Digital Commons Network^™

The Durability Of Antibody Responses Of Two Doses Of High-Dose Relative To Two Doses Of Standard-Dose Inactivated Influenza Vaccine In Pediatric Hematopoietic Cell Transplant Recipients: A Multi-Center Randomized Controlled Trial., Jennifer E. Schuster, Lubna Hamdan, Daniel E. Dulek, Carrie L. Kitko, Einas Batarseh, Zaid Haddadin, Laura S. Stewart, Anna Stahl, Molly Potter, Herdi Rahman, Spyros A. Kalams, Claire E. Bocchini, Elizabeth A. Moulton, Susan E. Coffin, Monica I. Ardura, Rachel L. Wattier, Gabriela Maron, Michael Grimley, Grant Paulsen, Christopher J. Harrison, Jason L. Freedman, Paul A. Carpenter, Janet A. Englund, Flor M. Munoz, Lara Danziger-Isakov, Andrew J. Spieker, Natasha B. Halasa, Pediatric Hct Flu Study

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown.

METHODS: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each …

How Do Women Feel Cold Water Swimming Affects Their Menstrual And Perimenopausal Symptoms?, Megan Pound, Heather Massey, Sasha Roseneil, Ruth Williamson, C. Mark Harper, Mike Tipton, Jill Shawe, Malika Felton, Joyce C. Harper

School of Nursing and Midwifery

Objective: This study aimed to determine how women felt cold water swimming affected their menstrual and perimenopausal symptoms. Study design: An online survey that asked women who regularly swim in cold water about their experiences. The survey was advertised for 2 months on social media. Questions related to cold water swimming habits and menstrual and perimenopausal symptoms were analysed. Main outcome measures: Quantitative and qualitative data including; frequency of menstrual and menopause symptoms, the effect of cold water swimming on these symptoms. Results: 1114 women completed the survey. Women reported that cold water swimming reduced their menstrual symptoms, notably psychological …

Genetics And Pathologic Landscape Of Lineage Switch Of Acute Leukemia During Therapy, Ting Zhou, Choladda V Curry, Mahsa Khanlari, Min Shi, Wei Cui, Deniz Peker, Weina Chen, Endi Wang, Juehua Gao, Qi Shen, Wei Xie, Fatima Z Jelloul, Rebecca L King, Ji Yuan, Xiaoqiong Wang, Chen Zhao, Ifeyinwa E Obiorah, Elizabeth L Courville, Eric Nomura, Sindhu Cherian, Mina L Xu, W Richard Burack, Hong-Xing Liu, Elias J Jabbour, Koichi Takahashi, Wei Wang, Sa A Wang, Joseph D Khoury, L Jeffrey Medeiros, Shimin Hu

Faculty, Staff and Students Publications

No abstract provided.

Human Whole-Exome Genotype Data For Alzheimer's Disease, Yuk Yee Leung, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and …

Adverse Outcomes And An Immunosuppressed Endotype In Septic Patients With Reduced Ifn-Γ Elispot, Evan L. Barrios, Drew E. Del Toro, Alexandra Dram, Sandra Meszaros, Sydney Miles, Andrew H. Walton, Anne M. Drewry, Isaiah R. Turnbull, Richard S Hotchkiss, Et Al.

2020-Current year OA Pubs

BACKGROUNDSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients generally relies on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision.METHODSAn ex vivo whole-blood enzyme-linked immunosorbent spot (ELISpot) assay for cellular production of interferon γ (IFN-γ) was evaluated in 107 septic and 68 nonseptic patients from 5 academic health centers using blood samples collected on days 1, 4, and 7 …

An Orally Available Compound Suppresses Glucagon Hypersecretion And Normalizes Hyperglycemia In Type 1 Diabetes, Farzad Asadi, Subhadra C. Gunawardana, Roland E. Dolle, David W. Piston

