Digital Commons Network^™

Targeting Ccl2/Ccr2 Signaling Overcomes Mek Inhibitor Resistance In Acute Myeloid Leukemia, Rucha V Modak, Katia G De Oliveira Rebola, John Mcclatchy, Mona Mohammadhosseini, Alisa Damnernsawad, Stephen E Kurtz, Christopher A Eide, Guanming Wu, Ted Laderas, Tamilla Nechiporuk, Marina A Gritsenko, Joshua R Hansen, Chelsea Hutchinson, Sara J C Gosline, Paul Piehowski, Daniel Bottomly, Nicholas Short, Karin Rodland, Shannon K Mcweeney, Jeffrey W Tyner, Anupriya Agarwal

Faculty, Staff and Student Publications

Purpose: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML.

Experimental design: We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 …

Integrative Molecular Analyses Of The Md Anderson Prostate Cancer Patient-Derived Xenograft (Mda Pca Pdx) Series, Nicolas Anselmino, Estefania Labanca, Peter D A Shepherd, Jiabin Dong, Jun Yang, Xiaofei Song, Subhiksha Nandakumar, Ritika Kundra, Cindy Lee, Nikolaus Schultz, Jianhua Zhang, John C Araujo, Ana M Aparicio, Sumit K Subudhi, Paul G Corn, Louis L Pisters, John F Ward, John W Davis, Elba S Vazquez, Geraldine Gueron, Christopher J Logothetis, Andrew Futreal, Patricia Troncoso, Yu Chen, Nora M Navone

Faculty, Staff and Student Publications

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.

EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived …

Ire1Α Determines Ferroptosis Sensitivity Through Regulation Of Glutathione Synthesis, Dadi Jiang, Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan, Albert C Koong

Faculty, Staff and Student Publications

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is …

Optical Coherence Tomography-Guided Brillouin Microscopy Highlights Regional Tissue Stiffness Differences During Anterior Neural Tube Closure In The Mthfd1l Murine Mutant, Yogeshwari S Ambekar, Carlo Donato Caiaffa, Bogdan J Wlodarczyk, Manmohan Singh, Alexander W Schill, John W Steele, Jitao Zhang, Salavat R Aglyamov, Giuliano Scarcelli, Richard H Finnell, Kirill V Larin

Faculty, Staff and Students Publications

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos …

Jag1/2 Maintain Esophageal Homeostasis And Suppress Foregut Tumorigenesis By Restricting The Basal Progenitor Cell Pool, Haidi Huang, Yu Jiang, Jiangying Liu, Dan Luo, Jianghong Yuan, Rongzi Mu, Xiang Yu, Donglei Sun, Jihong Lin, Qiyue Chen, Xinjing Li, Ming Jiang, Jianming Xu, Bo Chu, Chengqian Yin, Lei Zhang, Youqiong Ye, Bo Cao, Qiong Wang, Yongchun Zhang

Faculty, Staff and Students Publications

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and …

Quantitative T2 Mapping-Based Longitudinal Assessment Of Brain Injury And Therapeutic Rescue In The Rat Following Acute Organophosphate Intoxication, Alita Jesal D Almeida, Brad A Hobson, Naomi Saito, Donald A Bruun, Valerie A Porter, Danielle J Harvey, Joel R Garbow, Abhijit J Chaudhari, Pamela J Lein

2020-Current year OA Pubs

Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T

Optical Coherence Tomography-Guided Brillouin Microscopy Highlights Regional Tissue Stiffness Differences During Anterior Neural Tube Closure In The Mthfd1l Murine Mutant, Yogeshwari S Ambekar, Carlo Donato Caiaffa, Bogdan J Wlodarczyk, Manmohan Singh, Alexander W Schill, John W Steele, Jitao Zhang, Salavat R Aglyamov, Giuliano Scarcelli, Richard H Finnell, Kirill V Larin

Faculty, Staff and Students Publications

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos …

C-Terminal Binding Protein 2 Is A Novel Tumor Suppressor Targeting The Myc-Irf4 Axis In Multiple Myeloma, Coty Hing Yau Cheung, Chi Keung Cheng, Kam Tong Leung, Chi Zhang, Chi Yan Ho, Xi Luo, Angel Yuet Fong Kam, Tian Xia, Thomas Shek Kong Wan, Herbert Augustus Pitts, Natalie Pui Ha Chan, Joyce Sin Cheung, Raymond Siu Ming Wong, Xiao-Bing Zhang, Margaret Heung Ling Ng

