Digital Commons Network^™

Quinoline-Based Compounds Can Inhibit Diverse Enzymes That Act On Dna, Jujun Zhou, Qin Chen, Ren Ren, Jie Yang, Bigang Liu, John R Horton, Caleb Chang, Chuxuan Li, Leora Maksoud, Yifei Yang, Dante Rotili, Abhinav K Jain, Xing Zhang, Robert M Blumenthal, Taiping Chen, Yang Gao, Sergio Valente, Antonello Mai, Xiaodong Cheng

Faculty, Staff and Students Publications

DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (9) or methylpiperazine (11), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and Clostridioides difficile CamA. These compounds (9 and 11) intercalate into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA. This study …

Health Equity Innovation In Precision Medicine: Data Stewardship And Agency To Expand Representation In Clinicogenomics, Patrick J Silva, Vasiliki Rahimzadeh, Reid Powell, Junaid Husain, Scott Grossman, Adam Hansen, Jennifer Hinkel, Rafael Rosengarten, Marcia G Ory, Kenneth S Ramos

Center for Medical Ethics and Health Policy Staff Publications

Most forms of clinical research examine a very minute cross section of the patient journey. Much of the knowledge and evidence base driving current genomic medicine practice entails blind spots arising from underrepresentation and lack of research participation in clinicogenomic databases. The flaws are perpetuated in AI models and clinical practice guidelines that reflect the lack of diversity in data being used. Participation in clinical research and biobanks is impeded in many populations due to a variety of factors that include knowledge, trust, healthcare access, administrative barriers, and technology gaps. A recent symposium brought industry, clinical, and research participants in …

Transforming Growth Factor-Beta Is Increased In Sputum From Individuals With Rheumatoid Arthritis-Associated Pulmonary Fibrosis, Timothy M. Wilson, Matthew Bolt, Andrew Stahly, Joyce S. Lee, Tami J. Bang, Peter B. Sachs, Kevin D. Deane, Stephen M. Humphries, Joshua J. Solomon, M. Kristen Demoruelle

Division of Rheumatology Faculty Papers

BACKGROUND: Interstitial lung disease (ILD) develops in 5-10% of patients with RA and contributes significantly to morbidity and mortality, particularly in those with a fibrotic phenotype. Yet, biomarkers to reliably identify RA patients with underlying pulmonary fibrosis are inadequate. Herein, we used sputum to identify lung-based biomarkers that distinguish RA patients with underlying pulmonary fibrosis and may better inform underlying pathogenesis in RA-ILD.

METHODS: We included 37 RA patients with pulmonary fibrosis (RA-PF) and 30 RA patients without ILD (RA-no-ILD). Induced sputum and serum were tested for TGF-β levels by immunoassay. DNA was extracted to determine presence of the MUC5B …

The Biomechanics Of Fibrillin Microfibrils: Lessons From The Ciliary Zonule, Pooja Rathaur, Juan Rodriguez, John Kuchtey, Samuel Insignares, Wendell B Jones, Rachel W Kuchtey, Steven Bassnett

2020-Current year OA Pubs

Marfan syndrome is an inherited connective tissue disorder that affects the cardiovascular, musculoskeletal, and ocular systems. It is caused by pathogenic variants in the fibrillin-1 gene (

Influenza Knowledge And Barriers To Vaccination In Immunosuppressed Patients In The Pediatric Rheumatology Clinic., Julia G. Harris, Leslie Favier, Jordan T. Jones, Maria Ibarra, Michael J. Holland, Emily Fox, Kelly Jensen, Ashley K. Sherman, Ashley M. Cooper

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Most patients with a pediatric rheumatic disease are at increased risk of influenza due to immunosuppressive medication use. Despite initial quality improvement efforts, our influenza vaccination rate plateaued at 72%, which prompted a survey of patients and families to assess provider vaccine recommendations, influenza knowledge, and barriers to influenza vaccination.

