Medical Specialties Commons^™

Challenges And Opportunities In Cancer Immunotherapy: A Society For Immunotherapy Of Cancer (Sitc) Strategic Vision, Leisha A Emens, Pedro J Romero, Ana Carrizosa Anderson, Tullia C Bruno, Christian M Capitini, Deborah Collyar, James L Gulley, Patrick Hwu, Avery D Posey, Ann W Silk, Jennifer A Wargo

Faculty, Staff and Student Publications

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor …

Keep Fingers On The Cpg Islands, Xing Zhang, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

The post-genomic era has ushered in the extensive application of epigenetic editing tools, allowing for precise alterations of gene expression. The use of reprogrammable editors that carry transcriptional corepressors has significant potential for long-term epigenetic silencing for the treatment of human diseases. The ideal scenario involves precise targeting of a specific genomic location by a DNA-binding domain, ensuring there are no off-target effects and that the process yields no genetic remnants aside from specific epigenetic modifications (i.e., DNA methylation). A notable example is a recent study on the mouse

Microglial P2y6 Calcium Signaling Promotes Phagocytosis And Shapes Neuroimmune Responses In Epileptogenesis, Anthony D Umpierre, Bohan Li, Katayoun Ayasoufi, Whitney L Simon, Shunyi Zhao, Manling Xie, Grace Thyen, Benjamin Hur, Jiaying Zheng, Yue Liang, Dale B Bosco, Mark A Maynes, Zhaofa Wu, Xinzhu Yu, Jaeyun Sung, Aaron J Johnson, Yulong Li, Long-Jun Wu

Faculty, Staff and Student Publications

Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium …

The Cdk9 Inhibitor Enitociclib Overcomes Resistance To Btk Inhibition And Car-T Therapy In Mantle Cell Lymphoma, Vivian Jiang, William Lee, Tianci Zhang, Alexa Jordan, Fangfang Yan, Qingsong Cai, Joseph Mcintosh, Jovanny Vargas, Yang Liu, Michael Wang

Faculty, Staff and Student Publications

Inhibitors of Bruton's tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes …

Fate-Mapping And Functional Dissection Reveal Perilous Influence Of Type I Interferon Signaling In Mouse Brain Aging, Ethan R Roy, Sanming Li, Sepideh Saroukhani, Yanyu Wang, Wei Cao

Faculty, Staff and Student Publications

Background: Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth.

Methods: To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- …

Neurogranin Modulates The Rate Of Association Between Calmodulin And Target Peptides, John A Putkey, Laurel Hoffman, Vladimir Berka, Xu Wang

Faculty, Staff and Student Publications

The best-known mode of action of calmodulin (CaM) is binding of Ca2+ to its N- and C-domains, followed by binding to target proteins. An underappreciated facet of this process is that CaM is typically bound to proteins at basal levels of free Ca2+, including the small, intrinsically disordered, neuronal IQ-motif proteins called PEP-19 and neurogranin (Ng). PEP-19 and Ng would not be effective competitive inhibitors of high-affinity Ca2+-dependent CaM targets at equilibrium because they bind to CaM with relatively low affinity, but they could influence the time course of CaM signaling by affecting the rate of association of CaM with …

Targeting Il-11r/Ezh2 Signaling Axis As A Therapeutic Strategy For Osteosarcoma Lung Metastases, Eswaran Devarajan, R Eric Davis, Hannah C Beird, Wei-Lien Wang, V Behrana Jensen, Arumugam Jayakumar, Cheuk Hong Leung, Heather Y Lin, Chia-Chin Wu, Stephanie A Ihezie, Jen-Wei Tsai, P Andrew Futreal, Valerae O Lewis

Faculty, Staff and Student Publications

Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα signaling. We used shRNA to deplete IL-11Rα from OS cells; as a complementary approach, we added IL-11 exogenously to OS cells. The resulting changes in gene expression identified EZH2 as a downstream candidate. This was confirmed by knockdown of IL-11Rα in OS cells, which led to increased expression …

Repeat Controlled Human Plasmodium Falciparum Infections Delay Bloodstream Patency And Reduce Symptoms, Patricia Ferrer, Andrea A Berry, Allison N Bucsan, Surendra K Prajapati, Karthik Krishnan, Michelle C Barbeau, David M Rickert, Sandra Mendoza Guerrero, Miho Usui, Yonas Abebe, Asha Patil, Sumana Chakravarty, Peter F Billingsley, Faith Pa'ahana-Brown, Kathy Strauss, Biraj Shrestha, Effie Nomicos, Gregory A Deye, B Kim Lee Sim, Stephen L Hoffman, Kim C Williamson, Kirsten E Lyke