2020-Current year OA Pubs

Suppression of glucagon hypersecretion can normalize hyperglycemia during type 1 diabetes (T1D). Activating erythropoietin-producing human hepatocellular receptor type-A4 (EphA4) on α cells reduced glucagon hypersecretion from dispersed α cells and T1D islets from both human donor and mouse models. We synthesized a high-affinity small molecule agonist for the EphA4 receptor, WCDD301, which showed robust plasma and liver microsome metabolic stability in both mouse and human preparations. In islets and dispersed islet cells from nondiabetic and T1D human donors, WCDD301 reduced glucagon secretion comparable to the natural EphA4 ligand, Ephrin-A5. In diabetic NOD and streptozotocin-treated mice, once-daily oral administration of WCDD301 …

Neuronal Deletion Of The Circadian Clock Gene Bmal1 Induces Cell-Autonomous Dopaminergic Neurodegeneration, Michael K. Kanan, Patrick W. Sheehan, Jessica N. Haines, Pedro G. Gomez, Adya Dhuler, Collin J. Nadarajah, Zachary M. Wargel, Brittany M. Freeberg, Hemanth R. Nelvagal, Mariko Izumo, Joseph S. Takahashi, Jonathan D. Cooper, Albert A. Davis, Erik S. Musiek

2020-Current year OA Pubs

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia …

A Co2 Sensing Module Modulates Β-1,3-Glucan Exposure In Candida Albicans, Gabriela M. Avelar, Arnab Pradhan, Qinxi Ma, Emer Hickey, Ian Leaves, Corin Liddle, Alejandra V. Rodriguez Rondon, Ann Kristin Kaune, Sophie Shaw, Corinne Maufrais, Natacha Sertour, Judith M. Bain, Daniel E. Larcombe, Leandro J. De Assis, Mihai G. Netea, Carol A. Munro, Delma S. Childers, Lars P. Erwig, Gordon D. Brown, Neil A.R. Gow, Marie Elisabeth Bougnoux, Christophe D'Enfert, Alistair J.P. Brown

Peninsula Medical School

Microbial species capable of co-existing with healthy individuals, such as the commensal fungus Candida albicans, exploit multifarious strategies to evade our immune defenses. These strategies include the masking of immunoinflammatory pathogen-associated molecular patterns (PAMPs) at their cell surface. We reported previously that C. albicans actively reduces the exposure of the proinflammatory PAMP, β-1,3-glucan, at its cell surface in response to host-related signals such as lactate and hypoxia. Here, we show that clinical isolates of C. albicans display phenotypic variability with respect to their lactate- and hypoxia-induced β-1,3-glucan masking. We have exploited this variability to identify responsive and non-responsive clinical isolates. …

Crispr Screening Identifies Bet And Mtor Inhibitor Synergy In Cholangiocarcinoma Through Serine Glycine One Carbon, Yan Zhu, Dengyong Zhang, Pooja Shukla, Young-Ho Jung, Prit Benny Malgulwar, Sharmeen Chagani, Medina Colic, Sarah Benjamin, John A Copland, Lin Tan, Philip L Lorenzi, Milind Javle, Jason T Huse, Jason Roszik, Traver Hart, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged …

Human Whole-Exome Genotype Data For Alzheimer's Disease, Yuk Yee Leung, Adam C Naj, Yi-Fan Chou, Otto Valladares, Michael Schmidt, Kara Hamilton-Nelson, Nicholas Wheeler, Honghuang Lin, Prabhakaran Gangadharan, Liming Qu, Kaylyn Clark, Amanda B Kuzma, Wan-Ping Lee, Laura Cantwell, Heather Nicaretta, Jonathan Haines, Lindsay Farrer, Sudha Seshadri, Zoran Brkanac, Carlos Cruchaga, Margaret Pericak-Vance, Richard P Mayeux, William S Bush, Anita Destefano, Eden Martin, Gerard D Schellenberg, Li-San Wang

Faculty, Staff and Student Publications

The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and …

Trex2 Deficiency Suppresses Spontaneous And Genotoxin-Associated Mutagenesis, Teresa Marple, Mi Young Son, Xiaodong Cheng, Jun Ho Ko, Patrick Sung, Paul Hasty

