Digital Commons Network^™

Stat3 Inhibits Autocrine Ifn Signaling In Type I Conventional Dendritic Cells, Taylor T Chrisikos, Yifan Zhou, Laura M Kahn, Bhakti Patel, Nina L Denne, Athena Brooks, Li Shen, Jing Wang, Stephanie S Watowich

Faculty, Staff and Student Publications

Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli regulate cDC1 function remain unclear. We previously demonstrated that the cytokine-responsive transcriptional regulator STAT3 inhibits polyinosinic:polycytidylic acid [poly(I:C)]-induced cDC1 maturation and cDC1-mediated antitumor immunity in murine breast cancer, indicating an intrinsic, suppressive role for STAT3 in cDC1s. To probe transcriptional mechanisms regulating cDC1 function, we generated novel RNA sequencing datasets representing poly(I:C)-, IL-10-, and STAT3-mediated gene expression responses in murine cDC1s. Bioinformatics analyses …

Preconditioning By Voluntary Wheel Running Attenuates Later Neuropathic Pain Via Nuclear Factor E2-Related Factor 2 Antioxidant Signaling In Rats, Suzanne M Green-Fulgham, Michael E Harland, Jayson B Ball, Jiahe Li, Michael J Lacagnina, Heather D'Angelo, Renee A Dreher, Kendal F Willcox, Sabina A Lorca, Andrew J Kwilasz, Steven F Maier, Linda R Watkins, Peter M Grace

Faculty, Staff and Student Publications

Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases the formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury across both sexes. This attenuation was associated with reduced nitrotyrosine immunoreactivity-a marker for peroxynitrite-at the sciatic nerve injury site. Our data suggest …

A Hydrogen-Sulfide Derivative Of Mesalamine Reduces The Severity Of Intestinal And Lung Injury In Necrotizing Enterocolitis Through Endothelial Nitric Oxide Synthase, Brian D Hosfield, Chelsea E Hunter, Hongge Li, Natalie A Drucker, Anthony R Pecoraro, Krishna Manohar, W Christopher Shelley, Troy A Markel

Faculty, Staff and Student Publications

Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H2S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H2S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: 1) breastfed controls, 2) NEC, 3) NEC + 50 mg/kg mesalamine, and …

Role Of Sam68 In Sunitinib Induced Renal Cell Carcinoma Apoptosis, Zeshen Wu, Yulu Peng, Longbin Xiong, Jun Wang, Zhen Li, Kang Ning, Minhua Deng, Ning Wang, Wensu Wei, Zhiyong Li, Pei Dong, Chunping Yu, Fangjian Zhou, Zhiling Zhang

Faculty, Staff and Student Publications

Sunitinib is one of the first-line targeted drugs for metastatic renal cell carcinoma (RCC) with dual effects of antiangiogensis and proapoptosis. Sam68 (Src-associated in mitosis, 68 KDa), is found being involved in cell apoptosis. This article reveals that Sam68 impacts the sensitivity to sunitinib by mediating the apoptosis of RCC cells. Immunohistochemical staining indicated that the Sam68 expression levels in sunitinib sensitive tumor tissues were markedly higher than those in sunitinib resistant tumor tissues. Sunitinib induced RCC cell apoptosis in a concentration-dependent manner and inhibited the expression of total and phosphorylated Sam68 (p-Sam68). Downregulation of Sam68 expression inhibited RCC cell …

Selective Iga Deficiency In Spontaneously Hypertensive Rats With Gut Dysbiosis, Piu Saha, Blair Mell, Rachel M Golonka, Venugopal R Bovilla, Ahmed A Abokor, Xue Mei, Beng San Yeoh, Peter A Doris, Andrew T Gewirtz, Bina Joe, Matam Vijay-Kumar

Faculty, Staff and Student Publications

BACKGROUND: The spontaneously hypertensive rat (SHR) is extensively used to study hypertension. Gut microbiota dysbiosis is a notable feature in SHR for reasons unknown. Immunoglobulin A (IgA) is a major host factor required for gut microbiota homeostasis. We hypothesized that inadequate IgA contributes to gut microbiota dysbiosis in SHR.

