Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Pediatric Status Epilepticus Management By Emergency Medical Services (The Pserg Cohort), Marta Amengual-Gual, Iván Sánchez Fernández, Alejandra Vasquez, Nicholas S Abend, Anne Anderson, Ravindra Arya, Cristina Barcia Aguilar, J Nicholas Brenton, Jessica L Carpenter, Kevin E Chapman, Justice Clark, Raquel Farias-Moeller, William D Gaillard, Tracy A Glauser, Joshua L Goldstein, Howard P Goodkin, Yi-Chen Lai, Mohamad A Mikati, Lindsey A Morgan, Edward J Novotny, Adam P Ostendorf, Eric T Payne, Katrina Peariso, Juan Piantino, Latania Reece, James J Riviello, Kumar Sannagowdara, Theodore Sheehan, Robert C Tasker, Dmitry Tchapyjnikov, Alexis A Topjian, Mark S Wainwright, Angus Wilfong, Korwyn Williams, Tobias Loddenkemper

Faculty, Staff and Students Publications

Purpose: Delayed treatment in status epilepticus (SE) is independently associated with increased treatment resistance, morbidity, and mortality. We describe the prehospital management pathway and Emergency Medical Services (EMS) timeliness in children who developed refractory convulsive status epilepticus (RCSE).

Methods: Retrospective multicenter study in the United States using prospectively collected observational data from June 2011 to March 2020. We selected pediatric patients (one month-21 years) with RCSE initiated outside the hospital and transported to the hospital by EMS.

Results: We included 91 patients with a median (percentile25-percentile75) age of 3.0 (1.5-7.3) years. The median time from seizure onset to hospital arrival …

Time To Establish An International Vaccine Candidate Pool For Potential Highly Infectious Respiratory Disease: A Community’S View, Lan Yao, Hiam Chemaitelly, Emanuel Goldman, Esayas Kebede Gudina, Asma Khalil, Rahaman Ahmed, Ayorinde Babatunde James, Anna Roca, Mosoka Papa Fallah, Andrew Macnab, William C Cho, John Eikelboom, Farah Naz Qamar, Peter Kremsner, Miquel Oliu-Barton, Ivan Sisa, Birkneh Tilahun Tadesse, Florian Marks, Lishi Wang, Jerome H Kim, Xia Meng, Yongjun Wang, Alyce D Fly, Cong-Yi Wang, Sara W Day, Scott C Howard, J Carolyn Graff, Marcello Maida, Kunal Ray, Carlos Franco-Paredes, Tapfumanei Mashe, Ngashi Ngongo, Jean Kaseya, Nicaise Ndembi, Yu Hu, Maria Elena Bottazzi, Peter J Hotez, Ken J Ishii, Gang Wang, Dianjun Sun, Lotfi Aleya, Weikuan Gu

Faculty, Staff and Students Publications

In counteracting highly infectious and disruptive respiratory diseases such as COVID-19, vaccination remains the primary and safest way to prevent disease, reduce the severity of illness, and save lives. Unfortunately, vaccination is often not the first intervention deployed for a new pandemic, as it takes time to develop and test vaccines, and confirmation of safety requires a period of observation after vaccination to detect potential late-onset vaccine-associated adverse events. In the meantime, nonpharmacologic public health interventions such as mask-wearing and social distancing can provide some degree of protection. As climate change, with its environmental impacts on pathogen evolution and international …

A Recombinant Protein Xbb15 Rbd/Alum/Cpg Vaccine Elicits High Neutralizing Antibody Titers Against Omicron Subvariants Of Sars-Cov-2, Syamala Rani Thimmiraju, Rakesh Adhikari, Maria Jose Villar, Jungsoon Lee, Zhuyun Liu, Rakhi Kundu, Yi-Lin Chen, Suman Sharma, Karm Ghei, Brian Keegan, Leroy Versteeg, Portia M Gillespie, Allan Ciciriello, Nelufa Y Islam, Cristina Poveda, Nestor Uzcategui, Wen-Hsiang Chen, Jason T Kimata, Bin Zhan, Ulrich Strych, Maria Elena Bottazzi, Peter J Hotez, Jeroen Pollet