Faculty, Staff and Student Publications

Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody …

Phase 2 Study Of Neoadjuvant Enzalutamide And Paclitaxel For Luminal Androgen Receptor-Enriched Tnbc: Trial Results And Insights Into “Arness”, Bora Lim, Sahil Seth, Clinton Yam, Lei Huo, Takeo Fujii, Jangsoon Lee, Roland Bassett, Sara Nasser, Lisa Ravenberg, Jason White, Alyson Clayborn, Gil Guerra, Jennifer K Litton, Senthil Damodaran, Rachel Layman, Vicente Valero, Debasish Tripathy, Michael Lewis, Lacey E Dobrolecki, Jonathan Lei, Rosalind Candelaria, Banu Arun, Gaiane Rauch, Li Zhao, Jianhua Zhang, Qingqing Ding, W Fraser Symmans, Jeffrey T Chang, Alastair M Thompson, Stacy L Moulder, Naoto T Ueno

Faculty, Staff and Student Publications

Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m2 weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC. Eligibility criteria included a percentage of cells expressing nuclear AR by immunohistochemistry (iAR) of at least 10% and a reduction in sonographic volume of less than 70% after four cycles of doxorubicin and cyclophosphamide. Twenty-four patients were enrolled. Ten achieved a …

Sod1 Is A Synthetic-Lethal Target In Ppm1d-Mutant Leukemia Cells, Linda Zhang, Joanne I Hsu, Etienne D Braekeleer, Chun-Wei Chen, Tajhal D Patel, Alejandra G Martell, Anna G Guzman, Katharina Wohlan, Sarah M Waldvogel, Hidetaka Uryu, Ayala Tovy, Elsa Callen, Rebecca L Murdaugh, Rosemary Richard, Sandra Jansen, Lisenka Vissers, Bert B A De Vries, Andre Nussenzweig, Shixia Huang, Cristian Coarfa, Jamie Anastas, Koichi Takahashi, George Vassiliou, Margaret A Goodell

Faculty, Staff and Student Publications

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our …

Sting Agonist 8803 Reprograms The Immune Microenvironment And Increases Survival In Preclinical Models Of Glioblastoma, Hinda Najem, Spencer T Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Ivana William, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Corey Dussold, Sebastian Pacheco, Crismita Dmello, Catalina Lee-Chang, Kathleen Mccortney, Alicia Steffens, Jordain Walshon, Martina Ott, Jun Wei, Anantha Marisetty, Irina Balyasnikova, Roger Stupp, Rimas V Lukas, Jian Hu, Charles David James, Craig M Horbinski, Maciej S Lesniak, David M Ashley, Waldemar Priebe, Leonidas C Platanias, Michael A Curran, Amy B Heimberger

Faculty, Staff and Student Publications

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 …

Maldi Imaging Mass Spectrometry Visualizes The Distribution Of Antidepressant Duloxetine And Its Major Metabolites In Mouse Brain, Liver, Kidney, And Spleen Tissues, Saleh M Khalil, Xuan Qin, John M Hakenjos, Jian Wang, Zhaoyong Hu, Xinli Liu, Jin Wang, Mirjana Maletic-Savatic, Kevin R Mackenzie, Martin M Matzuk, Feng Li

Faculty, Staff and Student Publications

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none …

Prevalence And Relevant Factors Of Nocturia And Its Impact On Sleep Quality In Chinese University Students, Yakai Liu, Zhenwei Zhang, Huijie Hu, Xiangfei He, Pengchao Xu, Qifeng Dou, Cuiping Song, Huiqing Zhang, Israel Franco, Konstantinos Kamperis, Søren Rittig, Jianguo Wen

Faculty, Staff and Student Publications

The purpose of this study was to investigate the prevalence and relevant factors of nocturia and its impact on sleep quality in university students in Mainland China. A large-scale survey was conducted on 14,000 university students from 3 universities in Henan province, China by using an anonymous questionnaire. The questionnaire collected the information from the past six months. The relationships between the prevalence of nocturia and its relevant factors were evaluated. A total of 13,874 questionnaires were collected and 13,104 qualified for statistical analysis. A total of 659 students suffered from clinically relevant nocturia (CRN) (4.56% in male and 5.34% …

Association Between Helicobacter Pylori Infection, Mismatch Repair, Her2 And Tumor-Infiltrating Lymphocytes In Gastric Cancer, Carlos A Castaneda, Miluska Castillo, Luis A Bernabe, Joselyn Sanchez, Matteo Fassan, Katherine Tello, Ignacio Ivan Wistuba, Ivan Chavez Passiuri, Eloy Ruiz, Juvenal Sanchez, Fernando Barreda, Daniel Valdivia, Yaqueline Bazan, Milagros Abad-Licham, Claudio Mengoa, Hugo Fuentes, Paola Montenegro, Ebert Poquioma, Raul Alatrista, Claudio J Flores, Luis Taxa

Faculty, Staff and Student Publications

BACKGROUND: The influence of Helicobacter-pylori (H. pylori) infection and the characteristics of gastric cancer (GC) on tumor-infiltrating lymphocyte (TIL) levels has not been extensively studied. Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.