METHODS: IgA was measured in feces, cecum, serum, liver, gut-associated lymphoid tissue, and milk from SHR and Wistar Kyoto rats. IgA regulatory factors like IgM, IgG, and

RESULTS: Compared with Wistar Kyoto rats, SHR displayed remarkably near-deficient IgA levels accompanied by compensatory increases in serum IgM and IgG and gut-liver

CONCLUSIONS: …

Ags And Nia Bench-To Bedside Conference Summary: Cancer And Cardiovascular Disease, Supriya Mohile, Caroline S Blaum, Peter M Abadir, William Dale, Daniel E Forman, Chunkit Fung, Holly M Holmes, Javid Moslehi, Karen M Mustian, Michael W Rich, Heather E Whitson

Faculty, Staff and Student Publications

This report summarizes the presentations, discussions, and recommendations of the most recent American Geriatrics Society and National Institute on Aging research conference, "Cancer and Cardiovascular Disease," on October 18-19, 2021. The purpose of this virtual meeting was to address the interface between cancer and heart disease, which are the two leading causes of death among older Americans. Age-related physiologic changes are implicated in the pathogenesis of both conditions. Emerging data suggest that cancer-related cardiovascular disease (CVD) involves disrupted cell signaling and cellular senescence. The risk factors for CVD are also risk factors for cancer and an increased likelihood of cancer …

Mesenchymal Stromal Cells For The Treatment Of Alzheimer’S Disease: Strategies And Limitations, Shobha Regmi, Daniel Dan Liu, Michelle Shen, Bhavesh D Kevadiya, Abantika Ganguly, Rosita Primavera, Shashank Chetty, Reza Yarani, Avnesh S Thakor

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a major cause of age-related dementia and is characterized by progressive brain damage that gradually destroys memory and the ability to learn, which ultimately leads to the decline of a patient's ability to perform daily activities. Although some of the pharmacological treatments of AD are available for symptomatic relief, they are not able to limit the progression of AD and have several side effects. Mesenchymal stem/stromal cells (MSCs) could be a potential therapeutic option for treating AD due to their immunomodulatory, anti-inflammatory, regenerative, antioxidant, anti-apoptotic, and neuroprotective effects. MSCs not only secret neuroprotective and anti-inflammatory factors …

Epigenetic Modifications And Their Potential Contribution To Traumatic Brain Injury Pathobiology And Outcome, Laura Zima, Rebecca West, Paul Smolen, Nobuhide Kobori, Georgene Hergenroeder, Huimahn A Choi, Anthony N Moore, John B Redell, Pramod K Dash

Faculty, Staff and Student Publications

Epigenetic information is not permanently encoded in the DNA sequence, but rather consists of reversible, heritable modifications that regulate the gene expression profile of a cell. Epigenetic modifications can result in cellular changes that can be long lasting and include DNA methylation, histone methylation, histone acetylation, and RNA methylation. As epigenetic modifications are reversible, the enzymes that add (epigenetic writers), the proteins that decode (epigenetic readers), and the enzymes that remove (epigenetic erasers) these modifications can be targeted to alter cellular function and disease biology. While epigenetic modifications and their contributions are intense topics of current research in the context …

Heterozygous Variants In Myh10 Associated With Neurodevelopmental Disorders And Congenital Anomalies With Evidence For Primary Cilia-Dependent Defects In Hedgehog Signaling, Alexander M Holtz, Rachel Vancoillie, Elizabeth A Vansickle, Deanna Alexis Carere, Kara Withrow, Erin Torti, Jane Juusola, Francisca Millan, Richard Person, Maria J Guillen Sacoto, Yue Si, Ingrid M Wentzensen, Jada Pugh, Georgia Vasileiou, Melissa Rieger, André Reis, Emanuela Argilli, Elliott H Sherr, Kimberly A Aldinger, William B Dobyns, Theresa Brunet, Julia Hoefele, Matias Wagner, Benjamin Haber, Urania Kotzaeridou, Boris Keren, Delphine Heron, Cyril Mignot, Solveig Heide, Thomas Courtin, Julien Buratti, Serini Murugasen, Kirsten A Donald, Emily O'Heir, Shade Moody, Katherine H Kim, Barbara K Burton, Grace Yoon, Miguel Del Campo, Diane Masser-Frye, Mariya Kozenko, Christina Parkinson, Susan L Sell, Patricia L Gordon, Jeremy W Prokop, Amel Karaa, Caleb Bupp, Benjamin A Raby

Faculty, Staff and Student Publications

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.

METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.

RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a …

A Potent Antibiotic-Loaded Bone-Cement Implant Against Staphylococcal Bone Infections, Sumana Ghosh, Mau Sinha, Ritwik Samanta, Suresh Sadhasivam, Anamika Bhattacharyya, Ashis Nandy, Swamini Saini, Nupur Tandon, Himanshi Singh, Swati Gupta, Anjali Chauhan, Keerthi Kumar Aavula, Sneha Susan Varghese, Pujie Shi, Sudip Ghosh, Mukesh Kumar Garg, Tanmoy Saha, Aparna Padhye, Shamik Ghosh, Hae Lin Jang, Shiladitya Sengupta

Faculty, Staff and Student Publications

New antibiotics should ideally exhibit activity against drug-resistant bacteria, delay the development of bacterial resistance to them and be suitable for local delivery at desired sites of infection. Here, we report the rational design, via molecular-docking simulations, of a library of 17 candidate antibiotics against bone infection by wild-type and mutated bacterial targets. We screened this library for activity against multidrug-resistant clinical isolates and identified an antibiotic that exhibits potent activity against resistant strains and the formation of biofilms, decreases the chances of bacterial resistance and is compatible with local delivery via a bone-cement matrix. The antibiotic-loaded bone cement exhibited …

Age Cutoff For Early‐Onset Parkinson's Disease:Recommendations From The International Parkinson And Movement Disorder Society Task Force On Early Onset Parkinson's Disease, Raja Mehanna, Katarzyna Smilowska, Jori Fleisher, Bart Post, Taku Hatano, Maria Elisa Pimentel Piemonte, Kishore Raj Kumar, Victor Mcconvey, Baorong Zhang, Eng-King Tan, Rodolfo Savica, International Parkinson And Movement Disorder Society Task Force On Early Onset Parkinson's Disease

Faculty, Staff and Student Publications

BACKGROUND: Early-onset Parkinson's disease (EOPD)/young-onset Parkinson's disease (YOPD) is defined as Parkinson's disease (PD) with an age at onset (AAO) after age 21 years but before the usual AAO for PD. Consensus is lacking, and the reported maximal age for EOPD/YOPD has varied from 40 to 60 years, leading to a lack of uniformity in published studies and difficulty in harmonization of data. EOPD and YOPD have both been used in the literature, somewhat interchangeably.

OBJECTIVE: To define the nomenclature and AAO cutoff for EOPD/YOPD.

METHODS: An extensive review of the literature and task force meetings were conducted. Conclusions were …

Mismatch Repair And Microsatellite Instability Testing For Immune Checkpoint Inhibitor Therapy: Guideline From The College Of American Pathologists In Collaboration With The Association For Molecular Pathology And Fight Colorectal Cancer, Angela N Bartley, Anne M Mills, Eric Konnick, Michael Overman, Christina B Ventura, Lesley Souter, Carol Colasacco, Zsofia K Stadler, Sarah Kerr, Brooke E Howitt, Heather Hampel, Sarah F Adams, Wenora Johnson, Cristina Magi-Galluzzi, Antonia R Sepulveda, Russell R Broaddus

Faculty, Staff and Student Publications

Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.

Objective.—: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.

Design.—: The College of American Pathologists convened an expert panel to perform a systematic review …

Experiential Learning In Patient Safety: A Multi-Center Study Examining Emergency Medicine Residents' Situational Awareness Of Hazards Via Simulation, Kamna S Balhara, Nathan Olson, Jessica L Wilson, Rosemarie G Ramos, Harlan J Goode, Andrew E Muck, Adriana S Olson

Faculty, Staff and Student Publications

Introduction The 2016 Clinical Learning Environment Review established that experiential patient safety curricula for residents are uncommon. Moreover, these curricula do not incorporate non-technical skills linked to safety, such as situational awareness (SA). We developed an in-situ patient safety simulation exercise incorporating core SA concepts and subsequently assessed exercise feasibility and acceptability, and measured residents' safety SA. Methods A simulation scenario and mock chart were designed, incorporating 16 patient safety hazards. Residents at two institutions reviewed the chart and had 10 minutes in an emergency department room with the simulated scenario to document identified hazards, followed by a facilitated debriefing. …

