Digital Commons Network^™

Preclinical Models Of Melanoma Leptomeningeal Disease To Assess Intrathecal Checkpoint Blockade, Renato A Guerrieri, Grant M Fischer, Jacob R Cortez, Barbara G Knighton, Debora A Ledesma, Courtney W Hudgens, Yimmy F Delcid, Qianghua Hu, Christian Y B Onana, Fernando C L Carapeto, Michael T Tezlaff, Jason T Huse, Patrick Hwu, Elizabeth M Burton, Isabella C Glitza Oliva, Michael A Davies, Sherise D Ferguson

Faculty, Staff and Student Publications

Leptomeningeal disease (LMD) is a subtype of central nervous system metastatic disease that is associated with poor patient outcomes and limited treatment options. There is an unmet need to develop preclinical models of LMD to expedite and improve the development of new therapeutics. Here, we describe the development of multiple orthotopic immunocompetent murine models of melanoma LMD, including their use to assess the efficacy of systemic and/or intrathecal immunotherapy. LMD was established by direct intrathecal injection of murine cell lines (B16-F10, BP, D4M, D4M-UV2, MC38-gp100, RMS, YUMM3.1, and YUMMER1.7) into the cisterna magna of C57BL/6 mice. Tumor take rate, distribution, …

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

Faculty, Staff and Student Publications

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

Neuronal Activity-Dependent Gene Dysregulation In C9orf72 I3neuronal Models Of Als/Ftd Pathogenesis, Layla T. Ghaffari, Emily A. Welebob, Sarah E. Bond Newton, Ashley V. Boehringer, Kelly L. Cyliax, Piera Pasinelli, Davide Trotti, Aaron R. Haeusler

Farber Institute for Neuroscience Faculty Papers

The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9ORF72 (C9) gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE-induced pluripotent stem cell-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization or a blockade of K⁺ channels, followed by RNA sequencing, induces …

Pacap Signalling Network In The Nucleus Accumbens Core Regulates Reinstatement Behaviour In Rat, Samrat Bose, Gregory Simandl, Evan M. Hess, Linghai Kong, Nicholas Raddatz, Brian Maunze, Sujean Choi, David A. Baker

Biomedical Sciences Faculty Research and Publications

Cocaine use disorder (CUD) lacks FDA-approved treatments, partly due to the difficulty of creating therapeutics that target behaviour-related neural circuits without disrupting signalling throughout the brain. One promising candidate for circuit-selective neuromodulation is pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with pleiotropic behavioural actions whose signalling network spans the gut–brain axis. Here, we investigated the potential existence and function of an endogenous PACAP signalling network within the nucleus accumbens core (NAcc), which is a structure that integrates emotional, cognitive and reward processes underlying behaviour. We found that PACAP and its cognate receptor, PAC1R, are endogenously expressed in the rat NAcc …

Dean's Update, October 2025, Neil W. Schluger

SOM Dean's Research Newsletter

No abstract provided.

Escape Of Kdm6a From X Chromosome Is Detrimental To Ischemic Brains Via Irf5 Signaling, Conelius Ngwa, Afzal Misrani, Kanaka Valli Manyam, Yan Xu, Shaohua Qi, Romana Sharmeen, Juneyoung Lee, Long-Jun Wu, Louise Mccullough, Fudong Liu

The Brown Foundation: Institute of Molecular Medicine

The role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our previous study has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia, respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17–20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the …

Predictive Gene Expression Signatures For Alzheimer's Disease Using Post-Mortem Brain Tissue, Ashley Duche, Oliver Tan, Andrius Baskys, Rachita K. Sumbria, Moom R. Roosan

Pharmacy Faculty Articles and Research

Background: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau protein aggregates in the brain. These pathological features manifest in specific regions, but mechanisms rendering some areas more susceptible to early AD-related changes remain poorly understood. To address this, we developed predictive gene expression signatures to explore molecular mechanisms underlying regional vulnerability to AD pathology.

