Biomedical Informatics Commons^™

Targeted Therapeutic Strategies For Melanoma, Shiwei Zhang, Ruxin Xie, Ai Zhong, Junjie Chen

Faculty, Staff and Student Publications

Melanoma accounts for a small proportion of skin cancers diagnosed each year, but it has a high degree of malignancy and rapid progression, resulting in a short survival period for patients. The incidence of melanoma continues to rise, and now melanoma accounts for 1.7% of cancer diagnoses worldwide and is the fifth most common cancer in the United States. With the development of high-throughput sequencing technologies, the understanding of the pathophysiology of melanoma had also been improved. The most common activating mutations in melanoma cells are BRAF , NRAS , and KIT mutations, which disrupt cell signaling pathways related to …

The Potential For Development Of Clinically Relevant Microbial Resistance To Rifaximin-Α: A Narrative Review, Herbert L Dupont

Faculty, Staff and Student Publications

Rifaximin-α is a gut-targeted antibiotic indicated for numerous gastrointestinal and liver diseases. Its multifaceted mechanism of action goes beyond direct antimicrobial effects, including alterations in bacterial virulence, cytoprotective effects on host epithelial cells, improvement of impaired intestinal permeability, and reduction of proinflammatory cytokine expression via activation of the pregnane X receptor. Rifaximin-α is virtually non-absorbed, with low systemic drug levels contributing to its excellent safety profile. While there are high concentrations of drug in the colon, low water solubility leads to low colonic drug bioavailability, protecting the gut microbiome. Rifaximin-α appears to be more active in the bile-rich small bowel. …

Abnormal Patterns Of Sleep And Waking Behaviors Are Accompanied By Neocortical Oscillation Disturbances In An Ank3 Mouse Model Of Epilepsy-Bipolar Disorder Comorbidity, Juan E Villacres, Nicholas Riveira, Sohmee Kim, Laura L Colgin, Jeffrey L Noebels, Angel Y Lopez

Faculty, Staff and Students Publications

ANK3 is a leading bipolar disorder (BD) candidate gene in humans and provides a unique opportunity for studying epilepsy-BD comorbidity. Previous studies showed that deletion of Ank3-1b, a BD-associated variant of Ank3 in mice leads to increased firing threshold and diminished action potential dynamic range of parvalbumin (PV) interneurons and absence epilepsy, thus providing a biological mechanism linking epilepsy and BD. To explore the behavioral overlap of these disorders, we characterized behavioral patterns of Ank3-1b KO mice during overnight home-cage activity and examined network activity during these behaviors using paired video and EEG recordings. Since PV interneurons contribute to the …

Colonization Of Larval Zebrafish (Danio Rerio) With Adherent-Invasive Escherichia Coli Prevents Recovery Of The Intestinal Mucosa From Drug-Induced Enterocolitis, Erika Flores, Soumita Dutta, Rachel Bosserman, Ambro Van Hoof, Anne-Marie Krachler

Faculty, Staff and Student Publications

Although inflammatory bowel diseases are on the rise, what factors influence IBD risk and severity, and the underlying mechanisms remain to be fully understood. Although host genetics, microbiome, and environmental factors have all been shown to correlate with the development of IBD, cause and effect are difficult to disentangle in this context. For example, AIEC is a known pathobiont found in IBD patients, but it remains unclear if gut inflammation during IBD facilitates colonization with AIEC, or if AIEC colonization makes the host more susceptible to pro-inflammatory stimuli. It is critical to understand the mechanisms that contribute to AIEC infections …

Blue-Shift Photoconversion Of Near-Infrared Fluorescent Proteins For Labeling And Tracking In Living Cells And Organisms, Francesca Pennacchietti, Jonatan Alvelid, Rodrigo A Morales, Martina Damenti, Dirk Ollech, Olena S Oliinyk, Daria M Shcherbakova, Eduardo J Villablanca, Vladislav V Verkhusha, Ilaria Testa

