Medicine and Health Sciences Commons^™

Identification Of Potent Pan-Ephrin Receptor Kinase Inhibitors Using Dna-Encoded Chemistry Technology, Chandrashekhar Madasu, Zian Liao, Sydney E Parks, Kiran L Sharma, Kurt M Bohren, Qiuji Ye, Feng Li, Murugesan Palaniappan, Zhi Tan, Fei Yuan, Chad J Creighton, Suni Tang, Ramya P Masand, Xiaoming Guan, Damian W Young, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

EPH receptors (EPHs) are highly sought-after drug targets owing to their essential roles in maintaining appropriate cellular functions in both physiological and disease conditions. However, limited potency and specificity pose significant obstacles to the development of small-molecule inhibitors for EPHs. Here, using high-throughput DNA-encoded chemical library screenings, we developed potent and selective inhibitors of the EPH receptor kinase family. Our results also emphasize the therapeutic potential of our EPH inhibitors in cancer and endometriosis, a global health concern that causes chronic pain and often leads to infertility in women. This study showcases the robust pipeline of using DNA-encoded chemistry technology …

Progress Toward A Vaccine For Extraintestinal Pathogenic Coli (Expec) Ii: Efficacy Of A Toxin-Autotransporter Dual Antigen Approach, Yikun Xing, Justin R Clark, James D Chang, Jacob J Zulk, Dylan M Chirman, Felipe-Andres Piedra, Ellen E Vaughan, Haroldo J Hernandez Santos, Kathryn A Patras, Anthony W Maresso

Faculty, Staff and Students Publications

Extraintestinal pathogenic Escherichia coli (ExPEC) is a leading cause of worldwide morbidity and mortality, the top cause of antimicrobial-resistant (AMR) infections, and the most frequent cause of life-threatening sepsis and urinary tract infections (UTI) in adults. The development of an effective and universal vaccine is complicated by this pathogen’s pan-genome, its ability to mix and match virulence factors and AMR genes via horizontal gene transfer, an inability to decipher commensal from pathogens, and its intimate association and co-evolution with mammals. Using a pan virulome analysis of >20,000 sequenced E. coli strains, we identified the secreted cytolysin α-hemolysin (HlyA) as a …

05.06.2024 Orsp Connect, Liz Williamson

ORED Newsletter

Library Faculty Win NIH Award, Uniform Guidance Updates,

Data Normalization For Addressing The Challenges In The Analysis Of Single-Cell Transcriptomic Datasets, Raquel Cuevas-Diaz Duran, Haichao Wei, Jiaqian Wu

Faculty, Staff and Student Publications

BACKGROUND: Normalization is a critical step in the analysis of single-cell RNA-sequencing (scRNA-seq) datasets. Its main goal is to make gene counts comparable within and between cells. To do so, normalization methods must account for technical and biological variability. Numerous normalization methods have been developed addressing different sources of dispersion and making specific assumptions about the count data.

MAIN BODY: The selection of a normalization method has a direct impact on downstream analysis, for example differential gene expression and cluster identification. Thus, the objective of this review is to guide the reader in making an informed decision on the most …

Hormonal Basis Of Brain Fog In Cancer Treatment, Yuan Pan, Jian Hu

Faculty, Staff and Student Publications

The cognitive side effects of cancer treatment are common, but no targeted therapy exists yet to treat or prevent such neurological sequelae. We explore the role of hormones as mediators between cancer therapy and cognitive impairment, discussing potential future directions.

Serine Deamination By Human Serine Racemase Synergizes With Antibiotics To Curtail The Replication Of Chlamydia Trachomatis, Patricia D. Mott, Arnold H. Zea, Jamiya Lewis, Oygul Mirzalieva, Ashok A. Aiyar

School of Medicine Faculty Publications

The obligate intracellular bacterium, Chlamydia trachomatis, has evolved to depend on its human host for many metabolites, including most amino acids and three of the four nucleotides. Given this, it is not surprising that depletion of a single amino acid in the host cell growth medium blocks chlamydial replication. Paradoxically, supra-normal levels of some amino acids also block productive replication of Chlamydia. Here, we have determined how elevated serine levels, generated by exogenous supplementation, impede chlamydial inclusion development and reduce the generation of infectious progeny. Our findings reveal that human serine racemase, which is broadly expressed in multiple tissues, potentiates …

