Biomedical Informatics Commons^™

Fibrinogen-Like Protein 2: Its Biological Function Across Cell Types And The Potential To Serve As An Immunotherapy Target For Brain Tumors, Sheng Zhang, Ganesh Rao, Amy Heimberger, Shulin Li

Faculty, Staff and Student Publications

Brain tumors are among the 10 leading causes of cancer-related death and present unique treatment challenges due to their critical location, genetic heterogeneity, and the blood-brain barrier. Recent advances in targeted immunotherapy and immune checkpoint blocking therapy provide alternative therapeutic strategies for brain tumors. Fibrinogen-like protein 2 (FGL2), which induces transformation from low-grade glioma to high-grade glioblastoma, is a type II membrane protein that is highly expressed in both host immune cells and tumor cells. Studies have uncovered multiple forms of FGL2 proteins with a broad range of roles in inducing immune tolerance and avoiding immune surveillance in tumor cells. …

Inhibition Of Colorectal Cancer Tumorigenesis By Ursolic Acid And Doxorubicin Is Mediated By Targeting The Akt Signaling Pathway And Activating The Hippo Signaling Pathway, Dan Hu, Ruo Yu Meng, Thi Van Nguyen, Ok Hee Chai, Byung Hyun Park, Ju-Seog Lee, Soo Mi Kim

Faculty, Staff and Student Publications

Colorectal cancer (CRC) is one of the deadliest malignant tumors worldwide and its prevalence is increasing in South Korea. The efficacy of combined treatment with natural product‑derived and chemotherapy agents including curcumin combined with 5‑fluorouracil, resveratrol combined with cisplatin and epigallocatechin‑3‑gallate (EGCG) combined with cisplatin in preventing cancer progression and killing cancer cells has emerged. The Akt and Hippo signaling pathways serve a key role in colorectal tumor growth; however, the exact role of the crosstalk between Akt and Hippo signaling pathways in CRC remains poorly elucidated. The combined effect of UA and DOX on the cell proliferation, apoptosis, migration …

Cbx5 Loss Drives Egfr Inhibitor Resistance And Results In Therapeutically Actionable Vulnerabilities In Lung Cancer, Suresh Bugide, Yvonne J K Edwards, Romi Gupta, Michael R Green, Narendra Wajapeyee

Faculty, Staff and Student Publications

Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 …

Interfering With Lipid Metabolism Through Targeting Ces1 Sensitizes Hepatocellular Carcinoma For Chemotherapy, Gang Li, Xin Li, Iqbal Mahmud, Jazmin Ysaguirre, Baharan Fekry, Shuyue Wang, Bo Wei, Kristin L Eckel-Mahan, Philip L Lorenzi, Richard Lehner, Kai Sun

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, …

A Novel Defined Tlr3 Agonist As An Effective Vaccine Adjuvant, Kwang Hyun Ko, Seung Bin Cha, Seung-Hwan Lee, Hyun Shik Bae, Chul Soo Ham, Min-Gyu Lee, Dong-Ho Kim, Seung Hyun Han

Faculty, Staff and Student Publications

Synthetic double-stranded RNA analogs recognized by Toll-like receptor 3 (TLR3) are an attractive adjuvant candidate for vaccines, especially against intracellular pathogens or tumors, because of their ability to enhance T cell and antibody responses. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been limited due to heterogeneous molecular size, inconsistent activity, poor stability, and toxicity. To overcome these limitations, we developed a novel dsRNA-based TLR3 agonist named NexaVant (NVT) by using PCR-coupled bidirectional in vitro transcription. Agarose gel electrophoresis and reverse phase-HPLC analysis demonstrated that NVT is a single 275-kDa homogeneous molecule. NVT appears to …