AIM: To determine the rates of deficient mismatch-repair (dMMR), HER2-status and H. pylori infection and their association with TIL levels in GC.

METHODS: Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral (IT), stromal (ST) and invasive-border (IB) compartments. The density of CD3, CD8 and CD163 …

Spatial Modulation Of Primate Inferotemporal Responses By Eye Position, Kievershen Nargan, Joel N Glasgow, Sajid Nadeem, Threnesan Naidoo, Gordon Wells, Robert L Hunter, Anneka Hutton, Kapongo Lumamba, Mpumelelo Msimang, Paul V Benson, Adrie J C Steyn

Faculty, Staff and Student Publications

BACKGROUND: The ability to detect evidence of Mycobacterium tuberculosis (Mtb) infection within human tissues is critical to the study of Mtb physiology, tropism, and spatial distribution within TB lesions. The capacity of the widely-used Ziehl-Neelsen (ZN) staining method for identifying Mtb acid-fast bacilli (AFB) in tissue is highly variable, which can limit detection of Mtb bacilli for research and diagnostic purposes. Here, we sought to circumvent these limitations via detection of Mtb mRNA and secreted antigens in human tuberculous tissue.

METHODS: We adapted RNAscope, an RNA in situ hybridisation (RISH) technique, to detect Mtb mRNA in ante- and postmortem human …

Spatiotemporal Analysis Of Hpv Vaccination And Associated Neighborhood-Level Disparities In Texas-An Ecological Study, Ryan Ramphul, Abigail S Zamorano, Saswati Upadhyay, Manali Desai, Cici Bauer

Faculty, Staff and Student Publications

BACKGROUND: HPV is responsible for most cervical, oropharyngeal, anal, vaginal, and vulvar cancers. The HPV vaccine has decreased cervical cancer incidence, but only 49% of Texas adolescents have initiated the vaccine. Texas shows great variation in HPV vaccination rates. We used geospatial analysis to identify areas with high and low vaccination rates and explored differences in neighborhood characteristics.

METHODS: Using Anselin's Local Moran's I statistic, we conducted an ecological analysis of hot and cold spots of adolescent HPV vaccination coverage in Texas from 2017 to 2021. Next, we utilized a Mann-Whitney U test to compare neighborhood characteristics of vaccination coverage …

In-Silico Analysis Of Tmem2 As A Pancreatic Adenocarcinoma And Cancer-Associated Fibroblast Biomarker, And Functional Characterization Of Nsc777201, For Targeted Drug Development, Prateeti Srivastava, Vijesh Kumar Yadav, Tzu-Hao Chang, Emily Chia-Yu Su, Bashir Lawal, Alexander Th Wu, Hsu-Shan Huang

Faculty, Staff and Student Publications

Pancreatic adenocarcinoma (PAAD), known as one of the deadliest cancers, is characterized by a complex tumor microenvironment, primarily comprised of cancer-associated fibroblasts (CAFs) in the extracellular matrix. These CAFs significantly alter the matrix by interacting with hyaluronic acid (HA) and the enzyme hyaluronidase, which degrades HA - an essential process for cancer progression and spread. Despite the critical role of this interaction, the specific functions of CAFs and hyaluronidase in PAAD development are not fully understood. Our study investigates this interaction and assesses NSC777201, a new anti-cancer compound targeting hyaluronidase. This research utilized computational methods to analyze gene expression data …

Variance-Components Tests For Genetic Association With Multiple Interval-Censored Outcomes, Jaihee Choi, Zhichao Xu, Ryan Sun

Faculty, Staff and Student Publications

Massive genetic compendiums such as the UK Biobank have become an invaluable resource for identifying genetic variants that are associated with complex diseases. Due to the difficulties of massive data collection, a common practice of these compendiums is to collect interval-censored data. One challenge in analyzing such data is the lack of methodology available for genetic association studies with interval-censored data. Genetic effects are difficult to detect because of their rare and weak nature, and often the time-to-event outcomes are transformed to binary phenotypes for access to more powerful signal detection approaches. However transforming the data to binary outcomes can …

