Digital Commons Network^™

Blockade Of A2ar Improved Brain Perfusion And Cognitive Function In A Mouse Model Of Alzheimer’S Disease, Mariana Sayuri Berto Udo, Julia Zaccarelli-Magalhães, Garrett Alan Clemons, Cristiane Teresinha Citadin, Julia Langman, Drew James Smith, Luiz Henrique Matuguma, Vesna Tesic, Hung Wen Lin

Faculty, Staff and Student Publications

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects more than 6.2 million Americans aged 65 and older, particularly women. Along with AD’s main hallmarks (formation of β-amyloid plaques and tau neurofibrillary tangles), there are vascular alterations that occurs in AD pathology. Adenosine A2 receptor (A2AR) is one of the key factors of brain vascular autoregulation and is overexpressed in AD patients. Our previous findings suggest that protein arginine methyltransferase 4 (PRMT4) is overexpressed in AD, which leads to decrease in cerebral blood flow in aged female 3xTg mice. We aimed to investigate the mechanism behind A2AR signaling in the …

Developmental Lead Exposure And Aggression In Male Rats: Influences Of Maternal Care And Environmental Enrichment, Shamaila Zafar, Courtney K. Williams, Jaehyun Joo, Blanca E. Himes, Jay S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Developmental lead (Pb) exposure results in a variety of cognitive deficits and behavioral issues including increased antisocial behavior and aggression. This study investigated the effect of developmental Pb exposure on aggression and violent behavior in male rats and the potential modulatory influences of quality of maternal care and enriched/non-enriched housing conditions. Long-Evans male rats with or without Pb exposure (perinatal or early postnatal) from low or high maternal care mothers (based on amounts of licking/grooming and arched- back nursing) were randomly assigned to live in enriched or non-enriched environments at weaning. At post- natal day 120–190, offensive aggression was assessed …

Predicting Discharge Destination And Length Of Stay After Open Reduction Internal Fixation Of Distal Femur Fractures, Akash A Shah, Brian K Zukotynski, Chohee Kim, Brendan Y Shi, Changhee Lee, Sai K Devana, Alexander Upfill-Brown, Erik N Mayer, Nelson F Soohoo, Christopher Lee

Faculty, Staff and Student Publications

Introduction: Prediction of nonhome discharge after open reduction internal fixation (ORIF) of distal femur fractures may facilitate earlier discharge planning, potentially decreasing costs and improving outcomes. We aim to develop algorithms predicting nonhome discharge and time to discharge after distal femur ORIF and identify features important for model performance.

Methods: This is a retrospective cohort study of adults in the American College of Surgeons National Surgical Quality Improvement Program database who underwent distal femur ORIF between 2010 and 2019. The primary outcome was nonhome discharge, and the secondary outcome was time to nonhome discharge. We developed logistic regression and machine …

The Macrophage Sterol Transport Protein Orp2 Promotes Cholesterol Efflux And Prevents Foam Cell Formation And Atherosclerosis, Xiaowei Wang, Kenan Peng, Yudi Zhao, Liwen Qiu, Chenxi Liang, Yaqian Dou, Qianqian Dong, Xiaoting Ma, Jinye Tang, Yidan Ma, Lin Liu, Mingqi Zheng, Hongyuan Yang, Mingming Gao

Faculty, Staff and Student Publications

Cholesterol-loaded macrophage foam cells are a key feature of atherosclerotic plaques. Oxysterol-binding protein-related protein 2 (ORP2) facilitates the transport of cholesterol from lysosomes to the plasma membrane in cultured cell lines. However, the role of ORP2 in macrophages and its involvement in atherosclerosis remain unclear. In this study, we found ORP2 expression was reduced in atherosclerotic vessels and in macrophages exposed to oxidized LDL (ox-LDL). Myeloid-specific human ORP2 overexpression (hORP2MOE) mice were generated and crossed with atherosclerotic-prone ApoE−/− mice and then fed a high-fat diet (HFD) to induce atherosclerosis. Our results showed that myeloid-specific hORP2 overexpression significantly reduced the atherosclerotic …