Faculty, Staff and Student Publications

Photolabeling of intracellular molecules is an invaluable approach to studying various dynamic processes in living cells with high spatiotemporal precision. Among fluorescent proteins, photoconvertible mechanisms and their products are in the visible spectrum (400-650 nm), limiting their in vivo and multiplexed applications. Here we report the phenomenon of near-infrared to far-red photoconversion in the miRFP family of near infrared fluorescent proteins engineered from bacterial phytochromes. This photoconversion is induced by near-infrared light through a non-linear process, further allowing optical sectioning. Photoconverted miRFP species emit fluorescence at 650 nm enabling photolabeling entirely performed in the near-infrared range. We use miRFPs as …

Interlaboratory Comparison Of Pseudomonas Aeruginosa Phage Susceptibility Testing, Krupa Parmar, Lauren Komarow, Damon W Ellison, Andrey A Filippov, Mikeljon P Nikolich, Joseph R Fackler, Martin Lee, Anjna Nair, Priyesh Agrawal, Pranita D Tamma, Maria Souli, Scott R Evans, Kerryl E Greenwood-Quaintance, Scott A Cunningham, Robin Patel, Antibacterial Resistance Leadership Group

Faculty, Staff and Student Publications

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these …

Pain Management By Chemogenetic Control Of Sensory Neurons, Yize Li, Xin Ge, Ru-Rong Ji

Faculty, Staff and Student Publications

In this study, Perez-Sanchez et al.1 developed a chemogenetic method aimed at alleviating pain in mouse models while dampening excitability in human sensory neurons. This analgesic effect was attained through the introduction of human α7 nicotinic acetylcholine receptor and glycine receptor pore domain via virus-mediated expression in sensory neurons, forming a chloride channel. The activation of this channel was made possible by specific agonists. This study highlights the potential for treating clinical pain by gene therapy.

Prmt Blockade Induces Defective Dna Replication Stress Response And Synergizes With Parp Inhibition, Yang Li, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Travis D Kerr, Deepa Bisht, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L Mendillo, Yiling Lu, Collene R Jeter, Guang Peng, Jinsong Liu, Shannon N Westin, Anil K Sood, Michael T Lewis, Jishnu Das, S Stephen Yi, Mark T Bedford, Daniel J Mcgrail, Nidhi Sahni

Faculty, Staff and Student Publications

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous …

Genetic And Epigenetic Features Of Bilateral Wilms Tumor Predisposition In Patients From The Children’S Oncology Group Aren18b5-Q, Andrew J Murphy, Changde Cheng, Justin Williams, Timothy I Shaw, Emilia M Pinto, Karissa Dieseldorff-Jones, Jack Brzezinski, Lindsay A Renfro, Brett Tornwall, Vicki Huff, Andrew L Hong, Elizabeth A Mullen, Brian Crompton, Jeffrey S Dome, Conrad V Fernandez, James I Geller, Peter F Ehrlich, Heather Mulder, Ninad Oak, Jamie Maciezsek, Carolyn M Jablonowski, Andrew M Fleming, Prahalathan Pichavaram, Christopher L Morton, John Easton, Kim E Nichols, Michael R Clay, Teresa Santiago, Jinghui Zhang, Jun Yang, Gerard P Zambetti, Zhaoming Wang, Andrew M Davidoff, Xiang Chen

Faculty, Staff and Student Publications

Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of …

Pathway Centric Analysis For Single-Cell Rna-Seq And Spatial Transcriptomics Data With Gsdensity, Qingnan Liang, Yuefan Huang, Shan He, Ken Chen

Faculty, Staff and Student Publications

Advances in single-cell technology have enabled molecular dissection of heterogeneous biospecimens at unprecedented scales and resolutions. Cluster-centric approaches are widely applied in analyzing single-cell data, however they have limited power in dissecting and interpreting highly heterogenous, dynamically evolving data. Here, we present GSDensity, a graph-modeling approach that allows users to obtain pathway-centric interpretation and dissection of single-cell and spatial transcriptomics (ST) data without performing clustering. Using pathway gene sets, we show that GSDensity can accurately detect biologically distinct cells and reveal novel cell-pathway associations ignored by existing methods. Moreover, GSDensity, combined with trajectory analysis can identify curated pathways that are …

Lesion Detection In Women Breast’S Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using Deep Learning, Sudarshan Saikia, Tapas Si, Darpan Deb, Kangkana Bora, Saurav Mallik, Ujjwal Maulik, Zhongming Zhao