Metaplastic Regeneration In The Mouse Stomach Requires A Reactive Oxygen Species Pathway, Zhi-Feng Miao, Jing-Xu Sun, Xuan-Zhang Huang, Shi Bai, Min-Jiao Pang, Jia-Yi Li, Han-Yu Chen, Qi-Yue Tong, Shi-Yu Ye, Xin-Yu Wang, Xiao-Hai Hu, Jing-Ying Li, Jin-Wei Zou, Wen Xu, Jun-Hao Yang, Xi Lu, Jason C Mills, Zhen-Ning Wang

Faculty, Staff and Students Publications

In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which …

The Physiological Significance Of Nitric Oxide Synthase In Staphylococci, Ryan M. Singh

Theses & Dissertations

Staphylococci, particularly Staphylococcus epidermidis, are common causes of implant-associated infections that may result in notable morbidity and mortality. One of the ways the innate immune system attempts to combat these invading pathogens is via the respiratory burst, in which free radical species such as nitric oxide (NO^•), toxic to bacterial respiration, are released in large quantities. Despite the toxicity of NO^•, some bacteria, including staphylococci, encode an endogenous bacterial nitric oxide synthase (bNOS), whose physiological role has been unclear until now. In this dissertation, we demonstrate that S. epidermidis is able to overcome the toxicity …

Development Of Long-Acting Antiviral And Antimicrobial Prodrug Nanoformulations, Srijanee Das

Theses & Dissertations

Over the past decade, the global burden of infectious diseases has increased substantively, underscoring the need for more effective treatment strategies. However, the discovery and development of new drugs with desirable safety, pharmacokinetics, and efficacy is a time consuming and costly process with great uncertainty around success rate. As an alternative to new drug development, prodrugs and novel drug delivery systems have increasingly been explored. Both serve to overcome the drug development challenges. Such drug formulations that permit extended dosing intervals of potent native drugs serve multiple purposes by promoting patient adherence to in improving treatment outcomes. This is especially …

Sensory Dysfunction And The Role Of Nrf2 In The Production Of Pain In Chronic Hindlimb Ischemia, Oliver Kitzerow

Theses & Dissertations

Peripheral arterial disease (PAD) is a progressive and debilitating atherothrombotic disorder that is estimated to impact >200 million people worldwide. Higher physical activity levels are associated with better overall survival rates, slower decline of functional capability, and improved quality of life. However, intermittent claudication, pain produced by physical activity, severely limits functional capacity in PAD patients. Despite known sensory dysfunction and documented neuropathy in diseased patients, the neural mechanisms that produce pain in PAD are yet to be identified. Importantly, few animal models of hindlimb ischemia (HLI) successfully recapitulate chronic human PAD. We developed a chronic animal model of HLI …

Cis-Regulatory Mechanisms Through Stages Of Erythroid Regenration, Yichao Zhou

Theses & Dissertations

Produced by steady state erythropoiesis, erythrocytes serve as vital regulators of metabolism and life by delivering oxygen to all the cells and tissues. Under acute anemia, steady state erythropoiesis is not sufficient to produce enough erythrocytes, leading to distinct mechanisms needed to regenerate large numbers of mature erythrocytes rapidly. Erythroid regeneration occurs in four stages: activation, expansion and differentiation, resolution, and post-resolution, according to the dynamics of erythrocyte numbers and progenitor activity. Erythroid regeneration throughout this timeline requires some critical extracellular cues, but the intrinsic molecular mechanisms needed to accelerate and decelerate the activity of erythroid progenitors in anemia and …

The Effect Of Repetitive Transcranial Magnetic Stimulation On Brain And Cognitive Variables In Patients With Amnestic Mild Cognitive Impairment, Connor J. Phipps

