Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Whole Blood Resuscitation And Association With Survival In Injured Patients With An Elevated Probability Of Mortality, Jason L Sperry, Bryan A Cotton, James F Luther, Jeremy W Cannon, Martin A Schreiber, Ernest E Moore, Nicholas Namias, Joseph P Minei, Stephen R Wisniewski, Frank X Guyette, Shock, Whole Blood, And Assessment Of Traumatic Brain Injury (Swat) Study Group

Faculty, Staff and Student Publications

BACKGROUND: Low-titer group O whole blood (LTOWB) resuscitation is becoming common in both military and civilian settings and may represent the ideal resuscitation intervention. We sought to characterize the safety and efficacy of LTOWB resuscitation relative to blood component resuscitation.

STUDY DESIGN: A prospective, multicenter, observational cohort study was performed using 7 trauma centers. Injured patients at risk of massive transfusion who required both blood transfusion and hemorrhage control procedures were enrolled. The primary outcome was 4-hour mortality. Secondary outcomes included 24-hour and 28-day mortality, achievement of hemostasis, death from exsanguination, and the incidence of unexpected survivors.

RESULTS: A total …

Accelerated Epigenetic Aging In Older Adults With Hiv Disease: Associations With Serostatus, Hiv Clinical Factors, And Health Literacy, Steven Paul Woods, Antonio L Teixeira, Lais B Martins, Gabriel R Fries, Gabriela D Colpo, Natalia P Rocha

Faculty, Staff and Student Publications

The prevalence of older persons with HIV (PWH) disease has increased considerably in the last 20 years, but our understanding of biological factors of aging and their clinical correlates among PWH remains limited. Study participants were 149 persons aged 50 and older, including 107 PWH and 42 seronegatives. All participants completed a blood draw, research medical evaluation, structured psychiatric interview, neurocognitive assessment, questionnaires, and measures of health literacy. Four epigenetic clocks were generated from stored blood samples using standardized laboratory methods. In regression models adjusting for sex and smoking status, PWH had significantly higher epigenetic aging acceleration values than seronegatives …

Chromatin Architectural Factor Ctcf Is Essential For Progesterone-Dependent Uterine Maturation, Sylvia C Hewitt, Artiom Gruzdev, Cynthia J Willson, San-Pin Wu, John P Lydon, Niels Galjart, Francesco J Demayo

Faculty, Staff and Students Publications

Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes. Loss-of-function CTCF mutation in >20% of human endometrial tumors indicates its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcf

Trim28 Modulates Nuclear Receptor Signaling To Regulate Uterine Function, Rong Li, Tianyuan Wang, Ryan M Marquardt, John P Lydon, San-Pin Wu, Francesco J Demayo

Faculty, Staff and Students Publications

Estrogen and progesterone, acting through their cognate receptors the estrogen receptor α (ERα) and the progesterone receptor (PR) respectively, regulate uterine biology. Using rapid immunoprecipitation and mass spectrometry (RIME) and co-immunoprecipitation, we identified TRIM28 (Tripartite motif containing 28) as a protein which complexes with ERα and PR in the regulation of uterine function. Impairment of TRIM28 expression results in the inability of the uterus to support early pregnancy through altered PR and ERα action in the uterine epithelium and stroma by suppressing PR and ERα chromatin binding. Furthermore, TRIM28 ablation in PR-expressing uterine cells results in the enrichment of a …

Isolation And Characterization Of Porcine Endocardial Endothelial Cells, Kathleen N Brown, Hong Kim T Phan, Elysa L Jui, Marci K Kang, Jennifer P Connell, Sundeep G Keswani, K Jane Grande-Allen

Faculty, Staff and Students Publications

The heart contains diverse endothelial cell types. We sought to characterize the endocardial endothelial cells (EECs), which line the chambers of the heart. EECs are relatively understudied, yet their dysregulation can lead to various cardiac pathologies. Due to the lack of commercial availability of these cells, we reported our protocol for isolating EECs from porcine hearts and for establishing an EEC population through cell sorting. In addition, we compared the EEC phenotype and fundamental behaviors to a well-studied endothelial cell line, human umbilical vein endothelial cells (HUVECs). The EECs stained positively for classic phenotypic markers such as CD31, von Willebrand …