Tmem161b Regulates Cerebral Cortical Gyration, Sonic Hedgehog Signaling, And Ciliary Structure In The Developing Central Nervous System, Shyam K Akula, Jack H Marciano, Youngshin Lim, David Exposito-Alonso, Norma K Hylton, Grace H Hwang, Jennifer E Neil, Nicole Dominado, Rosie K Bunton-Stasyshyn, Janet H T Song, Maya Talukdar, Aloisia Schmid, Lydia Teboul, Alisa Mo, Taehwan Shin, Benjamin Finander, Samantha G Beck, Rebecca C Yeh, Aoi Otani, Xuyu Qian, Ellen M Degennaro, Fowzan S Alkuraya, Sateesh Maddirevula, Gregory D Cascino, Caterina Giannini, Undiagnosed Diseases Network, Lindsay C Burrage, Jill A Rosenfield, Shamika Ketkar, Gary D Clark, Carlos Bacino, Richard A Lewis, Rosalind A Segal, J Fernando Bazan, Kelly A Smith, Jeffrey A Golden, Ginam Cho, Christopher A Walsh

Faculty, Staff and Students Publications

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret …

The Nfib/Carm1 Partnership Is A Driver In Preclinical Models Of Small Cell Lung Cancer, Guozhen Gao, Simone Hausmann, Natasha M Flores, Ana Morales Benitez, Jianjun Shen, Xiaojie Yang, Maria D Person, Sitaram Gayatri, Donghang Cheng, Yue Lu, Bin Liu, Pawel K Mazur, Mark T Bedford

Faculty, Staff and Student Publications

The coactivator associated arginine methyltransferase (CARM1) promotes transcription, as its name implies. It does so by modifying histones and chromatin bound proteins. We identified nuclear factor I B (NFIB) as a CARM1 substrate and show that this transcription factor utilizes CARM1 as a coactivator. Biochemical studies reveal that tripartite motif 29 (TRIM29) is an effector molecule for methylated NFIB. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Here, we explore the possibility that CARM1 methylation of NFIB is important for its transforming activity. Using a SCLC mouse model, we show …

Control Of Craniofacial Development By The Collagen Receptor, Discoidin Domain Receptor 2, Fatma F Mohamed, Chunxi Ge, Shawn A Hallett, Alec C Bancroft, Randy T Cowling, Noriaki Ono, Abdul-Aziz Binrayes, Barry Greenberg, Benjamin Levi, Vesa M Kaartinen, Renny T Franceschi

Faculty, Staff and Student Publications

Development of the craniofacial skeleton requires interactions between progenitor cells and the collagen-rich extracellular matrix (ECM). The mediators of these interactions are not well-defined. Mutations in the discoidin domain receptor 2 gene (DDR2), which encodes a non-integrin collagen receptor, are associated with human craniofacial abnormalities, such as midface hypoplasia and open fontanels. However, the exact role of this gene in craniofacial morphogenesis is not known. As will be shown, Ddr2-deficient mice exhibit defects in craniofacial bones including impaired calvarial growth and frontal suture formation, cranial base hypoplasia due to aberrant chondrogenesis and delayed ossification at growth plate …

Harnessing The Therapeutic Vulnerability Of Mmr Heterogeneity In Colorectal Cancer, Gayathri Anandappa, Michael J Overman

Faculty, Staff and Student Publications

In a recent issue of Cancer Cell, Amodio and colleagues report an interesting method of modulating immunosurveillance in colorectal tumors with DNA mismatch repair (MMR) heterogeneity.1 By pharmacologically enriching the MMR deficient (MMRd) component using 6-thioguanine, they demonstrate improved tumor control in murine models.

Exploring Therapeutic Strategies For Infantile Neuronal Axonal Dystrophy (Inad/Park14), Guang Lin, Burak Tepe, Geoff Mcgrane, Regine C Tipon, Gist Croft, Leena Panwala, Amanda Hope, Agnes J H Liang, Zhongyuan Zuo, Seul Kee Byeon, Lily Wang, Akhilesh Pandey, Hugo J Bellen

Faculty, Staff and Students Publications

Infantile neuroaxonal dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models, the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, …