Deepcg: A Cell Graph Model For Predicting Prognosis In Lung Adenocarcinoma, Baoyi Zhang, Chenyang Li, Jia Wu, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung cancer is the first leading cause of cancer-related death in the United States, with lung adenocarcinoma as the major subtype accounting for 40% of all cases. To improve patient survival, image-based prognostic models were developed due to the ready availability of pathological images at diagnosis. However, the application of these models is hampered by two main challenges: the lack of publicly available image datasets with high-quality survival information and the poor interpretability of conventional convolutional neural network models. Here, we integrated matched transcriptomic and H&E staining data from TCGA (The Cancer Genome Atlas) to develop an image-based prognostic model, …

Assessing The Impact Of Storage Conditions On Rna From Human Saliva And Its Application To The Identification Of Mrna Biomarkers For Asthma, Poorna Manasa Bhamidimarri, David Fuentes, Laila Salameh, Bassam Mahboub, Rifat Hamoudi

Faculty, Staff and Student Publications

Introduction: Human saliva was used to develop non-invasive liquid biopsy biomarkers to establish saliva as an alternate to blood and plasma in translational research. The present study focused on understanding the impact of sample storage conditions on the extraction of RNA from saliva and the RNA yield, to be applied in clinical diagnosis. In this study, genes related to asthma were used to test the method developed.

Methods: Salivary RNA was extracted from three subjects using the Qiazol® based method and quantified by both spectrophotometric (NanoDrop) and fluorometric (Qubit®) methods. RNA integrity was measured using a bioanalyzer. Quantitative PCR was …

Persistent Gram-Negative Bloodstream Infection Increases The Risk Of Recurrent Bloodstream Infection With The Same Species, Paa Kwesi Ankrah, Andrew Bock, Felicia Ruffin, Blake M Hanson, Cesar A Arias, Stacey A Maskarinec, Joshua Parsons, Vance G Fowler, Joshua T Thaden

Faculty, Staff and Student Publications

The association between persistent gram-negative bloodstream infection (GN-BSI), or ongoing positive cultures, and recurrent GN-BSI has not been investigated. Among 992 adults, persistent GN-BSI was associated with increased recurrent GN-BSI with the same bacterial species and strain (6% vs 2%; P = .04). Persistent GN-BSI may be a marker of complicated infection.

Immunotherapy In Locally Advanced Cervical Cancer: Integrating Keynote-A18 Into Management Strategies, Jeffrey A How, Amir A Jazaeri

Faculty, Staff and Student Publications

In locally advanced cervical cancer (LACC), the benefit of PD-1 blockade was unknown. In KEYNOTE-A18, Lorusso et al.1 compared the efficacy and safety of adding pembrolizumab to chemoradiation in LACC and demonstrated favorable outcomes. Given multiple approved indications of pembrolizumab in cervical cancer, strategies for optimal integration into management will be needed to maximize overall survival.

Supporting Ontario Public Health Units To Address Adverse Childhood Experiences In Pandemic Recovery Planning: A Priority-Setting Exercise, Kimberly B Harding, Erica Di Ruggiero, Erick Gonzalez, Amanda Hicks, Daniel W Harrington, Sarah Carsley

Faculty, Staff and Student Publications

BACKGROUND: Adverse childhood experiences (ACEs) are potentially traumatic exposures experienced during childhood, for example, neglect. There is growing evidence that the coronavirus disease 2019 (COVID-19) pandemic and related socioeconomic conditions contributed to an increased risk of ACEs. As public health programs/services are re-evaluated and restored following the state of emergency, it is important to plan using an ACEs-informed lens. The aim of this study was to identify and prioritize initiatives or activities that Public Health Ontario (PHO) could undertake to support Ontario public health units' work towards ACEs-informed pandemic recovery plans.