Prdm16 Deletion Is Associated With Sex-Dependent Cardiomyopathy And Cardiac Mortality: A Translational, Multi-Institutional Cohort Study, Ryan J Kramer, Amir Nima Fatahian, Alice Chan, Jeffery Mortenson, Jennifer Osher, Bo Sun, Lauren E Parker, Michael B Rosamilia, Kyra B Potter, Kaila Moore, Sage L Atkins, Jill A Rosenfeld, Alona Birjiniuk, Edward Jones, Taylor S Howard, Jeffrey J Kim, Daryl A Scott, Seema Lalani, Omid M T Rouzbehani, Samantha Kaplan, Marissa A Hathaway, Jennifer L Cohen, S Yukiko Asaki, Hugo R Martinez, Sihem Boudina, Andrew P Landstrom

Faculty, Staff and Students Publications

BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor

METHODS: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific

RESULTS: The retrospective cohort included 71 patients. Among individuals with

CONCLUSIONS:

Broadening The Phenotypic And Molecular Spectrum Of Finca Syndrome: Biallelic Nhlrc2 Variants In 15 Novel Individuals, Henrike L Sczakiel, Max Zhao, Brigitte Wollert-Wulf, Magdalena Danyel, Nadja Ehmke, Corinna Stoltenburg, Nadirah Damseh, Motee Al-Ashhab, Tugce B Balci, Matthew Osmond, Andrea Andrade, Jens Schallner, Joseph Porrmann, Kimberly Mcdonald, Mingjuan Liao, Henry Oppermann, Konrad Platzer, Nadine Dierksen, Majid Mojarrad, Atieh Eslahi, Behnaz Bakaeean, Daniel G Calame, James R Lupski, Zahra Firoozfar, Seyed Mohammad Seyedhassani, Seyed Ahmad Mohammadi, Najwa Anwaar, Fatima Rahman, Dominik Seelow, Martin Janz, Denise Horn, Reza Maroofian, Felix Boschann

Faculty, Staff and Students Publications

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.

Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with …

Dental Pulp Stem Cells And Current In Vivo Approaches To Study Dental Pulp Stem Cells In Pulp Injury And Regeneration, Dongwook Yang, Jea Giezl Niedo Solidum, Dongsu Park

Faculty, Staff and Students Publications

Dental pulp stem cells (DPSCs) have garnered significant interest in dental research for their unique characteristics and potential in tooth development and regeneration. While there were many studies to define their stem cell-like characteristics and osteogenic differentiation functions that are considered ideal candidates for regenerating damaged dental pulp tissue, how endogenous DPSCs respond to dental pulp injury and supply new dentin-forming cells has not been extensively investigated in vivo. Here, we review the recent progress in identity, function, and regulation of endogenous DPSCs and their clinical potential for pulp injury and regeneration. In addition, we discuss current advances in new …

Contemporary Changes In Etiology For Hepatocellular Carcinoma In Liver Transplantation, Cameron Goff, Anjiya Shaikh, Karthik Goli, Hashem B El-Serag, Fasiha Kanwal, George Cholankeril

Faculty, Staff and Students Publications

No abstract provided.

The Sunbeam Birth Cohort: Protocol Design, Corinne Keet, Scott H Sicherer, Supinda Bunyavanich, Cynthia Visness, Patricia C Fulkerson, Alkis Togias, Wendy Davidson, Susan Perry, Sanaz Hamrah, Agustin Calatroni, Katina Robinson, Lars Dunaway, Carla M Davis, Sara Anvari, Susan M Leong-Kee, Gurjit Khurana Hershey, Emily Defranco, Ashley Devonshire, Haejin Kim, Christine Joseph, Brent Davidson, Noel K Strong, Angela J Tsuang, Marion Groetch, Julie Wang, Jennifer Dantzer, Kim Mudd, Abimbola Aina, Wayne Shreffler, Qian Yuan, Virginia Simmons, Donald Y M Leung, Jessica Hui-Beckman, Jania Arcia Ramos, Sharon Chinthrajah, Virginia Winn, Tina Sindher, Stacie M Jones, Nirvana A Manning, Amy M Scurlock, Edwin Kim, Alison Stuebe, James E Gern, Anne Marie Singh, Jennifer Krupp, Robert A Wood

Faculty, Staff and Students Publications

BACKGROUND: Food allergy (FA) and atopic dermatitis (AD) are common conditions that often present in the first year of life. Identification of underlying mechanisms and environmental determinants of FA and AD is essential to develop and implement effective prevention and treatment strategies. Objectives: We sought to describe the design of the Systems Biology of Early Atopy (SunBEAm) birth cohort.

