Medical Specialties Commons^™

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Multifaceted Roles For Stat3 In Gammaherpesvirus Latency Revealed Through In Vivo B Cell Knockout Models, Chad H Hogan, Shana M Owens, Glennys V Reynoso, Yifei Liao, Thomas J Meyer, Monika A Zelazowska, Bin Liu, Xiaofan Li, Anna K Grosskopf, Camille Khairallah, Varvara Kirillov, Nancy C Reich, Brian S Sheridan, Kevin M Mcbride, Benjamin E Gewurz, Heather D Hickman, J Craig Forrest, Laurie T Krug

Faculty, Staff and Student Publications

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). To better understand the role of STAT3 during gammaherpesvirus latency and the B cell response to infection, we used the model pathogen murine gammaherpesvirus 68 (MHV68). Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/f mice reduced peak MHV68 latency approximately sevenfold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to wild-type (WT) littermates. To circumvent the systemic immune alterations observed in …

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

In Vivo Dynamic Volumetric Imaging Of Mouse Testis And Epididymis With Optical Coherence Tomography†, Kohei Umezu, Guzel R Musina, Irina V Larina

Faculty, Staff and Students Publications

The implementation of live imaging in reproductive research is crucial for studying the physiological dynamics. Sperm transport is a highly dynamic process regulated by tubular contractions and luminal flows within the male reproductive tract. However, due to the lack of imaging techniques to capture these dynamics in vivo, there is little information on the physiological and biomechanical regulation of sperm transport through the male reproductive tract. Here, we present a functional in vivo imaging approach using optical coherence tomography, enabling live, label-free, depth-resolved, three-dimensional, high-resolution visualization of the mouse testis and epididymis. With this approach, we spatiotemporally captured tubular contractility …

Longitudinal Single-Cell Transcriptional Dynamics Throughout Neurodegeneration In Sca1, Leon Tejwani, Neal G Ravindra, Changwoo Lee, Yubao Cheng, Billy Nguyen, Kimberly Luttik, Luhan Ni, Shupei Zhang, Logan M Morrison, John Gionco, Yangfei Xiang, Jennifer Yoon, Hannah Ro, Fatema Haidery, Rosalie M Grijalva, Eunwoo Bae, Kristen Kim, Regina T Martuscello, Harry T Orr, Huda Y Zoghbi, Hayley S Mcloughlin, Laura P W Ranum, Vikram G Shakkottai, Phyllis L Faust, Siyuan Wang, David Van Dijk, Janghoo Lim

Duncan NRI Faculty and Staff Publications

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a …

Aspscr1-Tfe3 Reprograms Transcription By Organizing Enhancer Loops Around Hexameric Vcp/P97, Amir Pozner, Li Li, Shiv Prakash Verma, Shuxin Wang, Jared J Barrott, Mary L Nelson, Jamie S E Yu, Gian Luca Negri, Shane Colborne, Christopher S Hughes, Ju-Fen Zhu, Sydney L Lambert, Lara S Carroll, Kyllie Smith-Fry, Michael G Stewart, Sarmishta Kannan, Bodrie Jensen, Cini M John, Saif Sikdar, Hongrui Liu, Ngoc Ha Dang, Jennifer Bourdage, Jinxiu Li, Jeffery M Vahrenkamp, Katelyn L Mortenson, John S Groundland, Rosanna Wustrack, Donna L Senger, Franz J Zemp, Douglas J Mahoney, Jason Gertz, Xiaoyang Zhang, Alexander J Lazar, Martin Hirst, Gregg B Morin, Torsten O Nielsen, Peter S Shen, Kevin B Jones

Faculty, Staff and Student Publications

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its …

An Excitatory Projection From The Basal Forebrain To The Ventral Tegmental Area That Underlies Anorexia-Like Phenotypes, Jing Cai, Yanyan Jiang, Yuanzhong Xu, Zhiying Jiang, Claire Young, Hongli Li, Joshua Ortiz-Guzman, Yizhou Zhuo, Yulong Li, Yong Xu, Benjamin R Arenkiel, Qingchun Tong

Faculty, Staff and Students Publications

Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptations remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA) in mice. Glutamatergic neurons in both regions displayed correlated responses to various stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BF → VTA circuit reduces appetite, increases locomotion, and elicits avoidance. Consistently, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of …

Fluvoxamine Inhibits Th1 And Th17 Polarization And Function By Repressing Glycolysis To Attenuate Autoimmune Progression In Type 1 Diabetes, Yuan Zou, Jing Zhang, Fei Sun, Qianqian Xu, Longmin Chen, Xi Luo, Ting Wang, Qing Zhou, Shu Zhang, Fei Xiong, Wen Kong, Ping Yang, Qilin Yu, Shiwei Liu, Cong-Yi Wang

Faculty, Staff and Student Publications

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed.

METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune …

Efficacy Of Novel Agents Against Cellular Models Of Familial Platelet Disorder With Myeloid Malignancy (Fpd-Mm), Christopher P Mill, Warren C Fiskus, Courtney D Dinardo, Patrick Reville, John A Davis, Christine E Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and …

Aneuploid Embryonic Stem Cells Drive Teratoma Metastasis, Rong Xiao, Deshu Xu, Meili Zhang, Zhanghua Chen, Li Cheng, Songjie Du, Mingfei Lu, Tonghai Zhou, Ruoyan Li, Fan Bai, Yue Huang

Faculty, Staff and Student Publications

Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities …

Gestational Diabetes Augments Group B Streptococcus Infection By Disrupting Maternal Immunity And The Vaginal Microbiota, Vicki Mercado-Evans, Marlyd E Mejia, Jacob J Zulk, Samantha Ottinger, Zainab A Hameed, Camille Serchejian, Madelynn G Marunde, Clare M Robertson, Mallory B Ballard, Simone H Ruano, Natalia Korotkova, Anthony R Flores, Kathleen A Pennington, Kathryn A Patras

Faculty, Staff and Student Publications

Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals differential GBS adaptation to the GDM reproductive tract, including a putative glycosyltransferase (yfhO), and altered host responses. GDM immune disruptions include reduced uterine natural killer cell activation, impaired recruitment to placentae, …

Targeting Alk Averts Ribonuclease 1-Induced Immunosuppression And Enhances Antitumor Immunity In Hepatocellular Carcinoma, Chunxiao Liu, Chenhao Zhou, Weiya Xia, Yifan Zhou, Yufan Qiu, Jialei Weng, Qiang Zhou, Wanyong Chen, Ying-Nai Wang, Heng-Huan Lee, Shao-Chun Wang, Ming Kuang, Dihua Yu, Ning Ren, Mien-Chie Hung

Faculty, Staff and Student Publications

Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a …

Tumor-Specific Polycistronic Mirna Delivered By Engineered Exosomes For The Treatment Of Glioblastoma, Malcolm F Mcdonald, Anwar Hossain, Eric N Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang

Faculty, Staff and Student Publications

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

Methods: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to …

Targeting Prostate Tumor Low-Molecular Weight Tyrosine Phosphatase For Oxidation-Sensitizing Therapy, Stephanie M Stanford, Tiffany P Nguyen, Joseph Chang, Zixuan Zhao, G Lavender Hackman, Eugenio Santelli, Colton M Sanders, Madhusudhanarao Katiki, Eleonora Dondossola, Brooke L Brauer, Michael A Diaz, Yuan Zhan, Sterling H Ramsey, Philip A Watson, Banumathi Sankaran, Claudia Paindelli, Vanessa Parietti, Antonios G Mikos, Alessia Lodi, Aditya Bagrodia, Andrew Elliott, Rana R Mckay, Ramachandran Murali, Stefano Tiziani, Arminja N Kettenbach, Nunzio Bottini

Faculty, Staff and Student Publications

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor …

Sarin-Induced Neuroinflammation In Mouse Brain Is Attenuated By The Caspase Inhibitor Q-Vd-Oph, Ekta J. Shah, William C. Grunwald Jr., Teresa L. Garrett, Thomas L. Brown, David R. Cool

Neuroscience, Cell Biology & Physiology Faculty Publications

Organophosphates cause hyperstimulation of the central nervous system, leading to extended seizures, convulsions, and brain damage. Sarin is a highly toxic organophosphate nerve agent that has been employed in several terrorist attacks. The prolonged toxicity of sarin may be enhanced by the neuroinflammatory response initiated by the inflammasome, caspase involvement, and generation/release of proinflammatory cytokines. Since neurodegeneration and neuroinflammation are prevalent in sarin-exposed animals, we were interested in evaluating the capacity of quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh), a pan caspase inhibitor to attenuate neuroinflammation following sarin exposure. To test this hypothesis, sarin-exposed C57BL/6 mice were treated with Q-VD-OPh or negative control quinolyl-valyl-O-methylglutamyl-[-2,6-difluorophenoxy]-methyl …