METHODS: Patients on immunosuppressive medication or their parent were eligible to complete a survey between July 2019 and January 2020. Survey questions assessed demographics, rheumatology diagnosis, immunosuppressive medication(s), influenza vaccination recommendation, patient/parent influenza knowledge, and barriers to influenza vaccination. Influenza vaccination rates for immunosuppressed patients were acquired each influenza …

Structural Variant Allelic Heterogeneity In Mecp2 Duplication Syndrome Provides Insight Into Clinical Severity And Variability Of Disease Expression., Davut Pehlivan, Jesse D. Bengtsson, Sameer S. Bajikar, Christopher M. Grochowski, Ming Yin Lun, Mira Gandhi, Angad Jolly, Alexander J. Trostle, Holly K. Harris, Bernhard Suter, Sukru Aras, Melissa B. Ramocki, Haowei Du, Michele G. Mehaffey, Kyunghee Park, Ellen Wilkey, Cemal Karakas, Jesper J. Eisfeldt, Maria Pettersson, Lynn Liu, Marwan S. Shinawi, Virginia E. Kimonis, Wojciech Wiszniewski, Kyle Mckenzie, Timo Roser, Angela M. Vianna-Morgante, Alberto S. Cornier, Ahmed Abdelmoity, James P. Hwang, Shalini N. Jhangiani, Donna M. Muzny, Tadahiro Mitani, Kazuhiro Muramatsu, Shin Nabatame, Daniel G. Glaze, Jawid M. Fatih, Richard A. Gibbs, Zhandong Liu, Anna Lindstrand, Fritz J. Sedlazeck, James R. Lupski, Huda Y. Zoghbi, Claudia M B Carvalho

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive …

Transcriptomic Clustering Of Chronic Lymphocytic Leukemia: Molecular Subtypes Based On Bruton’S Tyrosine Kinase Expression Levels, Gorkem Kismali, Ganiraju Manyam, Nitin Jain, Cristina Ivan, Betty Lamothe, Mary L Ayres, Lakesla R Iles, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples …

Structural Variant Allelic Heterogeneity In Mecp2 Duplication Syndrome Provides Insight Into Clinical Severity And Variability Of Disease Expression, Davut Pehlivan, Jesse D Bengtsson, Sameer S Bajikar, Christopher M Grochowski, Ming Yin Lun, Mira Gandhi, Angad Jolly, Alexander J Trostle, Holly K Harris, Bernhard Suter, Sukru Aras, Melissa B Ramocki, Haowei Du, Michele G Mehaffey, Kyunghee Park, Ellen Wilkey, Cemal Karakas, Jesper J Eisfeldt, Maria Pettersson, Lynn Liu, Marwan S Shinawi, Virginia E Kimonis, Wojciech Wiszniewski, Kyle Mckenzie, Timo Roser, Angela M Vianna-Morgante, Alberto S Cornier, Ahmed Abdelmoity, James P Hwang, Shalini N Jhangiani, Donna M Muzny, Tadahiro Mitani, Kazuhiro Muramatsu, Shin Nabatame, Daniel G Glaze, Jawid M Fatih, Richard A Gibbs, Zhandong Liu, Anna Lindstrand, Fritz J Sedlazeck, James R Lupski, Huda Y Zoghbi, Claudia M B Carvalho

Faculty, Staff and Students Publications

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive …

Conventional Cytogenetic Analysis Of Solid Tumor Abnormalities: A 25-Year Review Of Proficiency Test Results From The College Of American Pathologists/American College Of Medical Genetics And Genomics Cytogenetics Committee, Rachel K Vanderscheldon, Yang Cao, Et Al.

2020-Current year OA Pubs

No abstract provided.

The C-Terminal Activating Domain Promotes Pannexin 1 Channel Opening, Erik Henze, Jacqueline J Ehrlich, Janice L Robertson, Eric Gelsleichter, Toshimitsu Kawate

2020-Current year OA Pubs

Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of adenosine triphosphate (ATP) from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of the C-terminus promotes the opening of the Panx1 channel by unplugging the pore. However, this simple pore-plugging mechanism alone cannot account for the observation that a Panx1 construct ending before the caspase cleavage site remains closed. Here, we show that a helical region located immediately before the caspase cleavage site, referred to as the "C-terminal activating domain (CAD)", plays a pivotal role in facilitating Panx1 activation. Electrophysiology and mutagenesis studies uncovered that two conserved …

Clover (Clostridium Difficile Vaccine Efficacy Trial) Study: A Phase 3, Randomized Trial Investigating The Efficacy And Safety Of A Detoxified Toxin A/B Vaccine In Adults 50 Years And Older At Increased Risk Of Clostridioides Difficile Infection, Curtis J Donskey, Erik R Dubberke, Et Al.