Theses & Dissertations

Healthy and pathological aging processes can impact human memory. Current interventions for clinical memory impairment offer little opportunity for restoration of memory ability. Fortunately, a novel therapy in the form of repetitive transcranial magnetic stimulation (rTMS) has exhibited promise in this regard. In healthy adults, rTMS of the angular gyrus (AG) has been reported to improve memory. The current study sought to determine the generalizability of these findings to individuals with clinical memory impairment by administering a clinical trial replicating an rTMS protocol reported to improve hippocampal-dependent memory in healthy individuals to individuals with amnestic mild cognitive impairment (aMCI). Individuals …

Novel Spirocyclic Dimer (Spid3) Displays Potent Preclinical Effects In Hematological Malignancies, Alexandria Eiken

Theses & Dissertations

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by the accumulation of mature CD5⁺ B-cells in the peripheral blood, bone marrow, and secondary lymphoid tissues (e.g., spleen and lymph nodes).Despite the efficacy of front-line therapies, CLL is still an incurable disease, highlighting the need for development of novel therapeutics and further study of resistance mechanisms. Within the lymph node CLL tumor microenvironment (TME), there is an upregulation of gene signatures associated with B-cell receptor (BCR) and downstream nuclear factor kappa B (NF-κB) signaling compared to CLL cells found within the blood or bone marrow niches. Additionally, BCR signaling …

Therapeutic Effects Of Bet Protein Inhibition In B-Cell Malignancies And Beyond, Audrey L. Smith

Theses & Dissertations

Chronic lymphocytic leukemia (CLL) develops through a combination of intrinsic genetic defects, constitutively active survival/proliferation signaling pathways, and complex microenvironment interactions. Redundant tumor microenvironment (TME) immuno-suppressive mechanisms and epigenetic maintenance of terminal T-cell dysfunction also greatly hinder anti-tumor T-cell responses in CLL. Small-molecule agents targeting the B-cell receptor (BCR) pathway and anti-apoptotic proteins alone or in combination with chemo-immunotherapy have revolutionized the management of CLL, yet there is still a significant need for novel therapeutic strategies to yield durable tumor elimination. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetyl-lysine residues on histones to regulate gene …

Identifying The Molecular Determinants Of Lung Metastatic Adaptation In Prostate Cancer, Grace M. Waldron

Theses & Dissertations

Prostate cancer (PC) stands as the primary diagnosed cancer in men in the US at approximately 299,010 cases in 2024 and ranks second globally, posing a significant public health challenge. Clinical presentations vary widely, from indolent to aggressive forms, necessitating stage-specific treatment regimens. Understanding its metastatic nature is critical due to the impact of cancer cell dissemination on disease morbidity, with bone and visceral organs serving as key sites of metastasis. Despite bone metastasis being the most common site for metastasis, visceral metastases at sites such as the liver and lungs correlate with poorer survival, emphasizing the role of microenvironmental …

Heavy Metals In Afforested Mangrove Sediment From The World's Largest Delta: Distributional Mapping, Contamination Status, Risk Assessment And Source Tracing, Md Saifur Rahman, Moshiur Rahman, Yeasmin N Jolly, Md Kamal Hossain, Sanjida Afrin Semme, Bilal Ahamad Paray, Takaomi Arai, Jimmy Yu, M Belal Hossain

Faculty, Staff and Student Publications

This study aims to assess seasonal and spatial variations, contamination status, ecological risks, and metal sources (Ni, Pb, Cr, Cu, Mn, and Zn) in human-afforested mangrove sediments in a deltaic region. Five sampling locations were sampled during dry and wet seasons. Heavy metal concentrations followed the order: Mn > Zn > Ni > Cr > Cu > Pb. Metal loads, except Cu and Pb, were higher during the dry season, aligning with national and international recommendations. Sediment quality guidelines, contamination factor, geoaccumulation index, enrichment factors, and pollution load index indicated uncontaminated sediment in both seasons. Potential ecological risk assessment showed low risk conditions in all …

Pharmacodynamic Effects Of Zsj-0228 On Complement Protein Deposition In The Kidneys Of Focal Segmental Glomerulosclerosis-Afflicted Mice., Braeden Pinkerton