Faculty, Staff and Student Publications

Breast cancer is one of the most common cancers in women and the second foremost cause of cancer death in women after lung cancer. Recent technological advances in breast cancer treatment offer hope to millions of women in the world. Segmentation of the breast's Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) is one of the necessary tasks in the diagnosis and detection of breast cancer. Currently, a popular deep learning model, U-Net is extensively used in biomedical image segmentation. This article aims to advance the state of the art and conduct a more in-depth analysis with a focus on the use …

Acidosis-Mediated Increase In Ifn-Γ-Induced Pd-L1 Expression On Cancer Cells As An Immune Escape Mechanism In Solid Tumors, Philipp Knopf, Dimitri Stowbur, Sabrina H L Hoffmann, Natalie Hermann, Andreas Maurer, Valentina Bucher, Marilena Poxleitner, Bredi Tako, Dominik Sonanini, Balaji Krishnamachary, Sanhita Sinharay, Birgit Fehrenbacher, Irene Gonzalez-Menendez, Felix Reckmann, David Bomze, Lukas Flatz, Daniela Kramer, Martin Schaller, Stephan Forchhammer, Zaver M Bhujwalla, Leticia Quintanilla-Martinez, Klaus Schulze-Osthoff, Mark D Pagel, Marieke F Fransen, Martin Röcken, André F Martins, Bernd J Pichler, Kamran Ghoreschi, Manfred Kneilling

Faculty, Staff and Student Publications

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription …

Differences In Set-Based Tests For Sparse Alternatives When Testing Sets Of Outcomes Compared To Sets Of Explanatory Factors In Genetic Association Studies, Ryan Sun, Andy Shi, Xihong Lin

Faculty, Staff and Student Publications

Set-based association tests are widely popular in genetic association settings for their ability to aggregate weak signals and reduce multiple testing burdens. In particular, a class of set-based tests including the Higher Criticism, Berk-Jones, and other statistics have recently been popularized for reaching a so-called detection boundary when signals are rare and weak. Such tests have been applied in two subtly different settings: (a) associating a genetic variant set with a single phenotype and (b) associating a single genetic variant with a phenotype set. A significant issue in practice is the choice of test, especially when deciding between innovated and …

Bayesian Longitudinal Tensor Response Regression For Modeling Neuroplasticity, Suprateek Kundu, Alec Reinhardt, Serena Song, Joo Han, M Lawson Meadows, Bruce Crosson, Venkatagiri Krishnamurthy

Faculty, Staff and Student Publications

A major interest in longitudinal neuroimaging studies involves investigating voxel-level neuroplasticity due to treatment and other factors across visits. However, traditional voxel-wise methods are beset with several pitfalls, which can compromise the accuracy of these approaches. We propose a novel Bayesian tensor response regression approach for longitudinal imaging data, which pools information across spatially distributed voxels to infer significant changes while adjusting for covariates. The proposed method, which is implemented using Markov chain Monte Carlo (MCMC) sampling, utilizes low-rank decomposition to reduce dimensionality and preserve spatial configurations of voxels when estimating coefficients. It also enables feature selection via joint credible …

Combining The Tyrosine Kinase Inhibitor Cabozantinib And The Mtorc1/2 Inhibitor Sapanisertib Blocks Erk Pathway Activity And Suppresses Tumor Growth In Renal Cell Carcinoma, Yige Wu, Siqi Chen, Xiaolu Yang, Kazuhito Sato, Preet Lal, Yuefan Wang, Andrew T Shinkle, Michael C Wendl, Tina M Primeau, Yanyan Zhao, Alanna Gould, Hua Sun, Jacqueline L Mudd, Jeremy Hoog, R Jay Mashl, Matthew A Wyczalkowski, Chia-Kuei Mo, Ruiyang Liu, John M Herndon, Sherri R Davies, Di Liu, Xi Ding, Yvonne A Evrard, Bryan E Welm, David Lum, Mei Yee Koh, Alana L Welm, Jeffrey H Chuang, Jeffrey A Moscow, Funda Meric-Bernstam, Ramaswamy Govindan, Shunqiang Li, James Hsieh, Ryan C Fields, Kian-Huat Lim, Cynthia X Ma, Hui Zhang, Li Ding, Feng Chen

Faculty, Staff and Student Publications

Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor …

Timigp: An R Package To Depict The Tumor Microenvironment From Bulk Transcriptomics, Chenyang Li, Jianjun Zhang, Chao Cheng

