Digital Commons Network^™

Viral Oncogenes Drive Biphenotypic Lymphoproliferative Malignancy In Transgenic Mice, Daniel A Rauch, John Harding, Ancy Joseph, Lee Ratner

2020-Current year OA Pubs

Human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia/lymphoma (ATLL) and viral oncogenic proteins, Tax and Hbz, are critical drivers of malignancy. Expression of both CD2 and CD20 has been described in a subset of ATLL cases. Transgenic mice were engineered to monitor lymphoma and leukemia after expression of Hbz and doxycycline-inducible Tax in activated T cells under the regulation of the human granzyme B (GZMB) promoter. These mice spontaneously developed lymphoproliferative disease characterized by the expansion and transformation of Cd2 + Cd20 + cells resulting in lymphoma and / or leukemia with involvement of …

Type I Hybrid Effectiveness-Implementation Randomised Controlled Trial To Address Intergenerational Impact Of War Trauma And Resilience Among Second-Generation Refugee Children In The Usa: Resettled Refugee Families For Healing (Rrf4h) Study Protocol, Nhial T Tutlam, Tewodros W Liyew, Theresa S Betancourt, Byron J Powell, Shenyang Guo, Mary Mckay, Fred M Ssewamala

2020-Current year OA Pubs

INTRODUCTION: Children from refugee families resettled in the USA face higher risks of serious mental health challenges compared with their native-born peers. Research shows that refugee youth in high-income countries frequently suffer from trauma-associated disorders such as post-traumatic stress disorder (PTSD), depression and anxiety. The high prevalence of trauma-associated mental health problems among these youth may be attributed to their own trauma exposure, especially if born in conflict zones, and post-resettlement challenges like poverty, acculturation difficulties, racism and discrimination. However, they may also suffer from the effects of intergenerational trauma, where parental war trauma impacts them. This study aims to …

Hydralazine Inhibits Cysteamine Dioxygenase To Treat Preeclampsia And Senesce Glioblastoma, Kyosuke Shishikura, Jiasong Li, Yiming Chen, Nate R. Mcknight, Thomas P. Keeley, Katelyn A. Bustin, Eric W. Barr, Snehil R. Chilkamari, Mahaa Ayub, Sun Woo Kim, Zongtao Lin, Ren-Ming Hu, Kelly Hicks, Xie Wang, Donald M. O'Rourke, J. Martin Bollinger, Zev A. Binder, William H. Parsons, Kirill A. Martemyanov, Aimin Liu, Megan L. Matthews

SKMC Student Presentations and Publications

Hydralazine (HYZ), a treatment for preeclampsia and hypertensive crisis, is listed by the World Health Organization as an essential medicine. Its mode of action has remained unknown through its seven decades of clinical use. Here, we identify 2-aminoethanethiol dioxygenase (ADO), a key mediator of targeted protein degradation, as a selective HYZ target. The drug chelates ADO's metallocofactor and can alkylate one of its ligands. The resultant inactivation stabilizes regulators of G protein signaling (RGS4 and RGS5) that ADO normally marks for proteolysis, explaining the drug's vasodilatory activity and comporting with observations of diminished RGS levels in both clinical preeclampsia and …

Tng260 Is A Small-Molecule Corest Inhibitor That Sensitizes Stk11-Mutant Tumors To Anti-Pd-1 Immunotherapy, Leanne G Ahronian, Soumyadip Sahu, Minjie Zhang, Ayushi S Patel, Ke Geng, Reshmee Bhattacharya, Gerald S Falchook, Jonathan W Goldman, Alexander I Spira, Salman R Punekar, David R Spigel, Judy S Wang, Ferdinandos Skoulidis, Janaye Stephens, Mary Meynardie, Jaylen M Powell, Alfonso Lopez, Michela Ranieri, Magdalena A Ploszaj, Yi Jer Tan, Yeuan Ting Lee, Yi Yu, Jiehui Deng, Ting Chen, Patrick Mccarren, Alice Tsai, Suleman S Hussain, Brian Doyon, Kenjie Amemiya, Jacques Ermolieff, Preksha Shahagadkar, Nikitha M Das, Lauren R Flynn, Julie A Shields, Laney Danielczyk, Brian J Mcmillan, Andre Mignault, Samuel R Meier, Hsin-Jung Wu, David J Guerin, Douglas A Whittington, Chengyin Min, Iga Sienczylo, John P Maxwell, Heather J Dibenedetto, Hideo Watanabe, Brian B Haines, Alan Huang, Adam Crystal, Jannik N Andersen, Xinyuan Wu, Kwok-Kin Wong

