Medicine and Health Sciences Commons^™

Immune Checkpoint Therapy-Current Perspectives And Future Directions, Padmanee Sharma, Sangeeta Goswami, Deblina Raychaudhuri, Bilal A Siddiqui, Pratishtha Singh, Ashwat Nagarajan, Jielin Liu, Sumit K Subudhi, Candice Poon, Kristal L Gant, Shelley M Herbrich, Swetha Anandhan, Shajedul Islam, Moran Amit, Gayathri Anandappa, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

The Role Of Extracellular Vesicles In Cancer, Raghu Kalluri, Kathleen M Mcandrews

Faculty, Staff and Student Publications

Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics.

Targeting Mirnas And Other Non-Coding Rnas As A Therapeutic Approach: An Update, Emine Bayraktar, Recep Bayraktar, Hulya Oztatlici, Gabriel Lopez-Berestein, Paola Amero, Cristian Rodriguez-Aguayo

Faculty, Staff and Student Publications

Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression, and because miRNAs act as tumor suppressors or oncogenes (oncomiRs), they have emerged as attractive tools and, more importantly, as a new class of targets for drug development in cancer therapeutics. With the use of miRNA mimics or molecules targeting miRNAs (i.e., small-molecule inhibitors such …

Targeting Of Epigenetic Co-Dependencies Enhances Anti-Aml Efficacy Of Menin Inhibitor In Aml With Mll1-R Or Mutant Npm1, Warren Fiskus, Christopher P Mill, Christine Birdwell, John A Davis, Kaberi Das, Steffen Boettcher, Tapan M Kadia, Courtney D Dinardo, Koichi Takahashi, Sanam Loghavi, Michael J Soth, Tim Heffernan, Gerard M Mcgeehan, Xinjia Ruan, Xiaoping Su, Christopher R Vakoc, Naval Daver, Kapil N Bhalla

Faculty, Staff and Student Publications

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A …

Cancer Neuroscience: State Of The Field, Emerging Directions, Frank Winkler, Humsa S Venkatesh, Moran Amit, Tracy Batchelor, Ihsan Ekin Demir, Benjamin Deneen, David H Gutmann, Shawn Hervey-Jumper, Thomas Kuner, Donald Mabbott, Michael Platten, Asya Rolls, Erica K Sloan, Timothy C Wang, Wolfgang Wick, Varun Venkataramani, Michelle Monje

Faculty, Staff and Student Publications

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new …

Development Of A Corticosteroid-Immunosuppressed Mouse Model To Study The Pathogenesis And Therapy Of Influenza-Associated Pulmonary Aspergillosis, Sebastian Wurster, Jezreel Pantaleón García, Nathaniel D Albert, Ying Jiang, Keerthi Bhoda, Vikram V Kulkarni, Yongxing Wang, Thomas J Walsh, Scott Evans, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.

Physio-Psycho-Social Interaction Mechanism In Dyadic Health Of Young And Middle-Aged Stroke Survivors And Their Spousal Caregivers: A Longitudinal Observational Study Protocol, Dandan Xiang, Zhen-Xiang Zhang, Song Ge, Wen Na Wang, Bei-Lei Lin, Su-Yan Chen, Er-Feng Guo, Peng-Bo Zhang, Zhi-Wei Liu, Hui Li, Yong-Xia Mei

Faculty, Staff and Student Publications

Introduction: In recent years, stroke has become more common among young people. Stroke not only has a profound impact on patients' health but also incurs stress and health threats to their caregivers, especially spousal caregivers. Moreover, the health of stroke survivors and their caregivers is interdependent. To our knowledge, no study has explored dyadic health of young and middle-aged stroke survivors and their spousal caregivers from physiological, psychological and social perspectives. Therefore, this proposed study aims to explore the mechanism of how physiological, psychological and social factors affect dyadic health of young and middle-aged stroke survivors and their spousal caregivers. …

Quantitative Proteomic Screening Uncovers Candidate Diagnostic And Monitoring Serum Biomarkers Of Ankylosing Spondylitis, Mark Hwang, Shervin Assassi, Jim Zheng, Jessica Castillo, Reyna Chavez, Kamala Vanarsa, Chandra Mohan, John Reveille

Faculty, Staff and Student Publications

BACKGROUND: We sought to discover serum biomarkers of ankylosing spondylitis (AS) for diagnosis and monitoring disease activity.