Adar1 Deletion Causes Degeneration Of The Exocrine Pancreas Via Mavs-Dependent Interferon Signaling, Dhwani N Rupani, Fredrik I Thege, Vidhi Chandra, Hajar Rajaei, Robert W Cowan, Sonja M Wörmann, Olivereen Le Roux, Prerna Malaney, Sara L Manning, Jack Hashem, Jennifer Bailey-Lundberg, Andrew D Rhim, Florencia Mcallister

Faculty, Staff and Student Publications

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a …

A Gain-Of-Function Tpc2 Variant R210c Increases Affinity To Pi(3,5)P2 And Causes Lysosome Acidification And Hypopigmentation, Qiaochu Wang, Zengge Wang, Yizhen Wang, Zhan Qi, Dayong Bai, Chentong Wang, Yuanying Chen, Wenjian Xu, Xili Zhu, Jaepyo Jeon, Jian Xiong, Chanjuan Hao, Michael Xi Zhu, Aihua Wei, Wei Li

Faculty, Staff and Student Publications

Albinism is a group of inherited disorders mainly affecting skin, hair and eyes. Here we identify a de novo point mutation, p.R210C, in the TPCN2 gene which encodes Two Pore Channel 2 (TPC2) from a patient with albinism. TPC2 is an endolysosome and melanosome localized non-selective cation channel involved in regulating pigment production. Through inside-out recording of plasma membrane targeted TPC2 and direct recording of enlarged endolysosomal vacuoles, we reveal that the R210C mutant displays constitutive channel activation and markedly increased affinity to PI(3,5)P2. Mice harboring the homologous mutation, R194C, also exhibit hypopigmentation in the fur and skin, as well …

Expansion And Mechanistic Insights Into De Novo Deaf1 Variants In Deaf1-Associated Neurodevelopmental Disorders, Stacey R Mcgee, Shivakumar Rajamanickam, Sandeep Adhikari, Oluwatosin C Falayi, Theresa A Wilson, Brian J Shayota, Jessica A Cooley Coleman, Cindy Skinner, Raymond C Caylor, Roger E Stevenson, Caio Robledo D' Angioli Costa Quaio, Berenice Cunha Wilke, Jennifer M Bain, Kwame Anyane-Yeboa, Kaitlyn Brown, John M Greally, Emilia K Bijlsma, Claudia A L Ruivenkamp, Keren Politi, Lydia A Arbogast, Michael W Collard, Jodi I Huggenvik, Sarah H Elsea, Philip J Jensik

Faculty, Staff and Students Publications

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants …

Tlr5 Agonists Enhance Anti-Tumor Immunity And Overcome Resistance To Immune Checkpoint Therapy, Caleb Gonzalez, Sarah Williamson, Seth T Gammon, Sarah Glazer, Joon Haeng Rhee, David Piwnica-Worms

Faculty, Staff and Student Publications

Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive immunity. Low serum levels of G-CSF …

A Molecular Switch Between Mammalian Mll Complexes Dictates Response To Menin-Mll Inhibition, Yadira M Soto-Feliciano, Francisco J Sánchez-Rivera, Florian Perner, Douglas W Barrows, Edward R Kastenhuber, Yu-Jui Ho, Thomas Carroll, Yijun Xiong, Disha Anand, Alexey A Soshnev, Leah Gates, Mary Clare Beytagh, David Cheon, Shengqing Gu, X Shirley Liu, Andrei V Krivtsov, Maximiliano Meneses, Elisa De Stanchina, Richard M Stone, Scott A Armstrong, Scott W Lowe, C David Allis

Faculty, Staff and Student Publications

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin-modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors …

Treatment Strategies And Mechanisms Associated With The Prevention Of Nash-Associated Hcc By A Toll-Like Receptor 4 Inhibitor, Suet-Ying Kwan, Alyssa N Slayden, Aubrey R Coronado, Rosamaria C Marquez, Huiqin Chen, Peng Wei, Michelle I Savage, Lana A Vornik, Jennifer T Fox, Shizuko Sei, Dong Liang, Heather L Stevenson, Gregory K Wilkerson, Mihai Gagea, Powel H Brown, Laura Beretta

Faculty, Staff and Student Publications

UNLABELLED: We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-β-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated …

Microenvironmental Ammonia Enhances T Cell Exhaustion In Colorectal Cancer, Hannah N Bell, Amanda K Huber, Rashi Singhal, Navyateja Korimerla, Ryan J Rebernick, Roshan Kumar, Marwa O El-Derany, Peter Sajjakulnukit, Nupur K Das, Samuel A Kerk, Sumeet Solanki, Jadyn G James, Donghwan Kim, Li Zhang, Brandon Chen, Rohit Mehra, Timothy L Frankel, Balázs Győrffy, Eric R Fearon, Marina Pasca Di Magliano, Frank J Gonzalez, Ruma Banerjee, Daniel R Wahl, Costas A Lyssiotis, Michael Green, Yatrik M Shah

Faculty, Staff and Student Publications

Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and …

Follistatin Regulates The Specification Of The Apical Cochlea Responsible For Low-Frequency Hearing In Mammals, Hei Yeun Koo, Min-A Kim, Hyehyun Min, Jae Yeon Hwang, Meenakshi Prajapati-Dinubila, Kwan Soo Kim, Martin M Matzuk, Juw Won Park, Angelika Doetzlhofer, Un-Kyung Kim, Jinwoong Bok

Faculty, Staff and Students Publications

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in …

Antisense Oligonucleotide Therapy Rescues Disturbed Brain Rhythms And Sleep In Juvenile And Adult Mouse Models Of Angelman Syndrome, Dongwon Lee, Wu Chen, Heet Naresh Kaku, Xinming Zhuo, Eugene S Chao, Armand Soriano, Allen Kuncheria, Stephanie Flores, Joo Hyun Kim, Armando Rivera, Frank Rigo, Paymaan Jafar-Nejad, Arthur L Beaudet, Matthew S Caudill, Mingshan Xue

Faculty, Staff and Students Publications

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we …

Mitochondrial Dysfunction Reactivates Α-Fetoprotein Expression That Drives Copper-Dependent Immunosuppression In Mitochondrial Disease Models, Kimberly A Jett, Zakery N Baker, Amzad Hossain, Aren Boulet, Paul A Cobine, Sagnika Ghosh, Philip Ng, Orhan Yilmaz, Kris Barreto, John Decoteau, Karen Mochoruk, George N Ioannou, Christopher Savard, Sai Yuan, Osama Hmh Abdalla, Christopher Lowden, Byung-Eun Kim, Hai-Ying Mary Cheng, Brendan J Battersby, Vishal M Gohil, Scot C Leary

Faculty, Staff and Students Publications

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative …

Receptor-Interacting Protein 1 And 3 Kinase Activity Are Required For High-Fat Diet Induced Liver Injury In Mice, Xiaoqin Wu, Rakesh K Arya, Emily Huang, Megan R Mcmullen, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND: The RIP1-RIP3-MLKL-mediated cell death pathway is associated with progression of non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Previous work identified a critical role for MLKL, the key effector regulating necroptosis, but not RIP3, in mediating high fat diet-induced liver injury in mice. RIP1 and RIP3 have active N-terminus kinase domains essential for activation of MLKL and subsequent necroptosis. However, little is known regarding domain-specific roles of RIP1/RIP3 kinase in liver diseases. Here, we hypothesized that RIP1/RIP3 kinase activity are required for the development of high fat diet-induced liver injury.

METHODS:Rip1K45A/K45A and Rip3K51A/K51A kinase-dead mice on a C57BL/6J background and their littermate …

Ribonuclease 1 Enhances Antitumor Immunity Against Breast Cancer By Boosting T Cell Activation, Ying-Nai Wang, Heng-Huan Lee, Zhou Jiang, Li-Chuan Chan, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

The secretory enzyme human ribonuclease 1 (RNase1) is involved in innate immunity and anti-inflammation, achieving host defense and anti-cancer effects; however, whether RNase1 contributes to adaptive immune response in the tumor microenvironment (TME) remains unclear. Here, we established a syngeneic immunocompetent mouse model in breast cancer and demonstrated that ectopic RNase1 expression significantly inhibited tumor progression. Overall changes in immunological profiles in the mouse tumors were analyzed by mass cytometry and showed that the RNase1-expressing tumor cells significantly induced CD4+ Th1 and Th17 cells and natural killer cells and reduced granulocytic myeloid-derived suppressor cells, supporting that RNase1 favors an antitumor …