Methods: Post-mortem brain tissues from participants of the Religious Orders Study and Memory and Aging Project (ROSMAP), Mayo Clinic, and Mount Sinai Brain Bank (MSBB) were used to derive gene expression signatures from six brain regions affected at varying …

Irf6 Regulates Adherens Junction Proteins And Inflammatory Cytokines In Salivary Acinar Cells And Its Expression Is Elevated In Sjӧgren’S Syndrome, Vi Pham, Antonio Hernandes Chaves Neto, Julia Zheng, Mary Elmeniawi, Krishna Kumar Kookal, Muhammad F Walji, Mary C Farach-Carson, Walid D Fakhouri

Faculty, Staff and Student Publications

Objective: To investigate the mechanism of Interferon Regulatory Factor 6 (IRF6) function in regulating adherens junction proteins and inflammatory cytokines in human salivary acinar cells and Sjögren's syndrome biopsies.

Design: We used mouse model, salivary cell lines, and human salivary gland (SG) biopsies to investigate IRF6 function in SG cellular integrity and immunomodulation.

Results: In Irf6-null mice, we observed myoepithelial cell detachment from acinar cells of major SGs, and the acini were remarkably disorganized compared to wild-type littermates. At the molecular level, the acinar differentiation markers E-cadherin and MIST1 were markedly reduced in Irf6-null embryonic SG, while the proinflammatory cytokines, …

Carotenoids As Neuroprotective Agents In Multiple Sclerosis: Pathways, Mechanisms, And Clinical Prospects, Elham Nadimi, Shirin Jamal Omidi, Mahshad Ghasemi, Mohammad Hashem Hashempur, Aida Iraji

Faculty, Staff and Student Publications

Multiple sclerosis (MS) is a chronic autoimmune andneurodegenerative disorder affecting the central nervous system (CNS), characterized by demyelination and neuroinflammatory responses, oxidative stress, and immune dysregulation. The global incidence of MS is rising, demonstrating the necessity for new therapeutic agents against its complex pathophysiology. Carotenoids, naturally pigments with strong antioxidant, anti-inflammatory, immunomodulatory, and neuroprotective activities, have been recognized as promising candidates to target MS.The antioxidant effect of astaxanthin, lycopene, β-carotene, crocin, and lutein resulted from the deactivation of reactive oxygen species (ROS), preservation of mitochondrial integrity, and prevention of lipid peroxidation. Additionally, carotenoids regulate inflammatory pathways by suppressing NF-κB activation, …

Cervical And Tumor-Associated Microbiomes In Botswana Women With And Without Hiv With Carcinoma Of The Cervix Before And After Definitive Chemoradiation, Travis T Sims, Kyoko Yoshida-Court, Molly B El Alam, Pleasure Ramatlho, Rebecca Ketlametswe, Matthew S Ning, Erle S Robertson, Kathleen M Schmeler, Lauren E Colbert, Ann H Klopp, Surbhi Grover

Faculty, Staff and Student Publications

Purpose: Cervical cancer remains a significant public health concern globally and particularly in sub-Saharan Africa, where high rates of HIV infection exacerbate cervical cancer incidence. Understanding the cervical microbiome and its role in cancer progression is essential, especially in regions where both cervical cancer incidence and HIV prevalence are high. This study aimed to characterize the cervical microbiome in women living with HIV (WLWH) and HIV-negative women with squamous cell carcinoma of the cervix in Botswana, compare the microbiome between before and after chemoradiation therapy (CRT) in WLWH, and assess the prognostic value of specific microbial taxa for overall survival …

Site-Specific Drug Release Of Monomethyl Fumarate To Treat Oxidative Stress Disorders, Thomas D Avery, Jiahe Li, Dion J L Turner, Mohd S U Rasheed, Fisher R Cherry, Damian L Stachura, Fátima Rivera-Escalera, David M Ruiz, Michael J Lacagnina, Caitlyn M Gaffney, Clarissa Aguilar, Jingxian Yu, Yang Wang, Huan Xie, Dong Liang, Andrew J Shepherd, Andrew D Abell, Peter M Grace

Faculty, Staff and Student Publications

Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer-Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress.

First Experience With Third-Party Validations: A Robust Calibration And Qa Procedure For Proton Flash Delivery, Chih-Chiang Chang, Balaji Selvaraj, Xingyi Zhao, Jacob Rembish, Paige A Taylor, Alexander Bookbinder, Chingyun Cheng, J Isabelle Choi, Charles B Simone, Haibo Lin, Minglei Kang

Faculty, Staff and Student Publications

Background: Proton FLASH radiotherapy, delivering ultra-high dose rates, shows promise in reducing normal tissue toxicity while maintaining tumor control. However, accurate dosimetry and quality assurance (QA) for FLASH remain challenging due to the extreme dose rates involved. Developing reliable calibration and QA procedures is crucial for advancing FLASH towards clinical implementation.