2020-Current year OA Pubs

BACKGROUND: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention.

METHODS: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were …

Co-Inhibition Of Tgli1 And Gp130 Using Fda-Approved Ketoconazole And Bazedoxifene Is Synergistic Against The Growth And Metastasis Of Her2-Enriched And Triple-Negative Breast Cancers, Sara Manore, Chuling Zhuang, Mariana K Najjar, Grace L Wong, Shivani Bindal, Kounosuke Watabe, Jiayuh Lin, Hui-Wen Lo

Faculty, Staff and Student Publications

Breast cancer stem cells (CSCs) are resistant to most cancer therapeutics and contribute to tumor recurrence and metastasis. Two breast CSC-promoting transcription factors, truncated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3), have been reported to be frequently co-expressed in HER2-enriched breast cancer and triple-negative breast cancer (TNBC), undergo protein-protein interactions for gene regulation and activation, and functionally cooperate to promote breast CSCs. STAT3 can be activated by activated interleukin-6 receptor/glycoprotein-130 (IL-6R/GP130). Co-targeting of tGLI1 and IL-6R/GP130 has not been investigated in breast cancer or any tumor type. Here, we report that tGLI1 and …

Uba1 Inhibition Sensitizes Cancer Cells To Parp Inhibitors, Sharad Awasthi, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Yang Li, Sima Khazaei, Sumanta Ghosh, Collene R Jeter, Jinsong Liu, Gordon B Mills, Shannon N Westin, Michael T Lewis, Weiyi Peng, Anil K Sood, Timothy A Yap, S Stephen Yi, Daniel J Mcgrail, Nidhi Sahni

Faculty, Staff and Students Publications

Therapeutic strategies targeting the DNA damage response, such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have revolutionized cancer treatment in tumors deficient in homologous recombination (HR). However, overcoming innate and acquired resistance to PARPi remains a significant challenge. Here, we employ a genome-wide CRISPR knockout screen and discover that the depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARPi in HR-proficient ovarian cancer cells. We show that silencing or pharmacological inhibition of UBA1 sensitizes multiple cell lines and organoid models to PARPi. Mechanistic studies uncover that UBA1 inhibition not only impedes HR repair to sensitize cells to PARP inhibition …

Large-Scale Crispr/Cas9 Deletions Within The Wfdc Gene Cluster Uncover Gene Functionality And Critical Roles In Mammalian Reproduction, Katarzyna Kent, Kaori Nozawa, Rachel Parkes, Laura Dean, Frey Daniel, Mei Leng, Antrix Jain, Anna Malovannaya, Martin M Matzuk, Thomas X Garcia

Faculty, Staff and Students Publications

Despite 96 million years of evolution separating humans and rodents, 11 closely related reproductive tract-specific genes in humans—SPINT3, WFDC6, EPPIN, WFDC8, WFDC9, WFDC10A, WFDC11, WFDC10B, WFDC13, SPINT4, and WFDC3—and the 13 reproductive tract-specific orthologous genes in mice, form highly conserved syntenic gene clusters indicative of conserved, combined critical functions. Further, despite significant progress toward a nonhormonal male contraceptive targeting the protein encoded by one of these genes, epididymal peptidase inhibitor (EPPIN), and associations found between mutations in EPPIN and an increased risk of male infertility, neither EPPIN nor …

First-In-Human Dose-Escalation Study Of Fianlimab, An Antilymphocyte Activation Gene-3 Antibody, With Cemiplimab In Patients With Advanced Malignancies, Nehal J Lakhani, Haeseong Park, Et Al.

2020-Current year OA Pubs

PURPOSE: Preclinical data indicate that fianlimab (antilymphocyte activation gene-3) plus cemiplimab (anti-PD-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies.

