Medical Genetics Commons^™

Loss Of Adar1 In Macrophages In Combination With Interferon Gamma Suppresses Tumor Growth By Remodeling The Tumor Microenvironment, Weiwei Lin, Yikai Luo, Jie Wu, Haowan Zhang, Ge Jin, Chahua Guo, Hang Zhou, Han Liang, Xiaoyan Xu

Faculty, Staff and Student Publications

Background: ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown.

Methods: We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)-γ treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain …

Immune Cell Identity Behind The Ktrans Mapping Of Mouse Glioblastoma, Yanrong Zhang, Olivier Keunen, Anna Golebiewska, Marco Gerosa, Jing Wang, Sara Natasha Ghobadi, Ai Huang, Qingyi Hou, Frezghi G Habte, Ningrui Li, Gerry Grant, Ramasamy Paulmurugan, Kevin S Lee, Max Wintermark

Faculty, Staff and Student Publications

Dynamic contrast-enhanced MR imaging (DCE-MRI) can assess the integrity of the blood brain barrier (BBB) and has been used in GBM patients to determine glioma grade, predict prognosis, evaluate treatment response, and differentiate treatment-induced effect from recurrence. The volume transfer constant Ktrans is the most frequently used metric in tumor assessment. Based on previous studies that a higher WHO grade of brain tumor was associated with greater impairments of immunity and and that Ktrans value was associated with the pathological grading, the relationship between differential composition of immune cells in GBM tissue and dynamic changes in Ktrans mapping was anticipated …

Circulating Micrornas And Cytokines As Prognostic Biomarkers For Doxorubicin-Induced Cardiac Injury And For Evaluating The Effectiveness Of An Exercise Intervention, Prince Jeyabal, Anchit Bhagat, Fei Wang, Michael Roth, J Andrew Livingston, Susan C Gilchrist, Jose Banchs, Michelle A T Hildebrandt, Joya Chandra, Anita Deswal, Efstratios Koutroumpakis, Jian Wang, Najat C Daw, Theresa A Honey, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Purpose: To define a set of biomarkers that can be used to identify patients at high risk of developing late doxorubicin (DOX)-induced cardiac morbidity with the goal of focused monitoring and early interventions.

Experimental design: Mice received phosphate buffered saline or DOX 2.5 mg/kg 2x/week for 2 weeks. Blood samples were obtained before and after therapy for quantification of miRNAs (6 and 24 hours), cytokines (24 hours), and troponin (24 hours, 4 and 6 weeks). Cardiac function was evaluated using echocardiography before and 24 hours after therapy. To assess the effectiveness of exercise intervention in preventing DOX-induced cardiotoxicity blood samples …

Cell-Autonomous Effects Of Apoe4 In Restricting Microglial Response In Brain Homeostasis And Alzheimer’S Disease, Chia-Chen Liu, Na Wang, Yuanxin Chen, Yasuteru Inoue, Francis Shue, Yingxue Ren, Minghui Wang, Wenhui Qiao, Tadafumi C Ikezu, Zonghua Li, Jing Zhao, Yuka Martens, Sydney V Doss, Cassandra L Rosenberg, Suren Jeevaratnam, Lin Jia, Ana-Caroline Raulin, Fangfang Qi, Yiyang Zhu, Alla Alnobani, Joshua Knight, Yixing Chen, Cynthia Linares, Aishe Kurti, John D Fryer, Bin Zhang, Long-Jun Wu, Betty Y S Kim, Guojun Bu

Faculty, Staff and Student Publications

Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes …

The Lin28b/Wnt5a Axis Drives Pancreas Cancer Through Crosstalk Between Cancer Associated Fibroblasts And Tumor Epithelium, Zhaoqi Shu, Minghe Fan, Bo Tu, Zhiheng Tang, Haojie Wang, Haimeng Li, Hengchao Li, Meng Yuan, Jingru Bai, Sihan Huo, Lina Wang, Wei-Guo Zhu, Wei Wang, Xiaoyun Liu, Shaokun Shu, Ying Zhao