METHODS: We studied biologic-treatment-naïve AS and healthy control (HC) patients' sera. Eighty samples matched by age, gender, and race (1:1:1 ratio) for AS patients with active disease, inactive disease, and HC were analyzed with SOMAscan™, an aptamer-based discovery platform. T-tests tests were performed for high/low-disease activity AS patients versus HCs (diagnosis) and high versus low disease activity (Monitoring) in a 2:1 and 1:1 ratio, respectively, to identify differentially expressed proteins (DEPs). We used the Cytoscape Molecular Complex Detection (MCODE) plugin to find clusters …

Risk Of Early Death In Adolescents And Young Adults With Cancer: A Population-Based Study, Amy M Berkman, Clark R Andersen, Michelle A T Hildebrandt, J A Livingston, Adam L Green, Vidya Puthenpura, Susan K Peterson, Joel Milam, Kimberly A Miller, David R Freyer, Michael E Roth

Faculty, Staff and Student Publications

BACKGROUND: Advancements in treatment and supportive care have led to improved survival for adolescents and young adults (AYAs) with cancer; however, a subset of those diagnosed remain at risk for early death (within 2 months of diagnosis). Factors that place AYAs at increased risk of early death have not been well studied.

METHODS: The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death in AYAs with hematologic malignancies, central nervous system tumors, and solid tumors. Associations between age at diagnosis, sex, race, ethnicity, socioeconomic status, insurance status, rurality, and early death were assessed.

RESULTS: A …

Upper Age Limits For Us Male Human Papillomavirus Vaccination For Oropharyngeal Cancer Prevention: A Microsimulation-Based Modeling Study, Rebecca Landy, Gregory Haber, Barry I Graubard, Nicole G Campos, Stephen Sy, Jane J Kim, Emily A Burger, Li C Cheung, Hormuzd A Katki, Maura L Gillison, Anil K Chaturvedi

Faculty, Staff and Student Publications

BACKGROUND: Human papillomavirus (HVP)-positive oropharyngeal cancer is the most common HPV-associated cancer in the United States. The age at acquisition of oral HPV infections that cause oropharyngeal cancer (causal infections) is unknown; consequently, the benefit of vaccination of US men aged 27-45 years remains uncertain.

METHODS: We developed a microsimulation-based, individual-level, state-transition model of oral HPV16 and HPV16-positive oropharyngeal cancer among heterosexual US men aged 15-84 years, calibrated to population-level data. We estimated the benefit of vaccination of men aged 27-45 years for prevention of oropharyngeal cancer, accounting for direct- and indirect effects (ie, herd effects) of male and female …

Molecular Mechanisms Of Ferroptosis And Updates Of Ferroptosis Studies In Cancers And Leukemia, Hiroki Akiyama, Bing Z Carter, Michael Andreeff, Jo Ishizawa

Faculty, Staff and Student Publications

Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is …

Hypoxia Increases Atx Expression By Histone Crotonylation In A Hif-2Α-Dependent Manner, Mengxia Qu, Yang Long, Yuqin Wang, Nan Yin, Xiaotian Zhang, Junjie Zhang

Faculty, Staff and Student Publications

Autotaxin (ATX), the key enzyme that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), is involved in tumorigenesis through the ATX-LPA axis and is regarded as a valuable target in tumor therapy. Hypoxia is a major feature of solid tumors and contributes to tumor development with striking alterations in the gene expression profile. Here, we show that hypoxia induces ATX expression in a hypoxia-inducible factor (HIF) 2α-dependent fashion in human colon cancer SW480 cells. HIF-2α is directly bound to specific hypoxia response elements (HREs) in the ATX promoter. Under hypoxic conditions, knockout or inhibition of ATX suppressed the migration of SW480 …

Mapping The Metabolic Reprogramming Induced By Sodium-Glucose Cotransporter 2 Inhibition, Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz

Faculty, Staff and Student Publications

Diabetes is associated with increased risk for kidney disease, heart failure, and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent these adverse outcomes; however, the mechanisms involved are not clear. We generated a roadmap of the metabolic alterations that occur in different organs in diabetes and in response to SGLT2i. In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without dapagliflozin, followed by metabolomics and metabolic flux analyses, showed that, in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis. SGLT2 inhibition increased glucose oxidation …

Targeting The Mevalonate Pathway Suppresses Arid1a-Inactivated Cancers By Promoting Pyroptosis, Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R Goldman, Toshitha Kannan, Andrew V Kossenkov, Ronny Drapkin, Luis J Montaner, Daniel T Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang

Faculty, Staff and Student Publications

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC …

Metabolic Dysregulation Impairs Lymphocyte Function During Severe Sars-Cov-2 Infection, Sanjeev Gurshaney, Anamaria Morales-Alvarez, Kevin Ezhakunnel, Andrew Manalo, Thien-Huong Huynh, Jun-Ichi Abe, Nhat-Tu Le, Daniela Weiskopf, Alessandro Sette, Daniel S Lupu, Stephen J Gardell, Hung Nguyen

Faculty, Staff and Student Publications

Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose …

Distribution Of Serum Uric Acid Concentration And Its Association With Lipid Profiles: A Single-Center Retrospective Study In Children Aged 3 To 12 Years With Adenoid And Tonsillar Hypertrophy, Jiating Yu, Xin Liu, Honglei Ji, Yawei Zhang, Hanqiang Zhan, Ziyin Zhang, Jianguo Wen, Zhimin Wang

Faculty, Staff and Student Publications

BACKGROUND: Presently, there is no consensus regarding the optimal serum uric acid (SUA) concentration for pediatric patients. Adenoid and tonsillar hypertrophy is considered to be closely associated with pediatric metabolic syndrome and cardiovascular risk and is a common condition in children admitted to the hospital. Therefore, we aimed to evaluate the relationship between SUA and dyslipidemia and propose a reference range for SUA concentration that is associated with a healthy lipid profile in hospitalized children with adenoid and tonsillar hypertrophy.

METHODS: Preoperative data from 4922 children admitted for elective adenoidectomy and/or tonsillectomy surgery due to adenoid and tonsillar hypertrophy were …

Prmt3-Mediated Arginine Methylation Of Igf2bp1 Promotes Oxaliplatin Resistance In Liver Cancer, Yunxing Shi, Yi Niu, Yichuan Yuan, Kai Li, Chengrui Zhong, Zhiyu Qiu, Keren Li, Zhu Lin, Zhiwen Yang, Dinglan Zuo, Jiliang Qiu, Wei He, Chenwei Wang, Yadi Liao, Guocan Wang, Yunfei Yuan, Binkui Li

Faculty, Staff and Student Publications

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance …

A Distinct Pattern Of Growth And Rac1 Signaling In Melanoma Brain Metastasis Cells, Ioana Stejerean-Todoran, Phyllis A Gimotty, Andrea Watters, Patricia Brafford, Clemens Krepler, Tetiana Godok, Haiyin Li, Zuriñe Bonilla Del Rio, Anke Zieseniss, Dörthe M Katschinski, Sinem M Sertel, Silvio O Rizzoli, Bradley Garman, Katherine L Nathanson, Xiaowei Xu, Qing Chen, Jack H Oswald, Michal Lotem, Gordon B Mills, Michael A Davies, Michael P Schön, Ivan Bogeski, Meenhard Herlyn, Adina Vultur

Faculty, Staff and Student Publications

Background: Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood.

Methods: We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo.

Results: Brain-specific genetic alterations were not detected; however, MBM cells in vitro …

Mutation-Agnostic Detection Of Colorectal Cancer Using Liquid Biopsy-Based Methylation-Specific Signatures, Mohamed A Gouda, Dzifa Y Duose, Morten Lapin, Stephanie Zalles, Helen J Huang, Yuanxin Xi, Xiaofeng Zheng, Amira I Aldesoky, Alshimaa M Alhanafy, Mohamed A Shehata, Jing Wang, Scott Kopetz, Funda Meric-Bernstam, Ignacio I Wistuba, Rajyalakshmi Luthra, Filip Janku

