel Boytz, Mary Ayres, Eun Jung Kim, J J Patten, Donghoon Chung, Varsha Gandhi, Robert A Davey, David B Sykes, Nadim Shohdy, John C Pottage, Vikram S Kumar

Faculty, Staff and Student Publications

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the associated global pandemic resulting in >400 million infections worldwide and several million deaths. The continued evolution of SARS-CoV-2 to potentially evade vaccines and monoclonal antibody (mAb)-based therapies and the limited number of authorized small-molecule antivirals necessitates the need for development of new drug treatments. There remains an unmet medical need for effective and convenient treatment options for SARS-CoV-2 infection. SARS-CoV-2 is an RNA virus that depends on host intracellular ribonucleotide pools for its replication. Dihydroorotate dehydrogenase (DHODH) is a ubiquitous host …

First-In-Human Study Of An Ox40 (Ivuxolimab) And 4-1bb (Utomilumab) Agonistic Antibody Combination In Patients With Advanced Solid Tumors, Omid Hamid, Alberto A Chiappori, John A Thompson, Toshihiko Doi, Siwen Hu-Lieskovan, Ferry A L M Eskens, Willeke Ros, Adi Diab, Jean-Philippe Spano, Naiyer A Rizvi, Jeffrey S Wasser, Eric Angevin, Patrick A Ott, Alison Forgie, Wenjing Yang, Cen Guo, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

Background: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.

Methods: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every …

Causal Evidence For A Role Of Cerebellar Lobulus Simplex In Prefrontal-Hippocampal Interaction In Spatial Working Memory Decision-Making, Yu Liu, Samuel S Mcafee, Meike E Van Der Heijden, Mukesh Dhamala, Roy V Sillitoe, Detlef H Heck

Duncan NRI Faculty and Staff Publications

Spatial working memory (SWM) is a cerebrocerebellar cognitive skill supporting survival-relevant behaviors, such as optimizing foraging behavior by remembering recent routes and visited sites. It is known that SWM decision-making in rodents requires the medial prefrontal cortex (mPFC) and dorsal hippocampus. The decision process in SWM tasks carries a specific electrophysiological signature of a brief, decision-related increase in neuronal communication in the form of an increase in the coherence of neuronal theta oscillations (4-12 Hz) between the mPFC and dorsal hippocampus, a finding we replicated here during spontaneous exploration of a plus maze in freely moving mice. We further evaluated …

Potential Interactions Between Cerebellar Dysfunction And Sleep Disturbances In Dystonia, Luis E Salazar Leon, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is the third most common movement disorder. It causes debilitating twisting postures that are accompanied by repetitive and sometimes intermittent co- or over-contractions of agonist and antagonist muscles. Historically diagnosed as a basal ganglia disorder, dystonia is increasingly considered a network disorder involving various brain regions including the cerebellum. In certain etiologies of dystonia, aberrant motor activity is generated in the cerebellum and the abnormal signals then propagate through a "dystonia circuit" that includes the thalamus, basal ganglia, and cerebral cortex. Importantly, it has been reported that non-motor defects can accompany the motor symptoms; while their severity is not …

Identifying Phenotypic Expansions For Congenital Diaphragmatic Hernia Plus (Cdh+) Using Decipher Data, Amy Hardcastle, Aliska M Berry, Ian M Campbell, Xiaonan Zhao, Pengfei Liu, Amanda E Gerard, Jill A Rosenfeld, Saumya D Sisoudiya, Andres Hernandez-Garcia, Sara Loddo, Silvia Di Tommaso, Antonio Novelli, Maria L Dentici, Rossella Capolino, Maria C Digilio, Ludovico Graziani, Cecilie F Rustad, Katherine Neas, Giovanni B Ferrero, Alfredo Brusco, Eleonora Di Gregorio, Diana Wellesley, Claire Beneteau, Madeleine Joubert, Kris Van Den Bogaert, Anneleen Boogaerts, Dominic J Mcmullan, John Dean, Maria G Giuffrida, Laura Bernardini, Vinod Varghese, Nora L Shannon, Rachel E Harrison, Wayne W K Lam, Shane Mckee, Peter D Turnpenny, Trevor Cole, Jenny Morton, Jacqueline Eason, Marilyn C Jones, Rebecca Hall, Michael Wright, Karen Horridge, Chad A Shaw, Wendy K Chung, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, …

Pin-Pointing The Key Hubs In The Ifn-Γ Pathway Responding To Sars-Cov-2 Infection, Ayelen Toro, Sofia Lage-Vickers, Juan Bizzotto, Felipe Vilicich, Agustina Sabater, Gaston Pascual, Sabrina Ledesma-Bazan, Pablo Sanchis, Maria Sol Ruiz, Ana Paula Arevalo, Jorge L Porfido, Mercedes Abbate, Rocio Seniuk, Estefania Labanca, Nicolas Anselmino, Nora M Navone, Daniel F Alonso, Elba Vazquez, Martina Crispo, Javier Cotignola, Geraldine Gueron

Faculty, Staff and Student Publications

Interferon gamma (IFN-γ) may be potential adjuvant immunotherapy for COVID-19 patients. In this work, we assessed gene expression profiles associated with the IFN-γ pathway in response to SARS-CoV-2 infection. Employing a case-control study from SARS-CoV-2-positive and -negative patients, we identified IFN-γ-associated pathways to be enriched in positive patients. Bioinformatics analyses showed upregulation of MAP2K6, CBL, RUNX3, STAT1, and JAK2 in COVID-19-positive vs. -negative patients. A positive correlation was observed between STAT1/JAK2, which varied alongside the patient's viral load. Expression of MX1, MX2, ISG15, and OAS1 (four well-known IFN-stimulated genes (ISGs)) …

Sex-Specific Epigenetic Development In The Mouse Hypothalamic Arcuate Nucleus Pinpoints Human Genomic Regions Associated With Body Mass Index, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Duncan NRI Faculty and Staff Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …