Medical Sciences Commons^™

A Phase I, Open-Label, Dose-Escalation Study Of The Ox40 Agonist Ivuxolimab In Patients With Locally Advanced Or Metastatic Cancers, Adi Diab, Omid Hamid, John A Thompson, Willeke Ros, Ferry A L M Eskens, Toshihiko Doi, Siwen Hu-Lieskovan, Samuel J Klempner, Bishu Ganguly, Catherine Fleener, Xiao Wang, Tenshang Joh, Ken Liao, Shahram Salek-Ardakani, Carrie Turich Taylor, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

PURPOSE: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4

PATIENTS AND METHODS: Adult patients (

RESULTS: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4

CONCLUSIONS: Ivuxolimab …

Tumor Microenvironment Enriches The Stemness Features: The Architectural Event Of Therapy Resistance And Metastasis, Palanisamy Nallasamy, Rama Krishna Nimmakayala, Seema Parte, Abhirup C. Are, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of …

Checkpoint Inhibitors As Immunotherapy For Fungal Infections: Promises, Challenges, And Unanswered Questions, Sebastian Wurster, Stephanie S Watowich, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Opportunistic fungal infections have high mortality in patients with severe immune dysfunction. Growing evidence suggests that the immune environment of invasive fungal infections and cancers share common features of immune cell exhaustion through activation of immune checkpoint pathways. This observation gave rise to several preclinical studies and clinical case reports describing blockade of the Programmed Cell Death Protein 1 and Cytotoxic T-Lymphocyte Antigen 4 immune checkpoint pathways as an adjunct immune enhancement strategy to treat opportunistic fungal infections. The first part of this review summarizes the emerging evidence for contributions of checkpoint pathways to the immunopathology of fungal sepsis, opportunistic …

Multiplexed Engineering And Precision Gene Editing In Cellular Immunotherapy, Alexander Biederstädt, Gohar Shahwar Manzar, May Daher

Faculty, Staff and Student Publications

The advent of cellular immunotherapy in the clinic has entirely redrawn the treatment landscape for a growing number of human cancers. Genetically reprogrammed immune cells, including chimeric antigen receptor (CAR)-modified immune effector cells as well as T cell receptor (TCR) therapy, have demonstrated remarkable responses across different hard-to-treat patient populations. While these novel treatment options have had tremendous success in providing long-term remissions for a considerable fraction of treated patients, a number of challenges remain. Limited

Granuloma Annulare: An Updated Review Of Epidemiology, Pathogenesis, And Treatment Options, Tejas P Joshi, Madeleine Duvic

Faculty, Staff and Student Publications

Granuloma annulare (GA) is an inflammatory granulomatous skin disease that can be localized (localized GA) or disseminated (generalized GA), with patch, perforating, and subcutaneous subtypes being less common variants of this benign condition. Recently, new research has emerged that further elucidates GA epidemiology and etiopathogenesis; importantly, new therapeutic options for GA have also been described, although there remains a paucity of randomized controlled studies. In this review, we summarize recent updates on GA epidemiology and etiopathogenesis and offer an updated review of the therapeutic options for GA currently reported in the literature. We hope that the current review galvanizes randomized …

Editorial: The Role Of The Igf Axis In Tumorigenesis And Cancer Treatment: From Genes To Metabolites, Guo Mengzhe, Xie Shanshan, Zhao Di, Wu Shihua

Faculty, Staff and Student Publications

No abstract provided.

Cancer Prevention Behaviors In Workers Of A Referral Cancer Center In Mexico City: A Pilot Study On Early Detection Awareness For Cancer, Nancy Reynoso-Noverón, Shine Chang, Luis Alonso Herrera-Montalvo, Abelardo Meneses-García

Faculty, Staff and Student Publications

Background: Prevention strategies for cancer are necessary. Health workers who often serve as role models bear responsibility for prevention counseling and programs. However, whether their habits and behaviors reflect prevention goals are unknown. We describe the prevalence of cancer risk factors and prevention behaviors in health workers of a referral cancer center in Mexico City.

Methods: Cross-sectional study in which workers of the National Cancer Institute were invited to participate in a prevention program, risk factor survey, and nutrition, psychological, and genetic counseling were included. The likelihood of cancer was calculated based on the presence of risk factors. Factors associated …

Inhibition Of The Cd47-Sirpα Axis For Cancer Therapy: A Systematic Review And Meta-Analysis Of Emerging Clinical Data, Ji Son, Rodney Cheng-En Hsieh, Heather Y Lin, Kate J Krause, Ying Yuan, Amadeo B Biter, James Welsh, Michael A Curran, David S Hong

Faculty, Staff and Student Publications

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). …

Recurrent High-Impact Mutations At Cognate Structural Positions In Class A G Protein-Coupled Receptors Expressed In Tumors, Eunna Huh, Jonathan Gallion, Melina A Agosto, Sara J Wright, Theodore G Wensel, Olivier Lichtarge

Faculty, Staff and Students Publications

G protein-coupled receptors (GPCRs) are the largest family of human proteins. They have a common structure and, signaling through a much smaller set of G proteins, arrestins, and effectors, activate downstream pathways that often modulate hallmark mechanisms of cancer. Because there are many more GPCRs than effectors, mutations in different receptors could perturb signaling similarly so as to favor a tumor. We hypothesized that somatic mutations in tumor samples may not be enriched within a single gene but rather that cognate mutations with similar effects on GPCR function are distributed across many receptors. To test this possibility, we systematically aggregated …

Replication Stress Response Defects Are Associated With Response To Immune Checkpoint Blockade In Nonhypermutated Cancers, Daniel J Mcgrail, Patrick G Pilié, Hui Dai, Truong Nguyen Anh Lam, Yulong Liang, Leonie Voorwerk, Marleen Kok, Xiang H-F Zhang, Jeffrey M Rosen, Amy B Heimberger, Christine B Peterson, Eric Jonasch, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Treatment with immune checkpoint blockade (ICB) has resulted in durable responses for a subset of patients with cancer, with predictive biomarkers for ICB response originally identified largely in the context of hypermutated cancers. Although recent clinical data have demonstrated clinical responses to ICB in certain patients with nonhypermutated cancers, previously established ICB response biomarkers have failed to accurately identify which of these patients may benefit from ICB. Here, we demonstrated that a replication stress response (RSR) defect gene expression signature, but not other proposed biomarkers, is associated with ICB response in 12 independent cohorts of patients with nonhypermutated cancer across …

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, …

The Concurrence Of Dna Methylation And Demethylation Is Associated With Transcription Regulation, Jiejun Shi, Jianfeng Xu, Yiling Elaine Chen, Jason Sheng Li, Ya Cui, Lanlan Shen, Jingyi Jessica Li, Wei Li

Children’s Nutrition Research Center Staff Publications

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. …

The Detrimental Association Between Fear Of Falling And Motor Performance In Older Cancer Patients With Chemotherapy-Induced Peripheral Neuropathy, Gu Eon Kang, Tamiko K Murphy, Mark E Kunik, Hoda J Badr, Biruh T Workeneh, Sarvari V Yellapragada, Yvonne H Sada, Bijan Najafi

Faculty, Staff and Students Publications

BACKGROUND: Cancer patients with chemotherapy-induced peripheral neuropathy (CIPN) are at increased risk of falls and developing fear of falling (FoF). Although FoF may continue to impair motor performance and increase the risk of falling even further, this association remains unexplored in CIPN.

RESEARCH QUESTION: Does high FoF in patients with CIPN further deteriorate motor performance beyond the impairment from CIPN-related sensory deficits?

METHODS: In this secondary analysis of data collected from two clinical trials, gait parameters during habitual walking condition and postural sway parameters during 30-second quiet standing (eye-open and eyes-closed) were compared among older participants (≥ 65 years) with …

Two Mechanisms Of Chromosome Fragility At Replication-Termination Sites In Bacteria, Qian Mei, Devon M Fitzgerald, Jingjing Liu, Jun Xia, John P Pribis, Yin Zhai, Ralf B Nehring, Jacob Paiano, Heyuan Li, Andre Nussenzweig, P J Hastings, Susan M Rosenberg

Faculty, Staff and Students Publications

Chromosomal fragile sites are implicated in promoting genome instability, which drives cancers and neurological diseases. Yet, the causes and mechanisms of chromosome fragility remain speculative. Here, we identify three spontaneous fragile sites in the Escherichia coli genome and define their DNA damage and repair intermediates at high resolution. We find that all three sites, all in the region of replication termination, display recurrent four-way DNA or Holliday junctions (HJs) and recurrent DNA breaks. Homology-directed double-strand break repair generates the recurrent HJs at all of these sites; however, distinct mechanisms of DNA breakage are implicated: replication fork collapse at natural replication …