Glutamatergic Regulation Of Mirna-Containing Intraluminal Vesicle Trafficking And Extracellular Vesicle Secretion From Cortical Neurons, Marcela Bertolio, Qiyi Li, Francesca E Mowry, Kathryn E Reynolds, Rashed Alananzeh, Haichao Wei, Kyoeun Keum, Rachel Jarvis, Jiaqian Wu, Yongjie Yang

Faculty, Staff and Student Publications

Neuronal extracellular vesicles (microvesicles and exosomes) are emerging secreted vesicular signals that play important roles in the CNS. Currently, little is known about how glutamatergic signalling affects the subcellular localisation of exosome precursor intraluminal vesicles (ILVs), microRNA (miR) packaging into ILVs and in vivo spreading of neuronal EVs. By selectively labelling ILVs and exosomes (but not plasma membrane-derived MVs) with GFP-tagged human CD63 (hCD63-GFP) in cortical neurons, we found that glutamate stimulation significantly redistributes subcellular localisation of hCD63-GFP+ ILVs, especially decreasing its co-localisation with multi-vesicular body (MVB) marker Rab7 while substantially promoting EV secretion. Interestingly, glutamate stimulation only modestly alters …

International Multidisciplinary Consensus Recommendations On Clinical Application Of Three-Dimensional Visualization In Precision Surgery For Pediatric Liver Tumors, Qian Dong, Wenli Xiu, Benjie Tang, Eiso Hiyama, Mary T Austin, Yeming Wu, Xiaojun Yuan, Chengzhan Zhu, Chengli Liu, Hiroki Ishibashi, Karthik K Tappa, Huanmin Wang, Chuandong Sun, Yuntao Ma, Hongwei Xi, Jian Wang, Jianghua Zhan, Kyong Ihn, Mitsuo Shimada, Mingman Zhang, Mary E Brindle, Patrick B Thomas, Shigehisa Fumino, Tao Liu, Thom Lobe, Udo Rolle, Shan Wang, Xiaowen Zhai, Yoshinori Koga, Yoshiaki Kinoshita, Yuzuo Bai, Zhaozhu Li, Zhe Wen, Weikang Pan, Krysta M Sutyak, Pier C Giulianotti

Faculty, Staff and Student Publications

Background: Pediatric liver tumors are predominantly primary malignant tumors, and complete tumor resection with sufficient preservation of liver tissue is crucial for improving prognosis. However, due to the delicate anatomical structure of the pediatric liver and the relatively large size of the tumors, especially in difficult cases, the surgical challenges are substantial. While precision liver surgery are widely applied in clinical practice, pediatric cases require more customized approaches. The application of three-dimensional (3D) visualization technology is crucial for enhancing surgical accuracy, allowing for precise preoperative planning and intraoperative guidance.

Methods: This consensus was collaboratively developed by 36 experts from eight …

Surgical Management Of An Intracranial Injury Caused By A Handcrafted Arrow In Sub-Saharan Africa: A Global Neurosurgical Relevance., Allie L Heineman, Quinn Jackson, Chris Karas, Robert Galler, Victor Awuor, Hiren Patel

Trauma and Acute Care Articles

This case report and literature review describe an intracranial injury resulting from a handcrafted arrow that required emergent surgical management in a patient treated at a public hospital in Sub-Saharan Africa. The authors are members of the non-profit organizations Chunilal Initiative and Kisumu Intuitive, which deliver charitable neurosurgical care to the region on a quarterly basis. This unique neurotrauma case, involving a penetrating, contaminated, metallic object, highlights the surgical and antibacterial management of intracranial arrow injuries and emphasizes the importance of neurosurgical missions to underserved regions globally. The patient is a 16-year-old male tribal member with no known or reported …

Investigation Of Endotracheal Tube Versus Laryngeal Mask Airway Emergence Times For Surgical Patients., Samir M Patel, Rayyan Bhutta, Michelle Pershing, John Dillis, John O Elliott, Matthias J Franzen

OhioHealth Research Institute Articles

During surgical procedures requiring general anesthesia, an airway device is often placed to allow for adequate ventilation of the patient. Most commonly, endotracheal tubes (ETTs) or laryngeal mask airways (LMAs) are placed by the anesthesia provider. The difference between these two methods of ventilation is based on the location; ETTs pass through the glottis into the trachea, whereas the LMA sits above the glottis. This difference in placement may lend benefit to LMAs over ETTs, one of which includes a faster removal of the airway device. That is, after the surgical procedure is completed, there is a period when the …