Faculty, Staff and Student Publications

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in …

Irf1 Regulates Self-Renewal And Stress Responsiveness To Support Hematopoietic Stem Cell Maintenance, Alexandra J S Rundberg Nilsson, Hongxu Xian, Shabnam Shalapour, Jörg Cammenga, Michael Karin

Faculty, Staff and Student Publications

Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of IRF1 in …

Rna-Based Translation Activators For Targeted Gene Upregulation, Yang Cao, Huachun Liu, Shannon S Lu, Krysten A Jones, Anitha P Govind, Okunola Jeyifous, Christine Q Simmons, Negar Tabatabaei, William N Green, Jimmy L Holder, Soroush Tahmasebi, Alfred L George, Bryan C Dickinson

Duncan NRI Faculty and Staff Publications

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. …

Uracil-Dna Glycosylase Of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently Of Its Catalytic Residues, Kyle R Smith, Somnath Paul, Qiwen Dong, Orchi Anannya, Darby G Oldenburg, J Craig Forrest, Kevin M Mcbride, Laurie T Krug

Faculty, Staff and Student Publications

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect unless coupled with additional …

Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes In Advanced Pancreatic Cancer, Chi-Ling Chiang, Yifan Ma, Ya-Chin Hou, Junjie Pan, Sin-Yu Chen, Ming-Hsien Chien, Zhi-Xuan Zhang, Wei-Hsiang Hsu, Xinyu Wang, Jingjing Zhang, Hong Li, Lili Sun, Shannon Fallen, Inyoul Lee, Xing-Yu Chen, Yeh-Shiu Chu, Chi Zhang, Tai-Shan Cheng, Wen Jiang, Betty Y S Kim, Eduardo Reategui, Robert Lee, Yuan Yuan, Hsiao-Chun Liu, Kai Wang, Michael Hsiao, Chi-Ying F Huang, Yan-Shen Shan, Andrew S Lee, L James Lee

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted …

Dendritic Cells As Shepherds Of T Cell Immunity In Cancer, Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel

Faculty, Staff and Student Publications

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging …

Pls3 Missense Variants Affecting The Actin-Binding Domains Cause X-Linked Congenital Diaphragmatic Hernia And Body-Wall Defects, Florence Petit, Mauro Longoni, Julie Wells, Richard S Maser, Eric L Bogenschutz, Matthew J Dysart, Hannah T M Contreras, Frederic Frénois, Barbara R Pober, Robin D Clark, Philip F Giampietro, Hilger H Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne-Sophie Jourdain, Marie-Ange Delrue, Brigitte Gilbert-Dussardier, Louise Devisme, Boris Keren, David J Mcculley, Lu Qiao, Rebecca Hernan, Julia Wynn, Tiana M Scott, Daniel G Calame, Zeynep Coban-Akdemir, Patricia Hernandez, Andres Hernandez-Garcia, Hagith Yonath, James R Lupski, Yufeng Shen, Wendy K Chung, Daryl A Scott, Carol J Bult, Patricia K Donahoe, Frances A High

Faculty, Staff and Student Publications

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical …

Pirh2-Dependent Dna Damage In Neurons Induced By The G-Quadruplex Ligand Pyridostatin, Rocio Diaz Escarcega, Abhijeet A Patil, Jose F Moruno-Manchon, Akihiko Urayama, Sean P Marrelli, Nayun Kim, David Monchaud, Louise D Mccullough, Andrey S Tsvetkov

Faculty, Staff and Student Publications

Noncanonical base pairing between four guanines (G) within single-stranded G-rich sequences leads to formation of а G-quartet. Self-stacking of G-quartets results in a columnar four-stranded DNA structure known as the G-quadruplex (G4 or G4-DNA). In cancer cells, G4-DNA regulates multiple DNA-dependent processes, including transcription, replication, and telomere function. How G4s function in neurons is poorly understood. Here, we performed a genome-wide gene expression analysis (RNA-Seq) to identify genes modulated by a G4-DNA ligand, pyridostatin (PDS), in primary cultured neurons. PDS promotes stabilization of G4 structures, thus allowing us to define genes directly or indirectly responsive to G4 regulation. We found …