Shape Anisotropy-Governed High-Performance Nanomagnetosol For In Vivo Magnetic Particle Imaging Of Lungs, Saumya Nigam, Jeotikanta Mohapatra, Ashley V Makela, Hanaan Hayat, Jessi Mercedes Rodriguez, Aixia Sun, Elizabeth Kenyon, Nathan A Redman, Dana Spence, George Jabin, Bin Gu, Mohamed Ashry, Lorenzo F Sempere, Arijit Mitra, Jinxing Li, Jiahui Chen, Guo-Wei Wei, Steven Bolin, Brett Etchebarne, J Ping Liu, Christopher H Contag, Ping Wang

Faculty, Staff and Student Publications

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has shown extensive lung manifestations in vulnerable individuals, putting lung imaging and monitoring at the forefront of early detection and treatment. Magnetic particle imaging (MPI) is an imaging modality, which can bring excellent contrast, sensitivity, and signal-to-noise ratios to lung imaging for the development of new theranostic approaches for respiratory diseases. Advances in MPI tracers would offer additional improvements and increase the potential for clinical translation of MPI. Here, a high-performance nanotracer based on shape anisotropy of magnetic nanoparticles is developed and its use in MPI imaging …

Development Of Resistance To Type Ii Jak2 Inhibitors In Mpn Depends On Axl Kinase And Is Targetable, Tamara Codilupi, Jakub Szybinski, Stefanie Arunasalam, Sarah Jungius, Andrew C Dunbar, Simona Stivala, Sime Brkic, Camille Albrecht, Lenka Vokalova, Julie L Yang, Katarzyna Buczak, Nilabh Ghosh, Jakob R Passweg, Alicia Rovo, Anne Angelillo-Scherrer, Dmitry Pankov, Stefan Dirnhofer, Ross L Levine, Richard Koche, Sara C Meyer

Faculty, Staff and Student Publications

PURPOSE: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.

EXPERIMENTAL DESIGN: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.

RESULTS: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2,500 differential phospho-sites, MAPK pathway activation was …

Successful Reuse Of A Donor Heart, Isaac S Alderete, Qimeng Gao, Abigail Benkert, Katherine Sun, Riley Kahan, Kannan Samy, Vincenzo Villani, Joseph W Turek, Deepak Vikraman, Carmelo A Milano, Michael W Manning, Andrew S Barbas

Faculty, Staff and Student Publications

Advances in surgical technique and multidisciplinary management have improved long-term survival for patients born with single ventricle physiology. However, patients who have undergone Fontan completion remain at risk for long-term comorbidities associated with the complex hemodynamic changes following the procedure, including Fontan failure and Fontan-associated liver disease.1 Combined heart-liver transplantation (CHLT) is a rare but lifesaving procedure that has been described in the setting of heart and liver failure secondary to Fontan failure.2 As long-term survival continues to improve for Fontan patients, the incidence of Fontan-associated liver disease will increase. Thus, improving CHLT outcomes and access to both …

Brain Endothelial Cd200 Signaling Protects Brain Against Ischemic Damage, Afzal Misrani, Conelius Ngwa, Abdullah Al Mamun, Romana Sharmeen, Kanaka Valli Manyam, Rodney M Ritzel, Louise Mccullough, Fudong Liu

Faculty, Staff and Student Publications

Ischemic stroke induced inflammatory responses contribute significantly to neuronal damage and stroke outcomes. CD200 ligand and its receptor, CD200R, constitute an endogenous inhibitory signaling that is being increasingly recognized in studies of neuroinflammation in various central nervous system disorders. CD200 is a type 1 membrane glycoprotein that is broadly expressed by endothelia and neurons in the brain. In the present study, we have examined the role of endothelial CD200 signaling in acute ischemic stroke. Endothelial CD200 conditional knock out (CKO) mice were generated by breeding CD200 gene floxed mice with Cdh5^Cre mice. The mice were subjected to a 60-min …

