Biomedical Informatics Commons^™

The Roles Of Ferroptosis In Cancer: Tumor Suppression, Tumor Microenvironment, And Therapeutic Interventions, Guang Lei, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

In cancer treatment, the recurrent challenge of inducing apoptosis through conventional therapeutic modalities, often thwarted by therapy resistance, emphasizes the critical need to explore alternative cell death pathways. Ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides on cellular membranes, has emerged as one such promising frontier in oncology. Induction of ferroptosis not only suppresses tumor growth but also holds potential for augmenting immunotherapy responses and surmounting resistance to existing cancer therapies. This review navigates the role of ferroptosis in tumor suppression. Furthermore, we delve into the complex role of ferroptosis within the …

A Structured Curriculum Supporting Biomedical Trainees’ Transition Into Independent Academic Positions And Early Career Success, Mabel Perez-Oquendo, Gabriele Romano, David P Farris, Varsha Gandhi, Ignacio I Wistuba, Robert E Tillman, Ryan Udan, Paolo Mangahas, Rama Soundararajan

Faculty, Staff and Student Publications

The United States government makes a substantial investment in biomedical training programs each year. However, for most trainees, these opportunities do not translate into career progression in academic research pathways. Only about one-fifth of postdoctoral fellows eventually secure a tenure-track faculty position, and even among these candidates, attrition is high. Although a number of factors govern career choices and career longevity, the transition from trainee to faculty is a challenging process and requires knowledge and skills that are not necessarily developed during a traditional university experience. Many postdoctoral fellows receive adequate training in research skills and scientific communication, but new …

Enhanced Plant-Derived Vesicles For Nucleotide Delivery For Cancer Therapy, Sara Corvigno, Yuan Liu, Emine Bayraktar, Elaine Stur, Nazende Nur Bayram, Adrian Lankenau Ahumada, Supriya Nagaraju, Cristian Rodriguez-Aguayo, Hu Chen, Thanh Chung Vu, Yunfei Wen, Han Liang, Li Zhao, Sanghoon Lee, Gabriel Lopez-Berestein, Anil K Sood

Faculty, Staff and Student Publications

Small RNAs (microRNAs [miRNAs] or small interfering RNAs [siRNAs]) are effective tools for cancer therapy, but many of the existing carriers for their delivery are limited by low bioavailability, insufficient loading, impaired transport across biological barriers, and low delivery into the tumor microenvironment. Extracellular vesicle (EV)-based communication in mammalian and plant systems is important for many physiological and pathological processes, and EVs show promise as carriers for RNA interference molecules. However, some fundamental issues limit their use, such as insufficient cargo loading and low potential for scaling production. Plant-derived vesicles (PDVs) are membrane-coated vesicles released in the apoplastic fluid of …

The Saga Of E Faecium, Rishika Prasad, Robert R Jenq

Faculty, Staff and Student Publications

An enzyme that remodels the cell wall of Enterococcus faecium helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.

Application Of Deep Learning On Mammographies To Discriminate Between Low And High-Risk Dcis For Patient Participation In Active Surveillance Trials, Sena Alaeikhanehshir, Madelon M Voets, Frederieke H Van Duijnhoven, Esther H Lips, Emma J Groen, Marja C J Van Oirsouw, Shelley E Hwang, Joseph Y Lo, Jelle Wesseling, Ritse M Mann, Jonas Teuwen

Faculty, Staff and Student Publications

BACKGROUND: Ductal Carcinoma In Situ (DCIS) can progress to invasive breast cancer, but most DCIS lesions never will. Therefore, four clinical trials (COMET, LORIS, LORETTA, AND LORD) test whether active surveillance for women with low-risk Ductal carcinoma In Situ is safe (E. S. Hwang et al., BMJ Open, 9: e026797, 2019, A. Francis et al., Eur J Cancer. 51: 2296-2303, 2015, Chizuko Kanbayashi et al. The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA), L. E. Elshof et al., Eur J Cancer, 51, 1497-510, 2015). Low-risk is defined as grade I or II DCIS. Because …

Human Brain Glycoform Coregulation Network And Glycan Modification Alterations In Alzheimer's Disease, Qi Zhang, Cheng Ma, Lih-Shen Chin, Sheng Pan, Lian Li

Faculty, Staff and Student Publications

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain …

Deparylation Is Critical For S Phase Progression And Cell Survival, Litong Nie, Chao Wang, Min Huang, Xiaoguang Liu, Xu Feng, Mengfan Tang, Siting Li, Qinglei Hang, Hongqi Teng, Xi Shen, Li Ma, Boyi Gan, Junjie Chen

Faculty, Staff and Student Publications

Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S-phase-specific pADPr signaling, which …

The Hallmarks Of Precancer, Mary M Stangis, Zhengyi Chen, Jimin Min, Sarah E Glass, Jordan O Jackson, Megan D Radyk, Xen Ping Hoi, W Nathaniel Brennen, Ming Yu, Huy Q Dinh, Robert J Coffey, Martha J Shrubsole, Keith S Chan, William M Grady, Srinivasan Yegnasubramanian, Costas A Lyssiotis, Anirban Maitra, Richard B Halberg, Neelendu Dey, Ken S Lau

Faculty, Staff and Student Publications

Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.