Pyrolyzed Deketene Curcumin Controls Regulatory T Cell Generation And Gastric Cancer Metabolism Cooperate With 2-Deoxy-D-Glucose, Takashi Maruyama, Hirofumi Miyazaki, Yun-Ji Lim, Jian Gu, Masaki Ishikawa, Taichi Yoshida, Wanjun Chen, Yuji Owada, Hiroyuki Shibata

Faculty, Staff and Student Publications

Pyrolyzed deketene curcumin GO-Y022 prevents carcinogenesis in a gastric cancer mouse model. However, it is still less clear if GO-Y022 affects tumor-induced immune suppression. In this study, we found that GO-Y022 inhibited Treg generation in the presence of transforming growth factor beta 1 (TGF-β). However, GO-Y022 showed less impact on Foxp3+ Tregs in the gastric tumor microenvironment. Gastric tumor cells produce a large amount of L-lactate in the presence of GO-Y022 and diminish the inhibitory role of GO-Y022 against Treg generation in response to TGF-β. Therefore, naïve CD4+ T cells co-cultured with GO-Y022 treated gastric tumor cells increased Treg generation. …

C4b-Binding Protein Inhibits Particulate- And Crystalline-Induced Nlrp3 Inflammasome Activation, Damien Bierschenk, Nikolina Papac-Milicevic, Ian P Bresch, Valentina Kovacic, Serena Bettoni, Mateusz Dziedzic, Rick A Wetsel, Susanne Eschenburg, Christoph J Binder, Anna M Blom, Ben C King

Faculty, Staff and Student Publications

Dysregulated NLRP3 inflammasome activation drives a wide variety of diseases, while endogenous inhibition of this pathway is poorly characterised. The serum protein C4b-binding protein (C4BP) is a well-established inhibitor of complement with emerging functions as an endogenously expressed inhibitor of the NLRP3 inflammasome signalling pathway. Here, we identified that C4BP purified from human plasma is an inhibitor of crystalline- (monosodium urate, MSU) and particulate-induced (silica) NLRP3 inflammasome activation. Using a C4BP mutant panel, we identified that C4BP bound these particles

Multi-Faceted Role Of Lrp1 In The Immune System, Olga Sizova, Lisa St John, Qing Ma, Jeffrey J Molldrem

Faculty, Staff and Student Publications

Graft versus host disease (GVHD) represents the major complication after allogeneic hematopoietic stem cell transplantation (Allo-SCT). GVHD-prone patients rely on GVHD prophylaxis (e.g. methotrexate) and generalized anti-GVHD medical regimen (glucocorticoids). New anti-GVHD therapy strategies are being constantly explored, however there is an urgent need to improve current treatment, since GVHD-related mortality reaches 22% within 5 years in patients with chronic GVHD. This review is an attempt to describe a very well-known receptor in lipoprotein studies - the low-density lipoprotein receptor related protein 1 (LRP1) - in a new light, as a potential therapeutic target for GVHD prevention and treatment. Our …

Cd73-Generated Extracellular Adenosine Promotes Resolution Of Neutrophil-Mediated Tissue Injury And Restrains Metaplasia In Pancreatitis, Baylee J O'Brien, Erika Y Faraoni, Lincoln N Strickland, Zhibo Ma, Victoria Mota, Samantha Mota, Xuebo Chen, Tingting Mills, Holger K Eltzschig, Kathleen E Delgiorno, Jennifer M Bailey-Lundberg