Txnrd1 Drives The Innate Immune Response In Senescent Cells With Implications For Age-Associated Inflammation, Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V Kossenkov, Shelley L Berger, Peter D Adams, David W Speicher, David Schultz, Ronen Marmorstein, Kenneth S Zaret, Rugang Zhang

Faculty, Staff and Student Publications

Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) …

Enhancing Anti-Aml Activity Of Venetoclax By Isoflavone Me-344 Through Suppression Of Oxphos And/Or Purine Biosynthesis In Vitro, Katie H Hurrish, Yongwei Su, Shraddha Patel, Cassandra L Ramage, Jianlei Zhao, Brianna R Temby, Jenna L Carter, Holly Edwards, Steven A Buck, Sandra E Wiley, Maik Hüttemann, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Xun Bao, Jing Li, Jay Yang, Julie Boerner, Zhanjun Hou, Gheath Al-Atrash, Sergej N Konoplev, Jonathan Busquets, Stefano Tiziani, Larry H Matherly, Jeffrey W Taub, Marina Konopleva, Yubin Ge, Natalia Baran

Faculty, Staff and Student Publications

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that …

Age-Associated Disparity In Phagocytic Clearance Affects The Efficacy Of Cancer Nanotherapeutics, Yifan Wang, Weiye Deng, Daeyong Lee, Long Yan, Yifei Lu, Shiyan Dong, Kristin Huntoon, Abin Antony, Xuefeng Li, Rui Ye, Yan Zhao, Feiyan Zhao, Benjamin R Schrank, Jonghoon Ha, Minjeong Kang, Mingming Yang, Ping Gong, Philip L Lorenzi, Lin Tan, Thomas D Gallup, Sarah K Tang, Zhaogang Yang, Jing Li, Nina N Sanford, Hongmei Wang, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger …

Activation Of Testosterone-Androgen Receptor Mediates Cerebrovascular Protection By Photobiomodulation Treatment In Photothrombosis-Induced Stroke Rats, Yu Feng, Zhihai Huang, Xiaohui Ma, Xuemei Zong, Celeste Yin-Chieh Wu, Reggie Hui-Chao Lee, Hung Wen Lin, Michael R Hamblin, Quanguang Zhang

Faculty, Staff and Student Publications

RATIONALE: Numerous epidemiological studies have reported a link between low testosterone levels and an increased risk of cerebrovascular disease in men. However, there is ongoing controversy surrounding testosterone replacement therapy due to potential side effects. PBMT has been demonstrated to improve cerebrovascular function and promote testosterone synthesis in peripheral tissues. Despite this, the molecular mechanisms that could connect PBMT with testosterone and vascular function in the brain of photothrombosis (PT)-induced stroke rats remain largely unknown.

METHODS: We measured behavioral performance, cerebral blood flow (CBF), vascular permeability, and the expression of vascular-associated and apoptotic proteins in PT-induced stroke rats treated with …

Circadian Dysfunction Induces Nafld-Related Human Liver Cancer In A Mouse Model, Jennifer Padilla, Noha M Osman, Beatrice Bissig-Choisat, Sandra L Grimm, Xuan Qin, Angela M Major, Li Yang, Dolores Lopez-Terrada, Cristian Coarfa, Feng Li, Karl-Dimiter Bissig, David D Moore, Loning Fu

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Chronic circadian dysfunction increases the risk of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), but the underlying mechanisms and direct relevance to human HCC have not been established. In this study, we aimed to determine whether chronic circadian dysregulation can drive NAFLD-related carcinogenesis from human hepatocytes and human HCC progression.

METHODS: Chronic jet lag of mice with humanized livers induces spontaneous NAFLD-related HCCs from human hepatocytes. The clinical relevance of this model was analysed by biomarker, pathological/histological, genetic, RNA sequencing, metabolomic, and integrated bioinformatic analyses.