Faculty, Staff and Students Publications

(1) Background: We previously reported the development of a recombinant protein SARS-CoV-2 vaccine, consisting of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, adjuvanted with aluminum hydroxide (alum) and CpG oligonucleotides. In mice and non-human primates, our wild-type (WT) RBD vaccine induced high neutralizing antibody titers against the WT isolate of the virus, and, with partners in India and Indonesia, it was later developed into two closely resembling human vaccines, Corbevax and Indovac. Here, we describe the development and characterization of a next-generation vaccine adapted to the recently emerging XBB variants of SARS-CoV-2. (2) Methods: We conducted preclinical studies …

Prevalence Of Pathogenic Germline Variants In Adult-Type Diffuse Glioma, Malcolm F Mcdonald, Lyndsey L Prather, Cassandra R Helfer, Ethan B Ludmir, Alfredo E Echeverria, Shlomit Yust-Katz, Akash J Patel, Benjamin Deneen, Ganesh Rao, Ali Jalali, Shweta U Dhar, Chris I Amos, Jacob J Mandel

Faculty, Staff and Students Publications

BACKGROUND: No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma.

METHODS: A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected.

RESULTS: We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, …

A Pancreatic Player In Dementia: Pathological Role For Islet Amyloid Polypeptide Accumulation In The Brain, Angelina S Bortoletto, Ronald J Parchem

Faculty, Staff and Students Publications

Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia. While multiple factors contribute to this predisposition, one of these involves the increased secretion of amylin, or islet amyloid polypeptide, that accompanies the pathophysiology of type 2 diabetes mellitus. Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia, including Alzheimer’s disease and vascular dementia, but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear. In this review, we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage, ultimately leading to …

Mammalian Aging Driven By Transcription Going Awry, Brenna S Mccauley, Weiwei Dang

Faculty, Staff and Students Publications

The mechanisms that underlie increased cryptic transcription during senescence and aging have been poorly understood. Sen et al. recently identified cryptic transcription start sites (cTSSs) and chromatin state changes that may contribute to cTSS activation in mammals. Their results indicate that enhancer-promoter conversion may drive cryptic transcription in senescence.

Views Of Adolescents And Young Adults With Cancer And Their Oncologists Toward Patients' Participation In Genomic Research, Amanda M Gutierrez, Jill O Robinson, Robin Raesz-Martinez, Isabel Canfield, Mary A Majumder, Sarah Scollon, Lauren R Desrosiers, Rebecca L Hsu, Wendy Allen-Rhoades, D Williams Parsons, Sharon E Plon, Amy L Mcguire, Janet Malek

Faculty, Staff and Students Publications

Purpose:

With increased use of genomic testing in cancer research and clinical care, it is important to understand the perspectives and decision-making preferences of adolescents and young adults (AYAs) with cancer and their treating oncologists.

Methods:

We conducted an interview substudy of the BASIC3 Study, which enrolled newly diagnosed cancer patients <18 years of age with assent. Of 32 young adults (YAs) with cancer who reached the age of majority (AOM; 18 years) while on study, 12 were successfully approached and all consented to study continuation at AOM. Of those, seven completed an interview. Patients' oncologists, who enrolled and participated in return of clinical genomic results, were also interviewed (n = 12). Interviews were transcribed, deidentified, and analyzed using thematic analysis.

Results:

YAs cited the possibility of helping others and advancing science as major reasons for their assent to initial study enrollment and their willingness to consent at AOM. YAs thought obtaining informed consent from research participants for …

Germline Pathogenic Smarca4 Variants In Neuroblastoma, Leora Witkowski, Kim E Nichols, Marjolijn Jongmans, Nienke Van Engelen, Ronald R De Krijger, Jennifer Herrera-Mullar, Lieve Tytgat, Armita Bahrami, Helen Mar Fan, Aimee L Davidson, Thomas Robertson, Michael Anderson, Martin Hasselblatt, Sharon E Plon, William D Foulkes

Faculty, Staff and Students Publications

Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodeling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcemic type, atypical teratoid and malignant rhabdoid tumor, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma, including four previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4. Median age at diagnosis was 5 years (range 2 …

The Improving Medication Adherence In Adolescents And Young Adults Following Liver Transplantation (Imalt) Multisite Trial: Design And Trial Implementation Considerations, Eyal Shemesh, Sarah Duncan-Park, George Mazariegos, Rachel Annunziato, Ravinder Anand, Miguel Reyes-Mugica, Jeff Mitchell, Benjamin L Shneider

Faculty, Staff and Students Publications

Background/aims: Medication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection.