Faculty, Staff and Students Publications

Exploring the clinical relevance of diverse immune cell types within the tumor microenvironment is pivotal for unraveling cancer intricacies and developing treatments. Here, we present a protocol for using tumor immune microenvironment illustration based on gene pairs, an R package to deduce cell-cell interactions, unveiling the association between immune cell relative abundance and patient prognoses from bulk gene expression and survival data. We describe steps for harnessing cell-type markers derived from single-cell RNA sequencing data to map the tumor immune microenvironment across a spectrum of cancer types. For complete details on the use and execution of this protocol, please refer …

Lilrb3 Modulates Acute Myeloid Leukemia Progression And Acts As An Effective Target For Car T-Cell Therapy, Sunny Mai, Alan Hodges, Hui-Ming Chen, Jilu Zhang, Yi-Ling Wang, Yongbin Liu, Fumiko Nakatsu, Xiaoxuan Wang, Jing Fang, Yitian Xu, Vitaliy Davidov, Kyeongah Kang, Sai Ravi Pingali, Siddhartha Ganguly, Masataka Suzuki, Marina Konopleva, Brooke Prinzing, Youli Zu, Stephen Gottschalk, Yong Lu, Shu-Hsia Chen, Ping-Ying Pan

Faculty, Staff and Students Publications

Identifying novel cell surface receptors that regulate leukemia cell differentiation and can be targeted to inhibit cellular proliferation is crucial to improve current treatment modalities in acute myeloid leukemia (AML), especially for relapsed or chemotherapy-refractory leukemia. Leukocyte immunoglobulin-like receptor type B (LILRB) is an immunomodulatory receptor originally found to be expressed in myeloid cells. In this study, we found that LILRB receptors can be induced under inflammatory stimuli and chemotherapy treatment conditions. Blockade of LILRB3 inhibited leukemia cell proliferation and leukemia progression. Additionally, treatment with LILRB3 blocking antibodies upregulated myeloid lineage differentiation transcription factors, including PU.1, C/EBP family, and IRF, …

Gap Junctions Or Hemichannel-Dependent And Independent Roles Of Connexins In Fibrosis, Epithelial-Mesenchymal Transitions, And Wound Healing, Yuting Li, Francisca M Acosta, Jean X Jiang

Faculty, Staff and Student Publications

Fibrosis initially appears as a normal response to damage, where activated fibroblasts produce large amounts of the extracellular matrix (ECM) during the wound healing process to assist in the repair of injured tissue. However, the excessive accumulation of the ECM, unresolved by remodeling mechanisms, leads to organ dysfunction. Connexins, a family of transmembrane channel proteins, are widely recognized for their major roles in fibrosis, the epithelial-mesenchymal transition (EMT), and wound healing. Efforts have been made in recent years to identify novel mediators and targets for this regulation. Connexins form gap junctions and hemichannels, mediating communications between neighboring cells and inside …

Recombination-Mediated Dissemination Of Methicillin-Resistant S Aureus Clonal Complex 1 In The Egyptian Health Care Settings, Salma W Elsayed, Reem A Elghaish, Eman Badr, Shaimaa F Mouftah, Nehal A Saif, Iman S Naga, Ahmed H Shata, Ben Pascoe, Samuel K Sheppard, Mohamed Elhadidy

Faculty, Staff and Student Publications

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a rapidly evolving pathogen that is frequently associated with outbreaks and sustained epidemics. This study investigated the population structure, resistome, virulome, and the correlation between antimicrobial resistance determinants with phenotypic resistance profiles of 36 representative hospital-acquired MRSA isolates recovered from hospital settings in Egypt.