METHODS: Funded by the National Institute of Allergy and Infectious Diseases (NIAID) and administered through the Consortium for Food Allergy Research (CoFAR), SunBEAm is a US population-based, multicenter birth cohort that enrolls pregnant mothers, fathers, and their newborns and follows them …

Multiscale Analysis Of Pangenomes Enables Improved Representation Of Genomic Diversity For Repetitive And Clinically Relevant Genes, Chen-Shan Chin, Sairam Behera, Asif Khalak, Fritz J Sedlazeck, Peter H Sudmant, Justin Wagner, Justin M Zook

Faculty, Staff and Students Publications

Advancements in sequencing technologies and assembly methods enable the regular production of high-quality genome assemblies characterizing complex regions. However, challenges remain in efficiently interpreting variation at various scales, from smaller tandem repeats to megabase rearrangements, across many human genomes. We present a PanGenome Research Tool Kit (PGR-TK) enabling analyses of complex pangenome structural and haplotype variation at multiple scales. We apply the graph decomposition methods in PGR-TK to the class II major histocompatibility complex demonstrating the importance of the human pangenome for analyzing complicated regions. Moreover, we investigate the Y-chromosome genes, DAZ1/DAZ2/DAZ3/DAZ4, of which structural variants have been linked to …

Monocytic And Blastic Plasmacytoid Dendritic Cell Differentiation In Acute Leukemia With Kmt2a Rearrangement, Owen Xue, Choladda V Curry, Hong Fang, Carlos E Bueso-Ramos, L Jeffrey Medeiros, Wei Wang

Faculty, Staff and Students Publications

Acute leukemia with KMT2A rearrangement shows a spectrum of immunophenotypic presentation, but blastic plasmacytoid dendritic cell differentiation is extremely rare. Here we present a case of KMT2A rearranged acute leukemia with a hybrid immunophenotype in which a single blast population showed both blastic plasmacytoid dendritic cell and monocytic differentiation. This unusual case contributes to the diversity of the immunophenotypic spectrum in KMT2A rearranged acute leukemia and also sheds light on the cell of origin of plasmacytoid dendritic cells.

Cation Leak Through The Atp1a3 Pump Causes Spasticity And Intellectual Disability, Daniel G Calame, Cristina Moreno Vadillo, Seth Berger, Timothy Lotze, Marwan Shinawi, Javaher Poupak, Corina Heller, Julie Cohen, Richard Person, Aida Telegrafi, Chalongchai Phitsanuwong, Kaylene Fiala, Isabelle Thiffault, Florencia Del Viso, Dihong Zhou, Emily A Fleming, Tomi Pastinen, Ali Fatemi, Sruthi Thomas, Samuel I Pascual, Rosa J Torres, Carmen Prior, Clara Gómez-González, Saskia Biskup, James R Lupski, Dragan Maric, Miguel Holmgren, Debra Regier, Sho T Yano

Faculty, Staff and Students Publications

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear.

We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3 …

Loss Of Cytochrome P450 (Cyp)1b1 Mitigates Hyperoxia Response In Adult Mouse Lung By Reprogramming Metabolism And Translation, Sandra L Grimm, Rachel E Stading, Matthew J Robertson, Tanmay Gandhi, Chenlian Fu, Weiwu Jiang, Guobin Xia, Krithika Lingappan, Cristian Coarfa, Bhagavatula Moorthy

Faculty, Staff and Students Publications

Oxygen supplementation is life saving for premature infants and for COVID-19 patients but can induce long-term pulmonary injury by triggering inflammation, with xenobiotic-metabolizing CYP enzymes playing a critical role. Murine studies showed that CYP1B1 enhances, while CYP1A1 and CYP1A2 protect from, hyperoxic lung injury. In this study we tested the hypothesis that Cyp1b1-null mice would revert hyperoxia-induced transcriptomic changes observed in WT mice at the transcript and pathway level. Wild type (WT) C57BL/6J and Cyp1b1-null mice aged 8-10 weeks were maintained in room air (21% O