Utility Of Readily Available Sugammadex For Emergent Neuromuscular Blockade Reversal., Theodore Renner, Kevin Varner, Austin Shaffer, Elizabeth Johnson-Gray, Noah Le, Matthias Franzen

Surgery Articles

INTRODUCTION: Anesthesia providers are often called upon to assist with other providers during can't intubate, can't ventilate (CICV) scenarios. The current availability of doses of sugammadex sufficient to provide emergent reversal of neuromuscular blockade in an operating room environment requires visits to multiple operating rooms at our institution. The Anesthesiology Department at OhioHealth Doctors Hospital sought to evaluate the practicality of administering a rescue dose of sugammadex (16 mg/kg) in a CICV scenario. The current storage of sugammadex is six 200 mg vials maximum per operating room, which would provide insufficient dosing for emergent reversal dosing for most adult patients. …

Epidemiology Of Hip Dislocations In The United States From 1990 To 2019: A Temporal Study Using The Global Burden Of Disease Database., Ambrose Loc T Ngo, Gabrielle Dykhouse, Taylor J Manes, Phillip C Mckegg, Cameron J Sabet, Brett Barthman, Robert Golden

Trauma and Acute Care Articles

Introduction Hip dislocations are devastating injuries that require urgent intervention to minimize the development of severe complications. This study aimed to evaluate the epidemiology of hip dislocations in the United States (U.S.) from 1990 to 2019. Methods This study is a descriptive retrospective epidemiological study. The Global Burden of Disease (GBD) database was used to collect epidemiological data on hip dislocation in the U.S. from 1990 to 2019. Data included years lived with disability (YLDs), prevalence, and incidence rates per 100,000 people. Data were regionally stratified into Northeast, Midwest, South, and West by the U.S. Census definition. Bartlett's test was …

Alterations In Gut Microbiome Composition And Increased Inflammatory Markers In Post-Covid-19 Individuals, Tatiana Barichello, Bruno Kluwe-Schiavon, Laura A Borba, Lucas C Pedro, Flávia S Niero, Laísa N Dos Santos, Letícia M Leonardo, Zuleide M Ignácio, Rodrigo Morales, Luciane B Ceretta, Gislaine Z Reus

Faculty, Staff and Student Publications

Dysfunctions in the immune system and alterations in the microbiome composition following SARS-CoV-2 infection contribute to persistent neurological issues observed in long COVID-19 survivors. We hypothesize that alterations in the gut microbiome composition and peripheral inflammatory profile following COVID-19 may play pivotal roles in behavior changes among individuals experiencing long-term illness. This cross-sectional study included a sample of post-COVID-19 and non-COVID-19 subjects. We assessed the presence of psychiatric conditions utilizing standardized diagnostic criteria, Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression (HAM-D), Biological Rhythms in Neuropsychiatry Assessment Interview (BRIAN), and Functional Assessment Short Test (FAST). Plasma samples …

Self-Reported Audiological And Vestibular Symptoms Associated With Lyme Disease, Daniella A. Bryan

Dissertations, Theses, and Capstone Projects

Background:

Lyme disease, an infectious vector-borne illness, is carried by the deer tick, Ixodes scapularis, which harbor the spirochete, Borrelia burgdorferi, affecting hundreds of thousands of people in the United States annually. Lyme disease has a multitude of clinical presentations and overlaps with other complex illnesses, making diagnosis and treatment a medical challenge. This distinct bacterium can migrate into any organ system through the mediums of soft tissue, the lymphatic system, and the circulatory system. Despite its prevalence and range in symptomatology, minimal research has been conducted to identify distinct audiological and vestibular symptoms associated with a Lyme …

Comparative Genotoxicological Analysis Of Occupational Pesticide Exposures: An Experimental Approach And Systematic Review, Moustafa Samy Sherif

Dissertations

This dissertation investigates the genotoxic and cytotoxic effects of pesticide exposure through three complementary research components: a systematic review of occupational pesticide exposure in Arab countries (AraSys), a systematic review on encapsulated versus conventional pesticide formulations (Encap-Sys), and experimental toxicological assessments of various pesticide formulations in human cell lines (Pyr-Ex). This experimental component includes cytotoxicity assays using propidium iodide and DNA damage assessments via alkaline comet assays in HL60 and HepG2 cell lines exposed to pyrethroid insecticides and glyphosate-based formulations.