T-Cell Dysfunctions In Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Simona Colla

Faculty, Staff and Student Publications

Escape from immune surveillance is a hallmark of cancer. Immune deregulation caused by intrinsic and extrinsic cellular factors, such as altered T-cell functions, leads to immune exhaustion, loss of immune surveillance, and clonal proliferation of tumoral cells. The T-cell immune system contributes to the pathogenesis, maintenance, and progression of myelodysplastic syndrome (MDS). Here, we comprehensively reviewed our current biological knowledge of the T-cell compartment in MDS and recent advances in the development of immunotherapeutic strategies, such as immune checkpoint inhibitors and T-cell- and antibody-based adoptive therapies that hold promise to improve the outcome of patients with MDS.

Somatic Mutations In Normal Tissues: Calm Before The Storm, Zahraa Rahal, Paul Scheet, Humam Kadara

Faculty, Staff and Student Publications

We explore the phenomenon of somatic mutations, including those in cancer driver genes, that are present in healthy, normal-appearing tissues and their potential implications for cancer development. We also examine the landscape of these somatic mutations, discuss the role of clonal cell competition and external factors like inflammation in enhancing the fitness of mutant clones, and conclude by considering how understanding these mutations will aid in prevention and/or interception of cancer.

First-In-Human Phase I Study Of Tinengotinib (Tt-00420), A Multiple Kinase Inhibitor, As A Single Agent In Patients With Advanced Solid Tumors, Sarina A Piha-Paul, Binghe Xu, Ecaterina E Dumbrava, Siqing Fu, Daniel D Karp, Funda Meric-Bernstam, David S Hong, Jordi A Rodon, Apostolia M Tsimberidou, Kanwal Raghav, Jaffer A Ajani, Anthony P Conley, Frank Mott, Ying Fan, Jean Fan, Peng Peng, Hui Wang, Shumao Ni, Caixia Sun, Xiaoyan Qiang, Wendy J Levin, Brenda Ngo, Qinhua Cindy Ru, Frank Wu, Milind M Javle

Faculty, Staff and Student Publications

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy.

RESULTS: Forty-eight patients were enrolled (dose escalation, …

Nodal Variants Are Associated With A Continuum Of Laterality Defects From Simple D-Transposition Of The Great Arteries To Heterotaxy, Zain Dardas, Jawid M Fatih, Angad Jolly, Moez Dawood, Haowei Du, Christopher M Grochowski, Edward G Jones, Shalini N Jhangiani, Xander H T Wehrens, Pengfei Liu, Weimin Bi, Eric Boerwinkle, Jennifer E Posey, Donna M Muzny, Richard A Gibbs, James R Lupski, Zeynep Coban-Akdemir, Shaine A Morris

Faculty, Staff and Student Publications

BACKGROUND: NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects.

METHODS: We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with …

Oncogenic Oral Human Papillomavirus Clearance Patterns Over 10 Years, Gypsyamber D'Souza, Sakshi R Tewari, Tanya Troy, Jennifer Webster-Cyriaque, Dorothy J Wiley, Cecile Delille Lahiri, Frank Joseph Palella, Maura L Gillison, Howard D Strickler, Linda Struijk, Tim Waterboer, Ken Ho, Jennafer Kwait, Jason Lazar, Kathleen M Weber, Carole Fakhry

Faculty, Staff and Student Publications

Background: Effective screening for oropharyngeal cancer is lacking. Four oncogenic HPV clearance definitions were explored to understand long-term natural history for persistent oncogenic oral HPV (oncHPV), the precursor of oropharyngeal cancer.

Methods: Prospective multicenter cohort of participants living with/at-risk for HIV, with oral rinse and gargle samples collected every 6 to 12 months for up to 10 years and tested for oncHPV. HPV clearance definitions included 1 (clear1), 2 (clear2), 3 (clear3) consecutive negatives, or being negative at last two visits (clearlast).