Theses & Dissertations

Chronic inflammation, when left untreated, may result in significant morbidity and in severe cases, mortality. While glucocorticoids (GCs) are still being extensively used clinically as a class of very potent anti-inflammatory agents, they are also notorious for diverse adverse side effects. To mitigate these side effects, we have developed a polyethylene glycol (PEG)-based prodrug (ZSJ-0228) of dexamethasone (Dex). When tested on rodent models of Lupus Nephritis and Focal Segmental Glomerulosclerosis (FSGS), ZSJ-0228 was found to provide potent and sustained therapeutic efficacy without any detectable typical GC-associated side effects. Given ZSJ-0228’s transient renal exposure after systemic administration, it is yet to …

Assessment Of In-Vitro And In-Vivo Pre-Clinical Pharmacokinetics Of Epz015666; A Novel Small Molecule For Medulloblastoma Treatment, Pratiksha U. Kshirsagar

Theses & Dissertations

Group 3 medulloblastoma (MB) has the worst prognosis of the MB subgroups associated with elevated MYC expression and a 5-year survival rate of

Quantitation of EPZ was performed on a Shimadzu LC-MS/MS system utilizing electrospray ionization operated in positive mode. The validated assay was linear from 0.2 to 500 ng/mL. Metabolic stability studies demonstrated slow intrinsic clearance of EPZ in mouse and human liver microsomes, suggesting no CYP-mediated metabolism. Additionally, EPZ exhibited low binding affinity to plasma and brain proteins and high apparent permeability across artificial membranes, indicating efficient membrane penetration. Drug transporter studies identified EPZ as a substrate of …

Genetic Variants For Head Size Share Genes And Pathways With Cancer, Maria J Knol, Raymond A Poot, Tavia E Evans, Claudia L Satizabal, Aniket Mishra, Muralidharan Sargurupremraj, Sandra Van Der Auwera, Marie-Gabrielle Duperron, Xueqiu Jian, Isabel C Hostettler, Dianne H K Van Dam-Nolen, Sander Lamballais, Mikolaj A Pawlak, Cora E Lewis, Amaia Carrion-Castillo, Theo G M Van Erp, Céline S Reinbold, Jean Shin, Markus Scholz, Asta K Håberg, Anders Kämpe, Gloria H Y Li, Reut Avinun, Joshua R Atkins, Fang-Chi Hsu, Alyssa R Amod, Max Lam, Ami Tsuchida, Mariël W A Teunissen, Nil Aygün, Yash Patel, Dan Liang, Alexa S Beiser, Frauke Beyer, Joshua C Bis, Daniel Bos, R Nick Bryan, Robin Bülow, Svenja Caspers, Gwenaëlle Catheline, Charlotte A M Cecil, Shareefa Dalvie, Jean-François Dartigues, Charles Decarli, Maria Enlund-Cerullo, Judith M Ford, Barbara Franke, Barry I Freedman, Nele Friedrich, Melissa J Green, Simon Haworth, Catherine Helmer, Per Hoffmann, Georg Homuth, M Kamran Ikram, Clifford R Jack, Neda Jahanshad, Christiane Jockwitz, Yoichiro Kamatani, Annchen R Knodt, Shuo Li, Keane Lim, W T Longstreth, Fabio Macciardi, Outi Mäkitie, Bernard Mazoyer, Sarah E Medland, Susumu Miyamoto, Susanne Moebus, Thomas H Mosley, Ryan Muetzel, Thomas W Mühleisen, Manabu Nagata, Soichiro Nakahara, Nicholette D Palmer, Zdenka Pausova, Adrian Preda, Yann Quidé, William R Reay, Gennady V Roshchupkin, Reinhold Schmidt, Pamela J Schreiner, Kazuya Setoh, Chin Yang Shapland, Stephen Sidney, Beate St Pourcain, Jason L Stein, Yasuharu Tabara, Alexander Teumer, Anne Uhlmann, Aad Van Der Lugt, Meike W Vernooij, David J Werring, B Gwen Windham, A Veronica Witte, Katharina Wittfeld, Qiong Yang, Kazumichi Yoshida, Han G Brunner, Quentin Le Grand, Kang Sim, Dan J Stein, Donald W Bowden, Murray J Cairns, Ahmad R Hariri, Ching-Lung Cheung, Sture Andersson, Arno Villringer, Tomas Paus, Sven Cichon, Vince D Calhoun, Fabrice Crivello, Lenore J Launer, Tonya White, Peter J Koudstaal, Henry Houlden, Myriam Fornage, Fumihiko Matsuda, Hans J Grabe, M Arfan Ikram, Stéphanie Debette, Paul M Thompson, Sudha Seshadri, Hieab H H Adams