The AraSys systematic review revealed a critical positive association between occupational pesticide exposure and DNA damage in agricultural workers in …

Associations Between Vitamin D Deficiency And Sociodemographic Factors, Lifestyle Behaviors, And Metabolic Conditions: A Cross-Sectional Study From The Hnnhs In Greece, Asmae Mohamad Sadek

Theses

Vitamin D deficiency (VDD) is a widespread global health concern associated with various sociodemographic, lifestyle, dietary, and metabolic factors. While previous studies examined VDD in Greece, few provided a comprehensive analysis across multiple determinants using representative national data. This study aimed to assess the prevalence and predictors of VDD among Greek adults and to examine its associations with sociodemographic, dietary, behavioral, and metabolic variables using data from the Hellenic National Nutrition and Health Survey (HNNHS). A cross-sectional analysis was conducted among 978 adults (≥19 years) from the HNNHS. Serum 25-hydroxyvitamin D [25(OH)D] concentrations < 20 ng/mL were defined as deficient and ≥20 ng/mL as normal. The median age of participants was 40.2 years, and 62.0% were female. The overall prevalence of VDD was 46.0%, with the highest rate observed among adults aged ≥60 years (62.2%). VDD was significantly associated with older age (p < 0.001), retirement status (62.9% among retired; p < 0.001), low and sedentary physical activity (32.7% and 32.6% vs. 50.8% among highly active; p < 0.001), higher HDL (median 52.0 vs. 49.0 mg/dL among VDD vs Normal; p = 0.001), elevated serum calcium (median 9.4 vs. 9.2 mg/dL among VDD vs Normal; p = 0.020), and lower insulin levels (median 7.5 vs. 8.0 μIU/mL among VDD vs Normal; p = 0.044). Dietary intake (total energy and macronutrients) and body composition were not significantly associated with VDD. In the multivariate model, significant independent predictors of VDD included being retired (AOR = 2.383; 95% CI: 1.596–3.558; p < 0.001), having higher serum calcium levels (AOR = 1.563; 95% CI: 1.078–2.266; p = 0.019), and higher HDL levels (AOR = 1.016; 95% CI: 1.005–1.027; p = 0.001). Physical activity level was also a key determinant; participants classified as sedentary or low active had significantly higher odds of deficiency compared to highly active individuals (AOR = 0.468; 95% CI: 0.319–0.690; p < 0.001). This counterintuitive result may be influenced by factors such as increased indoor physical activity, and warrants further investigation. Dietary intake and body composition were not significantly associated with VDD. The findings underscore the importance of incorporating sociodemographic and lifestyle factors into prevention strategies. Interventions should particularly focus on older adults, retired individuals, even if they have higher HDL and calcium levels, and are physically active.

Salicylamide Derivative Jmx0312 Protects Immunosuppressed Syrian Hamsters Against Adenovirus Lethal Challenge, Marta Carretero-Ledesma, Jun Li, Javier Martín-Escolano, Soraya Herrera-Espejo, Jimin Xu, Haiying Chen, Caridad Díaz-Navarro, Jerónimo Pachón, Javier Sánchez-Céspedes, Jia Zhou, María Eugenia Pachón-Ibáñez

Faculty, Staff and Student Publications

Despite the fact that human adenovirus (HAdV) causes severe infections in immunosuppressed and immunocompetent individuals, especially in children, there is currently no specific treatment for these infections. Previously we reported a new salicylamide analogue, JMX0312, as a potent inhibitor of HAdV infection with low cytotoxicity in vitro. Here we evaluate the in vivo efficacy and safety of this molecule in the immunosuppressed Syrian hamster model of HAdV infection. JMX0312 administration at a dose of 6.25 mg/kg did not affect the body weight of the animals, and reduced the viral load in liver and blood in a similar way than cidofovir. …