Cardio-Onco-Metabolism – Metabolic Vulnerabilities In Cancer And The Heart, Anja Karlstaedt, Heinrich Taegtmeyer

Faculty, Staff and Student Publications

Cancer and cardiovascular diseases (CVDs) are the leading cause of death worldwide. Metabolic remodeling is a hallmark of both cancer and the failing heart. Tumors reprogram metabolism to optimize nutrient utilization and meet increased demands for energy provision, biosynthetic pathways, and proliferation. Shared risk factors for cancer and CVDs suggest intersecting mechanisms for disease pathogenesis and progression. In this review, we aim to highlight the role of metabolic remodeling in cancer and its potential to impair cardiac function. Understanding these mechanisms will help us develop biomarkers, better therapies, and identify patients at risk of developing heart disease after surviving cancer.

First-In-Human Phase 1/1b Study To Evaluate Sitravatinib In Patients With Advanced Solid Tumors, Todd Bauer, Byong Chul Cho, Rebecca Heist, Lyudmila Bazhenova, Theresa Werner, Sanjay Goel, Dong-Wan Kim, Douglas Adkins, Richard D Carvajal, Ajjai Alva, Keith Eaton, Judy Wang, Yong Liu, Xiaohong Yan, Jamie Christensen, Saskia Neuteboom, Richard Chao, Shubham Pant

Faculty, Staff and Student Publications

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10-200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = …

Spatiotemporal Microrna-Gene Expression Network Related To Orofacial Clefts, F Yan, L M Simon, A Suzuki, C Iwaya, P Jia, J Iwata, Z Zhao

Faculty, Staff and Student Publications

Craniofacial structures change dynamically in morphology during development through the coordinated regulation of various cellular molecules. However, it remains unclear how these complex mechanisms are regulated in a spatiotemporal manner. Here we applied natural cubic splines to model gene and microRNA (miRNA) expression from embryonic day (E) 10.5 to E14.5 in the proximal and distal regions of the maxillary processes to identify spatiotemporal patterns of gene and miRNA expression, followed by constructing corresponding regulatory networks. Three major groups of differentially expressed genes (DEGs) were identified, including 3,927 temporal, 314 spatial, and 494 spatiotemporal DEGs. Unsupervised clustering further resolved these spatiotemporal …

Sex Differences In Clinical Outcomes And Biological Profiles In Systemic Sclerosis-Associated Interstitial Lung Disease: A Post-Hoc Analysis Of Two Randomised Controlled Trials, Elizabeth R Volkmann, Donald P Tashkin, Richard Silver, Carol Feghali Bostwick, Shervin Assassi, Deanna Baker Frost, Mei Leng, Holly Wilhalme, Grace Hyun Kim, Jonathan Goldin, Michael D Roth

Faculty, Staff and Student Publications

BACKGROUND: Observational studies have shown that men with systemic sclerosis have an increased risk of interstitial lung disease (ILD) and mortality compared with women. However, previous studies have not controlled for treatment effect or evaluated the biological mechanism or mechanisms underlying this sex difference. We aimed to compare ILD progression and long-term morbidity and mortality outcomes in male and female participants of two randomised controlled trials for systemic sclerosis-associated ILD.

METHODS: For this post-hoc analysis, data from all participants in the Scleroderma Lung Study (SLS) I and SLS II were analysed. The primary objective was to explore the effect of …

Nerve Density And Neuronal Biomarkers In Cancer, Shahrukh R Ali, Madeleine Jordan, Priyadharsini Nagarajan, Moran Amit

Faculty, Staff and Student Publications

Certain histologic characteristics of neurons, novel neuronal biomarkers, and nerve density are emerging as important diagnostic and prognostic tools in several cancers. The tumor microenvironment has long been known to promote tumor development via promoting angiogenesis and cellular proliferation, but new evidence has shown that neural proliferation and invasion in the tumor microenvironment may also enable tumor growth. Specific neuronal components in peripheral nerves and their localization in certain tumor sites have been identified and associated with tumor aggressiveness. In addition, dense neural innervation has been shown to promote tumorigenesis. In this review, we will summarize the histological components of …