Faculty, Staff and Student Publications

Detection of methylation patterns in circulating tumor DNA (ctDNA) can offer a novel approach for cancer diagnostics given the unique signature for each tumor type. We developed a next-generation sequencing (NGS)-based assay targeting 32 CpG sites to detect colorectal cancer-specific ctDNA. NGS was performed on bisulfite-converted libraries and status dichotomization was done using median methylation ratios at all targets. We included plasma samples from patients with metastatic colorectal (n = 20) and non-colorectal cancers (n = 8); and healthy volunteers (n = 4). Median methylation ratio was higher in colorectal cancer compared with non-colorectal cancers (P = .001) and normal …

An Expedited Strategy For Accurate And Timely Integrated Molecular Diagnosis Of Gliomas, Timothy A Gregory, Garret L Williford, Jacob M Maronge, Kristin Alfaro, Gregory N Fuller, John De Groot, Vinay K Puduvalli, Leomar Y Ballester, Nazanin K Majd

Faculty, Staff and Student Publications

No abstract provided.

Brain Metastases From Biliary Tract Cancer: Case Series And Clinicogenomic Analysis, Grace N Dodoo, Brian De, Sunyoung S Lee, Joseph Abi Jaoude, Jean-Nicolas Vauthey, Ching-Wei D Tzeng, Hop S Tran Cao, Kalman A Katlowitz, Jacob J Mandel, Thomas H Beckham, Bruce D Minsky, Grace L Smith, Emma B Holliday, Albert C Koong, Prajnan Das, Cullen M Taniguchi, Milind Javle, Eugene J Koay, Ethan B Ludmir

Faculty, Staff and Student Publications

BACKGROUND: Limited data from small series have suggested that brain metastases from biliary tract cancers (BrM-BTC) affect ≤2% of patients with BTC. We sought to review our experience with patients with BrM-BTC and to identify associations of tumor-related molecular alterations with outcomes.

MATERIALS AND METHODS: A retrospective review of patients with BTC seen at a tertiary referral center from 2005 to 2021 was performed; patients with BrM-BTC were identified, and clinical and molecular data were collected.

RESULTS: Twenty-one of 823 patients with BTC (2.6%) developed BrM. For patients with BrM-BTC, median follow-up time was 27.9 months after primary BTC diagnosis …

Temporal Machine Learning Analysis Of Prior Mammograms For Breast Cancer Risk Prediction, Hui Li, Kayla Robinson, Li Lan, Natalie Baughan, Chun-Wai Chan, Matthew Embury, Gary J Whitman, Randa El-Zein, Isabelle Bedrosian, Maryellen L Giger

Faculty, Staff and Student Publications

The identification of women at risk for sporadic breast cancer remains a clinical challenge. We hypothesize that the temporal analysis of annual screening mammograms, using a long short-term memory (LSTM) network, could accurately identify women at risk of future breast cancer. Women with an imaging abnormality, which had been biopsy-confirmed to be cancer or benign, who also had antecedent imaging available were included in this case-control study. Sequences of antecedent mammograms were retrospectively collected under HIPAA-approved guidelines. Radiomic and deep-learning-based features were extracted on regions of interest placed posterior to the nipple in antecedent images. These features were input to …

Pattern Dynamics And Stochasticity Of The Brain Rhythms, Clarissa Hoffman, Jingheng Cheng, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Student Publications

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored is the actual structure of the waves-their shapes and patterns over finite timescales. Here, we study brain wave patterning in different physiological contexts using two independent approaches: The first is based on quantifying stochasticity relative to the underlying mean behavior, and the second assesses "orderliness" of the waves' features. The corresponding measures capture the waves' characteristics and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns' dynamics and the animal's location, speed, and acceleration. Specifically, we …

Il6 Mediates Suppression Of T- And Nk-Cell Function In Emt-Associated Tki-Resistant Egfr-Mutant Nsclc, Sonia A Patel, Monique B Nilsson, Yan Yang, Xiuning Le, Hai T Tran, Yasir Y Elamin, Xiaoxing Yu, Fahao Zhang, Alissa Poteete, Xiaoyang Ren, Li Shen, Jing Wang, Seyed Javad Moghaddam, Tina Cascone, Michael Curran, Don L Gibbons, John V Heymach

Faculty, Staff and Student Publications

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype.