Enabling Precision Medicine In Cancer Care Through A Molecular Data Warehouse: The Moffitt Experience, Steven A Eschrich, Jamie K Teer, Phillip Reisman, Erin Siegel, Chandan Challa, Patricia Lewis, Katherine Fellows, Everin Malpica, Rodrigo Carvajal, Guillermo Gonzalez, Scott Cukras, Miguel Betin-Montes, Garrick Aden-Buie, Melissa Avedon, Daniel Manning, Aik Choon Tan, Brooke L Fridley, Travis Gerke, Mattias Van Looveren, Amilcar Blake, Jennifer Greenman, Dana E Rollison

Faculty, Staff and Students Publications

PURPOSE: The use of genomics within cancer research and clinical oncology practice has become commonplace. Efforts such as The Cancer Genome Atlas have characterized the cancer genome and suggested a wealth of targets for implementing precision medicine strategies for patients with cancer. The data produced from research studies and clinical care have many potential secondary uses beyond their originally intended purpose. Effective storage, query, retrieval, and visualization of these data are essential to create an infrastructure to enable new discoveries in cancer research.

METHODS: Moffitt Cancer Center implemented a molecular data warehouse to complement the extensive enterprise clinical data warehouse …

Automated Software-Assisted Diagnosis Of Esophageal Squamous Cell Neoplasia Using High-Resolution Microendoscopy, Mimi C Tan, Sheena Bhushan, Timothy Quang, Richard Schwarz, Kalpesh H Patel, Xinying Yu, Zhengqi Li, Guiqi Wang, Fan Zhang, Xueshan Wang, Hong Xu, Rebecca R Richards-Kortum, Sharmila Anandasabapathy

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: High-resolution microendoscopy (HRME) is an optical biopsy technology that provides subcellular imaging of esophageal mucosa but requires expert interpretation of these histopathology-like images. We compared endoscopists with an automated software algorithm for detection of esophageal squamous cell neoplasia (ESCN) and evaluated the endoscopists' accuracy with and without input from the software algorithm.

METHODS: Thirteen endoscopists (6 experts, 7 novices) were trained and tested on 218 post-hoc HRME images from 130 consecutive patients undergoing ESCN screening/surveillance. The automated software algorithm interpreted all images as neoplastic (high-grade dysplasia, ESCN) or non-neoplastic. All endoscopists provided their interpretation (neoplastic or non-neoplastic) …

Is Covid-19-Induced Platelet Activation A Cause Of Concern For Patients With Cancer?, Lenard M Lichtenberger, K Vinod Vijayan

Faculty, Staff and Students Publications

Patients with cancer are more susceptible to be infected by SARS-CoV-2 and develop severe outcomes including ICU admittance, mechanical ventilator support, and a high rate of mortality. Like mid-to late-stage cancer, SARS-CoV-2 infection is associated with platelet hyperactivity, systemic inflammation, thrombotic complications, and coagulopathy. Platelets also promote cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. In this article, we will discuss the potential for platelets in the development of systemic inflammation and thrombosis in SARS-CoV-2-infected patients with cancer, with the concern that the platelet-induced pathogenic events are likely magnified in cancer patients with COVID-19.

Conservation Of Epithelial-To-Mesenchymal Transition Process In Neural Crest Cells And Metastatic Cancer, April Zhang, Hira Aslam, Neha Sharma, Aryeh Warmflash, Walid D Fakhouri

Faculty, Staff and Student Publications

Epithelial to mesenchymal transition (EMT) is a highly conserved cellular process in several species, from worms to humans. EMT plays a fundamental role in early embryogenesis, wound healing, and cancer metastasis. For neural crest cell (NCC) development, EMT typically results in forming a migratory and potent cell population that generates a wide variety of cell and tissue, including cartilage, bone, connective tissue, endocrine cells, neurons, and glia amongst many others. The degree of conservation between the signaling pathways that regulate EMT during development and metastatic cancer (MC) has not been fully established, despite ample studies. This systematic review and meta-analysis …

A Case Of Simpson-Golabi-Behmel Syndrome Presenting With Cutaneous Findings, Tessa Mullins, Abigail Russell, Chad Johnston

HCA Healthcare Journal of Medicine

Simpson-Golabi-Behmel syndrome is a rare, X-linked recessive syndrome associated with mutations in the genes encoding glypican 3 (GPC3). The majority of cases have been described in pediatric males, with those affected showing manifestations of overgrowth, congenital heart defects, and increased incidence of neoplasia. Due to the X-linked nature of this disorder, penetrance is not well understood in female cases. Very few cases of female presentations of Simpson-Golabi-Behmel syndrome have been described, and this case highlights that there may be an association between mutated GPC3 carrier status and other cancers. We present a case of GPC3 gene mutation suggestive …

