Internal Medicine Commons^™

Breast Cancer-Derived Extracellular Vesicle Mir-425-5p (Mir-425) Promotes Brain Metastasis Via Activating Astrocytes Through The Novel Mir-425-Znf24-Ccl8 Signaling Axis, Grace L Wong, Munazza S Khan, Sara Manore, Shivani Bindal, Ravi Singh, Hui-Wen Lo

Faculty, Staff and Student Publications

Mechanisms underlying breast cancer brain metastasis (BCBM) are still not well understood. Here, we identified that BCBM patient serum contained extracellular vesicles (EVs) with high levels of microRNAs (miRNAs)-107 and -425. Levels of miR-107 and miR-425 were elevated in brain metastases, and the elevation was associated with poor patient prognoses. Ectopic expression of miR-107 and miR-425 promoted mammospheres; however, the inhibition of miR-425, but not miR-107, suppressed breast cancer mammosphere formation. We further observed that EVs from miR-425-overexpressing breast cancer cells strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-425-activated astrocytes promoted mammospheres. To elucidate how …

Maternal Dysbiosis Produces Long-Lasting Behavioral Changes In Offspring, Jacob Hudobenko, Claudia M Di Gesù, Patrick R Mooz, Joseph Petrosino, Nagireddy Putluri, Bhanu P Ganesh, Kristen Rebeles, Frank W Blixt, Venugopal R Venna, Louise D Mccullough

Faculty, Staff and Student Publications

Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization …

Non-Invasive Real-Time Pulsed Doppler Assessment Of Blood Flow In Mouse Ophthalmic Artery, Iraida Sharina, Radwa Awad, Soren Cobb, Emil Martin, Sean P Marrelli, Anilkumar K Reddy

Faculty, Staff and Student Publications

Non-invasive and high-temporal resolution methods for characterizing blood flow in mouse cranial arteries, such as the ophthalmic artery (OphA), are lacking. We present an application of pulsed Doppler ultrasound to provide real-time, non-invasive measurement of blood flow velocity in the OphA through an identified soft tissue window in the mouse head. We confirmed the identity of the artery and mapped its origin from the internal carotid artery by a combination of microcomputed tomography (microCT) vascular imaging and transient occlusion of the internal carotid artery. Application of our approach demonstrated sex differences in the OphA vasodilative response to agonists. We also …

Membrane Lipids Augment Cell Envelope Stress Signaling Via The Madrs System To Defend Against Antimicrobial Peptides And Antibiotics In Enterococcus Faecalis, William R Miller, April Nguyen, Kavindra V Singh, Samie Rizvi, Ayesha Khan, Sam G Erickson, Stephanie L Egge, Melissa Cruz, An Q Dinh, Lorena Diaz, Philip C Thornton, Rutan Zhang, Libin Xu, Danielle A Garsin, Yousif Shamoo, Cesar A Arias

Faculty, Staff and Student Publications

Enterococci have evolved resistance mechanisms to protect their cell envelopes against bacteriocins and host cationic antimicrobial peptides (CAMPs) produced in the gastrointestinal environment. Activation of the membrane stress response has also been tied to resistance to the lipopeptide antibiotic daptomycin. However, the actual effectors mediating resistance have not been elucidated. Here, we show that the MadRS (formerly YxdJK) membrane antimicrobial peptide defense system controls a network of genes, including a previously uncharacterized 3-gene operon (madEFG) that protects the Enterococcus faecalis cell envelope from antimicrobial peptides. Constitutive activation of the system confers protection against CAMPs and daptomycin in the absence of …