Effect Of Exogenous L-Carnitine On Aortic Stiffness In Dyslipidemic Adolescents: Design Of A Quadruple-Blind, Randomized, Controlled Interventional Trial, Justin P Zachariah, Sandra Pena, Philip J Lupo, Nagireddy Putluri, Daniel J Penny, Melissa A Richard

Faculty, Staff and Students Publications

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) risk factors including vascular remodeling leading to hypertension and dyslipidemia are prevalent among children and adolescents. Conflicting observational and Mendelian randomization data suggest endogenous carnitine may affect arterial stiffness and lipid traits. Because of this, we developed a study to evaluate the causal role for carnitine in arterial stiffness at a point when the lifecourse trajectory to hypertension can be modified.

METHODS: This study is a mechanistic, double-blinded, randomized control trial (RCT) in 166 adolescents with dyslipidemia for the effect of 6 months of maximum dose 3 g daily oral l-carnitine supplementation (CS+) versus placebo …

Delayed Skeletal Development And Igf-1 Deficiency In A Mouse Model Of Lysinuric Protein Intolerance, Bridget M Stroup, Xiaohui Li, Sara Ho, Haonan Zhouyao, Yuqing Chen, Safa Ani, Brian Dawson, Zixue Jin, Ronit Marom, Ming-Ming Jiang, Isabel Lorenzo, Daniel Rosen, Denise Lanza, Nathalie Aceves, Sara Koh, John R Seavitt, Jason D Heaney, Brendan Lee, Lindsay C Burrage

Faculty, Staff and Students Publications

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents …

Why Animal Experiments Are Still Indispensable In Bone Research: A Statement By The European Calcified Tissue Society, Merle Stein, Florent Elefteriou, Björn Busse, Imke Ak Fiedler, Ronald Young Kwon, Eric Farrell, Mubashir Ahmad, Anita Ignatius, Liam Grover, Liesbet Geris, Jan Tuckermann

Faculty, Staff and Students Publications

Major achievements in bone research have always relied on animal models and in vitro systems derived from patient and animal material. However, the use of animals in research has drawn intense ethical debate and the complete abolition of animal experimentation is demanded by fractions of the population. This phenomenon is enhanced by the reproducibility crisis in science and the advance of in vitro and in silico techniques. 3D culture, organ-on-a-chip, and computer models have improved enormously over the last years. Nevertheless, the overall complexity of bone tissue-cross talk and the systemic and local regulation of bone physiology can often only …

Shinybioheat: An Interactive Shiny App To Identify Phenotype Driver Genes In Ecoli And Bsubtilis, Chen Wang, Harikumar Govindarajan, Panagiotis Katsonis, Olivier Lichtarge

Faculty, Staff and Students Publications

SUMMARY: In any population under selective pressure, a central challenge is to distinguish the genes that drive adaptation from others which, subject to population variation, harbor many neutral mutations de novo. We recently showed that such genes could be identified by supplementing information on mutational frequency with an evolutionary analysis of the likely functional impact of coding variants. This approach improved the discovery of driver genes in both lab-evolved and environmental Escherichia coli strains. To facilitate general adoption, we now developed ShinyBioHEAT, an R Shiny web-based application that enables identification of phenotype driving gene in two commonly used model bacteria, …