Methods: Improving …

The Role Of Alcohol Extract Of Cranberry In Improving Serum Indices Of Experimental Metaproterenol-Induced Heart Damage In Rats, Kimia Salmasi, Ali Hassanpour, Bahram Amouoghli Tabrizi, Sina Moghaddam

Faculty, Staff and Students Publications

Cranberry offers numerous cardiovascular benefits. According to several studies, this fruit promotes the oxidation of low‐density lipoprotein, enhances high‐density lipoprotein, reduces platelet coagulation, and improves vascular activity. Albino male rats were divided into five groups (n = 5 per group). The control group received intraperitoneal administration of normal saline. The second group was injected with metaproterenol (MET) 3 days a week for 4 weeks. The third, fourth, and fifth groups were given cranberry extract in doses of 75, 100, and 150, respectively, along with heart‐damaging drugs. Blood samples were collected and sent to the laboratory on the fourth weekend …

Current Perspectives On Mass Spectrometry-Based Immunopeptidomics: The Computational Angle To Tumor Antigen Discovery, Bing Zhang, Michal Bassani-Sternberg

Faculty, Staff and Students Publications

Identification of tumor antigens presented by the human leucocyte antigen (HLA) molecules is essential for the design of effective and safe cancer immunotherapies that rely on T cell recognition and killing of tumor cells. Mass spectrometry (MS)-based immunopeptidomics enables high-throughput, direct identification of HLA-bound peptides from a variety of cell lines, tumor tissues, and healthy tissues. It involves immunoaffinity purification of HLA complexes followed by MS profiling of the extracted peptides using data-dependent acquisition, data-independent acquisition, or targeted approaches. By incorporating DNA, RNA, and ribosome sequencing data into immunopeptidomics data analysis, the proteogenomic approach provides a powerful means for identifying …

Human Glp1r Variants Affecting Glp1r Cell Surface Expression Are Associated With Impaired Glucose Control And Increased Adiposity, Wenwen Gao, Lei Liu, Eunna Huh, Florence Gbahou, Erika Cecon, Masaya Oshima, Ludivine Houzé, Panagiotis Katsonis, Alan Hegron, Zhiran Fan, Guofei Hou, Guillaume Charpentier, Mathilde Boissel, Mehdi Derhourhi, Michel Marre, Beverley Balkau, Philippe Froguel, Raphael Scharfmann, Olivier Lichtarge, Julie Dam, Amélie Bonnefond, Jianfeng Liu, Ralf Jockers

Faculty, Staff and Students Publications

The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in patients with type 2 diabetes (T2D) and obesity 1, 2. The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we performed a functional profiling of 60 GLP1R variants across four signaling pathways and revealed an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain- (GoF) and loss-of-functions (LoF). The defective insulin secretion of GLP1R LoF variants was rescued by allosteric GLP1R ligands …

Scalable Nanopore Sequencing Of Human Genomes Provides A Comprehensive View Of Haplotype-Resolved Variation And Methylation, Mikhail Kolmogorov, Kimberley J Billingsley, Mira Mastoras, Melissa Meredith, Jean Monlong, Ryan Lorig-Roach, Mobin Asri, Pilar Alvarez Jerez, Laksh Malik, Ramita Dewan, Xylena Reed, Rylee M Genner, Kensuke Daida, Sairam Behera, Kishwar Shafin, Trevor Pesout, Jeshuwin Prabakaran, Paolo Carnevali, Jianzhi Yang, Arang Rhie, Sonja W Scholz, Bryan J Traynor, Karen H Miga, Miten Jain, Winston Timp, Adam M Phillippy, Mark Chaisson, Fritz J Sedlazeck, Cornelis Blauwendraat, Benedict Paten

Faculty, Staff and Students Publications

Long-read sequencing technologies substantially overcome the limitations of short-reads but have not been considered as a feasible replacement for population-scale projects, being a combination of too expensive, not scalable enough or too error-prone. Here we develop an efficient and scalable wet lab and computational protocol, Napu, for Oxford Nanopore Technologies long-read sequencing that seeks to address those limitations. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the National Institutes of Health Center for Alzheimer's and Related Dementias. Using a single PromethION flow cell, we can detect single nucleotide polymorphisms with …