Purpose: To present an effective routine calibration and QA procedure for proton FLASH delivery to ensure high-quality dosimetry performance for preclinical and clinical delivery.

Methods: A high temporospatial resolution strip ionization chamber array (SICA) detector was mounted to the treatment nozzle, which was calibrated using an Advanced Markus ion …

Tofacitinib Ameliorates Campylobacter-Induced Intestinal Pathology By Suppressing Ifnγ Producing Ilcs And T Cells, Anna A Korchagina, Sergey A Shein, Wayne T Muraoka, Justin Nguyen, Qiangxing Chen, Anna A Tumanova, Austin W Todd, Carlos E Rivera, Rita Tamayo, Paolo Casali, Ekaterina Koroleva, Alexei V Tumanov

Faculty, Staff and Student Publications

Patients with autoimmune diseases are more susceptible to foodborne infections, which can be exacerbated by immunosuppressive therapy. Tofacitinib, a JAK/STAT pathway inhibitor, was recently approved for the treatment of ulcerative colitis, yet its effects on the pathogenesis of intestinal infections remain unclear. Here, we examined the impact of oral tofacitinib treatment in a mouse model of Campylobacter jejuni (C. jejuni) infection. Our results show that early tofacitinib administration attenuates intestinal pathology without affecting bacterial colonization. Specifically, tofacitinib suppressed CXCL1, CXCL2, CCL2 chemokine expression by intestinal epithelial cells, limiting recruitment of monocytes and neutrophils to the gut. In addition, JAK/STAT inhibition …

Epigenetic Age Acceleration Mediates Treatment Effects On Cardiometabolic And Cardiovascular Risk In Childhood Cancer Survivors, Xiaoxi Meng, Tiffany Eulalio, Yoonji Kim, John Easton, Heather L Mulder, Emily Walker, Geoffrey Neale, Nan Song, Kyla Shelton, Rebecca M Howell, Mengqi Xing, Sedigheh Mirzaei, Deo Kumar Srivastava, Bonnie Ky, Stephanie B Dixon, Melissa M Hudson, Kirsten K Ness, Gregory T Armstrong, Zhaoming Wang

Faculty, Staff and Student Publications

BACKGROUND: Childhood cancer survivors are at increased risk for epigenetic age acceleration (EAA) and subsequent morbidities, including cardiometabolic risk factors (CMRFs) and cardiovascular diseases, because of prior genotoxic treatments.

OBJECTIVES: The aim of this study was to evaluate the mediating role of EAA in the relationship between cancer treatment exposures and risk for CMRFs and cardiovascular diseases.

METHODS: This study included 2,939 5-year survivors from SJLIFE (St. Jude Lifetime Cohort) who underwent DNA methylation profiling using peripheral blood mononuclear cells. EAA was calculated using 3 established epigenetic clocks: DunedinPACE, PCPhenoAge, and GrimAge2. Treatment data, including body region-specific radiotherapy (RT) and …

Mapping Cardiac Electrical Abnormalities In Rodents, Ashish Kapoor, Peter A Doris

Faculty, Staff and Student Publications

No abstract provided.

Cancer-Associated Fibroblasts As Mediators Of Tissue Microenvironment Remodeling In Cancer, Fernanda G Kugeratski, Emily J Kay, Sara Zanivan

Faculty, Staff and Student Publications

Cancer-associated fibroblasts (CAFs) are a multifunctional cell population of solid tumors that substantially remodel the tumor microenvironment (TME). The combination of single-cell and spatial technologies with elegant mouse models and analysis of patient samples is enabling unprecedented advances in the characterization of CAF origins, heterogeneity, and functions within the TME. As such, the field is now evolving to delineate tissue-specific subpopulations of CAFs, their markers, and the biological context in which each subset presents with a tumor-promoting or a tumor-restraining function. In this timely review, we discuss recent advances in CAF biology in the context of emerging areas of interest …