PATIENTS AND METHODS: Adult patients received 1 to 40 mg/kg of fianlimab plus 350 mg of cemiplimab every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were the rate of dose-limiting toxicities, adverse events (including immune mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of …

Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation For B-Lineage Acute Lymphoblastic Leukemia, Yuanxin Wang, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Ziyi Li, Ken Chen

Faculty, Staff and Student Publications

Decoding cellular state transitions is crucial for understanding complex biological processes in development and disease. While recent advancements in single-cell RNA sequencing (scRNA-seq) offer insights into cellular trajectories, existing tools primarily study expressional rather than regulatory state shifts. We present CellTran, a statistical approach utilizing paired-gene expression correlations to detect transition cells from scRNA-seq data without explicitly resolving gene regulatory networks. Applying our approach to various contexts, including tissue regeneration, embryonic development, preinvasive lesions, and humoral responses post-vaccination, reveals transition cells and their distinct gene expression profiles. Our study sheds light on the underlying molecular mechanisms driving cellular state transitions, …

A Statistical Approach For Systematic Identification Of Transition Cells From Scrna-Seq Data, Yuanxin Wang, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Ziyi Li, Ken Chen

Faculty, Staff and Student Publications

Decoding cellular state transitions is crucial for understanding complex biological processes in development and disease. While recent advancements in single-cell RNA sequencing (scRNA-seq) offer insights into cellular trajectories, existing tools primarily study expressional rather than regulatory state shifts. We present CellTran, a statistical approach utilizing paired-gene expression correlations to detect transition cells from scRNA-seq data without explicitly resolving gene regulatory networks. Applying our approach to various contexts, including tissue regeneration, embryonic development, preinvasive lesions, and humoral responses post-vaccination, reveals transition cells and their distinct gene expression profiles. Our study sheds light on the underlying molecular mechanisms driving cellular state transitions, …

Pharmacologic Blockade Of A Pioneer Transcription Factor, Katerina Cermakova, H Courtney Hodges

Faculty, Staff and Students Publications

Cancers frequently co-opt lineage-specific transcription factors (TF) utilized in normal development to sustain proliferation. However, the effects of these TFs on tumor development depend considerably on where in the genome they bind. A new article by Taylor and colleagues expands on previously developed diamidine compounds that obstruct the DNA binding sites of the pioneer TF PU.1 (SPI1) in acute myeloid leukemia. Immobilization and sequencing of genomic DNA targeted by these compounds revealed that these inhibitors alter the genomic binding patterns of PU.1. The authors report that their strategy constrains the genomic binding preferences of PU.1, leading to redistribution of PU.1 …

Development Of A Ripk1 Degrader To Enhance Antitumor Immunity, Xin Yu, Dong Lu, Xiaoli Qi, Rishi Ram Paudel, Hanfeng Lin, Bryan L Holloman, Feng Jin, Longyong Xu, Lang Ding, Weiyi Peng, Meng C Wang, Xi Chen, Jin Wang

Faculty, Staff and Students Publications

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports …

Estimation Of Prevalence Of Autoimmune Diseases In The United States Using Electronic Health Record Data, Aaron H. Abend, Albert M. Lai, Et Al.

2020-Current year OA Pubs

BACKGROUNDPrevious epidemiologic studies of autoimmune diseases in the US have included a limited number of diseases or used metaanalyses that rely on different data collection methods and analyses for each disease.METHODSTo estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from 6 large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time.RESULTSOur findings indicate that over 15 million people, or 4.6% of …

Ire1Α Silences Dsrna To Prevent Taxane-Induced Pyroptosis In Triple-Negative Breast Cancer, Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E Dobrolecki, Weijie Zhang, Dong Han, Na Zhao, Eric Jaehnig, Jingyi Wang, Weiche Wu, Davis A Graham, Yumei Li, Rui Chen, Weiyi Peng, Yiwen Chen, Andre Catic, Zhibin Zhang, Bing Zhang, Anthony M Mustoe, Albert C Koong, George Miles, Michael T Lewis, Meng C Wang, Susan M Rosenberg, Bert W O'Malley, Thomas F Westbrook, Han Xu, Xiang H-F Zhang, C Kent Osborne, Jin Billy Li, Matthew J Ellis, Mothaffar F Rimawi, Jeffrey M Rosen, Xi Chen

Faculty, Staff and Students Publications

Chemotherapy is often combined with immune checkpoint inhibitor (ICI) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane-chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced dsRNA through RIDD (Regulated IRE1-Dependent Decay) to prevent NLRP3 inflammasome–dependent pyroptosis. Inhibition of IRE1α in Trp53−/− TNBC allows taxane to induce extensive dsRNAs that are sensed …