Results: Median time to clearance of oncHPV exceeded 2 years for conservative definitions (clear3: 2.38, clearlast: 2.43), but …

Evaluation Of Four Computed Tomography Reconstruction Algorithms Using A Coronary Artery Phantom, Shungo Sawamura, Shingo Kato, Yoshinori Funama, Seitaro Oda, Harumi Mochizuki, Sayuri Inagaki, Yuka Takeuchi, Tsubasa Morioka, Toshiharu Izumi, Yoichiro Ota, Hironori Kawagoe, Shihyao Cheng, Naoki Nakayama, Kazuki Fukui, Takashi Tsutsumi, Tae Iwasawa, Daisuke Utsunomiya

Faculty, Staff and Student Publications

BACKGROUND: Despite advancements in coronary computed tomography angiography (CTA), challenges in positive predictive value and specificity remain due to limited spatial resolution. The purpose of this experimental study was to investigate the effect of 2nd generation deep learning-based reconstruction (DLR) on the quantitative and qualitative image quality in coronary CTA.

METHODS: A vessel model with stepwise non-calcified plaque was scanned using 320-detector CT. Image reconstruction was performed using four techniques: hybrid iterative reconstruction (HIR), model-based iterative reconstruction (MBIR), DLR, and 2nd generation DLR. The luminal peak CT number, contrast-to-noise ratio (CNR), and edge rise slope (ERS) were quantitatively evaluated via …

Author Correction: Automating Data Analysis For Hydrogen/Deuterium Exchange Mass Spectrometry Using Data-Independent Acquisition Methodology, Frantisek Filandr, Vladimir Sarpe, Shaunak Raval, D Alex Crowder, Morgan F Khan, Pauline Douglas, Stephen Coales, Rosa Viner, Aleem Syed, John A Tainer, Susan P Lees-Miller, David C Schriemer

Faculty, Staff and Student Publications

No abstract provided.

Ai Is A Viable Alternative To High Throughput Screening: A 318-Target Study, The Atomwise Aims Program

Faculty, Staff and Student Publications

High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, …

Identification Of Colorectal Cancer Cell Stemness From Single-Cell Rna Sequencing, Kangyu Lin, Saikat Chowdhury, Mohammad A Zeineddine, Fadl A Zeineddine, Nicholas J Hornstein, Oscar E Villarreal, Dipen M Maru, Cara L Haymaker, Jean-Nicolas Vauthey, George J Chang, Elena Bogatenkova, David Menter, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

UNLABELLED: Cancer stem cells (CSC) play a critical role in metastasis, relapse, and therapy resistance in colorectal cancer. While characterization of the normal lineage of cell development in the intestine has led to the identification of many genes involved in the induction and maintenance of pluripotency, recent studies suggest significant heterogeneity in CSC populations. Moreover, while many canonical colorectal cancer CSC marker genes have been identified, the ability to use these classical markers to annotate stemness at the single-cell level is limited. In this study, we performed single-cell RNA sequencing on a cohort of 6 primary colon, 9 liver metastatic …

Peritoneal Microenvironment Promotes Appendiceal Adenocarcinoma Growth: A Multi-Omics Approach Using Patient-Derived Xenografts, Vinay K Pattalachinti, Ichiaki Ito, Saikat Chowdhury, Abdelrahman Yousef, Yue Gu, Betul Beyza Gunes, Emma R Salle, Melissa W Taggart, Keith Fournier, Natalie W Fowlkes, John Paul Shen

Faculty, Staff and Student Publications

Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA. AA tumors implanted in the peritoneal microenvironment tended to grow faster and displayed greater nuclear expression of Ki-67 relative to the same tumors implanted in the flank. Comparing the tumor-specific transcriptome (excluding stromal transcription), the peritoneal microenvironment relatively upregulated genes related to proliferation, including …

Antigen-Clustered Nanovaccine Achieves Long-Term Tumor Remission By Promoting B/Cd 4 T Cell Crosstalk, Chengyi Li, Ryan Clauson, Luke F Bugada, Fang Ke, Bing He, Zhixin Yu, Hongwei Chen, Binyamin Jacobovitz, Hongxiang Hu, Polina Chuikov, Brett Dallas Hill, Syed M Rizvi, Yudong Song, Kai Sun, Pasieka Axenov, Daniel Huynh, Xinyi Wang, Lana Garmire, Yu Leo Lei, Irina Grigorova, Fei Wen, Marilia Cascalho, Wei Gao, Duxin Sun