Evidence That Crispr-Cas9 Y537s-Mutant Expressing Breast Cancer Cells Activate Yes-Associated Protein 1 To Driving The Conversion Of Normal Fibroblasts Into Cancer-Associated Fibroblasts, Luca Gelsomino, Amanda Caruso, Emine Tasan, Adele Elisabetta Leonetti, Rocco Malivindi, Giuseppina Daniela Naimo, Francesca Giordano, Salvatore Panza, Guowei Gu, Benedetta Perrone, Cinzia Giordano, Loredana Mauro, Bruno Nardo, Gianfranco Filippelli, Daniela Bonofiglio, Ines Barone, Suzanne A W Fuqua, Stefania Catalano, Sebastiano Andò

Faculty, Staff and Students Publications

BACKGROUND: Endocrine therapy (ET) has improved the clinical outcomes of Estrogen receptor alpha-positive (ERɑ +) breast cancer (BC) patients, even though resistance to ET remains a clinical issue. Mutations in the hormone-binding domain of ERɑ represent an acquired intrinsic mechanism of ET resistance. However, the latter also depends on the multiple functional interactions between BC cells and the tumor microenvironment (TME). Here, we investigated how the most common Y537S-ERɑ mutation may influence the behavior of fibroblasts, the most prominent component of the TME.

METHODS: We conducted coculture experiments with normal human foreskin fibroblasts BJ1-hTERT (NFs), cancer-associated fibroblasts (CAFs), isolated from …

Ephb4-Rasa1 Inhibition Of Piezo1 Ras Activation Drives Lymphatic Valvulogenesis, Di Chen, Yipei Tang, Philip E Lapinski, David Wiggins, Eva M Sevick, Michael J Davis, Philip D King

Faculty, Staff and Student Publications

BACKGROUND: EPHB4 (ephrin receptor B4) and the RASA1 (p120 Ras GTPase-activating protein) are necessary for the development of lymphatic vessel (LV) valves. However, precisely how EPHB4 and RASA1 regulate LV valve development is unknown. In this study, we examine the mechanisms by which EPHB4 and RASA1 regulate the development of LV valves.

METHODS: We used LV-specific inducible EPHB4-deficient mice and EPHB4 knockin mice that express a form of EPHB4 that is unable to bind RASA1 yet retains protein tyrosine kinase activity (EPHB4 2YP) to study the role of EPHB4 and RASA1 in LV valve development in the embryo and LV …

Macrophage Iron Dyshomeostasis Promotes Aging-Related Renal Fibrosis, Lingzhi Wu, Hongchun Lin, Shaomin Li, Yuebo Huang, Yuxiang Sun, Shuangshuang Shu, Ting Luo, Tiantian Liang, Weiyan Lai, Jialing Rao, Zhaoyong Hu, Hui Peng

Faculty, Staff and Students Publications

Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular …

Trβ Activation Confers At2-To-At1 Cell Differentiation And Anti-Fibrosis During Lung Repair Via Klf2 And Cebpa, Xin Pan, Lan Wang, Juntang Yang, Yingge Li, Min Xu, Chenxi Liang, Lulu Liu, Zhongzheng Li, Cong Xia, Jiaojiao Pang, Mengyuan Wang, Meng Li, Saiya Guo, Peishuo Yan, Chen Ding, Ivan O Rosas, Guoying Yu

Faculty, Staff and Students Publications

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the …

Pkmyt1 Is A Marker Of Treatment Response And A Therapeutic Target For Cdk4/6 Inhibitor-Resistance In Er+ Breast Cancer, Anran Chen, Beom-Jun Kim, Aparna Mitra, Craig T Vollert, Jonathan T Lei, Diana Fandino, Meenakshi Anurag, Matthew V Holt, Xuxu Gou, Jacob B Pilcher, Matthew P Goetz, Donald W Northfelt, Susan G Hilsenbeck, C Gary Marshall, Marc L Hyer, Robert Papp, Shou-Yun Yin, Carmine De Angelis, Rachel Schiff, Suzanne A W Fuqua, Cynthia X Ma, Charles E Foulds, Matthew J Ellis

Faculty, Staff and Students Publications

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast …

Dual Inhibition Of The Trka And Jak2 Pathways Using Entrectinib And Pacritinib Suppresses The Growth And Metastasis Of Her2-Positive And Triple-Negative Breast Cancers, Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo

Faculty, Staff and Student Publications

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness …

Vertebrate And Invertebrate Animal Infection Models Of Candida Auris Pathogenicity, Melissa Martinez, Danielle A Garsin, Michael C Lorenz

Faculty, Staff and Student Publications

Candida auris is an emerging fungal pathogen with several concerning qualities. First recognized in 2009, it has arisen in multiple geographically distinct genomic clades nearly simultaneously. C. auris strains are typically multidrug resistant and colonize the skin much better than most other pathogenic fungi; it also persists on abiotic surfaces, enabling outbreaks due to transmission in health care facilities. All these suggest a biology substantially different from the 'model' fungal pathogen, Candida albicans and support intensive investigation of C. auris biology directly. To uncover novel virulence mechanisms in this species requires the development of appropriate animal infection models. Various studies …

Human Platelet Lysate Enhances In Vivo Activity Of Car-Vδ2 T Cells By Reducing Cellular Senescence And Apoptosis, Feiyan Mo, Chiou-Tsun Tsai, Rong Zheng, Chonghui Cheng, Helen E Heslop, Malcolm K Brenner, Maksim Mamonkin, Norihiro Watanabe

Faculty, Staff and Students Publications

BACKGROUND AIMS: Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain.

METHODS: Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet …

T-Bet Regulates Ion Channels And Transporters And Induces Apoptosis In Intestinal Epithelial Cells, Lang Chen, Hongwei Yi, Qingtian Li, Tianhao Duan, Xin Liu, Linfeng Li, Helen Y Wang, Changsheng Xing, Rong-Fu Wang

Faculty, Staff and Students Publications

T-bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T-bet in non-immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet-O-T-bet transgenic mouse strain is generated for doxycycline-inducible T-bet expression in adult animals. Unexpectedly, ubiquitous T-bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell-type-specific analyses reveal that T-bet-driven pathology is not attributable to its overexpression in CD4

Aging- And Alcohol-Associated Spatial Transcriptomic Signature In Mouse Acute Pancreatitis Reveals Heterogeneity Of Inflammation And Potential Pathogenic Factors, Rachel R Tindall, Yuntao Yang, Isabella Hernandez, Amy Qin, Jiajing Li, Yinjie Zhang, Thomas H Gomez, Mamoun Younes, Qiang Shen, Jennifer M Bailey-Lundberg, Zhongming Zhao, Daniel Kraushaar, Patricia Castro, Yanna Cao, W Jim Zheng, Tien C Ko

Faculty, Staff and Student Publications

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via …

Hemojuvelin-Mediated Hepcidin Induction Requires Both Bone Morphogenetic Protein Type I Receptors Alk2 And Alk3, Deniz Y Dogan, Eugen I Urzica, Isabelle Hornung, Philipp Kastl, David Oguama, Franca M Fette, Lien H Nguyen, Frank Rosenbauer, Kai Zacharowski, Ursula Klingmüller, Elise Gradhand, Andreas Von Knethen, Rüdiger Popp, Ingrid Fleming, Lisa Schrader, Andrea U Steinbicker

Faculty, Staff and Student Publications

Hemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) …

Persistent ∆Fosb Expression Limits Recurrent Seizure Activity And Provides Neuroprotection In The Dentate Gyrus Of App Mice, Gabriel S Stephens, Jin Park, Andrew Eagle, Jason You, Manuel Silva-Pérez, Chia-Hsuan Fu, Sumin Choi, Corey P St Romain, Chiho Sugimoto, Shelly A Buffington, Yi Zheng, Mauro Costa-Mattioli, Yin Liu, A J Robison, Jeannie Chin