Cancer-Induced Nerve Injury Promotes Resistance To Anti-Pd-1 Therapy, Erez N Baruch, Frederico O Gleber-Netto, Priyadharsini Nagarajan, Xiayu Rao, Shamima Akhter, Tuany Eichwald, Tongxin Xie, Mohammad Balood, Adebayo Adewale, Shorook Naara, Hinduja N Sathishkumar, Shajedul Islam, William Mccarthy, Brandi J Mattson, Renata Ferrarotto, Michael K Wong, Michael A Davies, Sonali Jindal, Sreyashi Basu, Karine Roversi, Amin Reza Nikpoor, Maryam Ahmadi, Ali Ahmadi, Catherine Harwood, Irene Leigh, Dennis Gong, Paulino Tallón De Lara, Derrick L Tao, Tara M Davidson, Nadim J Ajami, Andrew Futreal, Kunal Rai, Veena Kochat, Micah Castillo, Preethi Gunaratne, Ryan P Goepfert, Sharia D Hernandez, Nikhil I Khushalani, Jing Wang, Stephanie S Watowich, George A Calin, Michael R Migden, Mona Yuan, Naijiang Liu, Yi Ye, William L Hwang, Paola D Vermeer, Nisha J D'Silva, Yuri L Bunimovich, Dan Yaniv, Jared K Burks, Javier Gomez, Patrick M Dougherty, Kenneth Y Tsai, James P Allison, Padmanee Sharma, Jennifer A Wargo, Jeffrey N Myers, Sebastien Talbot, Neil D Gross, Moran Amit

Faculty, Staff and Student Publications

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated …

Relationship Between Quantitative Mri Ute T2* Of Acl Autografts And Bmi-Normalized Knee Laxity Within The First Year After Acl Reconstruction, Alonso Figueroa, Tomasz Bugajski, Dillon Humpal, Manickam Kumaravel, Walter Lowe, Payam Zandiyeh

Faculty, Staff and Student Publications

Background: The anterior cruciate ligament reconstruction (ACLR) graft undergoes a remodeling process that affects its structural properties. Ultrashort echo time T2* (UTE-T2*) imaging has been instrumental in examining this process. However, more research is needed on the postoperative relationship between UTE-T2* of the graft and its mechanical properties.

Purpose: To longitudinally examine ACL graft changes after ACLR using UTE-T2* decay coefficients and knee laxity and explore their relationship.

Study design: Case series; Level of evidence, 4.

Methods: A total of 31 patients who underwent ACLR had magnetic resonance imaging of their knees at 1, 6, and 12 months after surgery …

Pka-Driven Spp1 Activation As A Novel Mechanism Connecting The Bone Microenvironment To Prostate Cancer Progression, Pablo Sanchis, Agustina Sabater, Julia Lechuga, Jimena Rada, Rocio Seniuk, Gaston Pascual, Mora Gatti, Juan Bizzotto, Peter D A Shepherd, Jun Yang, Javier Cotignola, Elba Vazquez, Joaquin Mateo, Pia Valacco, Estefania Labanca, Christopher Logothetis, Geraldine Gueron, Nicolas Anselmino

Faculty, Staff and Student Publications

Prostate cancer (PCa) bone metastasis (BM) poses a significant clinical challenge due to the heterogeneity of treatment responses and patient outcomes. In this study, we examined the role of Protein Kinase A (PKA) signaling in modulating the expression of osteopontin (SPP1/OPN), a protein associated with poor prognosis, within a subset of PCa BM patients. By integrating multi-omics results we identified a novel mechanism in which bone-derived type-I collagen (Col1a1) and fibronectin (Fn1) stimulate SPP1 expression in PCa cells through the activation of PKA signaling. This bone-induced regulation of SPP1 was confirmed both in vitro, using PCa-bone co-culture systems (PC3 or …

From Nociception In Aneural Animals To Human Suffering: Toward A Comparative Biology Of Pain, Edgar T Walters

Faculty, Staff and Student Publications

Pain is a core feature of human life, but systematic comparisons of this biological trait across taxa have been rare. A broadly accepted definition based on human experience emphasizes dual features of pain: a sensory (discriminative) component for sensing and monitoring tissue injury, and an affective (emotional) component to motivate avoidance of tissue distress. Conscious pain is coupled to unconscious nociception (detection of incipient or existing injury). This Review considers nociception and pain across phyla within a comparative framework, addressing basic questions about evolutionary origins, mechanisms and functions of pain. The occurrence of adaptive cellular responses to injury in virtually …

Suturing Education For Athletic Trainers: An Evidence-To-Practice Review, Morgan K. Webb, Brett T. Heim, Allyson E. Ritchey, Kenya Moore, Zachary K. Winkelmann