Faculty, Staff and Student Publications

Current cancer vaccines using T cell epitopes activate antitumor T cell immunity through dendritic cell/macrophage-mediated antigen presentation, but they lack the ability to promote B/CD4 T cell crosstalk, limiting their anticancer efficacy. We developed antigen-clustered nanovaccine (ACNVax) to achieve long-term tumor remission by promoting B/CD4 T cell crosstalk. The topographic features of ACNVax were achieved using an iron nanoparticle core attached with an optimal number of gold nanoparticles, where the clusters of HER2 B/CD4 T cell epitopes were conjugated on the gold surface with an optimal intercluster distance of 5-10 nm. ACNVax effectively trafficked to lymph nodes and cross-linked with …

Targeting Branched N-Glycans And Fucosylation Sensitizes Ovarian Tumors To Immune Checkpoint Blockade, Hao Nie, Pratima Saini, Taito Miyamoto, Liping Liao, Rafal J Zielinski, Heng Liu, Wei Zhou, Chen Wang, Brennah Murphy, Martina Towers, Tyler Yang, Yuan Qi, Toshitha Kannan, Andrew Kossenkov, Hiroaki Tateno, Daniel T Claiborne, Nan Zhang, Mohamed Abdel-Mohsen, Rugang Zhang

Faculty, Staff and Student Publications

Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their …

Neutrophil Elastase Remodels Mammary Tumors To Facilitate Lung Metastasis, Amriti R Lulla, Said Akli, Cansu Karakas, Joseph A Caruso, Lucas D Warma, Natalie W Fowlkes, Xiayu Rao, Jing Wang, Kelly K Hunt, Stephanie S Watowich, Khandan Keyomarsi

Faculty, Staff and Student Publications

Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways …

Transcriptional Signature Of Durable Effector T Cells Elicited By A Replication Defective Hcmv Vaccine, Xiaohua Ye, David J H Shih, Zhiqiang Ku, Junping Hong, Diane F Barrett, Richard E Rupp, Ningyan Zhang, Tong-Ming Fu, W Jim Zheng, Zhiqiang An

Faculty, Staff and Student Publications

Human cytomegalovirus (HCMV) is a leading infectious cause of birth defects and the most common opportunistic infection that causes life-threatening diseases post-transplantation; however, an effective vaccine remains elusive. V160 is a live-attenuated replication defective HCMV vaccine that showed a 42.4% efficacy against primary HCMV infection among seronegative women in a phase 2b clinical trial. Here, we integrated the multicolor flow cytometry, longitudinal T cell receptor (TCR) sequencing, and single-cell RNA/TCR sequencing approaches to characterize the magnitude, phenotype, and functional quality of human T cell responses to V160. We demonstrated that V160 de novo induces IE-1 and pp65 specific durable polyfunctional …

Unveiling Gene Interactions In Alzheimer's Disease By Integrating Genetic And Epigenetic Data With A Network-Based Approach, Keith L Sanders, Astrid M Manuel, Andi Liu, Boyan Leng, Xiangning Chen, Zhongming Zhao

Faculty, Staff and Student Publications

Alzheimer’s Disease (AD) is a complex disease and the leading cause of dementia in older people. We aimed to uncover aspects of AD’s pathogenesis that may contribute to drug repurposing efforts by integrating DNA methylation and genetic data. Implementing the network-based tool, a dense module search of genome-wide association studies (dmGWAS), we integrated a large-scale GWAS dataset with DNA methylation data to identify gene network modules associated with AD. Our analysis yielded 286 significant gene network modules. Notably, the foremost module included the BIN1 gene, showing the largest GWAS signal, and the GNAS gene, the most significantly hypermethylated. We conducted …

Identification Of Novel F2-Isoprostane Metabolites By Specific Udp-Glucuronosyltransferases, Ginger L Milne, Marina S Nogueira, Benlian Gao, Stephanie C Sanchez, Warda Amin, Sarah Thomas, Camille Oger, Jean-Marie Galano, Harvey J Murff, Gong Yang, Thierry Durand

Faculty, Staff and Student Publications

UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of glucuronic acid with endogenous and exogenous lipophilic small molecules to facilitate their inactivation and excretion from the body. This represents approximately 35 % of all phase II metabolic transformations. Fatty acids and their oxidized eicosanoid derivatives can be metabolized by UGTs. F2-isoprostanes (F2-IsoPs) are eicosanoids formed from the free radical oxidation of arachidonic acid. These molecules are potent vasoconstrictors and are widely used as biomarkers of endogenous oxidative damage. An increasing body of evidence demonstrates the efficacy of measuring the β-oxidation metabolites of F2-IsoPs rather than the unmetabolized F2-IsoPs to quantify oxidative damage in …

Social And Behavior Factors Of Alzheimer's Disease And Related Dementias: A National Study In The Us, David Ciciora, Elizabeth Vásquez, Edward Valachovic, Lifang Hou, Yinan Zheng, Hua Xu, Xiaoqian Jiang, Kun Huang, Kelley Pettee Gabriel, Hong-Wen Deng, Mary P Gallant, Kai Zhang

Faculty, Staff and Student Publications

Introduction: Considerable research has linked many risk factors to Alzheimer's Disease and Related Dementias (ADRD). Without a clear etiology of ADRD, it is advantageous to rank the known risk factors by their importance and determine if disparities exist. Statistical-based ranking can provide insight into which risk factors should be further evaluated.