Faculty, Staff and Student Publications

Patients with non–small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti–PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 as a target to reverse anti–PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti–PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11 …

Optimal Control In Combination Therapy For Heterogeneous Cell Populations With Drug Synergies., Simon F. Martina-Perez, Samuel W S Johnson, Rebecca M. Crossley, Jennifer C. Kasemeier, Paul M. Kulesa, Ruth E. Baker

Manuscripts, Articles, Book Chapters and Other Papers

Cell heterogeneity plays an important role in patient responses to drug treatments. In many cancers, it is associated with poor treatment outcomes. Many modern drug combination therapies aim to exploit cell heterogeneity, but determining how to optimise responses from heterogeneous cell populations while accounting for multi-drug synergies remains a challenge. In this work, we introduce and analyse a general optimal control framework that can be used to model the treatment response of multiple cell populations that are treated with multiple drugs that mutually interact. In this framework, we model the effect of multiple drugs on the cell populations using a …

Inhibition Of Osteosarcoma Lung Metastases By Β-Glucan And Cd40 Agonist Is Mediated By Activation Of Macrophages And Nk Cells, Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.

Methods: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.

Results: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion …

Targeting The Bcl2 Family: Advances And Challenges In Bh3 Mimetic-Based Therapies, Nabanita Mukherjee, James Sheetz, Yiqun Shellman

Student Papers, Posters & Projects

The BCL2 family of proteins plays a pivotal role in regulating apoptosis and cellular homeostasis, making them critical therapeutic targets in cancer and other diseases characterized by pathological cell survival. BH3 mimetics, small molecules that selectively inhibit anti-apoptotic BCL2 family members, have achieved significant clinical success, particularly in hematologic malignancies. However, several challenges remain, including resistance mechanisms, toxicity (such as MCL1 inhibitor-associated cardiotoxicity), and the intricate balance between apoptotic and non-apoptotic functions. This review provides a comprehensive overview of BCL2 family biology, the development and clinical application and outcomes of BH3 mimetics, and the emerging resistance mechanism known as double-bolt …

Vaccine And Treatment Evaluation Units: A Historical Perspective, Robert B Belshe, David I Bernstein, Kathryn M Edwards, Sharon E Frey, Wendy A Keitel, Myron M Levine, John J Treanor, Peter F Wright

Faculty, Staff and Students Publications

On 27 February 1962, Surgeon General Luther Terry announced a new vaccine development program within the National Institute of Allergy and Infectious Diseases (NIAID). Initially, the plan had three components: (1) special laboratories and facilities for development of prototype vaccines; (2) pilot lot production facilities and preliminary vaccine trial sites; and (3) larger lot production capacity and expanded human testing. Respiratory viruses were targeted as the top priority for vaccine development. Over 5 decades, this program has evolved and expanded to include multiple academic vaccine evaluation sites within the network, now labeled as the Vaccine and Treatment Evaluation Units (VTEUs). …

Ligand-Receptor Interactions Induce And Mediate Regulatory Functions Of Batf3+ B Cells, Hui Yan, Rui Wang, Suryavathi Viswanadhapalli, Christian Cervantes, Funan He, Shuai Wu, Azad Khosh, Weiwei Luo, Jingwei Wang, Maria J Fernandez, Uday P Pratap, Mustafa Khan, Karli Hinton, Sai Eashan Vankamamidi, Dariela Perez, Carlos E Rivera, Harshita B Gupta, Fushun Zhang, Zhenqing Ye, Yidong Chen, Xiao-Dong Li, Gangadhara R Sareddy, Hong Zan, Yue Li, Exing Wang, Evelien M Bunnik, Guangming Zhong, Christopher A Hunter, Ross M Kedl, Zhinan Yin, Booki Min, Diako Ebrahimi, Siyuan Zheng, Tyler J Curiel, Yan Xiang, Ratna K Vadlamudi, Paolo Casali, Zhenming Xu