Large-Scale Characterization Of Drug Responses Of Clinically Relevant Proteins In Cancer Cell Lines, Wei Zhao, Jun Li, Mei-Ju M Chen, Yikai Luo, Zhenlin Ju, Nicole K Nesser, Katie Johnson-Camacho, Christopher T Boniface, Yancey Lawrence, Nupur T Pande, Michael A Davies, Meenhard Herlyn, Taru Muranen, Ioannis K Zervantonakis, Erika Von Euw, Andre Schultz, Shwetha V Kumar, Anil Korkut, Paul T Spellman, Rehan Akbani, Dennis J Slamon, Joe W Gray, Joan S Brugge, Yiling Lu, Gordon B Mills, Han Liang

Faculty, Staff and Students Publications

Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity …

The Cancer Patient And Cardiology, José Luis Zamorano, Christer Gottfridsson, Riccardo Asteggiano, Dan Atar, Lina Badimon, Jeroen J Bax, Daniela Cardinale, Antonella Cardone, Elizabeth A M Feijen, Péter Ferdinandy, Teresa López-Fernández, Chris P Gale, John H Maduro, Javid Moslehi, Torbjørn Omland, Juan Carlos Plana Gomez, Jessica Scott, Thomas M Suter, Giorgio Minotti

Faculty, Staff and Students Publications

Advances in cancer treatments have improved clinical outcomes, leading to an increasing population of cancer survivors. However, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach that includes expertise in oncology, cardiology and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and …

Research Amidst The Pandemic, Howard Burris

HCA Healthcare Journal of Medicine

Cancer patients need access to promising investigational therapies, available only through clinical trials, and the emergence of COVID-19 and the resulting pandemic became an emerging threat to fulfilling that need. Many academic medical centers were pausing their clinical research programs, diverting their resources and sheltering their teams. Sarah Cannon, the Cancer Institute of HCA Healthcare, made the decision to stay safe, but stay the course.

Tumor Somatic Mutations Also Existing As Germline Polymorphisms May Help To Identify Functional Snps From Genome-Wide Association Studies, Ivan P Gorlov, Xiangjun Xia, Spiridon Tsavachidis, Olga Y Gorlova, Christopher I Amos

Faculty, Staff and Students Publications

We hypothesized that a joint analysis of cancer risk-associated single-nucleotide polymorphism (SNP) and somatic mutations in tumor samples can predict functional and potentially causal SNPs from GWASs. We used mutations reported in the Catalog of Somatic Mutations in Cancer (COSMIC). Confirmed somatic mutations were subdivided into two groups: (1) mutations reported as SNPs, which we call mutational/SNPs and (2) somatic mutations that are not reported as SNPs, which we call mutational/noSNPs. It is generally accepted that the number of times a somatic mutation is reported in COSMIC correlates with its selective advantage to tumors, with more frequently reported mutations being …

The Srg Rat, A Sprague-Dawley Rag2/Il2rg Double-Knockout Validated For Human Tumor Oncology Studies, Fallon K. Noto, Jaya Sangodkar, Bisoye Towobola Adedeji, Sam Moody, Christopher B. Mcclain, Ming Tong, Eric Ostertag, Jack Crawford, Xiaohua Gao, Lauren Hurst, Caitlin M. O'Connor, Erika N. Hanson, Sudeh Izadmehr, Rita Tohmé, Jyothsna Narla, Kristin Lesueur, Kajari Bhattacharya, Amit Rupani, Marwan K. Tayeh, Jeffrey W. Innis, Matthew D. Galsky, B. Mark Evers, Analisa Difeo, Goutham Narla, Tseten Y. Jamling

Markey Cancer Center Faculty Publications

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in …

Investigation Of A Peculiar Case Of Childhood Lymphadenopathy, Chade Aribo, Alonso Al, Allison Woodall, Tommy Y. Kim

HCA Healthcare Journal of Medicine

Introduction: Lymphadenopathy is a common physical finding often associated with an infectious etiology. We present a case of a patient with generalized cervical and supraclavicular lymphadenopathy diagnosed with a rare malignancy. Health care providers should be aware of some uncommon historical or physical examination findings that warrant further investigation.

Clinical Findings: A 16-year-old female presented to the emergency department with 3 days of a fever, congestion and sore throat with swelling around the jaw. Her physical examination findings included bilateral mandibular swelling and generalized cervical lymphadenopathy with palpable supraclavicular lymph nodes.