Association Of Sirt6 Expression With Risk Of Pneumonitis Induced By Radiotherapy In Cancer Patients, Fengyuan Yu, Zheng Gong, Yuan Li, Danial F Naseem, Chen Li, Miaowei Wen, Bingying Zhao, Zhezhe Xu, Shanshan Zhang, Rukun Zang, Ailu Wu, Qingxin Han, Shuhui Wu, Hongwei Li, Yipeng Song

Faculty, Staff and Student Publications

Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients …

Emerging Technologies Of Single-Cell Multi-Omics, Yi June Kim, Koichi Takahashi

Faculty, Staff and Student Publications

The heterogeneity of the hematopoietic system was largely veiled by traditional bulk sequencing methods, which measure the averaged signals from mixed cellular populations. In contrast, single-cell sequencing has enabled the direct measurement of individual signals from each cell, significantly enhancing our ability to unveil such heterogeneity. Building on these advances, numerous single-cell multi-omics techniques have been developed into high-throughput, routinely accessible platforms, delineating the precise relationships among different layers of the central dogma in molecular biology. These technologies have uncovered the intricate landscape of genetic clonality and transcriptional heterogeneity in both normal and malignant hematopoietic systems, highlighting their roles in …

Norovirus Replication, Host Interactions And Vaccine Advances, B V Venkataram Prasad, Robert L Atmar, Sasirekha Ramani, Timothy Palzkill, Yongcheng Song, Sue E Crawford, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis worldwide in all age groups and cause significant disease and economic burden globally. To date, no approved vaccines or antiviral therapies are available to treat or prevent HuNoV illness. Several candidate vaccines are in clinical trials, although potential barriers to successful development must be overcome. Recently, significant advances have been made in understanding HuNoV biology owing to breakthroughs in virus cultivation using human intestinal tissue-derived organoid (or enteroid) cultures, advances in structural biology technology combined with epitope mapping and increased metagenomic sequencing. New and unexpected strain-specific differences in pandemic versus …

Building Community Through Data: The Value Of A Researcher Driven Open Science Ecosystem, Meredith C B Adams, Carla M Bann, Emine Ozgur Bayman, Maria Chao, Georgene W Hergenroeder, Charles Knott, Martin A Lindquist, Z David Luo, Rosemarie Martin, Maryann E Martone, John Mccarthy, Micah Mccumber, Sharon B Meropol, Ty A Ridenour, Lissette M Saavedra, Abeed Sarker, Kevin J Anstrom, Wesley K Thompson

Faculty, Staff and Student Publications

No abstract provided.

Functional Vs Structural Cortical Deficit Pattern Biomarkers For Major Depressive Disorder, Peter Kochunov, Bhim M Adhikari, David Keator, Daniel Amen, Si Gao, Nicole R Karcher, Demetrio Labate, Robert Azencott, Yewen Huang, Hussain Syed, Hongjie Ke, Paul M Thompson, Danny J J Wang, Braxton D Mitchell, Jessica A Turner, Theo G M Van Erp, Neda Jahanshad, Yizhou Ma, Xiaoming Du, William Burroughs, Shuo Chen, Tianzhou Ma, Jair C Soares, L Elliot Hong

Faculty, Staff and Student Publications

Importance: Major depressive disorder (MDD) is a severe mental illness characterized more by functional rather than structural brain abnormalities. The pattern of regional homogeneity (ReHo) deficits in MDD may relate to underlying regional hypoperfusion. Capturing this functional deficit pattern provides a brain pattern-based biomarker for MDD that is linked to the underlying pathophysiology.