Malaria Parasites Require A Divergent Heme Oxygenase For Apicoplast Gene Expression And Biogenesis, Amanda Mixon Blackwell, Yasaman Jami-Alahmadi, Armiyaw S Nasamu, Shota Kudo, Akinobu Senoo, Celine Slam, Kouhei Tsumoto, James A Wohlschlegel, Jose Manuel Martinez Caaveiro, Daniel E Goldberg, Paul A Sigala

2020-Current year OA Pubs

Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection,

Mexican Health And Aging Study Biomarker And Genetic Data Profile, Rafael Samper-Ternent, Jesús Daniel Zazueta-Borboa, Alejandra Michaels-Obregon, Dolly Reyes-Dumeyer, Sandra Barral, Giuseppe Tosto, Rebeca Wong

Faculty, Staff and Student Publications

The Mexican Health and Aging Study (MHAS) is one of the largest ongoing longitudinal studies of aging in Latin America, with six waves over 20 years. MHAS includes sociodemographic, economic, and health data from a nationally representative sample of adults 50 years and older in urban and rural Mexico. MHAS is designed to study the impact of diseases on adults' health, function, and mortality. As Mexico is experiencing rapid population aging, providing adequate information to study this phenomenon is vital for designing and implementing public policies. The availability of biomarker and genetic data and longitudinal survey data elevates opportunities for …

Diversity And Characteristics Of The Oral Microbiome Associated With Self-Reported Ancestral/Ethnic Groups, Qingguo Wang, Bing-Yan Wang, She'neka Williams, Hua Xie

Faculty, Staff and Student Publications

Periodontitis disproportionately affects genetic ancestral/ethnic groups. To characterize the oral microbiome from different genetic ancestral/ethnic groups, we collected 161 dental plaque samples from self-identified African Americans (AAs), Caucasian Americans (CAs), and Hispanic Americans (HAs) with clinical gingival health or biofilm-induced gingivitis on an intact periodontium. DNA was extracted from these samples, and then DNA libraries were prepared and sequenced using an Illumina NovaSeq high-throughput sequencer. We found significant differences in the diversity and abundance of microbial taxa among dental plaque samples of the AA, CA, and HA groups. We also identified unique microbial species in a self-reported ancestral/ethnic group. Moreover, …

Nomenclature For Human And Animal Fungal Pathogens And Diseases: A Proposal For Standardized Terminology, Sybren De Hoog, Thomas J Walsh, Sarah A Ahmed, Ana Alastruey-Izquierdo, Maiken Cavling Arendrup, Andrew Borman, Sharon Chen, Anuradha Chowdhary, Robert C Colgrove, Oliver A Cornely, David W Denning, Philippe J Dufresne, Laura Filkins, Jean-Pierre Gangneux, Josepa Gené, Andreas H Groll, Jaques Guillot, Gerhard Haase, Catriona Halliday, David L Hawksworth, Roderick Hay, Martin Hoenigl, Vit Hubka, Tomasz Jagielski, Hazal Kandemir, Sarah E Kidd, Julianne V Kus, June Kwon-Chung, Shawn R Lockhart, Jacques F Meis, Leonel Mendoza, Wieland Meyer, M Hong Nguyen, Yinggai Song, Tania C Sorrell, J Benjamin Stielow, Rachel Vilela, Roxana G Vitale, Nancy L Wengenack, P Lewis White, Luis Ostrosky-Zeichner, Sean X Zhang

Faculty, Staff and Student Publications

Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host's immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately …

Imlunestrant, An Oral Selective Estrogen Receptor Degrader, As Monotherapy And In Combination With Targeted Therapy In Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Phase Ia/Ib Ember Study, Komal L Jhaveri, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

PURPOSE: Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in

METHODS: An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label.

RESULTS: Overall, 262 patients with ER+/HER2- ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 …

Prenatal Social Disadvantage Is Associated With Alterations In Functional Networks At Birth, Ashley N Nielsen, Regina L Triplett, Lourdes M Bernardez, Ursula A Tooley, Max P Herzberg, Rachel E Lean, Sydney Kaplan, Dominique Meyer, Jeanette K Kenley, Dimitrios Alexopoulos, David Losielle, Aidan Latham, Tara A Smyser, Arpana Agrawal, Josh S Shimony, Joshua J Jackson, J Philip Miller, Marcus E Raichle, Barbara B Warner, Cynthia E Rogers, Chad M Sylvester, Deanna M Barch, Joan L Luby, Christopher D Smyser