Faculty, Staff and Student Publications

Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent …

Differential Gene Expression Analysis Of Spatial Transcriptomic Experiments Using Spatial Mixed Models., Oscar E. Ospina, Alex C. Soupir, Roberto Manjarres-Betancur, Guillermo Gonzalez-Calderon, Xiaoqing Yu, Brooke L. Fridley

Manuscripts, Articles, Book Chapters and Other Papers

Spatial transcriptomics (ST) assays represent a revolution in how the architecture of tissues is studied by allowing for the exploration of cells in their spatial context. A common element in the analysis is delineating tissue domains or "niches" followed by detecting differentially expressed genes to infer the biological identity of the tissue domains or cell types. However, many studies approach differential expression analysis by using statistical approaches often applied in the analysis of non-spatial scRNA data (e.g., two-sample t-tests, Wilcoxon's rank sum test), hence neglecting the spatial dependency observed in ST data. In this study, we show that applying linear …

Astrocytes Remember Inflammation, Michael R Williamson, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes respond to all forms of central nervous system maladies. In a recent issue of Nature, Lee et al. demonstrate that astrocytes encode inflammatory stimuli as epigenetic memory, which strengthens responses to subsequent stimuli and exacerbates pathology in disease models.

The Crosstalk Between Macrophages And Cancer Cells Potentiates Pancreatic Cancer Cachexia, Mingyang Liu, Yu Ren, Zhijun Zhou, Jingxuan Yang, Xiuhui Shi, Yang Cai, Alex X Arreola, Wenyi Luo, Kar-Ming Fung, Chao Xu, Ryan D Nipp, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li

Faculty, Staff and Student Publications

With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis …

Targeting Cathepsin C Ameliorates Murine Acetaminophen-Induced Liver Injury, Jessica Raith, Malte Bachmann, Sina Gonther, Hendrik Stülb, Ali A Aghdassi, Christine T N Pham, Heiko Mühl

2020-Current year OA Pubs

Acetaminophen (APAP) overdosing is a major cause of acute liver failure worldwide and an established model for drug-induced acute liver injury (ALI). While studying gene expression during murine APAP-induced ALI by 3'mRNA sequencing (massive analysis of cDNA ends, MACE), we observed splenic mRNA accumulation encoding for the neutrophil serine proteases cathepsin G, neutrophil elastase, and proteinase-3 - all are hierarchically activated by cathepsin C (CtsC). This, along with increased serum levels of these proteases in diseased mice, concurs with the established phenomenon of myeloid cell mobilization during APAP intoxication.

Reverse Genetics Of Murine Rotavirus: A Comparative Analysis Of The Wild-Type And Cell-Culture-Adapted Murine Rotavirus Vp4 In Replication And Virulence In Neonatal Mice, Takahiro Kawagishi, Liliana Sánchez-Tacuba, Ningguo Feng, Harry B Greenberg, Siyuan Ding

2020-Current year OA Pubs

Small-animal models and reverse genetics systems are powerful tools for investigating the molecular mechanisms underlying viral replication, virulence, and interaction with the host immune response in vivo. Rotavirus (RV) causes acute gastroenteritis in many young animals and infants worldwide. Murine RV replicates efficiently in the intestines of inoculated suckling pups, causing diarrhea, and spreads efficiently to uninoculated littermates. Because RVs derived from human and other non-mouse animal species do not replicate efficiently in mice, murine RVs are uniquely useful in probing the viral and host determinants of efficient replication and pathogenesis in a species-matched mouse model. Previously, we established an …

Regulation Of Cerebral Blood Flow Boosts Precise Brain Targeting Of Vinpocetine-Derived Ionizable-Lipidoid Nanoparticles, Xufei Bian, Ling Yang, Dingxi Jiang, Adam J Grippin, Yifan Ma, Shuang Wu, Linchong Wu, Xiaoyou Wang, Zhongjie Tang, Kaicheng Tang, Weidong Pan, Shiyan Dong, Betty Y S Kim, Wen Jiang, Zhaogang Yang, Chong Li