Faculty, Staff and Student Publications

B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27–IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 …

Mechanistic Study Of Pexidartinib-Induced Toxicity In Human Hepatic Cells, Si Chen, Yuxi Li, Xilin Li, Nan Mei, Xiaobo He, Matthew S Bryant, Xuan Qin, Feng Li, Lei Guo

Faculty, Staff and Students Publications

Pexidartinib, a tyrosine kinase inhibitor, was approved by the U.S. Food and Drug Administration in 2019 for treating adult patients with symptomatic tenosynovial giant cell tumors. Because of its hepatotoxicity risks, pexidartinib received a boxed warning; however, mechanistic studies on this hepatotoxicity remain limited. In this study, we demonstrate that pexidartinib decreases cell viability in primary human hepatocytes and hepatic HepG2 cells. A 24-h treatment with pexidartinib led to apoptosis in HepG2 cells, as evidenced by increased caspase 3/7 activity and the induction of cleaved PARP and γ-H2A.X. Pexidartinib-induced endoplasmic reticulum (ER) stress was observed at early time points of …

Fiber Recruitment Drives A Phase Transition Of Cell Polarization At A Critical Cell Spacing In Matrix-Mediated Tissue Remodeling, Xiangjun Peng, Yuxuan Huang, Wenyu Kong, Yanan Du, Elliot L Elson, Xi-Qiao Feng, Guy M Genin

2020-Current year OA Pubs

Biological tissues exhibit sharp phase transitions where cells collectively transition from disordered to ordered states at critical densities. We demonstrate through bio-chemo-mechanical modeling that this emergent behavior arises from a nonmonotonic dependence on nonlinear extracellular matrix (ECM) mechanics: mechanical communication between cells is optimized at intermediate stiffness values where cells can both generate sufficient forces and create strain-stiffened tension bands in the ECM. This balance establishes a critical cell spacing threshold for cell-cell communication ([Formula: see text]100 to 200 [Formula: see text]m) that is conserved across experimental observations for a broad range of cell types and collagen densities. Our model …

Genetics-Nutrition Interactions Control Diurnal Enhancer-Promoter Dynamics And Liver Lipid Metabolism, Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan

Faculty, Staff and Student Publications

The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to …

Atg Conjugation-Dependent/Independent Mechanisms Underlie Lysosomal Stress-Induced Tfeb Regulation, Shiori Akayama, Takayuki Shima, Tatsuya Kaminishi, Mengying Cui, Jlenia Monfregola, Kohei Nishino, Andrea Ballabio, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura

Duncan NRI Faculty and Staff Publications

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and …

Rescue Epilepsy Medication And Training: A Comparison Between Midazolam Use, Guidelines, Clinical Practice, And Possibilities In The Uk And Norway, Rohit Shankar

Peninsula Medical School

Objectives: Status epilepticus (SE) is a prolonged epileptic seizure carrying significant risk of long-term disability and death. Rescue therapies are prescribedfor prehospital administration to terminate SE. This study compared prescribingpractices of rescue therapies of midazolam in the UK and Norway.Methods: A cross-sectional, online, 21-item Likert-style survey was administeredto epilepsy professionals in the UK circulated via ILAE/ESNA and in Norway viaILAE/Epilepsinet using a non-discriminatory exponential snowballing techniqueleading to non-probability sampling. Data were collected anonymously and analyzed using descriptive statistics, Mann–Whitney, Chi-square, and Fisher's exact tests. Significance was accepted at p<0.05.Results: All 86 UK and 53 Norway respondents identified buccal midazolam as the first-line rescue medication choice in the community for prolonged and/or generalized tonic–clonic seizures. Norwegian respondents had significantly more experience in epilepsy-related work (p=0.002), were more likely to have a larger caseload on buccal midazolam (p<0.001), prescribed higher midazolam doses (p<0.001), and provided training yearly (p<0.001). UK respondents were more likely to delegate rescue medication prescribing to primary care (p=0.006) and reviewed emergency management plans more frequently (p=0.006). There was an inter-country difference in the period of midazolam non-use that respondents required before withdrawing from treatment plans (p<0.001). Concern about inappropriate use of buccal midazolam was similarly high in both countries.Significance: This study compared epilepsy professionals in two neighboringhigh-income countries. Findings suggest an urgent need for international guidelines to recommend best practices on prescribing doses and withdrawal of buccal midazolam. The potential abuse of buccal midazolam by patients and carers warrants further investigation.