Objective: To examine whether cortical ReHo patterns provide a replicable biomarker for MDD that is more sensitive than reduced cortical thickness and evaluate whether the ReHo MDD deficit pattern reflects regional cerebral blood flow (RCBF) deficit patterns in MDD and whether a regional vulnerability index (RVI) thus …

A Gut-On-A-Chip Incorporating Human Faecal Samples And Peristalsis Predicts Responses To Immune Checkpoint Inhibitors For Melanoma, Mattia Ballerini, Serena Galiè, Punit Tyagi, Carlotta Catozzi, Hariam Raji, Amir Nabinejad, Angeli D G Macandog, Alessandro Cordiale, Bianca Ionela Slivinschi, Karol K Kugiejko, Martina Freisa, Paola Occhetta, Jennifer A Wargo, Pier F Ferrucci, Emilia Cocorocchio, Nicola Segata, Andrea Vignati, Andrey Morgun, Michela Deleidi, Teresa Manzo, Marco Rasponi, Luigi Nezi

Faculty, Staff and Student Publications

Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome-host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome-host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human …

Therapeutic Hurdles In Acute Myeloid Leukemia: Leukemic Stem Cells, Inflammation And Immune Dysfunction, Bofei Wang, Patrick K Reville, Hussein A Abbas

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is an aggressive and highly heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest in myeloid progenitor cells. Despite advancements in chemotherapy, allogeneic hematopoietic stem cell transplantation, and post-remission maintenance therapies, the long-term survival remains unsatisfactory with high rates of relapse and refractory. These therapeutic challenges are mediated by multiple factors, including the complexity of the cellular hierarchies in AML, the interaction of leukemic stem cells (LSCs) with the bone marrow niche, inflammation, and immune evasion mechanisms. Further, the absence of specific surface markers that distinguish LSCs from normal hematopoietic stem cells, together with LSCs' …

Trem2 Depletion In Pancreatic Cancer Elicits Pathogenic Inflammation And Accelerates Tumor Progression Via Enriching Il-1Β+ Macrophages, Daowei Yang, Xinlei Sun, Hua Wang, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a complex tumor microenvironment enriched with tumor-associated macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by a subset of macrophages in PDAC. However, the functional role of TREM2 in PDAC progression remains elusive.

Methods: We generated a novel transgenic mouse model (KPPC;Trem2-/-) that enables the genetic depletion of TREM2 in the context of spontaneous PDAC development. Single-cell RNA-sequencing analysis was used to identify changes in the tumor immune microenvironment on TREM2 depletion. We evaluated the impacts of TREM2 depletion on the tumor immune microenvironment to elucidate the functions …

Gsk-3484862, A Dnmt1 Degrader, Promotes Dnmt3b Expression In Lung Cancer Cells, Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng

Faculty, Staff and Student Publications

DNA methylation alterations, including hypermethylation and silencing of tumor suppressor genes, contribute to cancer formation and progression. The FDA-approved nucleoside analogs azacytidine and decitabine are effective demethylating agents for hematologic malignancies but their general use has been limited by their toxicity and ineffectiveness against solid tumors. GSK-3484862, a dicyanopyridine-containing, DNMT1-selective inhibitor and degrader, offers a promising lead for developing novel demethylating therapeutics. Here, we demonstrate that GSK-3484862 treatment upregulates DNMT3B expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting DNMT3B in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces …

Nlrp3 Inflammasome Activation Expands The Immunosuppressive Myeloid Stroma And Antagonizes The Therapeutic Benefit Of Sting Activation In Glioblastoma, Spencer T Lea, Chao-Hsien Chen, Jun Wei, Ivana William, Inés Lopez Del Castillo, Michael A Curran

Faculty, Staff and Student Publications

Glioblastoma (GBM) is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion have been observed in GBM, and NLRP3-driven myeloid-derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic double-stranded DNA-sensing stimulator of IFN gene (STING) pathway can mediate proinflammatory conversion of cancer MDSCs; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. In this study, we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects …

Egfr Controls Transcriptional And Metabolic Rewiring In Krasg12d Colorectal Cancer, Dana Krauß, Veronica Moreno-Viedma, Emi Adachi-Fernandez, Cristiano De Sá Fernandes, Jakob-Wendelin Genger, Ourania Fari, Bernadette Blauensteiner, Dominik Kirchhofer, Nikolina Bradaric, Valeriya Gushchina, Georgios Fotakis, Thomas Mohr, Ifat Abramovich, Inbal Mor, Martin Holcmann, Andreas Bergthaler, Arvand Haschemi, Zlatko Trajanoski, Juliane Winkler, Eyal Gottlieb, Maria Sibilia