Faculty, Staff and Student Publications

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size …

Focal Adhesion Kinase-Yap Signaling Axis Drives Drug-Tolerant Persister Cells And Residual Disease In Lung Cancer, Franziska Haderk, Yu-Ting Chou, Lauren Cech, Celia Fernández-Méndez, Johnny Yu, Victor Olivas, Ismail M Meraz, Dora Barbosa Rabago, D Lucas Kerr, Carlos Gomez, David V Allegakoen, Juan Guan, Khyati N Shah, Kari A Herrington, Oghenekevwe M Gbenedio, Shigeki Nanjo, Mourad Majidi, Whitney Tamaki, Yashar K Pourmoghadam, Julia K Rotow, Caroline E Mccoach, Jonathan W Riess, J Silvio Gutkind, Tracy T Tang, Leonard Post, Bo Huang, Pilar Santisteban, Hani Goodarzi, Sourav Bandyopadhyay, Calvin J Kuo, Jeroen P Roose, Wei Wu, Collin M Blakely, Jack A Roth, Trever G Bivona

Faculty, Staff and Student Publications

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling …

Treatment Outcomes In Patients With Metastatic Renal Cell Carcinoma With Sarcomatoid And/Or Rhabdoid Dedifferentiation After Progression On Immune Checkpoint Therapy, Andrew W Hahn, Devaki Shilpa Surasi, Paul V Viscuse, Tharakeswara K Bathala, Andrew J Wiele, Matthew T Campbell, Amado J Zurita, Amishi Y Shah, Eric Jonasch, Jianjun Gao, Sangeeta Goswami, Omar Alhalabi, Priya Rao, Kanishka Sircar, Nizar M Tannir, Pavlos Msaouel

Faculty, Staff and Student Publications

BACKGROUND: Metastatic RCC with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is an aggressive disease associated with improved response to immune checkpoint therapy (ICT). The outcomes of patients treated with VEGFR-targeted therapies (TT) following ICT progression have not been investigated.

PATIENTS AND METHODS: Retrospective review of 57 patients with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (S + R) dedifferentiation who received any TT after progression on ICT at an academic cancer center. Clinical endpoints of interest included time on TT, overall survival (OS) from initiation of TT, and objective response rate (ORR) by RECIST version 1.1. Multivariable models adjusted for …

Triggering Receptor Expressed On Myeloid Cells 2 (Trem2) Regulates Phagocytosis In Glioblastoma, Mekenzie M Peshoff, Pravesh Gupta, Shivangi Oberai, Rakesh Trivedi, Hiroshi Katayama, Prashanth Chakrapani, Minghao Dang, Simona Migliozzi, Joy Gumin, Divya B Kadri, Jessica K Lin, Nancy K Milam, Mark E Maynard, Brian D Vaillant, Brittany Parker-Kerrigan, Frederick F Lang, Jason T Huse, Antonio Iavarone, Linghua Wang, Karen Clise-Dwyer, Krishna P Bhat

Faculty, Staff and Student Publications

Background: Glioblastomas (GBMs) are central nervous system tumors that resist standard-of-care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable antitumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation.

Methods: Our reverse translational investigations leveraged single-cell RNA sequencing and cytometry of human gliomas to characterize TREM2 expression across …

Evaluating The Heterogeneity Of Hippocampal Avoidant Whole Brain Radiotherapy Treatment Effect: A Secondary Analysis Of Nrg Cc001, Hua-Ren R Cherng, Kai Sun, Søren Bentzen, Terri S Armstrong, Vinai Gondi, Paul D Brown, Minesh Mehta, Mark V Mishra

Faculty, Staff and Student Publications

Background: Hippocampal avoidant whole brain radiotherapy (HA-WBRT) is the standard of care for patients needing WBRT for brain metastases. This study, using existing data from NRG Oncology CC001 including baseline tumor characteristics and patient-reported MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) scores, sought to identify subgroups of patients that demonstrate differential neuroprotective treatment response to HA-WBRT.