Ambient Fine Particulate Matter, Residential Greenness, And Childhood Cancer Risk By Trimester Of Exposure In Minnesota 2000 To 2014: A Case-Control Study, Cassandra J Clark, David Haynes, Zhanni Lu, Jeannette M Sample, Laura A Mcguinn, Thanh T Hoang, Philip J Lupo, Michael E Scheurer, Erin L Marcotte, Lindsay A Williams

Faculty, Staff and Students Publications

Background: Outdoor air pollution is a suspected risk factor for childhood cancer, and there is some evidence that greenness may reduce cancer risk. We examined relationships between prenatal exposure to ambient fine particle air pollution [particulate matter < 2.5 µg/m3 (PM2.5)], greenness, and childhood cancer risk in Minnesota.

Methods: Cases included individuals born in the state of Minnesota and reported to the Minnesota Cancer Reporting System between 2000 and 2014 (n = 1272, ages 0-14 years at diagnosis) and birth year-matched cancer-free controls (n = 5245). We used Network Common Data Form to estimate monthly PM2.5 exposure and the normalized difference vegetation index for census tract-level greenness. We estimated ORs and …

Oncopacket: Integration Of Cancer Research Data Using Ga4gh Phenopackets., Michael Sierk, Daniel Danis, Sujay Patil, Nobal Kishor, Rajdeep Mondal, Abhishek Jha, Qingrong Chen, Chunhua Yan, Monica Munoz-Torres, Daoud Meerzaman, Peter N Robinson, Justin T Reese

Faculty Research 2025

SUMMARY: Lack of data integration remains a significant impediment to cancer research, and many analyses still require customized software to transform and prepare cancer data. We describe a software package to harmonize genetic and clinical cancer data into the GA4GH Phenopacket schema, an ISO standard for representing clinical case data. We integrated demographic, mutation, morphology, diagnosis, intervention, and survival data using case data from the National Cancer Institute for 12 cancer types. The Phenopacket standard provides a foundation for downstream use, including sophisticated statistical and AI/ML analyses. We demonstrate fitness for purpose by using the integrated data to recapitulate a …

A Needed Nomenclature For Nucleosomes, Michael-Christopher Keogh, Genevieve Almouzni, Andrew J Andrews, Karim-Jean Armache, Cheryl H Arrowsmith, Sung Hee Baek, Mark T Bedford, Emily Bernstein, Jacques Côté, Yael David, John M Denu, Beat Fierz, Benjamin A Garcia, Karen C Glass, Or Gozani, Kristian Helin, Steven Henikoff, Ole N Jensen, Steven Z Josefowicz, Neil L Kelleher, Tatiana G Kutateladze, Herbert H Lindner, Chao Lu, Karolin Luger, Parag Mallick, Catherine A Musselman, Tom W Muir, Ljiljana Paša-Tolić, Robert Schneider, Xiaobing Shi, Yang Shi, Simone Sidoli, Lloyd M Smith, Jessica K Tyler, Cynthia Wolberger, Jerry L Workman, Brian D Strahl, Nicolas L Young

Faculty, Staff and Student Publications

Histone post-translational modifications (PTMs) are crucial to eukaryotic genome regulation, with a range of reported functions and mechanisms of action. Though often studied individually, it has long been recognized that the modifications function by combinatorial synergy or antagonism. Interplay may involve PTMs on the same histone, within the same nucleosome (containing a histone octamer), or between nucleosomes in higher-order chromatin. Given this, the field must distinguish ever greater complexity, and the context in which it is studied, with brevity and precision. The proteoform was introduced to define individual forms of a protein by sequence and PTMs, followed by the nucleoform …