The Clinical And Genetic Spectrum Of Autosomal-Recessive Tor1a-Related Disorders, Afshin Saffari, Tracy Lau, Homa Tajsharghi, Ehsan Ghayoor Karimiani, Ariana Kariminejad, Stephanie Efthymiou, Giovanni Zifarelli, Tipu Sultan, Mehran Beiraghi Toosi, Sahar Sedighzadeh, Victoria Mok Siu, Juan Darío Ortigoza-Escobar, Aisha M Alshamsi, Shahnaz Ibrahim, Nouriya Abbas Al-Sannaa, Walla Al-Hertani, Whalen Sandra, Mark Tarnopolsky, Shahryar Alavi, Chumei Li, Debra-Lynn Day-Salvatore, Maria Jesús Martínez-González, Kristin M Levandoski, Emma Bedoukian, Suneeta Madan-Khetarpal, Michaela J Idleburg, Minal Juliet Menezes, Aishwarya Siddharth, Konrad Platzer, Henry Oppermann, Martin Smitka, Felicity Collins, Monkol Lek, Mohmmad Shahrooei, Maryam Ghavideldarestani, Isabella Herman, John Rendu, Julien Faure, Janice Baker, Vikas Bhambhani, Laurel Calderwood, Javad Akhondian, Shima Imannezhad, Hanieh Sadat Mirzadeh, Narges Hashemi, Mohammad Doosti, Mojtaba Safi, Najmeh Ahangari, Paria Najarzadeh Torbati, Soheila Abedini, Vincenzo Salpietro, Elif Yilmaz Gulec, Safieh Eshaghian, Mohammadreza Ghazavi, Michael T Pascher, Marina Vogel, Angela Abicht, Sébastien Moutton, Ange-Line Bruel, Claudine Rieubland, Sabina Gallati, Tim M Strom, Hanns Lochmüller, Mohammad Hasan Mohammadi, Javeria Raza Alvi, Elaine H Zackai, Beth A Keena, Cara M Skraban, Seth I Berger, Erin H Andrew, Elham Rahimian, Michelle M Morrow, Ingrid M Wentzensen, Francisca Millan, Lindsay B Henderson, Hormos Salimi Dafsari, Heinz Jungbluth, Natalia Gomez-Ospina, Anne Mcrae, Merlene Peter, Danai Veltra, Nikolaos M Marinakis, Christalena Sofocleous, Farah Ashrafzadeh, Davut Pehlivan, Johannes R Lemke, Judith Melki, Audrey Benezit, Peter Bauer, Denisa Weis, James R Lupski, Jan Senderek, John Christodoulou, Wendy K Chung, Rose Goodchild, Amaka C Offiah, Andres Moreno-De-Luca, Mohnish Suri, Darius Ebrahimi-Fakhari, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of …

Clinical And Functional Heterogeneity Associated With The Disruption Of Retinoic Acid Receptor Beta, Véronique Caron, Nicolas Chassaing, Nicola Ragge, Felix Boschann, Angelina My-Hoa Ngu, Elisabeth Meloche, Sarah Chorfi, Saquib A Lakhani, Weizhen Ji, Laurie Steiner, Julien Marcadier, Philip R Jansen, Laura A Van De Pol, Johanna M Van Hagen, Alvaro Serrano Russi, Gwenaël Le Guyader, Magnus Nordenskjöld, Ann Nordgren, Britt-Marie Anderlid, Julie Plaisancié, Corinna Stoltenburg, Denise Horn, Anne Drenckhahn, Fadi F Hamdan, Mathilde Lefebvre, Tania Attie-Bitach, Peggy Forey, Vasily Smirnov, Françoise Ernould, Marie-Line Jacquemont, Sarah Grotto, Alberto Alcantud, Alicia Coret, Rosario Ferrer-Avargues, Siddharth Srivastava, Catherine Vincent-Delorme, Shelby Romoser, Nicole Safina, Dimah Saade, James R Lupski, Daniel G Calame, David Geneviève, Nicolas Chatron, Caroline Schluth-Bolard, Kenneth A Myers, William B Dobyns, Patrick Calvas, Ddd Study, Caroline Salmon, Richard Holt, Frances Elmslie, Marc Allaire, Daniil M Prigozhin, André Tremblay, Jacques L Michaud

Faculty, Staff and Students Publications

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.

METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.

RESULTS: We found that …

Deconvolution Of Cancer Cell States By The Xdec-Sm Method, Oscar D Murillo, Varduhi Petrosyan, Emily L Laplante, Lacey E Dobrolecki, Michael T Lewis, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

Proper characterization of cancer cell states within the tumor microenvironment is a key to accurately identifying matching experimental models and the development of precision therapies. To reconstruct this information from bulk RNA-seq profiles, we developed the XDec Simplex Mapping (XDec-SM) reference-optional deconvolution method that maps tumors and the states of constituent cells onto a biologically interpretable low-dimensional space. The method identifies gene sets informative for deconvolution from relevant single-cell profiling data when such profiles are available. When applied to breast tumors in The Cancer Genome Atlas (TCGA), XDec-SM infers the identity of constituent cell types and their proportions. XDec-SM also …