Faculty, Staff and Student Publications

TREX2, a 3'-5' exonuclease, is a part of the DNA damage tolerance (DDT) pathway that stabilizes replication forks (RFs) by ubiquitinating PCNA along with the ubiquitin E3 ligase RAD18 and other DDT factors. Mismatch repair (MMR) corrects DNA polymerase errors, including base mismatches and slippage. Here we demonstrate that TREX2 deletion reduces mutations in cells upon exposure to genotoxins, including those that cause base lesions and DNA polymerase slippage. Importantly, we show that TREX2 generates most of the spontaneous mutations in MMR-mutant cells derived from mice and people. TREX2-induced mutagenesis is dependent on the nuclease and DNA-binding attributes of TREX2. …

Prenatal Cocaine Exposure And Its Influence On Pediatric Epigenetic Clocks And Epigenetic Scores In Humans, Thiago Wendt Viola, Christina Danzer, Victor Mardini, Claudia Szobot, João Henrique Chrusciel, Laura Stertz, Joy M Schmitz, Consuelo Walss-Bass, Gabriel R Fries, Rodrigo Grassi-Oliveira

Faculty, Staff and Student Publications

The investigation of the effects of prenatal cocaine exposure (PCE) on offspring has been inconsistent, with few studies investigating biological outcomes in humans. We profiled genome-wide DNA methylation (DNAm) of umbilical cord blood (UCB) from newborns with (n = 35) and without (n = 47) PCE. We used DNAm data to (1) assess pediatric epigenetic clocks at birth and (2) to estimate epigenetic scores (ES) for lifetime disorders. We generated gestational epigenetic age estimates (DNAmGA) based on Knight and Bohlin epigenetic clocks. We also investigated the association between DNAmGA and UCB serum brain-derived neurotrophic factor (BDNF) levels. Considering the large-scale …

Non-Canonical Hedgehog Signaling Mediates Profibrotic Hematopoiesis-Stroma Crosstalk In Myeloproliferative Neoplasms, Jessica E Pritchard, Juliette E Pearce, Inge A M Snoeren, Stijn N R Fuchs, Katrin Götz, Fabian Peisker, Silke Wagner, Adam Benabid, Niklas Lutterbach, Vanessa Klöker, James S Nagai, Monica T Hannani, Anna K Galyga, Ellen Sistemich, Bella Banjanin, Niclas Flosdorf, Eric Bindels, Kathrin Olschok, Katharina Biaesch, Nicolas Chatain, Neha Bhagwat, Andrew Dunbar, Rita Sarkis, Olaia Naveiras, Marie-Luise Berres, Steffen Koschmieder, Ross L Levine, Ivan G Costa, Hélène F E Gleitz, Rafael Kramann, Rebekka K Schneider

Faculty, Staff and Student Publications

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a …

A Study To Assess The Efficacy Of Enasidenib And Risk-Adapted Addition Of Azacitidine In Newly Diagnosed Idh2-Mutant Aml, Sheng F Cai, Ying Huang, Jennie R Lance, Hsiaoyin Charlene Mao, Andrew J Dunbar, Samantha N Mcnulty, Todd Druley, Yan Li, Maria R Baer, Wendy Stock, Tibor Kovacsovics, William G Blum, Gary J Schiller, Rebecca L Olin, James M Foran, Mark Litzow, Tara Lin, Prapti Patel, Matthew C Foster, Michael Boyiadzis, Robert H Collins, Jordan Chervin, Abigail Shoben, Jo-Anne Vergilio, Nyla A Heerema, Leonard Rosenberg, Timothy L Chen, Ashley O Yocum, Franchesca Druggan, Sonja Marcus, Mona Stefanos, Brian J Druker, Alice S Mims, Uma Borate, Amy Burd, John C Byrd, Ross L Levine, Eytan M Stein