Methods: This observational, population-based study assessed 50 county-level measures and estimates related to ADRD in 3,155 counties in the U.S. using data from 2010 to 2021. Statistical analysis was performed in 2022-2023. The machine learning method, eXtreme Gradient Boosting, was utilized to rank the importance of these variables by …

Cytokine Release By Microglia Exposed To Neurologic Injury Is Amplified By Lipopolysaccharide, Michael C Scott, Olivia Leblanc, Harper Day, Candice Haase, Scott D Olson, Charles S Cox

Faculty, Staff and Student Publications

Introduction: Traumatic brain injury (TBI) is a leading cause of death and morbidity in the trauma population. Microglia drive the secondary neuroinflammatory response after TBI. We sought to determine if the microglial response to neurologic injury was exacerbated by a second stimulus after exposure to neurologic injury.

Methods: Sprague-Dawley rats (age 2-3 wk) were divided into injured and noninjured groups. Injured rats underwent a controlled cortical impact injury; noninjured rats remained naïve to any injury and served as the control group. Primary rat microglia were isolated and applied to in vitro cultures. After incubation for 24 h, the microglia were …

Combined Ion Beam Irradiation Platform And 3d Fluorescence Microscope For Cellular Cancer Research, Andrew D Harken, Naresh T Deoli, Citlali Perez Campos, Brian Ponnaiya, Guy Garty, Grace S Lee, Malte J Casper, Shikhar Dhingra, Wenze Li, Gary W Johnson, Sally A Amundson, Peter W Grabham, Elizabeth M C Hillman, David J Brenner

Faculty, Staff and Student Publications

To improve particle radiotherapy, we need a better understanding of the biology of radiation effects, particularly in heavy ion radiation therapy, where global responses are observed despite energy deposition in only a subset of cells. Here, we integrated a high-speed swept confocally-aligned planar excitation (SCAPE) microscope into a focused ion beam irradiation platform to allow real-time 3D structural and functional imaging of living biological samples during and after irradiation. We demonstrate dynamic imaging of the acute effects of irradiation on 3D cultures of U87 human glioblastoma cells, revealing characteristic changes in cellular movement and intracellular calcium signaling following ionizing irradiation.

Druggable Site Near The Upper Vestibule Determines The High Affinity And P2x3 Homotrimer Selectivity Of Sivopixant/S-600918 And Its Analogue Ddtpa, Dong-Ping Wang, Meng Zhang, Ming Li, Xiao-Na Yang, Changzhu Li, Peng Cao, Michael X Zhu, Yun Tian, Ye Yu, Yun-Tao Lei

Faculty, Staff and Student Publications

Background and purpose: The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF-219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S-600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3-(4-([3-chloro-4-isopropoxyphenyl]amino)-3-(4-methylbenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)propanoic acid (DDTPA), exhibit both high affinity …

Genome-Wide Crispr Screen Reveals The Synthetic Lethality Between Bcl2l1 Inhibition And Radiotherapy, Ling Yin, Xiaoding Hu, Guangsheng Pei, Mengfan Tang, You Zhou, Huimin Zhang, Min Huang, Siting Li, Jie Zhang, Citu Citu, Zhongming Zhao, Bisrat G Debeb, Xu Feng, Junjie Chen

Faculty, Staff and Student Publications

Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 …

The Tudor-Knot Domain Of Kat5 Regulates Nucleosomal Substrate Acetylation, Fan Xuan, Hongwen Xuan, Mengying Huang, Wei He, Han Xu, Xiaobing Shi, Hong Wen

Faculty, Staff and Student Publications

The lysine acetyltransferase KAT5 is a pivotal enzyme responsible for catalyzing histone H4 acetylation in cells. In addition to its indispensable HAT domain, KAT5 also encompasses a conserved Tudor-knot domain at its N-terminus. However, the function of this domain remains elusive, with conflicting findings regarding its role as a histone reader. In our study, we have employed a CRISPR tiling array approach and unveiled the Tudor-knot motif as an essential domain for cell survival. The Tudor-knot domain does not bind to histone tails and is not required for KAT5's chromatin occupancy. However, its absence leads to a global reduction in …