Faculty, Staff and Student Publications

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid …

Mitochondria Regulate Proliferation In Adult Cardiac Myocytes, Gregory B Waypa, Kimberly A Smith, Paul T Mungai, Vincent J Dudley, Kathryn A Helmin, Benjamin D Singer, Clara Bien Peek, Joseph Bass, Lauren Nelson, Sanjiv J Shah, Gaston Ofman, J Andrew Wasserstrom, William A Muller, Alexander V Misharin, G R Scott Budinger, Hiam Abdala-Valencia, Navdeep S Chandel, Danijela Dokic, Elizabeth Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B Thorp, Paul T Schumacker

Faculty, Staff and Student Publications

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes …

Activation Of Interleukin 33-Nfκb Axis In Granulosa Cells During Atresia And Its Role In Disposal Of Atretic Follicles, Jean Wu, Colin Carlock, Kiana Tatum, Junbo Shim, Cindy Zhou, Yahuan Lou

Faculty, Staff and Student Publications

It has been previously shown that the cytokine interleukin 33 is required for two processes, i.e., autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of interleukin 33-suppression of tumorigenicity 2-Nuclear Factor ĸB (NFκB) axis in granulosa in early atretic follicles may regulate those two events. Injection of human chorionic gonadotropin has been shown to induce a transient peak of interleukin 33 expression with synchronized atresia. In this model, interleukin 33-independent expression of suppression of tumorigenicity 2 in granulosa cells was detected in early atretic …

Modulation Of The Blood-Brain Barrier By Sigma-1r Activation, Eugen Brailoiu, Jeffrey L Barr, Hailey N Wittorf, Saadet Inan, Ellen M Unterwald, Gabriela Cristina Brailoiu

Faculty, Staff and Student Publications

Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein residing on the endoplasmic reticulum at the mitochondrial-associated membrane (MAM) region. Sigma-1R is abundant in the brain and is involved in several physiological processes as well as in various disease states. The role of Sigma-1R at the blood-brain barrier (BBB) is incompletely characterized. In this study, the effect of Sigma-1R activation was investigated in vitro on rat brain microvascular endothelial cells (RBMVEC), an important component of the blood-brain barrier (BBB), and in vivo on BBB permeability in rats. The Sigma-1R agonist PRE-084 produced a dose-dependent increase in mitochondrial calcium, …

Downregulation Of Mirlet7 Mirna Family Promotes Tc17 Differentiation And Emphysema Via De-Repression Of Rorγt, Phillip A Erice, Xinyan Huang, Matthew J Seasock, Matthew J Robertson, Hui-Ying Tung, Melissa A Perez-Negron, Shivani L Lotlikar, David B Corry, Farrah Kheradmand, Antony Rodriguez

Faculty, Staff and Students Publications

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with …

The Ire1Α/Xbp1 Pathway Sustains Cytokine Responses Of Group 3 Innate Lymphoid Cells In Inflammatory Bowel Disease, Siyan Cao, Jose L. Fachi, Kaiming Ma, Alina Ulezko Antonova, Qianli Wang, Zhangying Cai, Randal J. Kaufman, Matthew A. Ciorba, Parakkal Deepak, Marco Colonna

2020-Current year OA Pubs

Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. ER stress is linked to inflammatory bowel disease (IBD). Here, we used cell culture, mouse models, and human specimens to determine whether ER stress in ILC3s affects IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24-hour rhythmic expression pattern of the master ER stress response regulator inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1). Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial ROS (mtROS). IRE1α/XBP1 was activated in ILC3s from mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion …

A Rat-Based Preclinical Platform Facilitating Transcatheter Hepatic Arterial Infusion In Immunodeficient Rats With Liver Xenografts Of Patient-Derived Pancreatic Ductal Adenocarcinoma, Masanori Ozaki, Ken Kageyama, Kenjiro Kimura, Shinpei Eguchi, Akira Yamamoto, Ryota Tanaka, Takehito Nota, Hiroki Yonezawa, Hideyuki Nishiofuku, Yuki Sakai, Naoki Tani, Atsushi Jogo, Mizue Terai, Takami Sato, Takeaki Ishizawa, Yukio Miki