Clinical Practice in Athletic Training

Teaching suturing skills to medical students is a critical component of their education. Implementing suturing into a comprehensive framework is developed from how professors teach the skill. Suturing is a required skill by the General Medical Council that all medical students must have, and how it is being introduced to new students is changing. This review aimed to summarize different educational interventions and determine the most efficient and cost-effective way to teach future suturing skills. The original systematic review included 25 articles in the final data synthesis. Fourteen studies were randomized control trials, six were quasi-experimental, and five were observational. …

Dynamic Rewiring Of Microrna Networks In The Brainstem Autonomic Control Circuits During Hypertension Development In The Female Spontaneously Hypertensive Rat, Alison Moss, Ankita Srivastava, Lakshmi Kuttippurathu, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We describe global microRNA (miRNA) changes in the central autonomic control circuits during the development of neurogenic hypertension. Using the female spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY), we analyzed the dynamic miRNA expression changes in three brainstem regions-the nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla-as a time series beginning at 8 wk of age before hypertension onset through to extended chronic hypertension. Our analysis yielded nine miRNAs that were significantly differentially regulated in all three regions between SHR and WKY over time. We collated computationally predicted gene targets of these nine …

Hyaluronidase-1 Mediates Postprandial Suppression Of Hepatic Gluconeogenesis, Xi Chen, Sophie Dogné, Yanru Deng, Huiqiao Li, Jieyi Meng, Charlise Giang, Jan-Bernd Funcke, Leon G Straub, Michelle Dias, Sundararajah Thevananther, Qiang Tong, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Yu'e Liu, Nagireddy Putluri, Xia Gao, Miao-Hsueh Chen, Dongyin Guan, Hari Krishna Yalamanchili, Shangang Zhao, Nathalie Caron, Yi Zhu

Faculty, Staff and Students Publications

Hepatic gluconeogenesis is a critical process that generates glucose from non-carbohydrate precursors during fasting to support vital organs like the brain and red blood cells. Postprandially, this process is rapidly suppressed to allow for glucose storage as glycogen and lipids in the liver. Failure to suppress gluconeogenesis after meals leads to elevated postprandial glucose levels, a key feature of type 2 diabetes. This dynamic switch is regulated by insulin and glucagon, but insulin resistance impairs this regulation. In this study, we identified a novel mechanism involving postprandial circulating hyaluronan (HA) and lysosomal hyaluronidase-1 (HYAL1) that suppresses hepatic gluconeogenesis by rewiring …

Normal Urinary Oxalate Excretion In 4-Hydroxy-2-Oxo-Glutarate Aldolase 1 (Hoga1) Deficient Mice With Agt Expression In Peroxisomes And Not In Mitochondria, Iolanda Boffa, Rosa Ferriero, Mariarosaria Cancelliere, Edoardo Nusco, Leonardo Gatticchi, Donna Palmer, Philip Ng, Pasquale Piccolo, Barbara Cellini, Kyle Wood, John Knight, Nicola Brunetti-Pierri

Faculty, Staff and Students Publications

Primary hyperoxaluria type 3 (PH3) is caused by mutations in Hoga1 gene. PH3 individuals develop nephrolithiasis, but the mechanism underlying hyperoxaluria is unclear and a mouse model recapitulating the human disease can provide insights into the pathogenesis of PH3. Hoga1−/− mice do not have increased urinary oxalate excretion, probably due to the murine mitochondrial alanine-glioxylate-aminotransferase (AGT) activity, which in humans is only expressed in peroxisomes. However, Hoga1−/−/Agxt−/− mice with AGT installed on peroxisome and not on mitochondria did not show increased urinary oxalate, suggesting that AGT expression in both cellular compartments is not an explanation for …

Phosphorylation At Serine 214 Correlates With Tau Seeding Activity In An Age-Dependent Manner In Two Mouse Models For Tauopathies And Is Required For Tau Transsynaptic Propagation, Pablo Martinez, Nur Jury-Garfe, Henika Patel, Yanwen You, Abigail Perkins, Yingjian You, Audrey Lee-Gosselin, Ruben Vidal, Cristian A Lasagna-Reeves

Faculty, Staff and Students Publications

Background

Tau aggregation and propagation are hallmark features of Alzheimer's disease and related tauopathies. The molecular identity and post-translational modifications that contribute to tau seeding activity remain incompletely understood.

Objective

To characterize the temporal dynamics of tau seeding activity and identify specific phosphorylated tau species associated with tau propagation in vivo.