Faculty, Staff and Student Publications

Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size …

Targeted Sting Activation Using Modified Ultrasound-Responsive Microbubbles Enhances Immune Checkpoint Blockade Against Melanoma, Sina Khorsandi, Kristin Huntoon, Yifan Wang, Adam Woodward, Abin Antony, Connor Endsley, Nazia Hafeez, Jared L Edwards, Nicole Mccuen, Prasanna G Alluri, Betty Y S Kim, Wen Jiang, Jacques Lux

Faculty, Staff and Student Publications

Despite the recent successes of immune checkpoint inhibitors (ICIs) in treating advanced melanoma, durable clinical responses still remain limited. To boost immune responses, agents that target immune regulators, such as the Stimulator of Interferon Genes (STING) agonist cyclic GMP-AMP (cGAMP), are being investigated. However, their clinical translation is impeded by poor serum stability, rapid tissue clearance, and T-cell death due to off-target activation. Recently, a novel strategy termed Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) has been reported to selectively deliver cGAMP directly into the cytosol of antigen-presenting cells with spatiotemporal control. The resulting activation of STING and downstream proinflammatory pathways …

Biomolecular Condensates In Immune Cell Fate, Srikanth Kodali, Caroline M Sands, Lei Guo, Yun Huang, Bruno Di Stefano

Faculty, Staff and Students Publications

Fate decisions during immune cell development require temporally precise changes in gene expression. Evidence suggests that the dynamic modulation of these changes is associated with the formation of diverse, membrane-less nucleoprotein assemblies that are termed biomolecular condensates. These condensates are thought to orchestrate fate-determining transcriptional and post-transcriptional processes by locally and transiently concentrating DNA or RNA molecules alongside their regulatory proteins. Findings have established a link between condensate formation and the gene regulatory networks that ensure the proper development of immune cells. Conversely, condensate dysregulation has been linked to impaired immune cell fates, including ageing and malignant transformation. This Review …

Vitamin K: Metabolism, Genetic Influences, And Chronic Disease Outcomes, Montana Dupuy, Nicola P. Bondonno, Pratik Pokharel, Allan Linneberg, Itamar Levinger, Carl Schultz, Jonathan M. Hodgson, Marc Sim

Research outputs 2022 to 2026

Vitamin K refers to a group of lipid-soluble vitamins that exist in two natural isoforms; phylloquinone (PK, vitamin K1) and menaquinones (MKs, vitamin K2). Phylloquinone, the primary dietary source, is found abundantly in green vegetables and plant oils. Menaquinones (MK-4 through MK-13) are synthesized by anaerobic bacteria and may be obtained through the diet from fermented foods and animal products (e.g., meats, dairy and eggs). Originally recognized for its role in blood coagulation, vitamin K is an essential cofactor for the posttranslational carboxylation of vitamin K-dependent proteins (VKDPs), which are implicated in various physiological processes including; blood coagulation, calcium homeostasis, …

Baseline Habitual Dietary Nitrate Intake And Alzheimer's Disease Related Neuroimaging Biomarkers In The Australian Imaging, Biomarkers And Lifestyle Study Of Ageing, Anjana Rajendra, Nicola P. Bondonno, Kevin Murray, Liezhou Zhong, Stephanie R. Rainey-Smith, Samantha L. Gardener, Lauren C. Blekkenhorst, Vincent Doré, Victor L. Villemagne, Simon M. Laws, Belinda M. Brown, Kevin Taddei, Colin L. Masters, Christopher C. Rowe, Ralph N. Martins, Jonathan M. Hodgson, Catherine P. Bondonno

Research outputs 2022 to 2026

Background: Dietary nitrate, as a nitric oxide (NO) precursor, may support brain health and protect against dementia. Objective: Our primary aim was to investigate whether dietary nitrate is associated with neuroimaging markers of brain health linked with Alzheimer's disease (AD). Participants: Study participants were cognitively unimpaired individuals from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) who had β-amyloid positron emission tomography (PET) scans (n = 554) and magnetic resonance imaging (MRI) scans (n = 335) and had completed a Food Frequency Questionnaire at baseline. Methods: Source-specific nitrate intakes were estimated using comprehensive nitrate food composition databases. Rates …