Kunitz-Type Protease Inhibitor Tfpi2 Remodels Stemness And Immunosuppressive Tumor Microenvironment In Glioblastoma, Lizhi Pang, Madeline Dunterman, Songlin Guo, Fatima Khan, Yang Liu, Erfan Taefi, Atousa Bahrami, Changiz Geula, Wen-Hao Hsu, Craig Horbinski, Charles David James, Peiwen Chen

Faculty, Staff and Student Publications

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy …

A Peptide-Binding Domain Shared With An Antarctic Bacterium Facilitates, Cameron J Lloyd, Shuaiqi Guo, Brett Kinrade, Hossein Zahiri, Robert Eves, Syed Khalid Ali, Fitnat Yildiz, Ilja K Voets, Peter L Davies, Karl E Klose

Faculty, Staff and Student Publications

No abstract provided.

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KrasG12D (Kras*) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC), and a known repressor of tumor immunity. Conditional elimination of Kras* in genetic mouse models of PDAC leads to reactivation of Fas, CD8+ T cell mediated apoptosis, and complete eradication of tumors. Kras* elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen presenting cells. Mechanistically, Kras* mediated immune evasion involves epigenetic regulation of the Fas death receptor in cancer cells, via methylation of its promoter region. Further, analysis of human RNA sequencing identifies that high KRAS expressing PDAC tumors show …

Autotaxin Suppresses Cytotoxic T Cells Via Lpar5 To Promote Anti-Pd-1 Resistance In Non-Small Cell Lung Cancer, Jessica M Konen, B Leticia Rodriguez, Haoyi Wu, Jared J Fradette, Laura Gibson, Lixia Diao, Jing Wang, Stephanie Schmidt, Ignacio I Wistuba, Jianjun Zhang, Don L Gibbons

Faculty, Staff and Student Publications

Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and …

Aerobic Exercise Alters The Melanoma Microenvironment And Modulates Erk5 S496 Phosphorylatio, Hannah Savage, Sumedha Pareek, Jonghae Lee, Riccardo Ballarò, Darlan Conterno Minussi, Karma Hayek, Mumina Sadullozoda, Brooke S Lochmann, Jennifer L Mcquade, Emily C Lavoy, Enrica Marmonti, Hetal Patel, Guangyu Wang, Masaki Imanishi, Sivareddy Kotla, Jun-Ichi Abe, Keri Schadler

Faculty, Staff and Student Publications

Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors. Single-cell RNA sequencing and flow cytometry revealed exercise modulated the number and phenotype of tumor-infiltrating CD8+ T cells and myeloid cells. Specifically, exercise caused a …

A Review Of Pulmonary Neutrophilia And Insights Into The Key Role Of Neutrophils In Particle-Induced Pathogenesis In The Lung From Animal Studies Of Lunar Dusts And Other Poorly Soluble Dust Particles, Chiu-Wing Lam, Vincent Castranova, Kevin Driscoll, David Warheit, Valerie Ryder, Ye Zhang, Patti Zeidler-Erdely, Robert Hunter, Robert Scully, William Wallace, John James, Brian Crucian, Mayra Nelman, Richard Mccluskey, Donald Gardner, Roger Renne, Roger Mcclellan

Faculty, Staff and Student Publications

The mechanisms of particle-induced pathogenesis in the lung remain poorly understood. Neutrophilic inflammation and oxidative stress in the lung are hallmarks of toxicity. Some investigators have postulated that oxidative stress from particle surface reactive oxygen species (psROS) on the dust produces the toxicopathology in the lungs of dust-exposed animals. This postulate was tested concurrently with the studies to elucidate the toxicity of lunar dust (LD), which is believed to contain psROS due to high-speed micrometeoroid bombardment that fractured and pulverized lunar surface regolith. Results from studies of rats intratracheally instilled (ITI) with three LDs (prepared from an Apollo-14 lunar regolith), …