2020-Current year OA Pubs

Childhood exposure to social disadvantage is a major risk factor for psychiatric disorders and poor developmental, educational, and occupational outcomes, presumably because adverse exposures alter the neurodevelopmental processes that contribute to risk trajectories. Yet, given the limited social mobility in the United States and other countries, childhood social disadvantage is frequently preceded by maternal social disadvantage during pregnancy, potentially altering fetal brain development during a period of high neuroplasticity through hormonal, microbiome, epigenetic, and immune factors that cross the placenta and fetal blood-brain barrier. The current study examines prenatal social disadvantage to determine whether these exposures in utero are associated …

Angiogenin-Catalyzed Cleavage Within Trna Anticodon-Loops Identified By Cp-Rna-Seq, Megumi Shigematsu, Ryuma Matsubara, Justin Gumas, Takuya Kawamura, Yohei Kirino

Computational Medicine Center Faculty Papers

Angiogenin (Ang), an endoribonuclease belonging to the RNase A superfamily, cleaves the anticodon-loops of tRNAs to produce tRNA-half molecules. Although previous studies have demonstrated the involvement of Ang in the pathobiology of neurodegenerative disorders, the characterization of Ang-generated tRNA halves in neuronal cells remains limited. This is partly due to the technical limitations of standard RNA-seq methods, which cannot capture Ang-generated RNAs containing a 2',3'-cyclic phosphate (cP). In this report, we established an Ang-treatment model using SH-SY5Y, a human neuroblastoma cell line, and demonstrated Ang-dependent accumulation of tRNA halves. By performing cP-RNA-seq, which selectively captures cP-containing RNAs, we identified Ang-generated …

An Empirical Model Of Carbon-Ion Relative Biological Effectiveness Based On The Linear Correlation Between Radiosensitivity To Photons And Carbon Ions, David B Flint, Scott J Bright, Conor Mcfadden, Teruaki Konishi, David K J Martinus, Mandira Manandhar, Mariam Ben Kacem, Lawrence Bronk, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Objective.To develop an empirical model to predict carbon ion (C-ion) relative biological effectiveness (RBE).Approach.We used published cell survival data comprising 360 cell line/energy combinations to characterize the linear energy transfer (LET) dependence of cell radiosensitivity parameters describing the dose required to achieve a given survival level, e.g. 5% (D5%), which are linearly correlated between photon and C-ion radiations. Based on the LET response of the metrics D5%and D37%, we constructed a model containing four free parameters that predicts cells' linear quadratic model (LQM) survival curve parameters for C-ions,αCandβC, from the reference LQM parameters …

Impact Of Prior Inotuzumab Ozogamicin Treatment On Brexucabtagene Autoleucel Outcomes In Adults With B-Cell All, Ibrahim Aldoss, Gregory W Roloff, Rawan Faramand, Noam E Kopmar, Chenyu Lin, Anjali S Advani, Simone E Dekker, Vishal K Gupta, Timothy E O'Connor, Nikeshan Jeyakumar, Ibrahim N Muhsen, Yannis Valtis, Amy Zhang, Katharine Miller, Katherine Sutherland, Kaitlyn C Dykes, Mohamed Ahmed, Evan Chen, Hector Zambrano, Danielle Bradshaw, Santiago Mercadal, Marc Schwartz, Sean Tracy, Bhagirathbhai Dholaria, Michal Kubiak, Akash Mukherjee, Navneet Majhail, Minoo Battiwalla, Luke Mountjoy, Shahbaz A Malik, John Mathews, Paul Shaughnessy, Aaron C Logan, Abdullah Ladha, Maryann Stefan, Caitlin Guzowski, Rasmus T Hoeg, Talal Hilal, Jozal Moore, Matthew Connor, Kristen M O'Dwyer, Laquisa C Hill, Stephanie B Tsai, Joshua Sasine, Melhem M Solh, Catherine J Lee, Vamsi K Kota, Divya Koura, Muthu Veeraputhiran, Betsy Blunk, Caspian Oliai, Jessica T Leonard, Noelle V Frey, Jae H Park, Marlise R Luskin, Veronika Bachanova, Ahmed Galal, Michael R Bishop, Wendy Stock, Ryan D Cassaday, Vinod Pullarkat, Bijal D Shah, Lori S Muffly

Faculty, Staff and Students Publications

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). …