Department of Medical Oncology Faculty Papers

Liver metastases from pancreatic ductal adenocarcinoma (PDAC) are highly fatal. A rat-based patient-derived tumor xenograft (PDX) model is available for transcatheter therapy. This study aimed to create an immunodeficient rat model with liver xenografts of patient-derived primary PDAC and evaluate efficacy of hepatic arterial infusion chemotherapy with cisplatin in this model. Three patient-derived PDACs were transplanted into the livers of 21 rats each (totally, 63 rats), randomly assigned into hepatic arterial infusion, systemic venous infusion, and control groups (n = 7 each) four weeks post-implantation. Computed tomography evaluated tumor volumes before and four weeks after treatment. Post-euthanasia, resected tumor specimens …

Optimization Of The Antifungal Properties Of The Bacterial Peptide Entv By Variant Analysis, Shantanu Guha, Shane A Cristy, Giuseppe Buda De Cesare, Melissa R Cruz, Michael C Lorenz, Danielle A Garsin

Faculty, Staff and Student Publications

Fungal resistance to commonly used medicines is a growing public health threat, and there is a dire need to develop new classes of antifungals. We previously described a peptide produced by Enterococcus faecalis, EntV, that restricts Candida albicans to a benign form rather than having direct fungicidal activity. Moreover, we showed that one 12-amino acid (aa) alpha helix of this peptide retained full activity, with partial activity down to the 10aa alpha helix. Using these peptides as a starting point, the current investigation sought to identify the critical features necessary for antifungal activity and to screen for new variants …

Visual Deprivation During Mouse Critical Period Reorganizes Network-Level Functional Connectivity, Siyu Chen, Rachel M Rahn, Annie R Bice, Seana H Gaines, Jonah A Padawer-Curry, Keith B Hengen, Joseph D Dougherty, Joseph P Culver

2020-Current year OA Pubs

A classic example of experience-dependent plasticity is ocular dominance (OD) shift, in which the responsiveness of neurons in the visual cortex is profoundly altered following monocular deprivation (MD). It has been postulated that OD shifts also modify global neural networks, but such effects have never been demonstrated. Here, we use wide-field fluorescence optical imaging (WFOI) to characterize calcium-based resting-state functional connectivity during acute (3 d) MD in female and male mice with genetically encoded calcium indicators (

Chronic Stress-Induced Neuroinflammation: Relevance Of Rodent Models To Human Disease., Abigail G White, Elias Elias, Andrea Orozco, Shivon A Robinson, Melissa T Manners

College of Science & Mathematics Departmental Research

The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This can result in a persistent proinflammatory response in the peripheral and central nervous system (CNS), resulting in cellular, physiological, and behavioral effects. Compounding stressors may increase the risk of chronic-stress-induced inflammation, which can yield serious health consequences, including mental health disorders. This review summarizes the current knowledge surrounding the neuroinflammatory response in rodent models of chronic stress-a …

Updates To The Alliance Of Genome Resources Central Infrastructure., The Alliance Of Genome Resources Consortium

Faculty Research 2024

The Alliance of Genome Resources (Alliance) is an extensible coalition of knowledgebases focused on the genetics and genomics of intensively studied model organisms. The Alliance is organized as individual knowledge centers with strong connections to their research communities and a centralized software infrastructure, discussed here. Model organisms currently represented in the Alliance are budding yeast, Caenorhabditis elegans, Drosophila, zebrafish, frog, laboratory mouse, laboratory rat, and the Gene Ontology Consortium. The project is in a rapid development phase to harmonize knowledge, store it, analyze it, and present it to the community through a web portal, direct downloads, and application programming interfaces …

Human Il-6 Fosters Long-Term Engraftment Of Patient-Derived Disease-Driving Myeloma Cells In Immunodeficient Mice., Zainul S Hasanali, Alfred L Garfall, Lisa Burzenski, Leonard D. Shultz, Yan Tang, Siddhant Kadu, Neil C Sheppard, Wei Liu, Derek Dopkin, Dan T Vogl, Adam D Cohen, Adam J Waxman, Sandra P Susanibar-Adaniya, Martin Carroll, Edward A Stadtmauer, David Allman