Neurodevelopmental Deficits And Cell-Type-Specific Transcriptomic Perturbations In A Mouse Model Of Hnrnpu Haploinsufficiency, Sarah A Dugger, Ryan S Dhindsa, Gabriela De Almeida Sampaio, Andrew K Ressler, Elizabeth E Rafikian, Sabrina Petri, Verity A Letts, Jiajie Teoh, Junqiang Ye, Sophie Colombo, Yueqing Peng, Mu Yang, Michael J Boland, Wayne N Frankel, David B Goldstein

Faculty, Staff and Students Publications

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory …

Existing Evidence For Influenza B Virus Adaptations To Drive Replication In Humans As The Primary Host, Matthew J. Pekarek, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Influenza B virus (IBV) is one of the two major types of influenza viruses that circulate each year. Unlike influenza A viruses, IBV does not harbor pandemic potential due to its lack of historical circulation in non-human hosts. Many studies and reviews have highlighted important factors for host determination of influenza A viruses. However, much less is known about the factors driving IBV replication in humans. We hypothesize that similar factors influence the host restriction of IBV. Here, we compile and review the current understanding of host factors crucial for the various stages of the IBV viral replication cycle. While …

Pediatric Hepatocellular Adenomas: What Is Known And What Is New?, Andres F Espinoza, Sanjeev A Vasudevan, Prakash M Masand, Dolores H Lòpez-Terrada, Kalyani R Patel

Faculty, Staff and Students Publications

Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to pediatric tumors have led to several "unclassifiable" lesions. Although typically considered benign, few can show atypical features and those with beta-catenin mutations have a risk for malignant transformation. Small lesions can be monitored while larger (>5.0 cm) lesions are excised due to symptoms or risk of bleeding/rupture, etc. Management depends on gender, age, underlying liver disease, …

Lack Of Methylation Changes In Gjb2 And Rb1 Non-Coding Regions Of Cochlear Implant Patients With Sensorineural Hearing Loss, Angelo Augusto M Sumalde, Ivana V Yang, Talitha Karisse L Yarza, Celina Ann M Tobias-Grasso, Ma Leah C Tantoco, Elizabeth Davidson, Abner L Chan, Mahshid S Azamian, Teresa Luisa G Cruz, Seema R Lalani, Maria Rina T Reyes-Quintos, Eva Maria Cutiongco-De La Paz, Regie Lyn P Santos-Cortez, Charlotte M Chiong

Faculty, Staff and Students Publications

OBJECTIVE: Recent advances in epigenetic studies continue to reveal novel mechanisms of gene regulation and control, however little is known on the role of epigenetics in sensorineural hearing loss (SNHL) in humans. We aimed to investigate the methylation patterns of two regions, one in

METHODS: We investigated an RB1 promoter region that was previously identified as differentially methylated in children with SNHL and lead exposure. Additionally, we investigated a sequence in an enhancer-like region within GJB2 that contains four CpGs in close proximity. Bisulfite conversion was performed on salivary DNA samples from 15 children with SNHL and 45 unrelated ethnically-matched …

In Vivo Crispr/Cas9 Screening Identifies Pbrm1 As A Regulator Of Myeloid Leukemia Development In Mice, Bin E Li, Grace Y Li, Wenqing Cai, Qian Zhu, Davide Seruggia, Yuko Fujiwara, Christopher R Vakoc, Stuart H Orkin

Faculty, Staff and Students Publications

CRISPR/Cas9 screening approaches are powerful tool for identifying in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which the sequential acquisition of somatic mutations generates clonal diversity. Over time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We, first, modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs, followed by transplantation. We, then, performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and …

Icvd Polymer Thin Film Bio-Interface-Performance For Fibroblasts, Cancer-Cells, And Viruses Connected To Their Functional Groups And In Silico Studies, Torge Hartig, Asmaa T. Mohamed, Nasra F. Abdel Fattah, Aydin Gülses, Tim Tjardts, Esther Afiba Kangah, Kwing Pak Gabriel Chan, Salih Salih Veziroglu, Yahya Acil, Oral Cenk Aktas, Jörg Jörg Wiltfang, Samah A. Loutfy, Thomas Strunskus, Franz Faupel, Amal Amin, Stefan Schröder

Nanotechnology Research Centre

Thin polymer coatings are used to improve the interface between biological species and functional materials. Their interaction is significantly influenced by the functional groups and roughness of the polymer film and prediction of the interaction is thus of great interest. However, for conventional polymer films, this cannot be examined independently because of the interplay of defects, residual solvent molecules, roughness, and functional groups. Solvent-free polymer films prepared by initiated chemical vapor deposition (iCVD) exhibit conformal, defect-free characteristics and enable precise tailoring of the functional groups. This facilitates to isolate the contribution of functional groups on the bio-interface performance. Consequently, in …