Results: The community-acquired MRSA lineage, clonal complex 1 (CC1) was the most frequently detected clone, followed by three other globally disseminated clones, CC121, CC8, and CC22. Most isolates carried SCCmec type V and more than half of isolates demonstrated multi-drug resistant phenotypes. Resistance to linezolid, a last resort antibiotic for …

Identification Of Candidate Dna Methylation Biomarkers Related To Alzheimer’S Disease Risk By Integrating Genome And Blood Methylome Data, Yanfa Sun, Jingjing Zhu, Yaohua Yang, Zichen Zhang, Hua Zhong, Guanghua Zeng, Dan Zhou, Richard S Nowakowski, Jirong Long, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Alzheimer disease (AD) is a common neurodegenerative disease with a late onset. It is critical to identify novel blood-based DNA methylation biomarkers to better understand the extent of the molecular pathways affected in AD. Two sets of blood DNA methylation genetic prediction models developed using different reference panels and modelling strategies were leveraged to evaluate associations of genetically predicted DNA methylation levels with AD risk in 111,326 (46,828 proxy) cases and 677,663 controls. A total of 1,168 cytosine-phosphate-guanine (CpG) sites showed a significant association with AD risk at a false discovery rate (FDR) < 0.05. Methylation levels of 196 CpG sites were correlated with expression levels of 130 adjacent genes in blood. Overall, 52 CpG sites of 32 genes showed consistent association directions for the methylation-gene expression-AD risk, including nine genes (CNIH4, THUMPD3, SERPINB9, MTUS1, CISD1, FRAT2, CCDC88B, FES, and SSH2) firstly reported as AD risk genes. Nine of 32 genes were enriched in dementia and AD disease categories (P values ranged from 1.85 × 10-4 to 7.46 × 10-6), and 19 genes in a neurological disease network (score = 54) were also observed. Our findings improve the understanding of genetics and etiology for AD.

Monitoring Glucocorticoid Receptor In Plasma-Derived Extracellular Vesicles As A Marker Of Resistance To Androgen Receptor Signaling Inhibition In Prostate Cancer, Emanuela Gentile, Andrew W Hahn, Jian H Song, Anh Hoang, Peter D A Shepherd, Sumankalai Ramachandran, Nora M Navone, Eleni Efstathiou, Mark Titus, Paul G Corn, Sue-Hwa Lin, Christopher J Logothetis, Theocharis Panaretakis

Faculty, Staff and Student Publications

Disease progression following androgen ablation was shown to be associated with upregulation of the glucocorticoid receptor (GR). Longitudinal monitoring of GR expression in circulating extracellular vesicles (EV) may reflect changes in the tumor cell and facilitates detection of acquired resistance. We utilized LNCaP, LREX cells and a patient-derived xenograft, MDA PDX 322-2-6a, for in vitro and in vivo experiments. Plasma-derived EVs were isolated from patients with localized high-risk prostate cancer undergoing androgen ablation. The mRNA levels of GR in EVs and their responsive genes were detected by transcriptome analysis, qRT-PCR and the protein levels by Western blot analysis. We detected …

Genetic Determinants Underlying The Progressive Phenotype Of Β-Lactam/Β-Lactamase Inhibitor Resistance In Escherichia Coli, William C Shropshire, Hatim Amiji, Jordan Bremer, Selvalakshmi Selvaraj Anand, Benjamin Strope, Pranoti Sahasrabhojane, Marc Gohel, Samuel Aitken, Sarah Spitznogle, Xiaowei Zhan, Jiwoong Kim, David E Greenberg, Samuel A Shelburne

Faculty, Staff and Student Publications

Currently, whole-genome sequencing (WGS) data have not shown strong concordance with Escherichia coli susceptibility profiles to the commonly used β-lactam/β-lactamase inhibitor (BL/BLI) combinations: ampicillin-sulbactam (SAM), amoxicillin-clavulanate (AMC), and piperacillin-tazobactam (TZP). Progressive resistance to these BL/BLIs in the absence of cephalosporin resistance, also known as extended-spectrum resistance to BL/BLI (ESRI), has been suggested to primarily result from increased copy numbers of bla TEM variants, which is not routinely assessed in WGS data. We sought to determine whether addition of gene amplification could improve genotype-phenotype associations through WGS analysis of 147 E. coli bacteremia isolates with increasing categories of BL/BLI non-susceptibility ranging …

Oncogenic Kras Drives Lipofibrogenesis To Promote Angiogenesis And Colon Cancer Progression, Wen-Hao Hsu, Kyle A Labella, Yiyun Lin, Ping Xu, Rumi Lee, Cheng-En Hsieh, Lei Yang, Ashley Zhou, Jonathan M Blecher, Chang-Jiun Wu, Kangyu Lin, Xiaoying Shang, Shan Jiang, Denise J Spring, Yan Xia, Peiwen Chen, John Paul Shen, Scott Kopetz, Ronald A Depinho