Faculty, Staff and Student Publications

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of …

Virology-The Path Forward, Angela L Rasmussen, Gigi K Gronvall, Anice C Lowen, Felicia Goodrum, James Alwine, Kristian G Andersen, Simon J Anthony, Joel Baines, Arinjay Banerjee, Andrew J Broadbent, Christopher B Brooke, Samuel K Campos, Patrizia Caposio, Arturo Casadevall, Gary C Chan, Anna R Cliffe, Donna Collins-Mcmillen, Nancy Connell, Blossom Damania, Matthew D Daugherty, Kari Debbink, Terence S Dermody, Daniel Dimaio, W Paul Duprex, Michael Emerman, Denise A Galloway, Robert F Garry, Stephen A Goldstein, Alexander L Greninger, Amy L Hartman, Brenda G Hogue, Stacy M Horner, Peter J Hotez, Jae U Jung, Jeremy P Kamil, Stephanie M Karst, Lou Laimins, Seema S Lakdawala, Igor Landais, Michael Letko, Brett Lindenbach, Shan-Lu Liu, Micah Luftig, Grant Mcfadden, Andrew Mehle, Juliet Morrison, Anne Moscona, Elke Mühlberger, Joshua Munger, Karl Münger, Eain Murphy, Christopher J Neufeldt, Janko Z Nikolich, Christine M O'Connor, Andrew Pekosz, Sallie R Permar, Julie K Pfeiffer, Saskia V Popescu, John G Purdy, Vincent R Racaniello, Charles M Rice, Jonathan A Runstadler, Martin J Sapp, Rona S Scott, Gregory A Smith, Erin M Sorrell, Emily Speranza, Daniel Streblow, Scott A Tibbetts, Zsolt Toth, Koenraad Van Doorslaer, Susan R Weiss, Elizabeth A White, Timothy M White, Christiane E Wobus, Michael Worobey, Satoko Yamaoka, Andrew Yurochko

Faculty, Staff and Students Publications

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is …

B Cells Mediate Lung Ischemia/Reperfusion Injury By Recruiting Classical Monocytes Via Synergistic B Cell Receptor/Tlr4 Signaling, Khashayar Farahnak, Yun Zhu Bai, Yuhei Yokoyama, Deniz B. Morkan, Zhiyi Liu, Junedh M. Amrute, Alejandro De Filippis Falcon, Yuriko Terada, Fuyi Liao, Wenjun Li, Hailey M. Shepherd, Ramsey R. Hachem, Varun Puri, Kory J. Lavine, Andrew E. Gelman, Ankit Bharat, Daniel Kreisel, Ruben G. Nava

2020-Current year OA Pubs

Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte …

Targeting Efferocytosis In Inflammaging, Ivan K H Poon, Kodi S Ravichandran

2020-Current year OA Pubs

Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and tissue repair. However, impaired efferocytosis can result in the accumulation of apoptotic cells, subsequently triggering sterile inflammation through the release of endogenous factors such as DNA and nuclear proteins from membrane permeabilized dying cells. Here, we review the molecular basis of the three key phases of efferocytosis, that is, the detection, uptake, and degradation of apoptotic materials by phagocytes. We also discuss how defects in efferocytosis due to the alteration of phagocytes and dying cells …

Pangenome Graphs Improve The Analysis Of Structural Variants In Rare Genetic Diseases., Cristian Groza, Carl F. Schreck, Warren A. Cheung, Emily G. Farrow, Isabelle Thiffault, Juniper Lake, William B. Rizzo, Gilad Evrony, Tom Curran, Guillaume Bourque, T Pastinen

Manuscripts, Articles, Book Chapters and Other Papers

Rare DNA alterations that cause heritable diseases are only partially resolvable by clinical next-generation sequencing due to the difficulty of detecting structural variation (SV) in all genomic contexts. Long-read, high fidelity genome sequencing (HiFi-GS) detects SVs with increased sensitivity and enables assembling personal and graph genomes. We leverage standard reference genomes, public assemblies (n = 94) and a large collection of HiFi-GS data from a rare disease program (Genomic Answers for Kids, GA4K, n = 574 assemblies) to build a graph genome representing a unified SV callset in GA4K, identify common variation and prioritize SVs that are more likely to …