Blockade Of Interferon Signaling Decreases Gut Barrier Integrity And Promotes Severe West Nile Virus Disease, Shih-Ching Lin, Fang R Zhao, Hana Janova, Adrian Gervais, Summer Rucknagel, Kristy O Murray, Jean-Laurent Casanova, Michael S Diamond

Faculty, Staff and Students Publications

The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the capacity of WNV to directly infect gastrointestinal (GI) tract cells and contribute to disease severity. At baseline, WNV poorly infects human and mouse enteroid cultures and enterocytes in mice. However, when STAT1 or type I interferon (IFN) responses are absent, GI tract cells become infected, and this is associated with augmented GI tract and blood-brain barrier (BBB) permeability, accumulation of gut-derived …

Transcriptomic Analysis Of Stem Cells From Chorionic Villi Uncovers The Impact Of Chromosomes 2, 6 And 22 In The Clinical Manifestations Of Down Syndrome, Salvatore Vaiasicca, Gianmarco Melone, David W James, Marcos Quintela, Alessandra Preziuso, Richard H Finnell, Robert Steven Conlan, Lewis W Francis, Bruna Corradetti

Faculty, Staff and Students Publications

BACKGROUND: Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity.

METHODS: Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were …

Comparative Genomics Analysis Of Three Conserved Plasmid Families In The Western Hemisphere Soft Tick-Borne Relapsing Fever Borreliae Provides Insight Into Variation In Genome Structure And Antigenic Variation Systems, Alexander R Kneubehl, Job E Lopez

Faculty, Staff and Students Publications

Borrelia spirochetes, causative agents of Lyme disease and relapsing fever (RF), have uniquely complex genomes, consisting of a linear chromosome and both circular and linear plasmids. The plasmids harbor genes important for the vector-host life cycle of these tick-borne bacteria. The role of plasmids from Lyme disease causing spirochetes is more refined compared to RF Borrelia because of limited plasmid-resolved genome assemblies for the latter. We recently addressed this limitation and found that three linear plasmid families (F6, F27, and F28) were syntenic across all the RF Borrelia species that we examined. Given this conservation, we further investigated the three …

Critical Functions Of Extracellular Matrix In Brain Metastasis Seeding, Arseniy E Yuzhalin, Dihua Yu

Faculty, Staff and Student Publications

Human brain is characterized by extremely sparse extracellular matrix (ECM). Despite its low abundance, the significance of brain ECM in both physiological and pathological conditions should not be underestimated. Brain metastasis is a serious complication of cancer, and recent findings highlighted the contribution of ECM in brain metastasis development. In this review, we provide a comprehensive outlook on how ECM proteins promote brain metastasis seeding. In particular, we discuss (1) disruption of the blood-brain barrier in brain metastasis; (2) role of ECM in modulating brain metastasis dormancy; (3) regulation of brain metastasis seeding by ECM-activated integrin signaling; (4) functions of …

A Proteogenomics Data-Driven Knowledge Base Of Human Cancer, Yuxing Liao, Sara R Savage, Yongchao Dou, Zhiao Shi, Xinpei Yi, Wen Jiang, Jonathan T Lei, Bing Zhang

Faculty, Staff and Students Publications

By combining mass-spectrometry-based proteomics and phosphoproteomics with genomics, epi-genomics, and transcriptomics, proteogenomics provides comprehensive molecular characterization of cancer. Using this approach, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) has characterized over 1,000 primary tumors spanning 10 cancer types, many with matched normal tissues. Here, we present LinkedOmicsKB, a proteogenomics data-driven knowledge base that makes consistently processed and systematically precomputed CPTAC pan-cancer proteogenomics data available to the public through ∼40,000 gene-, protein-, mutation-, and phenotype-centric web pages. Visualization techniques facilitate efficient exploration and reasoning of complex, interconnected data. Using three case studies, we illustrate the practical utility of LinkedOmicsKB in providing …