Faculty, Staff and Student Publications

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. …

Formate Supplementation Enhances Antitumor Cd8+ T-Cell Fitness And Efficacy Of Pd-1 Blockade, Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W Lafleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe

Faculty, Staff and Student Publications

UNLABELLED: The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for …

Circulating Senescent Myeloid Cells Infiltrate The Brain And Cause Neurodegeneration In Histiocytic Disorders, C Matthias Wilk, Flurin Cathomas, Orsolya Török, Jessica Le Berichel, Matthew D Park, Camille Bigenwald, George R Heaton, Pauline Hamon, Leanna Troncoso, Brooks P Scull, Diana Dangoor, Aymeric Silvin, Ryan Fleischmann, Meriem Belabed, Howard Lin, Elias Merad Taouli, Steffen Boettcher, Long Li, Antonio Aubry, Markus G Manz, Julia K Kofler, Zhenyu Yue, Sergio A Lira, Florent Ginhoux, John F Crary, Kenneth L Mcclain, Jennifer L Picarsic, Scott J Russo, Carl E Allen, Miriam Merad

Faculty, Staff and Students Publications

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAFV600E

Labour Market Participation After Sickness Absence Due To Cancer: A Dynamic Cohort Study In Catalonia (Spain), Amaya Ayala-Garcia, Fernando G Benavides, Laura Serra

Faculty, Staff and Student Publications

BACKGROUND: The consequences of cancer on working until retirement age remain unclear. This study aimed to analyse working life considering all possible labour market states in a sample of workers after sickness absence (SA) due to cancer and to compare their working life paths to those of a sample of workers without SA and with an SA due to other diseases.

METHODS: This was a retrospective dynamic cohort study among social security affiliates in Catalonia from 2012-2018. Cases consisted of workers with an SA due to cancer between 2012-2015 (N = 516) and were individually age- and sex-matched with those …

A Phase I Trial Of Bevacizumab And Temsirolimus In Combination With Valproic Acid In Advanced Solid Tumors, Blessie Elizabeth Nelson, Apostolia M Tsimberidou, Xueyao Fu, Siqing Fu, Vivek Subbiah, Anil K Sood, Jordi Rodon, Daniel D Karp, George Blumenschein, Scott Kopetz, Shubham Pant, Sarina A Piha-Paul

Faculty, Staff and Student Publications

BACKGROUND: Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity.

METHODS: This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer.

RESULTS: Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis …

Metformin: A Potential Treatment For Acne, Hidradenitis Suppurativa And Rosacea, Minah Cho, Yu Ri Woo, Sang Hyun Cho, Jeong Deuk Lee, Hei Sung Kim

Faculty, Staff and Student Publications

Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial effects of metformin have enabled its use in various diseases. Considering the anti-androgenic, anti-angiogenic, anti-fibrotic and antioxidant properties of metformin, it may have the potential to improve chronic inflammatory skin diseases. However, further evidence is needed to confirm the efficacy of metformin in dermatological conditions, This review focuses on exploring the therapeutic targets of metformin in acne vulgaris, hidradenitis suppurativa and rosacea, by studying their pathogeneses.

Allelic Strengths Of Encephalopathy-Associated Uba5 Variants Correlate Between In Vivo And In Vitro Assays, Xueyang Pan, Albert N Alvarez, Mengqi Ma, Shenzhao Lu, Michael W Crawford, Lauren C Briere, Oguz Kanca, Shinya Yamamoto, David A Sweetser, Jenny L Wilson, Ruth J Napier, Jonathan N Pruneda, Hugo J Bellen

Faculty, Staff and Students Publications

Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least 12 different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remain to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype–phenotype relationships …

Taxane-Based Chemotherapy Is Effective In Metastatic Appendiceal Adenocarcinoma, Julia Dansby, Aditya More, Mohammad Zeineddine, Abdelrahman Yousef, Alisha Bent, Farshid Dayyani, Robert Wolff, Michael Overman, John Paul Shen

Faculty, Staff and Student Publications

Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably rare APC mutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance and that taxanes are effective in the treatment of other gastrointestinal tumors, including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center retrospective study …