METHODS: The Child Health and Nutrition Research Initiative method …

Identifying Mage-A4-Positive Tumors For Tcr T Cell Therapies In Hla-A∗02-Eligible Patients, Tianjiao Wang, Jean-Marc Navenot, Stavros Rafail, Cynthia Kurtis, Mark Carroll, Marian Van Kerckhoven, Sofie Van Rossom, Kelly Schats, Konstantinos Avraam, Robyn Broad, Karen Howe, Ashley Liddle, Amber Clayton, Ruoxi Wang, Laura Quinn, Joseph P Sanderson, Cheryl Mcalpine, Carly Carozza, Eric Pimpinella, Susan Hsu, Francine Brophy, Erica Elefant, Paige Bayer, Dennis Williams, Marcus O Butler, Jeffrey M Clarke, Justin F Gainor, Ramaswamy Govindan, Victor Moreno, Melissa Johnson, Janet Tu, David S Hong, George R Blumenschein

Faculty, Staff and Student Publications

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across …

Ikzf1 And Ubr4 Gene Variants Drive Autoimmunity And Th2 Polarization In Igg4-Related Disease, Qingxiang Liu, Yanyan Zheng, Ines Sturmlechner, Abhinav Jain, Maryam Own, Qiankun Yang, Huimin Zhang, Filippo Pinto E Vairo, Karen Cerosaletti, Jane H Buckner, Kenneth J Warrington, Matthew J Koster, Cornelia M Weyand, Jörg J Goronzy

Faculty, Staff and Student Publications

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, …

Identification And Characterization Of Cannabichromene's Major Metabolite Following Incubation With Human Liver Microsomes, Alexandra M Ward, Touraj Shokati, Jost Klawitter, Jelena Klawitter, Vu Nguyen, Laura Kozell, Atheir I Abbas, David Jones, Uwe Christians

Faculty, Staff and Student Publications

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2′-hydroxycannabicitran using gas chromatography–mass …

Durable Objective Response To Lurbinectedin In Small Cell Bladder Cancer With Tp53 Mutation: A Molecular-Directed Strategy, Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Sagar A Naik, Vivek Subbiah, Matthew T Campbell, Pavlos Msaouel, Parminder Singh, Omar Alhalabi

Faculty, Staff and Student Publications

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following …

Rest-Dependent Downregulation Of Von Hippel-Lindau Tumor Suppressor Promotes Autophagy In Shh-Medulloblastoma, Ashutosh Singh, Donghang Cheng, Jyothishmathi Swaminathan, Yanwen Yang, Yan Zheng, Nancy Gordon, Vidya Gopalakrishnan

Faculty, Staff and Student Publications

The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell proliferation, metastasis and vascular growth and blocks neuronal differentiation to drive progression of SHH medulloblastoma tumors. Here, we demonstrate that REST promotes autophagy, a pathway that is found to be significantly enriched in human medulloblastoma tumors relative to normal cerebella. In SHH medulloblastoma tumor xenografts, REST elevation is strongly correlated with increased expression of the hypoxia-inducible factor 1-alpha (HIF1α)-a positive regulator of autophagy, and with reduced expression of the von Hippel-Lindau (VHL) tumor suppressor protein - a …

Mycoplasmoides Genitalium Nucleic Acid Semi-Quantitation And Molecular Macrolide Resistance Detection Via Automated Assays: Gender And Specimen Source Considerations, Erik Munson, Josephine Moore, Trinity Krueger, Amanda Zapp, Stephen C Lavey, Kimber L Munson, Irene A Stafford, Brian Mustanski

Faculty, Staff and Student Publications

A laboratory-developed test (LDT) using analyte-specific reagents has been optimized on a commercial platform to detect macrolide resistance-associated mutations (MRM) in 23S rRNA from Mycoplasmoides genitalium from primary clinical specimens. In this study, MRM-LDT was applied to a multi-specimen source study set. One thousand four hundred ninety-five primary specimens testing positive for M. genitalium by commercial transcription-mediated amplification (TMA) were initially titered by the TMA assay using serial 10-fold dilutions to semi-quantitate target nucleic acid burden. Primary specimens were then processed for MRM detection using the MRM-LDT. Findings were stratified by gender and specimen source. The mean log10 target nucleic …

History Of Suicidal Behavior And Clozapine Prescribing Among People With Schizophrenia In China: A Cohort Study, Yi Yin, Chen Lin, Lijing Wei, Jinghui Tong, Junchao Huang, Baopeng Tian, Shuping Tan, Zhiren Wang, Fude Yang, Yongsheng Tong, Song Chen, L Elliot Hong, Yunlong Tan

Faculty, Staff and Student Publications

BACKGROUND: Clozapine is an off-label drug used in most countries to prevent suicide in individuals with schizophrenia. However, few studies have reported real-world prescription practices. This study aimed to explore the association between a history of suicidal behavior and clozapine prescribing during eight weeks of hospitalization for individuals with early-stage schizophrenia.

METHODS: This observational cohort study used routine health data collected from a mental health hospital in Beijing, China. The study included 1057 inpatients who had schizophrenia onset within 3 years. History of suicidal behavior was coded from reviewing medical notes according to the Columbia Suicide Severity Rating Scale. Information …