Design And Development Of An Intervention To Improve The Quality And Safety Of Pediatric Dental Sedation: A Human-Centered Design Approach, Kawtar Zouaidi, Jan Yeager, Suhasini Bangar, Sayali Tungare, Urvi Mehta, Janelle Urata, Alfa-Ibrahim Yansane, Thomas Tanbonliong, Jungsoo Kim, Emily Sedlock, Krishna Kumar Kookal, Yan Xiao, Tokede Oluwabunmi, Heiko Spallek, Amy Franklin, Gregory W Olson, Joel White, Elsbeth Kalenderian, Muhammad F Walji

Faculty, Staff and Student Publications

Background: There are gaps in understanding the experiences of children, parents, and providers during dental conscious sedation. This study aimed to capture and analyze these experiences to identify opportunities for improvement and enhance the quality and safety of pediatric dental conscious sedation.

Methods: A human-centered design approach was used to examine the conscious sedation experience in 2 US advanced education pediatric dental clinics. Researchers conducted field observations, interviews with providers and parents, and providers focus groups to explore experiential factors. Data were transcribed and analyzed using content thematic analysis. Insights from the data were used to explore and generate new …

Humanized Mouse Models For Type 1 Diabetes., David V. Serreze, Marissa Tousey-Pfarrer, Jeremy Racine

Faculty Research 2025

T cell-mediated autoimmune type 1 diabetes (T1D) is under complex polygenic control in both humans and the NOD mouse model. However, in both species, particular major histocompatibility complex (MHC; designated HLA in humans) haplotypes provide the primary T1D risk factor. Both MHC/HLA class I and II variants interactively contribute to T1D by respectively driving autoreactive CD8 and CD4 T cell responses that cooperatively destroy insulin-producing pancreatic β cells. While NOD mice have provided important insights to the pathogenic basis of T1D, the model has so far provided only a limited means to identify possible clinically translatable disease intervention approaches. This …

Evaluation Of Hippocampal Dlgap2 Overexpression On Cognition, Synaptic Function, And Dendritic Spine Structure In A Translationally Relevant Ad Mouse Model., Andrew R Ouellette, Kristen M S O'Connell, Catherine Kaczorowski

Faculty Research 2025

INTRODUCTION: Developing effective therapeutics for Alzheimer's disease (AD) requires a better understanding of the molecular drivers of the disease. Our previous work nominated DLGAP2 as a modifier of age-related cognitive decline and risk for AD. We tested the hypothesis that overexpression of DLGAP2 in the hippocampus would protect against cognitive and synaptic deficits in a susceptible F1 5XFAD model.

METHODS: DLGAP2 was overexpressed in the hippocampus of F1 hybrid 5XFAD and non-transgenic littermates using a viral approach. Cognitive function, electrophysiological properties, and dendritic spine morphology were assessed at 6 and 14 months of age.

RESULTS: DLGAP2 overexpression impaired synaptic plasticity …

Genetic And Epigenetic Screens In Primary Human T Cells Link Candidate Causal Autoimmune Variants To T Cell Networks., Ching-Huang Ho, Maxwell A Dippel, Meghan S Mcquade, Leann P Nguyen, Arpit Mishra, Stephan Pribitzer, Samantha Hardy, Harshpreet Chandok, Florence M Chardon, Troy A Mcdiarmid, Hannah A Deberg, Jane H Buckner, Jay Shendure, Carl G De Boer, Michael H Guo, Ryan Tewhey, John P Ray

Faculty Research 2025

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4⁺ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4⁺ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and …

Recapitulating The Immune Microenvironment In Pediatric Brain Cancer: Preclinical Modeling Strategies., Adip G. Bhargav, Joseph S. Domino, David Akhavan, Jo Ling Goh