RESULTS: Circadian dysfunction induces glucose intolerance, NAFLD-associated human HCCs, and human …

Genome-Wide P63-Target Gene Analyses Reveal Tap63/Nrf2-Dependent Oxidative Stress Responses, Marco Napoli, Avani A Deshpande, Deepavali Chakravarti, Kimal Rajapakshe, Preethi H Gunaratne, Cristian Coarfa, Elsa R Flores

Faculty, Staff and Students Publications

The p53 family member TP63 encodes two sets of N-terminal isoforms, TAp63 and ΔNp63 isoforms. They each regulate diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities have been extensively characterized, TAp63 prevents premature aging by regulating the quiescence and genomic stability of stem cells required for wound healing and hair regeneration, while ΔNp63 controls maintenance and terminal differentiation of epidermal basal cells. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical sequence for a DNA-binding domain. To understand the mechanisms of the transcriptional programs …

Sirt1 Safeguards Adipogenic Differentiation By Orchestrating Anti-Oxidative Responses And Suppressing Cellular Senescence, An Yu, Ruofan Yu, Haiying Liu, Chenliang Ge, Weiwei Dang

Faculty, Staff and Students Publications

Adipose tissue is an important endocrine organ that regulates metabolism, immune response and aging in mammals. Healthy adipocytes promote tissue homeostasis and longevity. SIRT1, a conserved NAD⁺-dependent deacetylase, negatively regulates adipogenic differentiation by deacetylating and inhibiting PPAR-γ. However, knocking out SIRT1 in mesenchymal stem cells (MSCs) in mice not only causes defects in osteogenesis, but also results in the loss of adipose tissues, suggesting that SIRT1 is also important for adipogenic differentiation.

Here, we report that severe impairment of SIRT1 function in MSCs caused significant defects and cellular senescence during adipogenic differentiation. These were observed only when inhibiting …

Generation Of A Dcx-Creert2 Knock-In Mouse For Genetic Manipulation Of Newborn Neurons, Gabriella A Perez, Kyung-Won Park, Denise Lanza, Jenna Cicardo, M Danish Uddin, Joanna L Jankowsky

Faculty, Staff and Students Publications

A wide variety of CreERT2 driver lines are available for genetic manipulation of adult-born neurons in the mouse brain. These tools have been instrumental in studying fate potential, migration, circuit integration, and morphology of the stem cells supporting lifelong neurogenesis. Despite a wealth of tools, genetic manipulation of adult-born neurons for circuit and behavioral studies has been limited by poor specificity of many driver lines targeting early progenitor cells and by the inaccessibility of lines selective for later stages of neuronal maturation. We sought to address these limitations by creating a new CreERT2 driver line targeted to the endogenous mouse …

In Vivo Cardiac Electrophysiology In Mice: Determination Of Atrial And Ventricular Arrhythmic Substrates, Jose Alberto Navarro-Garcia, Florian Bruns, Oliver M Moore, Marcel A Tekook, Dobromir Dobrev, Christina Y Miyake, Xander H T Wehrens

Faculty, Staff and Students Publications

Cardiac arrhythmias are a common cardiac condition that might lead to fatal outcomes. A better understanding of the molecular and cellular basis of arrhythmia mechanisms is necessary for the development of better treatment modalities. To aid these efforts, various mouse models have been developed for studying cardiac arrhythmias. Both genetic and surgical mouse models are commonly used to assess the incidence and mechanisms of arrhythmias. Since spontaneous arrhythmias are uncommon in healthy young mice, intracardiac programmed electrical stimulation (PES) can be performed to assess the susceptibility to pacing-induced arrhythmias and uncover the possible presence of a proarrhythmogenic substrate. This procedure …

Host Gastric Corpus Microenvironment Facilitates Ascaris Suum Larval Hatching And Infection In A Murine Model, Yifan Wu, Grace Adeniyi-Ipadeola, Mahliyah Adkins-Threats, Matthew Seasock, Charlie Suarez-Reyes, Ricardo Fujiwara, Maria Elena Bottazzi, Lizhen Song, Jason C Mills, Jill E Weatherhead

Faculty, Staff and Students Publications

Ascariasis (roundworm) is the most common parasitic helminth infection globally and can lead to significant morbidity in children including chronic lung disease. Children become infected with Ascaris spp. via oral ingestion of eggs. It has long been assumed that Ascaris egg hatching and larval translocation across the gastrointestinal mucosa to initiate infection occurs in the small intestine. Here, we show that A. suum larvae hatched in the host stomach in a murine model. Larvae utilize acidic mammalian chitinase (AMCase; acid chitinase; Chia) from chief cells and acid pumped by parietal cells to emerge from eggs on the surface of gastric …