Targeting The Alk-Cdk9-Tyr19 Kinase Cascade Sensitizes Ovarian And Breast Tumors To Parp Inhibition Via Destabilization Of The P-Tefb Complex, Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N Westin, Sanghoon Lee, Anil K Sood, Liuqing Yang, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor …

Semi-Parametric Bayes Regression With Network-Valued Covariates, Xin Ma, Suprateek Kundu, Jennifer Stevens

Faculty, Staff and Student Publications

Although there has been an explosive rise in network data in a variety of disciplines, there is very limited development of regression modeling approaches based on high-dimensional networks. The scarce literature in this area typically assume linear relationships between the outcome and the high-dimensional network edges that results in an inflated model plagued by the curse of dimensionality and these models are unable to accommodate non-linear relationships or higher order interactions. In order to overcome these limitations, we develop a novel two-stage Bayesian non-parametric regression modeling framework using high-dimensional networks as covariates, which first finds a lower dimensional node-specific representation …

In Vivo Evaluation Of A New Hybrid Graft Using Retrograde Visceral Perfusion For Thoracoabdominal Aortic Repair In An Animal Model, Sabine Wipper, Harleen K Sandhu, Tilo Kölbel, Anthony L Estrera, Constantin Trepte, Christoph Behem, Charles C Miller, E Sebastian Debus

Faculty, Staff and Student Publications

OBJECTIVES: The SPIDER technique for hybrid thoracoabdominal aortic aneurysm repair can avoid thoracotomy and extracorporeal circulation. To improve technical feasibility and safety, the new Thoracoflo graft, consisting of a proximal stent graft connected to a 7-branched abdominal prosthesis, was evaluated in a pig model for technical feasibility testing, before implantation in humans.

METHODS: Retroperitoneal exposure of the infradiaphragmatic aorta, including visceral and renal arteries, was performed in 7 pigs (75-85 kg). One iliac branch was temporarily attached to the distal aorta to maintain retrograde visceral and antegrade iliac perfusion after deployment of the thoracic stent graft segment (SPIDER technique). The …

Discovery Of An Orally Active Benzoxaborole Prodrug Effective In The Treatment Of Chagas Disease In Non-Human Primates, Angel M Padilla, Wei Wang, Tsutomu Akama, David S Carter, Eric Easom, Yvonne Freund, Jason S Halladay, Yang Liu, Sarah A Hamer, Carolyn L Hodo, Gregory K Wilkerson, Dylan Orr, Brooke White, Arlene George, Huifeng Shen, Yiru Jin, Michael Zhuo Wang, Susanna Tse, Robert T Jacobs, Rick L Tarleton

Faculty, Staff and Student Publications

Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA …

Revisiting The Multisite Phosphorylation That Produces The M-Phase Supershift Of Key Mitotic Regulators, Tan Tan, Chuanfen Wu, Boye Liu, Bih-Fang Pan, David H Hawke, Zehao Su, Shuaishuai Liu, Wei Zhang, Ruoning Wang, Sue-Hwa Lin, Jian Kuang

Faculty, Staff and Student Publications

The term M-phase supershift denotes the phosphorylation-dependent substantial increase in the apparent molecular weight of numerous proteins of varied biological functions during M-phase induction. Although the M-phase supershift of multiple key mitotic regulators has been attributed to the multisite phosphorylation catalyzed by the Cdk1/cyclin B/Cks complex, this view is challenged by multiple lines of paradoxical observations. To solve this problem, we reconstituted the M-phase supershift of Xenopus Cdc25C, Myt1, Wee1A, APC3, and Greatwall in Xenopus egg extracts and characterized the supershift-producing phosphorylations. Our results demonstrate that their M-phase supershifts are each due to simultaneous phosphorylation of a considerable portion of …

223ra Induces Transient Functional Bone Marrow Toxicity, Maria Parlani, Francesco Boccalatte, Anna Yeaton, Feng Wang, Jianhua Zhang, Iannis Aifantis, Eleonora Dondossola

Faculty, Staff and Student Publications

223Ra is a bone-seeking, α-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of 223Ra hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. Methods: In this study, we investigated the consequences of 223Ra treatment on bone marrow biology by combining flow cytometry, single-cell RNA sequencing, three-dimensional multiphoton microscopy and bone marrow transplantation analyses. Results: 223Ra accumulated in bones and induced zonal radiation damage confined to …