Faculty Research 2024

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned human IL-6-transgenic (hIL-6-transgenic) NSG (NSG+hIL6) mice reliably support the engraftment of malignant and premalignant human plasma cells, including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and postrelapse myeloma, plasma cell leukemia, and amyloid light chain amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single-cell RNA …

Mouse Genome Informatics: An Integrated Knowledgebase System For The Laboratory Mouse., Richard M. Baldarelli, Cynthia Smith, Martin Ringwald, Joel E Richardson, Carol J Bult, Mouse Genome Informatics

Faculty Research 2024

Mouse Genome Informatics (MGI) is a federation of expertly curated information resources designed to support experimental and computational investigations into genetic and genomic aspects of human biology and disease using the laboratory mouse as a model system. The Mouse Genome Database (MGD) and the Gene Expression Database (GXD) are core MGI databases that share data and system architecture. MGI serves as the central community resource of integrated information about mouse genome features, variation, expression, gene function, phenotype, and human disease models acquired from peer-reviewed publications, author submissions, and major bioinformatics resources. To facilitate integration and standardization of data, biocuration scientists …

Deficiency Of Il-22-Binding Protein Enhances The Ability Of The Gut Microbiota To Protect Against Enteric Pathogens, José L Fachi, Blanda Di Luccia, Susan Gilfillan, Hao-Wei Chang, Christina Song, Jiye Cheng, Marina Cella, Marco Aurelio Vinolo, Jeffrey I Gordon, Marco Colonna

2020-Current year OA Pubs

Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the

Endotrophin, A Key Marker And Driver For Fibroinflammatory Disease, Kim Henriksen, Federica Genovese, Alexander Reese-Petersen, Laurent P Audoly, Kai Sun, Morten A Karsdal, Philipp E Scherer

Faculty, Staff and Student Publications

Our overview covers several key areas related to recent results obtained for collagen type VI and endotrophin (ETP). (1) An introduction to the history of ETP, including how it was identified, how it is released, and its function and potential receptors. (2) An introduction to the collagen family, with a focus on what differentiates collagen type VI from an evolutionary standpoint. (3) An overview of collagen type VI, the 6 individual chains (COL6A1, A2, A3, A4, A5, and A6), their differences and similarities, as well as their expression profiles and function. (4) A detailed analysis of COL6A3, including the cleaved …

Progress Toward A Vaccine For Extraintestinal Pathogenic Coli (Expec) Ii: Efficacy Of A Toxin-Autotransporter Dual Antigen Approach, Yikun Xing, Justin R Clark, James D Chang, Jacob J Zulk, Dylan M Chirman, Felipe-Andres Piedra, Ellen E Vaughan, Haroldo J Hernandez Santos, Kathryn A Patras, Anthony W Maresso

Faculty, Staff and Students Publications

Extraintestinal pathogenic Escherichia coli (ExPEC) is a leading cause of worldwide morbidity and mortality, the top cause of antimicrobial-resistant (AMR) infections, and the most frequent cause of life-threatening sepsis and urinary tract infections (UTI) in adults. The development of an effective and universal vaccine is complicated by this pathogen’s pan-genome, its ability to mix and match virulence factors and AMR genes via horizontal gene transfer, an inability to decipher commensal from pathogens, and its intimate association and co-evolution with mammals. Using a pan virulome analysis of >20,000 sequenced E. coli strains, we identified the secreted cytolysin α-hemolysin (HlyA) as a …

Memory-Like Differentiation Enhances Nk Cell Responses Against Colorectal Cancer, Nancy D Marin, Michelle Becker-Hapak, Wilbur M Song, Quazim A Alayo, Lynne Marsala, Naomi Sonnek, Melissa M Berrien-Elliott, Mark Foster, Jennifer A Foltz, Jennifer Tran, Pamela Wong, Celia C Cubitt, Patrick Pence, Kimberly Hwang, Alice Y Zhou, Miriam T Jacobs, Timothy Schappe, David A Russler-Germain, Ryan C Fields, Matthew A Ciorba, Todd A Fehniger

2020-Current year OA Pubs

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the …