Manuscripts, Articles, Book Chapters and Other Papers

Primary brain and CNS tumors comprise the most common tumors in children and are the most common cause of cancer deaths in this population. Pediatric primary malignant brain tumors including high-grade glioma and medulloblastoma account for a significant proportion of these cancer deaths. Advances in the surgical management and adjuvant treatment paradigms have improved the prognosis of many patients with these tumors, but there remains a subset of treatment-resistant tumors or tumors with unique genetics aberrations and aggressive phenotypes that confer a poor prognosis. Immunotherapeutic strategies have demonstrated promise in pre-clinical studies and early clinical trials. However, high-fidelity evaluation of …

Chimeric Antigen Receptor Natural Killer (Car-Nk) Cells: From Preclinical Promise To Clinical Reality In Cancer Immunotherapy, Hunter Cassidy Cochran, Kevin Ashkan Ghobadi, Armin Ghobadi

2020-Current year OA Pubs

Chimeric antigen receptor (CAR) natural killer (NK) cell therapy represents an emerging frontier in cancer immunotherapy. CAR-NK cells offer the potential for "off-the-shelf" treatments with a favorable safety profile, due in part to their innate capacity for HLA-unrestricted tumor targeting and an absence of graft-versus-host disease. Landmark clinical studies using cord blood - derived CAR-NK cells and another employing iPSC-derived CAR-NK cells have reported impressive response rates, durable remissions, and minimal toxicity. Furthermore, a growing landscape of ongoing clinical trials is exploring innovative strategies to enhance persistence, overcome solid tumor challenges, and prevent antigen escape. These advances collectively underscore the …

Exposure To Household Air Pollution From Biomass Cooking And Severe Pneumonia In Infants, John P Mccracken, Lindsay J Underhill, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Household air pollution from biomass cooking is considered an important risk factor for child pneumonia.

OBJECTIVE: To evaluate the longitudinal association between exposure to particulate matter with a diameter of less than or equal to 2.5 µm (PM2.5) or carbon monoxide (CO) and severe pneumonia in infants.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included infants (aged ≤12 months) whose mothers participated in a 4-country randomized clinical trial. Conducted from May 2018 to September 2021, the trial tested whether an 18-month liquefied petroleum gas stove and fuel distribution intervention reduced the incidence of severe pneumonia in offspring during infancy …

Nrf2 Immunobiology In Cancer: Implications For Immunotherapy And Therapeutic Targeting, Harit Panda, Natalie G Rowland, Caroline M Krall, Brittany M Bowman, Michael B Major, Paul Zolkind

2020-Current year OA Pubs

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that acts as a key regulator in cellular defense mechanisms against oxidative stress and xenobiotics. NRF2 modulates the expression of over 200 genes involved in antioxidant response, drug metabolism, and cellular resilience. Constitutive activation of NRF2 is a common event in cancer and recent advances provide remarkable insights into the role of NRF2 in oncogenesis, immune evasion, and treatment resistance. This review aims to provide a comprehensive overview of the role of NRF2 in shaping the tumor immune microenvironment and the impact this has on clinical outcomes and treatment …

Tigit Affects Car Nk-Cell Effector Function In The Solid Tumor Microenvironment By Modulating Immune Synapse Strength, Ishwar Navin, Matthew Dysthe, Prashant S Menon, Corrine Baumgartner, Tim Sauer, Navin Varadarajan, Robin Parihar

Faculty, Staff and Students Publications

Therapies using NK cells that express chimeric antigen receptors (CAR-NK) have been successfully employed against hematologic malignancies. However, solid tumors resist CAR-NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) has been implicated in impaired antitumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR-NKs have not been explored. To address this gap, we compared TIGIT-expressing and TIGIT-deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment co-cultures and in vivo tumor immune …

Hydrogen Sulfide Inhibits Recruitment Of Monocyte-Derived Tumor Associated Macrophages In Glioblastoma By Downregulating Cxcl12, Joseph Camarano, Morgan Roque, Gabrielle Gahn, Stephen Garrett Whipple, Danielle Terrell, Charles Ronkon, Jamie Toms, Anthony Sin, Bharat Guthikonda, Khatri Latha, Yuhui Yang, Xinggui Shen, Christopher G Kevil, Ganesh Rao, Sungho Lee