Methods: An exploratory analysis of NRG CC001, a phase 3 trial in which 518 patients were randomly assigned to WBRT plus memantine or HA-WBRT plus memantine, was performed. Rates of neurocognitive function failure (NCFF) were estimated between subgroups and stratified by arm. Covariate and subgroup …

A Comprehensive Approach To Evaluate Genetic Abnormalities In Multiple Myeloma Using Optical Genome Mapping, Ying S Zou, Melanie Klausner, Jen Ghabrial, Victoria Stinnett, Patty Long, Laura Morsberger, Jaclyn B Murry, Katie Beierl, Christopher D Gocke, Rena R Xian, Kevin H Toomer, Jing Christine Ye, Robert Z Orlowski, Carol Ann Huff, Syed Abbas Ali, Philip H Imus, Christian B Gocke, Guilin Tang

Faculty, Staff and Student Publications

No abstract provided.

Gain-Of-Function And Loss-Of-Function Variants In Gria3 Lead To Distinct Neurodevelopmental Phenotypes, Berardo Rinaldi, Allan Bayat, Linda G Zachariassen, Jia-Hui Sun, Yu-Han Ge, Dan Zhao, Kristine Bonde, Laura H Madsen, Ilham Abdimunim Ali Awad, Duygu Bagiran, Amal Sbeih, Syeda Maidah Shah, Shaymaa El-Sayed, Signe M Lyngby, Miriam G Pedersen, Charlotte Stenum-Berg, Louise Claudia Walker, Ilona Krey, Andrée Delahaye-Duriez, Lisa T Emrick, Krystal Sully, Chaya N Murali, Lindsay C Burrage, Julie Ana Plaud Gonzalez, Mered Parnes, Jennifer Friedman, Bertrand Isidor, Jérémie Lefranc, Sylvia Redon, Delphine Heron, Cyril Mignot, Boris Keren, Mélanie Fradin, Christele Dubourg, Sandra Mercier, Thomas Besnard, Benjamin Cogne, Wallid Deb, Clotilde Rivier, Donatella Milani, Maria Francesca Bedeschi, Claudia Di Napoli, Federico Grilli, Paola Marchisio, Suzanna Koudijs, Danielle Veenma, Emanuela Argilli, Sally Ann Lynch, Ping Yee Billie Au, Fernando Eduardo Ayala Valenzuela, Carolyn Brown, Diane Masser-Frye, Marilyn Jones, Leslie Patron Romero, Wenhui Laura Li, Erin Thorpe, Laura Hecher, Jessika Johannsen, Jonas Denecke, Vanda Mcniven, Anna Szuto, Emma Wakeling, Vincent Cruz, Valerie Sency, Heng Wang, Juliette Piard, Fanny Kortüm, Theresia Herget, Tatjana Bierhals, Angelo Condell, Bruria Ben-Zeev, Simranpreet Kaur, John Christodoulou, Amelie Piton, Christiane Zweier, Cornelia Kraus, Alessia Micalizzi, Marina Trivisano, Nicola Specchio, Gaetan Lesca, Rikke S Møller, Zeynep Tümer, Maria Musgaard, Benedicte Gerard, Johannes R Lemke, Yun Stone Shi, Anders S Kristensen

Faculty, Staff and Students Publications

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1–GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally.

Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function or gain-of-function properties, whereas 13 appeared neutral.