Artificial Intelligence For Radiation Oncology Applications Using Public Datasets, Kareem A Wahid, Enrico Glerean, Jaakko Sahlsten, Joel Jaskari, Kimmo Kaski, Mohamed A Naser, Renjie He, Abdallah S R Mohamed, Clifton D Fuller

Faculty, Staff and Student Publications

Artificial intelligence (AI) has exceptional potential to positively impact the field of radiation oncology. However, large curated datasets - often involving imaging data and corresponding annotations - are required to develop radiation oncology AI models. Importantly, the recent establishment of Findable, Accessible, Interoperable, Reusable (FAIR) principles for scientific data management have enabled an increasing number of radiation oncology related datasets to be disseminated through data repositories, thereby acting as a rich source of data for AI model building. This manuscript reviews the current and future state of radiation oncology data dissemination, with a particular emphasis on published imaging datasets, AI …

Loss Of Lamp5 Interneurons Drives Neuronal Network Dysfunction In Alzheimer’S Disease, Yuanyuan Deng, Mian Bi, Fabien Delerue, Shelley L Forrest, Gabriella Chan, Julia Van Der Hoven, Annika Van Hummel, Astrid F Feiten, Seojin Lee, Ivan Martinez-Valbuena, Tim Karl, Gabor G Kovacs, Grant Morahan, Yazi D Ke, Lars M Ittner

Faculty, Staff and Student Publications

In Alzheimer's disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. …

Targeting Hemoglobin To Reduce Delayed Cerebral Ischemia After Subarachnoid Hemorrhage, Hussein A Zeineddine, Pedram Honarpisheh, Devin Mcbride, Peeyush Kumar Thankamani Pandit, Ari Dienel, Sung-Ha Hong, James Grotta, Spiros Blackburn

Faculty, Staff and Student Publications

Delayed cerebral ischemia (DCI) continues to be a sequela of aneurysmal subarachnoid hemorrhage (aSAH) that carries significant morbidity and mortality. Aside from nimodipine, no therapeutic agents are available to reduce the incidence of DCI. Pathophysiologic mechanisms contributing to DCI are poorly understood, but accumulating evidence over the years implicates several factors. Those have included microvessel vasoconstriction, microthrombosis, oxidative tissue damage, and cortical spreading depolarization as well as large vessel vasospasm. Common to these processes is red blood cell leakage into the cerebrospinal fluids (CSF) and subsequent lysis which releases hemoglobin, a central instigator in these events. This has led to …

Preventive And Therapeutic Reduction Of Amyloid Deposition And Behavioral Impairments In A Model Of Alzheimer’S Disease By Whole Blood Exchange, Akihiko Urayama, Ines Moreno-Gonzalez, Diego Morales-Scheihing, Vineetkumar Kharat, Sandra Pritzkow, Claudio Soto

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD. In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) …

Monkeypox: What Do Dental Professionals Need To Know?, Charifa Zemouri, Edgar O Beltrán, Richard Holliday, Nicholas S Jakubovics, James R Allison

Faculty, Staff and Student Publications

Infection control is critical for the safe delivery of dental care. Infection control practices must be responsive to emerging and re-emerging infectious diseases and outbreaks, as was clearly seen during the peak of the COVID-19 pandemic. An emerging global outbreak of the monkeypox virus has again raised potential challenges for infection control in dentistry. Monkeypox is an infectious disease, characterised by a rash affecting the skin and soft tissues, including the oral cavity. Previously, cases were mostly seen following contact with infected animals in Central and West Africa, with limited human-to-human transmission within and outside of these areas. However, since …

Association Of Renin Angiotensin Aldosterone System Inhibitors And Outcomes Of Hospitalized Patients With Covid-19, Neha Gupta, Lisa Settle, Brent R Brown, Donna L Armaignac, Michael Baram, Nicholas E Perkins, Margit Kaufman, Roman R Melamed, Amy B Christie, Valerie C Danesh, Joshua L Denson, Sreekanth R Cheruku, Karen Boman, Vikas Bansal, Vishakha K Kumar, Allan J Walkey, Juan P Domecq, Rahul Kashyap, Christopher E Aston

Faculty, Staff and Student Publications

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19.

DESIGN: Retrospective observational study.

SETTING: Multicenter, international COVID-19 registry.

SUBJECTS: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during …