Spatial Mapping Of The Dna Adducts In Cancer, Kimiko L Krieger, Elise K Mann, Kevin J Lee, Elyse Bolterstein, Deborah Jebakumar, Michael M Ittmann, Valeria L Dal Zotto, Mohamed Shaban, Arun Sreekumar, Natalie R Gassman

Faculty, Staff and Students Publications

DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability. While mutational burden offers some insight into the level of DNA damage a cell may have experienced and subsequently repaired, it does not quantify DNA adducts and strand breaks. Mutational burden also infers the identity of the DNA damage. With advances …

Loss Of Metabolic Fitness Drives Tumor Resistance After Car-Nk Cell Therapy And Can Be Overcome By Cytokine Engineering, Li Li, Vakul Mohanty, Jinzhuang Dou, Yuefan Huang, Pinaki P Banerjee, Qi Miao, Jens G Lohr, Tushara Vijaykumar, Julia Frede, Birgit Knoechel, Luis Muniz-Feliciano, Tamara J Laskowski, Shaoheng Liang, Judy S Moyes, Vandana Nandivada, Rafet Basar, Mecit Kaplan, May Daher, Enli Liu, Ye Li, Sunil Acharya, Paul Lin, Mayra Shanley, Hind Rafei, David Marin, Stephan Mielke, Richard E Champlin, Elizabeth J Shpall, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is promising, with early-phase clinical studies showing encouraging responses. However, the transcriptional signatures that control the fate of CAR-NK cells after infusion and factors that influence tumor control remain poorly understood. We performed single-cell RNA sequencing and mass cytometry to study the heterogeneity of CAR-NK cells and their in vivo evolution after adoptive transfer, from the phase of tumor control to relapse. Using a preclinical model of noncurative lymphoma and samples from a responder and a nonresponder patient treated with CAR19/IL-15 NK cells, we observed the emergence of NK cell …

Investigating The Physiological Mechanisms Between Resistance Training And Pain Relief In The Cancer Population: A Literature Review, Yvonne Jiang, Peter C. Angeletti, Amy J. Hoffman

Nebraska Center for Virology: Faculty Publications

This literature review examines the mechanisms of how exercise, specifically in the form of resistance training, may lead to pain relief in the cancer population. Primary data from three different cancer populations: breast, prostate, and lung, will be examined. A number of experimental studies have been conducted to confirm the effectiveness of resistance training on pain relief as well as the biochemical pathways that relate to this process. In this review, we will examine 5 randomized controlled trials. For the purposes of this review, pain is defined as physical suffering or discomfort associated with illness. Pain is the body’s natural …

Surface-Doped Zinc Gallate Colloidal Nanoparticles Exhibit Ph-Dependent Radioluminescence With Enhancement In Acidic Media, Navadeep Shrivastava, Jessa Guffie, Tamela L Moore, Burak Guzelturk, Amar S Kumbhar, Jianguo Wen, Zhiping Luo

Faculty, Staff and Student Publications

As abnormal acidic pH symbolizes dysfunctions of cells, it is highly desirable to develop pH-sensitive luminescent materials for diagnosing disease and imaging-guided therapy using high-energy radiation. Herein, we explored near-infrared-emitting Cr-doped zinc gallate ZnGa2O4 nanoparticles (NPs) in colloidal solutions with different pH levels under X-ray excitation. Ultrasmall NPs were synthesized via a facile hydrothermal method by controlling the addition of ammonium hydroxide precursor and reaction time, and structural characterization revealed Cr dopants on the surface of NPs. The synthesized NPs exhibited different photoluminescence and radioluminescence mechanisms, confirming the surface distribution of activators. It was observed that the colloidal NPs emit …

Pharmaco-Proteogenomic Characterization Of Liver Cancer Organoids For Precision Oncology, Shuyi Ji, Li Feng, Zile Fu, Gaohua Wu, Yingcheng Wu, Youpei Lin, Dayun Lu, Yuanli Song, Peng Cui, Zijian Yang, Chen Sang, Guohe Song, Shangli Cai, Yuanchuang Li, Hanqing Lin, Shu Zhang, Xiaoying Wang, Shuangjian Qiu, Xiaoming Zhang, Guoqiang Hua, Junqiang Li, Jian Zhou, Zhi Dai, Xiangdong Wang, Li Ding, Pei Wang, Daming Gao, Bing Zhang, Henry Rodriguez, Jia Fan, Hans Clevers, Hu Zhou, Yidi Sun, Qiang Gao