Faculty, Staff and Students Publications

Tumor associated macrophages (TAMs) directly contribute to the dismal prognosis of glioblastoma by preventing anti-tumor immunity and promoting tumor invasion and angiogenesis. Inhibiting TAM infiltration is a potential therapeutic strategy in glioblastoma, with several chemokine antagonists in early clinical development. Hydrogen sulfide, a gasotransmitter that regulates microglial accumulation in a wide range of CNS diseases, may be a novel therapeutic target to prevent TAM recruitment in glioblastoma. In this study, hydrogen sulfide concentrations were directly measured from 14 isocitrate dehydrogenase (IDH)-wildtype glioblastoma surgical samples and compared against overall survival as well as expression of TAM markers and chemokines. Effects of …

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma To Radiotherapy, Cory M Richman, Alexandra Rasnitsyn, Borja L Holgado, Maria Vladoiu, Namal Abeysundara, Sandra Majo, Sara Chabi, Lucie J Taunay, Hiromichi Suzuki, Ichiyo Shibahara, Joonas Haapasalo, Jonelle G Pallotta, Tajana Douglas, Kaitlin Kharas, Kyle Juraschka, Oliver Ocsenas, Sachin A Kumar, Kristiina Nordfors, Ana Guerreiro Stücklin, Raul A Suarez, Jiao Zhang, Xiaochong Wu, Craig Daniels, Livia Garzia, Jüri Reimand, Olivier Saulnier, Thomas E Merchant, Celio Pouponnot, David R Raleigh, Michael D Taylor, Pasqualino De Antonellis

Faculty, Staff and Students Publications

Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma …

Peritoneal Immunosurgery: Immunotherapy Augmented Surgery For The Treatment Of Peritoneal Cancers, Ada I Ozcan, Arianexys Aquino López, Mary K Mckenna, Malcolm K Brenner, Alastair M Thompson

Faculty, Staff and Students Publications

Peritoneal malignancy often indicates disruptions in multiple physiological systems resulting from widespread cancer. The heterogenous origin and dynamic nature of peritoneal cancer make it difficult to treat with standard approaches that fit into guidelines. We describe how successful treatment should address the underlying pathology, the systemic response to surgical treatments and target the immune perturbations that facilitate the establishment and propagation of this multifaceted disease.

High Prevalence Of Abnormal Baseline Lung Function In Pediatric And Young Adult Hematopoietic Stem Cell Transplant Recipients: A Report From The Transpire Study, Jane Koo, Richard Cooper, Stephanie L Edwards, Adam Lane, Sara Katherine Loveless, Lauren Strecker, Kelly E Lake, Kasiani C Myers, Christopher Towe, Jessica Patti, Laura L Walkup, Kathryn A Wikenheiser-Brokamp, Margaret L Macmillan, Philip Lacher, Tamara Griffin, Merve Tekman, Gabriel Salinas Cisneros, Kevin Wu, Matthew S Zinter, Fernando A Urrego, K Scott Baker, Matthew F Abts, Sheri Ballard, Jason L Freedman, Alexander Caraballo, Lisa R Young, Maureen B Josephson, Julian L Allen, Devaney M Camburn, Erin E Doherty, Mashid Sababi Azamian, Martha Arredondo, Manuel Silva-Carmona, Leslie E Lehmann, Wai Wong, Jonathan M Gaffin, William Mcalpine, Mona Li, Samuel B Goldfarb, Jason C Woods, Stella M Davies

Faculty, Staff and Students Publications

Background: Pulmonary complications are a major cause of morbidity and mortality in pediatric and young adult hematopoietic stem cell transplant (HSCT) recipients. The impact of preexisting lung dysfunction on posttransplant outcomes remains understudied.

Methods: In a multi-institutional prospective cohort of 444 patients (≤24 years) undergoing allogeneic HSCT at eight centers, baseline lung function was categorized as normal or abnormal using clinical history, imaging, pulmonary function tests (PFTs), and pulmonologist review. Spirometry and diffusion capacity were assessed at baseline, Day 100, 1 year, and 2 years post-HSCT.

Results: Baseline pulmonary dysfunction was present in 224 patients (50.4%), including impaired spirometry (46.4%), …