Self-Renewing Human Naïve Pluripotent Stem Cells Dedifferentiate In 3d Culture And Form Blastoids Spontaneously, Mingyue Guo, Jinyi Wu, Chuanxin Chen, Xinggu Wang, An Gong, Wei Guan, Rowan M Karvas, Kexin Wang, Mingwei Min, Yixuan Wang, Thorold W Theunissen, Shaorong Gao, José C R Silva

2020-Current year OA Pubs

Human naïve pluripotent stem cells (hnPSCs) can generate integrated models of blastocysts termed blastoids upon switch to inductive medium. However, the underlying mechanisms remain obscure. Here we report that self-renewing hnPSCs spontaneously and efficiently give rise to blastoids upon three dimensional (3D) suspension culture. The spontaneous blastoids mimic early stage human blastocysts in terms of structure, size, and transcriptome characteristics and are capable of progressing to post-implantation stages. This property is conferred by the glycogen synthase kinase-3 (GSK3) signalling inhibitor IM-12 present in 5iLAF self-renewing medium. IM-12 upregulates oxidative phosphorylation-associated genes that underly the capacity of hnPSCs to generate blastoids …

Fusionnw, A Potential Clinical Impact Assessment Of Kinases In Pan-Cancer Fusion Gene Network, Chengyuan Yang, Himansu Kumar, Pora Kim

Faculty, Staff and Student Publications

Kinase fusion genes are the most active fusion gene group in human cancer fusion genes. To help choose the clinically significant kinase so that the cancer patients that have fusion genes can be better diagnosed, we need a metric to infer the assessment of kinases in pan-cancer fusion genes rather than relying on the sample frequency expressed fusion genes. Most of all, multiple studies assessed human kinases as the drug targets using multiple types of genomic and clinical information, but none used the kinase fusion genes in their study. The assessment studies of kinase without kinase fusion gene events can …

Mypathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment Of A Tissue-Agnostic Cohort Of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors, Christopher J Sweeney, Ron Bose, Et Al.

2020-Current year OA Pubs

No abstract provided.

Mypathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment Of A Tissue-Agnostic Cohort Of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors, Christopher J Sweeney, John D Hainsworth, Ron Bose, Howard A Burris, Razelle Kurzrock, Charles Swanton, Claire F Friedman, David R Spigel, Tania Szado, Katja Schulze, Richard Price, Julia Malato, Amy A Lo, Jonathan Levy, Yong Wang, Wei Yu, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor …

Exploration Of Programmed Cell Death-Associated Characteristics And Immune Infiltration In Neonatal Sepsis: New Insights From Bioinformatics Analysis And Machine Learning, Yun Hang, Huanxia Qu, Juanzhi Yang, Zhang Li, Shiqi Ma, Chenlu Tang, Chuyan Wu, Yunlei Bao, Feng Jiang, Jin Shu

Faculty, Staff and Student Publications

BACKGROUND: Neonatal sepsis, a perilous medical situation, is typified by the malfunction of organs and serves as the primary reason for neonatal mortality. Nevertheless, the mechanisms underlying newborn sepsis remain ambiguous. Programmed cell death (PCD) has a connection with numerous infectious illnesses and holds a significant function in newborn sepsis, potentially serving as a marker for diagnosing the condition.

METHODS: From the GEO public repository, we selected two groups, which we referred to as the training and validation sets, for our analysis of neonatal sepsis. We obtained PCD-related genes from 12 different patterns, including databases and published literature. We first …

Epha2- And Hdac-Targeted Combination Therapy In Endometrial Cancer, Robiya Joseph, Santosh K Dasari, Sujanitha Umamaheswaran, Lingegowda S Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T Powell, Mary Sobieski, Yuan Liu, Mark Seungwook Kim, Sara Corvigno, Katherine Foster, Pahul Hanjra, Thanh Chung Vu, Mamur A Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N Westin, Anil K Sood

Faculty, Staff and Student Publications

Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival …

Evaluation Of Potential Biomarkers For Lenvatinib Plus Pembrolizumab Among Patients With Advanced Endometrial Cancer: Results From Study 111/Keynote-146, Vicky Makker, Matthew H Taylor, Carol Aghajanian, Allen L Cohn, Marcia S Brose, Christopher Di Simone, Zhu Alexander Cao, Leah Suttner, Andrey Loboda, Razvan Cristescu, Petar Jelinic, Robert Orlowski, Lea Dutta, Junji Matsui, Corina E Dutcus, Yukinori Minoshima, Mark J Messing

Faculty, Staff and Student Publications

BACKGROUND: Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.