Mir-146a Inhibits Ovarian Tumor Growth In Vivo Via Targeting Immunosuppressive Neutrophils And Enhancing Cd8+ T Cell Infiltration, Rui Chen, Elaina Coleborn, Chintan Bhavsar, Yue Wang, Louisa Alim, Andrew N Wilkinson, Michelle A Tran, Gowri Irgam, Sharat Atluri, Kiefer Wong, Jae-Jun Shim, Siddharth Adityan, Ju-Seog Lee, Willem W Overwijk, Raymond Steptoe, Da Yang, Sherry Y Wu

Faculty, Staff and Student Publications

Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53−/− and IG10 murine HGSC models. Increasing miR-146a expression …

Sepepquant Enhances The Detection Of Possible Isoform Regulations In Shotgun Proteomics, Yongchao Dou, Yuejia Liu, Xinpei Yi, Lindsey K Olsen, Hongwen Zhu, Qiang Gao, Hu Zhou, Bing Zhang

Faculty, Staff and Students Publications

Shotgun proteomics is essential for protein identification and quantification in biomedical research, but protein isoform characterization is challenging due to the extensive number of peptides shared across proteins, hindering our understanding of protein isoform regulation and their roles in normal and disease biology. We systematically assess the challenge and opportunities of shotgun proteomics-based protein isoform characterization using in silico and experimental data, and then present SEPepQuant, a graph theory-based approach to maximize isoform characterization. Using published data from one induced pluripotent stem cell study and two human hepatocellular carcinoma studies, we demonstrate the ability of SEPepQuant in addressing the key …

A Multicenter Analysis Of Abnormal Chromosomal Microarray Findings In Congenital Heart Disease, Benjamin J Landis, Lindsey R Helvaty, Gabrielle C Geddes, Jiuann-Huey Ivy Lin, Svetlana A Yatsenko, Cecilia W Lo, William L Border, Stephanie Burns Wechsler, Chaya N Murali, Mahshid S Azamian, Seema R Lalani, Robert B Hinton, Vidu Garg, Kim L Mcbride, Jennelle C Hodge, Stephanie M Ware

Faculty, Staff and Students Publications

Background

Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships.

Methods and Results

Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per …

Accuracy-Based Glomerular Filtration Rate Assessment By Plasma Iohexol Clearance In Kidney Transplant Donors, Zhicheng Jin, Rongrong Huang, Paul Christensen, Roger L Bertholf, Xin Yi

Faculty, Staff and Students Publications

Background: An accurate measurement of the glomerular filtration rate (GFR) is essential for detecting renal insufficiency in living kidney donors. Iohexol is a "near-ideal" exogenous filtration marker for GFR measurements that has attracted increasing interest in clinical practice because it is non-toxic, non-radioactive, readily available, and easy to measure. In this study, we aimed to set up a laboratory test to conveniently assess the plasma clearance of iohexol in living kidney donors.

Methods: A workflow was established in the institution's infusion clinic to administer iohexol and to collect three timed blood samples from renal transplant donors. Iohexol was thereafter measured …

A Review Of The Role Of Tendon Stem Cells In Tendon-Bone Regeneration, Junjie Chen, Chuanfeng Jiang, Lu Yin, Yingqi Liu, Yue He, Sen Li, Huarui Shen

Faculty, Staff and Student Publications

Tendon-bone injuries are a prevalent health concern associated with sports and other physically demanding activities. These injuries have a limited innate healing ability, often leading to the formation of scar tissue rather than the regeneration of healthy tendon tissue. This scar tissue results from excessive fibrosis during the early healing process and often leads to reduced tendon function and an increased risk of reinjury. Traditionally, surgical reconstruction has been the primary treatment for tendon-bone injuries. However, restoring the natural structure and mechanical properties of tendons after surgical reconstruction presents a considerable challenge. Recently, the potential of stem cell therapy has …

A High-Throughput Protocol For Measuring Solution Ph Of Bacterial Cultures Using Uv-Vis Absorption Spectrophotometry, Kristen A Engevik, Hyland Gonzalez, Clay Daniels, Ronald K Stavert, Numan Oezguen, Melinda A Engevik, Thomas D Horvath

Faculty, Staff and Students Publications

We present a protocol for measuring the pH of cell-free bacterial-conditioned media based on changes in the ultraviolet-visible (UV-Vis) absorbance spectrum using the pH indicator dye litmus. This protocol includes detailed procedures for performing bacterial culturing, examining bacterial growth, collecting cell-free supernatant, litmus dye addition, and pH-based calibration curve preparations. This assay has been designed for flexible formatting that can accommodate both high-volume and low-volume sample sets.