Experimental design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and …

Dna Damage Repair Kinase Dna-Pk And Cgas Synergize To Induce Cancer-Related Inflammation In Glioblastoma, Clara Taffoni, Johanna Marines, Hanane Chamma, Soumyabrata Guha, Mathilde Saccas, Amel Bouzid, Ana-Luiza Chaves Valadao, Clément Maghe, Jane Jardine, Mi Kyung Park, Katarzyna Polak, Mara De Martino, Claire Vanpouille-Box, Maguy Del Rio, Celine Gongora, Julie Gavard, Nicolas Bidère, Min Sup Song, Donovan Pineau, Jean-Philippe Hugnot, Karima Kissa, Laura Fontenille, Fabien P Blanchet, Isabelle K Vila, Nadine Laguette

Faculty, Staff and Student Publications

Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote …

Longitudinal Global Transcriptomic Profiling Of Preclinical Systemic Sclerosis Reveals Molecular Changes Associated With Disease Progression, Chiara Bellocchi, Lorenzo Beretta, Xuan Wang, Marka A Lyons, Maurizio Marchini, Maurizio Lorini, Vincenzo Carbonelli, Nicola Montano, Shervin Assassi

Faculty, Staff and Student Publications

Objective: To investigate peripheral blood cell (PBCs) global gene expression profile of SSc at its preclinical stage (PreSSc) and to characterize the molecular changes associated with progression to a definite disease over time.

Material and methods: Clinical data and PBCs of 33 participants with PreSSc and 16 healthy controls (HCs) were collected at baseline and follow-up (mean 4.2 years). Global gene expression profiling was conducted by RNA sequencing and a modular analysis was performed.

Results: Comparison of baseline PreSSc to HCs revealed 2889 differentially expressed genes. Interferon signalling was the only activated pathway among top over-represented pathways. Moreover, 10 modules …

Increases In Group A Streptococcal Infections In The Pediatric Population In Houston, Tx, 2022, Aya Aboulhosn, Misu A Sanson, Luis Alberto Vega, Maria G Segura, Lauren M Summer, Marritta Joseph, J Chase Mcneil, Anthony R Flores

Faculty, Staff and Student Publications

Beginning in October 2022, we observed a substantial increase in the total number of cases of invasive GAS disease (iGAS) in the pediatric population in Houston, TX. Emm12 GAS strains were disproportionately represented but the overall proportion of iGAS infections observed during the current spike was similar to pre-pandemic years.

Inhibition Of Stat6 With Antisense Oligonucleotides Enhances The Systemic Antitumor Effects Of Radiotherapy And Anti-Pd-1 In Metastatic Non-Small Cell Lung Cancer, Kewen He, Hampartsoum B Barsoumian, Nahum Puebla-Osorio, Yun Hu, Duygu Sezen, Mark D Wasley, Genevieve Bertolet, Jie Zhang, Carola Leuschner, Liangpeng Yang, Claudia S Kettlun Leyton, Natalie Wall Fowlkes, Morgan Maureen Green, Lisa Hettrick, Dawei Chen, Fatemeh Masrorpour, Meidi Gu, Hadi Maazi, Alexey S Revenko, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung …

Lecanemab For Patients With Early Alzheimer Disease: Bayesian Analysis Of A Phase 2b Dose-Finding Randomized Clinical Trial, Donald A Berry, Shobha Dhadda, Michio Kanekiyo, David Li, Chad J Swanson, Michael Irizarry, Lynn D Kramer, Scott M Berry

Faculty, Staff and Student Publications

IMPORTANCE: Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness.

OBJECTIVE: To explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in …

Intratumoral Heterogeneity And Clonal Evolution Induced By Hpv Integration, Keiko Akagi, David E Symer, Medhat Mahmoud, Bo Jiang, Sara Goodwin, Darawalee Wangsa, Zhengke Li, Weihong Xiao, Joe Dan Dunn, Thomas Ried, Kevin R Coombes, Fritz J Sedlazeck, Maura L Gillison

Faculty, Staff and Student Publications

The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, "heterocateny," characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host …