Inhibition Of Menin, Bcl-2, And Flt3 Combined With A Hypomethylating Agent Cures Npm1/Flt3-Itd/-Tkd Mutant Acute Myeloid Leukemia In A Patient-Derived Xenograft Model, Bing Z Carter, Po Yee Mak, Wenjing Tao, Lauren B Ostermann, Duncan H Mak, Baozhen Ke, Peter Ordentlich, Gerard M Mcgeehan, Michael Andreeff

Faculty, Staff and Student Publications

No abstract provided.

Triple-Negative Breast Tumors Are Dependent On Mutant P53 For Growth And Survival, Denada Dibra, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream …

Labeling Piezo2 Activity In The Peripheral Nervous System, Nicholas W Villarino, Yasmeen M F Hamed, Britya Ghosh, Adrienne E Dubin, Amanda H Lewis, Max A Odem, Meaghan C Loud, Yu Wang, M Rocio Servin-Vences, Ardem Patapoutian, Kara L Marshall

Duncan NRI Faculty and Staff Publications

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the …

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …

Piezo2 In Somatosensory Neurons Controls Gastrointestinal Transit, M Rocio Servin-Vences, Ruby M Lam, Alize Koolen, Yu Wang, Dimah N Saade, Meaghan Loud, Halil Kacmaz, Suzanne Frausto, Yunxiao Zhang, Arthur Beyder, Kara L Marshall, Carsten G Bönnemann, Alexander T Chesler, Ardem Patapoutian

Duncan NRI Faculty and Staff Publications

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in …

Combined Crispri And Proteomics Screening Reveal A Cohesin-Ctcf-Bound Allele Contributing To Increased Expression Of Ruvbl1 And Prostate Cancer Progression, Yijun Tian, Dandan Dong, Zixian Wang, Lang Wu, Jong Y Park, Gong-Hong Wei, Liang Wang

Faculty, Staff and Student Publications

Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR < 0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (p value = 1.2 × 10

Vincristine Enhances The Efficacy Of Mek Inhibitors In Preclinical Models Of Kras-Mutant Colorectal Cancer, Susmita Ghosh, Fan Fan, Reid T Powell, Jason Roszik, Yong Sung Park, Clifford Stephan, Manu Sebastian, Lin Tan, Alexey V Sorokin, Philip L Lorenzi, Scott Kopetz, Lee M Ellis, Rajat Bhattacharya

Faculty, Staff and Student Publications

Mutations in KRAS are found in more than 50% of tumors from patients with metastatic colorectal cancer (mCRC). However, direct targeting of most KRAS mutations is difficult; even the recently developed KRASG12C inhibitors failed to show significant benefit in patients with mCRC. Single agents targeting mitogen-activated protein kinase kinase (MEK), a downstream mediator of RAS, have also been ineffective in colorectal cancer. To identify drugs that can enhance the efficacy of MEK inhibitors, we performed unbiased high-throughput screening using colorectal cancer spheroids. We used trametinib as the anchor drug and examined combinations of trametinib with the NCI-approved Oncology Library version …

Divergent Structures Of Mammalian And Gammaherpesvirus Uracil Dna Glycosylases Confer Distinct Dna Binding And Substrate Activity, Yunxiang Mu, Monika A Zelazowska, Zaowen Chen, Joshua B Plummer, Qiwen Dong, Laurie T Krug, Kevin M Mcbride