Faculty, Staff and Student Publications

Pancreatitis is currently the leading cause of gastrointestinal hospitalizations in the US. This condition occurs in response to abdominal injury, gallstones, chronic alcohol consumption or, less frequently, the cause remains idiopathic. CD73 is a cell surface ecto‐5′‐nucleotidase that generates extracellular adenosine, which can contribute to resolution of inflammation by binding adenosine receptors on infiltrating immune cells. We hypothesized genetic deletion of CD73 would result in more severe pancreatitis due to decreased generation of extracellular adenosine. CD73 knockout (CD73 −/−) and C57BL/6 (wild type, WT) mice were used to evaluate the progression and response of caerulein‐induced acute and chronic pancreatitis. …

Association Of Cyclooxygenase-2 Expression With Endoplasmic Reticulum Stress And Autophagy In Triple-Negative Breast Cancer, Haechan Lee, Sungwook Jung, Gyungyub Gong, Bora Lim, Hee Jin Lee

Faculty, Staff and Student Publications

Cyclooxygenase-2 plays a role in oncogenesis and its overexpression is associated with triple-negative breast cancer. However, the mechanisms whereby cyclooxygenase-2 contribute to breast cancer are complex and not well understood. Cyclooxygenase-2 overexpression causes hypoxia, oxidative stress, and endoplasmic reticulum stress. The aim of this study is to investigate the correlations among cyclooxygenase-2 expression, endoplasmic reticulum stress-associated molecules, and autophagy-associated molecules in triple-negative breast cancer. Surgical specimens from two cohorts of triple-negative breast cancer patients without neoadjuvant systemic therapy were analyzed: cohorts 1 and 2 consisted of 218 cases from 2004 to 2006 and 221 cases from 2007 to 2009, respectively. …

Stellettin B Sensitizes Glioblastoma To Dna-Damaging Treatments By Suppressing Pi3k-Mediated Homologous Recombination Repair, Xin Peng, Shaolu Zhang, Yingying Wang, Zhicheng Zhou, Zixiang Yu, Zhenxing Zhong, Liang Zhang, Zhe-Sheng Chen, Francois X Claret, Moshe Elkabets, Feng Wang, Fan Sun, Ran Wang, Han Liang, Hou-Wen Lin, Dexin Kong

Faculty, Staff and Student Publications

Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage-inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA-damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα …

Combining Mek And Src Inhibitors For Treatment Of Colorectal Cancer Demonstrate Increased Efficacy In Vitro But Not In Vivo, Fan Fan, Susmita Ghosh, Reid Powell, Jason Roszik, Yongsun Park, Mary Sobieski, Alexey Sorokin, Clifford Stephan, Scott Kopetz, Lee M Ellis, Rajat Bhattacharya

Faculty, Staff and Student Publications

Metastatic colorectal cancer (mCRC) is the second leading cause of cancer deaths in the United States. More than 50% of patients with mCRC harbor mutations of the oncogenic driver RAS (KRAS or NRAS). Because directly targeting most mutations of RAS is technically challenging, researchers have concentrated on targeting MEK, a downstream mediator of RAS. However, targeting MEK as single-agent therapy is ineffective in patients with mCRC. We hypothesize that combining a MEK inhibitor with other agents can enhance the efficacy of MEK targeting in mCRC. Unbiased high-throughput screening (HTS) was performed to identify drugs that enhance the efficacy of MEK …

Effects Of Heterozygous Deletion Of Autism-Related Gene Cullin-3 In Mice, Qiang-Qiang Xia, Angela K Walker, Chenghui Song, Jing Wang, Anju Singh, James A Mobley, Zhong X Xuan, Jeffrey D Singer, Craig M Powell

Faculty, Staff and Student Publications

Autism Spectrum Disorder (ASD) is a developmental disorder in which children display repetitive behavior, restricted range of interests, and atypical social interaction and communication. CUL3, coding for a Cullin family scaffold protein mediating assembly of ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors, has been identified as a high-risk gene for autism. Although complete knockout of Cul3 results in embryonic lethality, Cul3 heterozygous mice have reduced CUL3 protein, demonstrate comparable body weight, and display minimal behavioral differences including decreased spatial object recognition memory. In measures of reciprocal social interaction, Cul3 heterozygous mice behaved similarly to their wild-type littermates. In area …