We collected detailed …

Interactions Between Repetitive Mild Traumatic Brain Injury And Methylphenidate Administration On Catecholamine Transporter Protein Levels Within The Rodent Prefrontal Cortex, Anna Abrimian, Eleni Papadopoulos, Christopher P. Knapp, J. Loweth, Barry Waterhouse, Rachel Navarra

Rowan-Virtua Research Day

It is theorized that low concentrations of dopamine (DA) and norepinephrine (NE) within in the prefrontal cortex (PFC) following traumatic brain injury (TBI) leads to increased risky behavior. Our lab has shown that repeated mild TBI (rmTBI) sex-differentially increases risky behavior in a rodent model. Methylphenidate (MPH) is a psychostimulant drug used to treat symptoms of Attention-Deficit Hyperactivity Disorder (ADHD), also driven by a hypo-catecholaminergic PFC. MPH elevates catecholamine levels by blocking DA and NE transporters, DAT and NET. While the potential of psychostimulants to treat post-TBI symptoms have been explored, the effects of sub-chronic MPH on transporter levels following …

Relationship Between Gut Microbiota And Dementia, Saad Ahmed, Zack Harris, Russell David Levi

Rowan-Virtua Research Day

This paper explores the complex relationship between gut microbiota, dietary habits, and dementia, focusing particularly on Alzheimer's disease (AD). Growing evidence suggests a significant link between the composition of gut bacteria, dietary choices, and susceptibility to dementia. Notably, individuals with dementia demonstrate a noticeable reduction in gut bacteria diversity, highlighting the crucial role of a balanced microbiome in maintaining cognitive health. Conversely, dietary preferences characterized by excessive consumption of processed foods and sugars are associated with an increased risk of dementia, emphasizing the critical influence of diet on shaping gut microbiota and subsequent neurocognitive outcomes. Importantly, dietary interventions featuring a …

Efficacy Of Mcl-1 Inhibitors In Multiple Myeloma Cells Resistant To Bortezomib, Emily Nelson, Omar S. Al-Odat, Sabrina M. Paparo, Daniel A. Guirguis, Gabriella Yao, Manoj Pandey, Subash Jonnalagadda, Tulin Budak-Alpdogan

Rowan-Virtua Research Day

Multiple myeloma (MM) is a type of cancer that affects plasma B cells. Patients with MM often experience frequent relapses and can develop resistance to drugs. As a medical researcher, it is important to understand the role of Mcl-1 in preventing intrinsic apoptosis and drug resistance. Mcl-1 belongs to the anti-apoptotic subgroup of Bcl-2 family proteins and plays a crucial role in these processes. Mcl-1 plays a crucial role in driving disease progression and contributing to drug resistance in MM. It has been observed that there is an increased expression of Mcl-1 in 52% of patients with MM during diagnosis, …

Investigating The Therapeutic Potential Of Soursop In Treating Hematologic Malignancies, Sabrina Marie Paparo, Rebeca Mendoza, Robert Chitren, Omar Al-Odat, Emily Nelson, Subash Jonnalagadda, Roger Strair, Manoj Pandey

Rowan-Virtua Research Day

Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM) are hematologic malignancies that originate in the bone marrow and account for approximately 1.3% and 2% of cancer cases, respectively. AML is characterized by an accumulation of myeloblasts, or immature myeloid cells, that have the potential to spread to the peripheral blood. There is an uncontrolled proliferation of plasma cells in the bone marrow in MM. While the current treatment options for both AML and MM show promise in achieving initial remission, it is unfortunately common for patients to experience relapse and develop drug resistance. There is a theory that relapse and …

A Preliminary Report On The Role Of Lipoxin A4 In Reinstating The Blood-Brain Barrier Integrity In A Rodent Model Of Acute Inflammation With Impaired Cerebrovasculature, Minjal Patel, Shruti Varshney, Ananya Nethikunta, George G. Godsey, Mary C. Kosciuk, Ana Rodriguez, Bernd Spur, Kingsley Yin, Randel L. Swanson, Venkat Venkataraman, Robert G. Nagele, Nimish Acharya

Rowan-Virtua Research Day

Background: The blood-brain barrier (BBB) is responsible for maintaining brain homeostasis and ultimately proper neuronal function. Disruption of the BBB, leading to increased BBB permeability, has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and traumatic brain injury (TBI). Lipoxins (LXs) are a class of arachidonate-derived eicosanoids, which are a class of specialized pro-resolving lipid mediators (SPMs). SPMs are known to inhibit immune response through inhibition of cellular infiltration, downregulation of pro-inflammatory mediators and upregulation of anti-inflammatory mediators. Hence, LXs are recognized as “breaking signals” in the inflammatory process. One form of LXs, Lipoxin A4 (LXA4) …