Faculty, Staff and Student Publications

Uracil DNA glycosylase (UNG) removes mutagenic uracil base from DNA to initiate base excision repair (BER). The result is an abasic site (AP site) that is further processed by the high-fidelity BER pathway to complete repair and maintain genome integrity. The gammaherpesviruses (GHVs), human Kaposi sarcoma herpesvirus (KSHV), Epstein-Barr virus (EBV), and murine gammaherpesvirus 68 (MHV68) encode functional UNGs that have a role in viral genome replication. Mammalian and GHVs UNG share overall structure and sequence similarity except for a divergent amino-terminal domain and a leucine loop motif in the DNA binding domain that varies in sequence and length. To …

Epinephrine-Induced Effects On Cerebral Microcirculation And Oxygenation Dynamics Using Multimodal Monitoring And Functional Photoacoustic Microscopy, Dong Zhang, Wei Wang, Xiaoyi Zhu, Ran Li, Wei Liu, Maomao Chen, Tri Vu, Laiming Jiang, Qifa Zhou, Cody L Evans, Dennis A Turner, Huaxin Sheng, Jerrold H Levy, Jianwen Luo, Wei Yang, Junjie Yao, Ulrike Hoffmann

Faculty, Staff and Student Publications

Background: The administration of epinephrine after severe refractory hypotension, shock, or cardiac arrest restores systemic blood flow and major vessel perfusion but may worsen cerebral microvascular perfusion and oxygen delivery through vasoconstriction. The authors hypothesized that epinephrine induces significant microvascular constriction in the brain, with increased severity after repetitive dosing and in the aged brain, eventually leading to tissue hypoxia.

Methods: The authors investigated the effects of intravenous epinephrine administration in healthy young and aged C57Bl/6 mice on cerebral microvascular blood flow and oxygen delivery using multimodal in vivo imaging, including functional photoacoustic microscopy, brain tissue oxygen sensing, and follow-up …

Image-Based Quantification Of Histological Features As A Function Of Spatial Location Using The Tissue Positioning System, Ruichen Rong, Yonglong Wei, Lin Li, Tao Wang, Hao Zhu, Guanghua Xiao, Yunguan Wang

Faculty, Staff and Student Publications

Background: Tissues such as the liver lobule, kidney nephron, and intestinal gland exhibit intricate patterns of zonated gene expression corresponding to distinct cell types and functions. To quantitatively understand zonation, it is important to measure cellular or genetic features as a function of position along a zonal axis. While it is possible to manually count, characterize, and locate features in relation to the zonal axis, it is labor-intensive and difficult to do manually while maintaining precision and accuracy.

Methods: We addressed this challenge by developing a deep-learning-based quantification method called the "Tissue Positioning System" (TPS), which can automatically analyze zonation …

Single-Cell Transcriptomic Analysis Uncovers Intratumoral Heterogeneity And Drug-Tolerant Persister In Alk-Rearranged Lung Adenocarcinoma, Hoi-Hin Kwok, Huiyu Li, Jiashuang Yang, Junyang Deng, Nerissa Chui-Mei Lee, Timmy Wing-Kuk Au, Alva Ko-Yung Sit, Michael Kuan-Yew Hsin, Stephanie Kwai-Yee Ma, Lydia Wai-Ting Cheung, Luc Girard, Junya Fujimoto, Ignacio Ivan Wistuba, Boning Gao, John Dorrance Minna, David Chi-Leung Lam

Faculty, Staff and Student Publications

No abstract provided.

Pitfalls In Machine Learning-Based Assessment Of Tumor-Infiltrating Lymphocytes In Breast Cancer: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Jeppe Thagaard, Glenn Broeckx, David B Page, Chowdhury Arif Jahangir, Sara Verbandt, Zuzana Kos, Rajarsi Gupta, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Mohamed Amgad, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Eva Balslev, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Anders B Dahl, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Johan Doré Hansen, Sarah N Dudgeon, Thomas Ebstrup, Mahmoud Elghazawy, Claudio Fernandez-Martín, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Søren Hauberg, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Roslind, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Ely Scott, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Susan Fineberg, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Reena Md Zin, Sylvia Adams, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. …