METHODS: Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell-inflamed gene expression profile (Tcell …

Induced Degradation Of Lineage-Specific Oncoproteins Drives The Therapeutic Vulnerability Of Small Cell Lung Cancer To Parp Inhibitors, Chiho Kim, Xu-Dong Wang, Zhengshuai Liu, Jianwei Hao, Shuai Wang, Peng Li, Zhenzhen Zi, Qing Ding, Seoyeon Jang, Jiwoong Kim, Yikai Luo, Kenneth E Huffman, Shreoshi Pal Choudhuri, Sofia Del Rio, Ling Cai, Han Liang, Benjamin J Drapkin, John D Minna, Yonghao Yu

Faculty, Staff and Student Publications

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this …

An Incidental Finding Of A High-Grade Glioma With Pleomorphic And Pseudopapillary Features (Hpap) With Pbrm1 Mutation, Maria A Gubbiotti, Jeffrey S Weinberg, Shiao-Pei Weathers, Pushan Dasgupta, Martin C Tom, Kenneth Aldape, Martha Quezado, Zied Abdullaev, Jason T Huse, Leomar Y Ballester

Faculty, Staff and Student Publications

No abstract provided.

Editorial: Recommendations On Inclusive Language And Transparent Reporting Relating To Diversity Dimensions For The Journal Of Pediatric Psychology And Clinical Practice In Pediatric Psychology, Avani C Modi, Sarah J Beal, Stephen P Becker, Katelynn E Boerner, E Thomaseo Burton, Diane Chen, Lori E Crosby, Marisa E Hilliard, Anna M Hood, Nicole A Kahhan, Emily Law, Kristin A Long, Meghan E Mcgrady, Rachel E Sweenie, Idia B Thurston, Cecelia Valrie, Yelena P Wu, Christina L Duncan

Faculty, Staff and Students Publications

No abstract provided.

Live Calcium Imaging Of Virus-Infected Human Intestinal Organoid Monolayers Using Genetically Encoded Calcium Indicators, J Thomas Gebert, Francesca J Scribano, Kristen A Engevik, Joseph M Hyser

Faculty, Staff and Students Publications

Calcium signaling is an integral regulator of nearly every tissue. Within the intestinal epithelium, calcium is involved in the regulation of secretory activity, actin dynamics, inflammatory responses, stem cell proliferation, and many other uncharacterized cellular functions. As such, mapping calcium signaling dynamics within the intestinal epithelium can provide insight into homeostatic cellular processes and unveil unique responses to various stimuli. Human intestinal organoids (HIOs) are a high-throughput, human-derived model to study the intestinal epithelium and thus represent a useful system to investigate calcium dynamics. This paper describes a protocol to stably transduce HIOs with genetically encoded calcium indicators (GECIs), perform …

Dietary Folate And Cofactors Accelerate Age-Dependent P16 Epimutation To Promote Intestinal Tumorigenesis, Li Yang, Robert C Peery, Leah M Farmer, Xia Gao, Yiqun Zhang, Chad J Creighton, Lanjing Zhang, Lanlan Shen

Faculty, Staff and Students Publications

The extent to which non-genetic environmental factors, such as diet, contribute to carcinogenesis has been long debated. One potential mechanism for the effects of environmental factors is through epigenetic modifications that affect gene expression without changing the underlying DNA sequence. However, the functional cooperation between dietary factors and cancer-causing epigenetic regulation is largely unknown. Here, we use a mouse model of age-dependent p16 epimutation, in which the p16 gene activity is directly controlled by promoter DNA methylation. We show p16 epimutation is modulated by folate and cofactors in dietary supplementation, which leads to increased colon cancer risk. Importantly, our findings …