Methods

We profiled tau seeding activity using a FRET-based biosensor cell line and correlated it with the abundance of phospho- and conformational tau species in two transgenic mouse models of tauopathy (P301S-1N4R and P301S-0N4R). Immunohistochemistry and subcellular fractionation were used to examine the spatial distribution of tau species. Functional …

Aging Affects Lipid Homeostasis In Lacrimal Glands By Upregulating Lipogenesis And Changing Its Specificity, Seher Yuksel, Prashant Kumar, Sydney E Krenz, Kaitlin K Scholand, Zhiyuan Yu, Anastasiia Ivanova, Helen P Makarenkova, Sarah F Hamm-Alvarez, Igor A Butovich, Cintia S De Paiva

Faculty, Staff and Students Publications

Purpose: The lacrimal gland (LG) develops age-related alterations. This study investigated the lipid content of the accumulated secretions within the murine aged LG.

Methods: C57BL/6J animals of different ages (3 months, 12 months, and 20-26 months) were used. Published data of bulk RNA sequencing of aged LGs were used to investigate lipid pathways. Exorbital LGs were excised for histology or PCR. Histologic sections were stained with standard histochemical stains or immunostained using anti-adiponectin, anti-perilipin 2 antibodies, and BODIPY dye. LG lipidomes were investigated using unbiased, untargeted high-resolution liquid chromatography/mass spectrometry (LC/MS), and the data were processed using unbiased, untargeted principal …

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

Faculty, Staff and Students Publications

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

Corneal Sensory Nerve Regulation Of Tear Production Through Stimulation Of Transient Receptor Potential Melastatin 8 (Trpm8) Channel: A Potential New Approach For Treating Dry Eye Disease, Juana Gallar, Stephen Pflugfelder, Anat Galor, Preeya K Gupta, Pedram Hamrah

Faculty, Staff and Students Publications

The lacrimal functional unit (LFU) tightly controls the secretion of all tear components, thus playing a critical role in maintaining ocular surface homeostasis. Forming an exquisitely sensitive neural network across the ocular surface, corneal sensory nerves detect environmental stimuli (e.g., temperature, chemicals, and mechanical pressure) through transient receptor potential (TRP) ion channels. Among these, TRP melastatin 8 (TRPM8) is a key regulator of basal tear production. Stimulated by the small temperature reductions and tear film osmolarity increases that arise due to evaporative cooling, TRPM8 activates the LFU, leading to increased basal tear production. Here, we focus on reviewing the topical …

Endoglin-Directed Car T Cells Comprehensively Target Tumors In Advanced Sarcomas, Harrison R Berger, Malina Maharana, Jeneffer Mirabal, Lyazat Kurenbekova, Alberto Delaidelli, Atreyi Dasgupta, Ahmed Z Gad, Mohamed F Sheha, Sybrina S Kerr, Ada I Ozcan, Jessica S Morris, Angela M Major, M John Hicks, Mary K Mckenna, Ben K Seon, Matthew L Baker, Poul H Sorensen, Meenakshi Hegde, Jason T Yustein, Nabil Ahmed, Sujith K Joseph

Faculty, Staff and Students Publications

There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their …

Fructose And Glucose From Sugary Drinks Enhance Colorectal Cancer Metastasis Via Sord, Tianshi Feng, Qin Luo, Yanlin Liu, Zeyu Jin, David Skwarchuk, Rumi Lee, Miso Nam, John M Asara, Daya R Adye, Philip L Lorenzi, Lin Tan, Guangsheng Pei, Zhongming Zhao, Neda Zarrin-Khameh, Adriana Paulucci-Holthauzen, Brian W Simons, Ju-Seog Lee, Scott Kopetz, Jihye Yun

Faculty, Staff and Students Publications

The consumption of sugar-sweetened beverages (SSBs), which contain high levels of fructose and glucose, has been causally and mechanistically linked to an increased risk of colorectal cancer (CRC). However, the effects of SSB consumption on advanced stages of disease progression, including metastasis, remain poorly understood. Here we show that exposure of CRC cells to a glucose and fructose formulation-reflecting the composition of both high-fructose corn syrup and sucrose found in SSBs-enhances cellular motility and metastatic potential compared to glucose alone. Given that CRC cells grow poorly in fructose alone, and cells in vivo are not physiologically exposed to fructose without …