Outcomes: Complete blood count showed pancytopenia with a white …

Proteolysis-Targeting Chimera (Protac) For Targeted Protein Degradation And Cancer Therapy, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several …

Insights From Immuno-Oncology: The Society For Immunotherapy Of Cancer Statement On Access To Il-6-Targeting Therapies For Covid-19., Paolo Antonio Ascierto, Bernard Fox, Walter Urba, Ana Carrizosa Anderson, Michael B Atkins, Ernest C Borden, Julie Brahmer, Lisa H Butterfield, Alessandra Cesano, Daniel Chen, Tanja De Gruijl, Robert O Dillman, Charles G Drake, Leisha A Emens, Thomas F Gajewski, James L Gulley, F Stephen Hodi, Patrick Hwu, David Kaufman, Howard Kaufman, Michael Lotze, Douglas G Mcneel, Kim Margolin, Francesco Marincola, Michael J Mastrangelo, Marcela V Maus, David R Parkinson, Pedro J Romero, Paul M Sondel, Stefani Spranger, Mario Sznol, George J Weiner, Jon M Wiggington, Jeffrey S Weber

Department of Microbiology and Immunology Faculty Papers

No abstract provided.

Outcomes Following Percutaneous Coronary Intervention In Patients With Cancer, Raymundo A Quintana, Dominique J Monlezun, Giovanni Davogustto, Humberto R Saenz, Francisco Lozano-Ruiz, Daisuke Sueta, Kenichi Tsujita, Uri Landes, Ali E Denktas, Mahboob Alam, David Paniagua, Daniel Addison, Hani Jneid

Faculty, Staff and Students Publications

BACKGROUND: Randomized clinical trials demonstrated the benefits of percutaneous coronary interventions (PCI) in diverse clinical settings. Patients with cancer were not routinely included in these studies.

METHODS/RESULTS: Literature search of PubMed, Cochrane, Medline, SCOPUS, EMBASE, and ClinicalTrials was conducted to identify studies that assessed one-year all-cause, cardiovascular and non-cardiovascular mortality in patients with historical or active cancer. Using the random effects model, we computed risk ratios (RRs) and standardized mean differences and their 95% confidence intervals for the dichotomous and continuous measures and outcomes, respectively. Of 171 articles evaluated in total, 5 eligible studies were included in this meta-analysis. In …

Identification Of Functional Regulatory Elements In The Human Genome Using Pooled Crispr Screens., Samantha M. Borys, Scott T. Younger

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Genome-scale pooled CRISPR screens are powerful tools for identifying genetic dependencies across varied cellular processes. The vast majority of CRISPR screens reported to date have focused exclusively on the perturbation of protein-coding gene function. However, protein-coding genes comprise < 2% of the sequence space in the human genome leaving a substantial portion of the genome uninterrogated. Noncoding regions of the genome harbor important regulatory elements (e.g. promoters, enhancers, silencers) that influence cellular processes but high-throughput methods for evaluating their essentiality have yet to be established.

RESULTS: Here, we describe a CRISPR-based screening approach that facilitates the functional profiling of thousands of noncoding regulatory elements in parallel. We selected the tumor suppressor p53 as a model system and designed a pooled CRISPR library targeting thousands of p53 binding sites throughout the genome. Following transduction into dCas9-KRAB-expressing cells we identified several regulatory elements that influence cell proliferation. Moreover, …

Deficient Histone H3 Propionylation By Brpf1-Kat6 Complexes In Neurodevelopmental Disorders And Cancer., Kezhi Yan, Justine Rousseau, Keren Machol, Laura A. Cross, Katherine E. Agre, Cynthia Forster Gibson, Anne Goverde, Kendra Engleman, Hannah Verdin, Elfride De Baere, Lorraine Potocki, Dihong Zhou, Maxime Cadieux-Dion, Gary A. Bellus, Monisa D. Wagner, Rebecca J. Hale, Natacha Esber, Alan F. Riley, Benjamin D. Solomon, Megan T. Cho, Kirsty Mcwalter, Roy Eyal, Meagan K. Hainlen, Bryce A. Mendelsohn, Hillary M. Porter, Brendan C. Lanpher, Andrea M. Lewis, Juliann Savatt, Isabelle Thiffault, Bert Callewaert, Philippe M. Campeau, Xiang-Jiao Yang

Manuscripts, Articles, Book Chapters and Other Papers

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the …