Faculty, Staff and Students Publications

Organoid models have the potential to recapitulate the biological and pharmacotypic features of parental tumors. Nevertheless, integrative pharmaco-proteogenomics analysis for drug response features and biomarker investigation for precision therapy of patients with liver cancer are still lacking. We established a patient-derived liver cancer organoid biobank (LICOB) that comprehensively represents the histological and molecular characteristics of various liver cancer types as determined by multiomics profiling, including genomic, epigenomic, transcriptomic, and proteomic analysis. Proteogenomic profiling of LICOB identified proliferative and metabolic organoid subtypes linked to patient prognosis. High-throughput drug screening revealed distinct response patterns of each subtype that were associated with specific …

Enabling Endpoint Development For Interventional Clinical Trials In Individuals With Angelman Syndrome: A Prospective, Longitudinal, Observational Clinical Study (Freesias), Jorrit Tjeertes, Carlos A Bacino, Terry Jo Bichell, Lynne M Bird, Mariana Bustamante, Rebecca Crean, Shafali Jeste, Robert W Komorowski, Michelle L Krishnan, Meghan T Miller, David Nobbs, Cesar Ochoa-Lubinoff, Kimberly A Parkerson, Alexander Rotenberg, Anjali Sadhwani, Mark D Shen, Lisa Squassante, Wen-Hann Tan, Brenda Vincenzi, Anne C Wheeler, Joerg F Hipp, Elizabeth Berry-Kravis

Faculty, Staff and Students Publications

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms.

METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits.

RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health …

When Phased Without Water: Biophysics Of Cellular Desiccation, From Biomolecules To Condensates, Paulette Sofia Romero-Perez, Yanniv Dorone, Eduardo Flores, Shahar Sukenik, Steven Boeynaems

Faculty, Staff and Students Publications

The molecular machinery that enables life has evolved in water, yet many of the organisms around us are able to survive even extreme desiccation. Especially remarkable are single-cell and sedentary organisms that rely on specialized biomolecular machinery to survive in environments that are routinely subjected to a near-complete lack of water. In this review, we zoom in on the molecular level of what is happening in the cellular environment under water stress. We cover the various mechanisms by which biochemical components of the cell can dysfunction in dehydrated cells and detail the different strategies that organisms have evolved to eliminate …

The Role Of Gut Dysbiosis In The Loss Of Intestinal Immune Cell Functions And Viral Pathogenesis, Farzaneh Fakharian, Siva Thirugnanam, David A. Welsh, Woong Ki Kim, Jay Rappaport, Kyle Bittinger, Namita Rout

School of Medicine Faculty Publications

The gut microbiome plays a critical role in maintaining overall health and immune function. However, dysbiosis, an imbalance in microbiome composition, can have profound effects on various aspects of human health, including susceptibility to viral infections. Despite numerous studies investigating the influence of viral infections on gut microbiome, the impact of gut dysbiosis on viral infection and pathogenesis remains relatively understudied. The clinical variability observed in SARS-CoV-2 and seasonal influenza infections, and the presence of natural HIV suppressors, suggests that host-intrinsic factors, including the gut microbiome, may contribute to viral pathogenesis. The gut microbiome has been shown to influence the …

Dynamic Mapping Of Proteome Trafficking Within And Between Living Cells By Transitid, Wei Qin, Joleen S Cheah, Charles Xu, James Messing, Brian D Freibaum, Steven Boeynaems, J Paul Taylor, Namrata D Udeshi, Steven A Carr, Alice Y Ting

Faculty, Staff and Students Publications

The ability to map trafficking for thousands of endogenous proteins at once in living cells would reveal biology currently invisible to both microscopy and mass spectrometry. Here, we report TransitID, a method for unbiased mapping of endogenous proteome trafficking with nanometer spatial resolution in living cells. Two proximity labeling (PL) enzymes, TurboID and APEX, are targeted to source and destination compartments, and PL with each enzyme is performed in tandem via sequential addition of their small-molecule substrates. Mass spectrometry identifies the proteins tagged by both enzymes. Using TransitID, we mapped proteome trafficking between cytosol and mitochondria, cytosol and nucleus, and …