Faculty, Staff and Student Publications

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection …

Loss Of Lpar6 And Cab39l Dysregulates The Basal-To-Luminal Urothelial Differentiation Program, Contributing To Bladder Carcinogenesis, Sangkyou Lee, Jolanta Bondaruk, Yishan Wang, Huiqin Chen, June Goo Lee, Tadeusz Majewski, Rachel D Mullen, David Cogdell, Jiansong Chen, Ziqiao Wang, Hui Yao, Pawel Kus, Joon Jeong, Ilkyun Lee, Woonyoung Choi, Neema Navai, Charles Guo, Colin Dinney, Keith Baggerly, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Marek Kimmel, Peng Wei, Bogdan Czerniak

Faculty, Staff and Student Publications

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two …

Mitochondria Regulate Proliferation In Adult Cardiac Myocytes, Gregory B Waypa, Kimberly A Smith, Paul T Mungai, Vincent J Dudley, Kathryn A Helmin, Benjamin D Singer, Clara Bien Peek, Joseph Bass, Lauren Nelson, Sanjiv J Shah, Gaston Ofman, J Andrew Wasserstrom, William A Muller, Alexander V Misharin, G R Scott Budinger, Hiam Abdala-Valencia, Navdeep S Chandel, Danijela Dokic, Elizabeth Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B Thorp, Paul T Schumacker

Faculty, Staff and Student Publications

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes …

Topographical And Cell Type-Specific Connectivity Of Rostral And Caudal Forelimb Corticospinal Neuron Populations, Lina Marcela Carmona, Eric D Thomas, Kimberly Smith, Bosiljka Tasic, Rui M Costa, Anders Nelson

Faculty, Staff and Student Publications

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, …

Hammerhead-Type Fxr Agonists Induce An Enhancer Rna Fincor That Ameliorates Nonalcoholic Steatohepatitis In Mice, Jinjing Chen, Ruoyu Wang, Feng Xiong, Hao Sun, Byron Kemper, Wenbo Li, Jongsook Kemper

Faculty, Staff and Student Publications

The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (

4r-Cembranoid Suppresses Glial Cells Inflammatory Phenotypes And Prevents Hippocampal Neuronal Loss In Lps-Treated Mice, Luis A Rojas-Colón, John B Redell, Pramod K Dash, Pedro E Vegas, Wanda Vélez-Torres

Faculty, Staff and Student Publications

Chronic neuroinflammation has been implicated in neurodegenerative disease pathogenesis. A key feature of neuroinflammation is neuronal loss and glial activation, including microglia and astrocytes. 4R-cembranoid (4R) is a natural compound that inhibits hippocampal pro-inflammatory cytokines and increases memory function in mice. We used the lipopolysaccharide (LPS) injection model to study the effect of 4R on neuronal density and microglia and astrocyte activation. C57BL/6J wild-type mice were injected with LPS (5 mg/kg) and 2 h later received either 4R (6 mg/kg) or vehicle. Mice were sacrificed after 72 h for analysis of brain pathology. Confocal images of brain sections immunostained for …

Single-Cell Analysis Of Age-Related Changes In Leukocytes Of Diabetic Mouse Hindpaws, James M Nichols, Hoang Vu Pham, Eric F Lee, Rajasekaran Mahalingam, Andrew J Shepherd

Faculty, Staff and Student Publications

Complications associated with Type 1 and Type 2 diabetes, such as diabetic peripheral neuropathy and diabetic foot ulcers, are a growing health-care concern. In addition, this concern increases as diabetic patients age due to their increased susceptibility to complications. To address this growing problem, it is important to understand fluctuations in physiology which lead to pathological changes associated with the metabolic disturbances of diabetes. Our study explores dysregulation of immune cell populations in the hindpaws of healthy and diabetic mice at 12 and 21 weeks of age using single-cell RNA sequencing to provide insight into immune disruptions occurring in the …

Cd69 Signaling In Eosinophils Induces Il-10 Production And Apoptosis Via The Erk1/2 And Jnk Pathways, Respectively, Dan Van Bui, Linh Manh Nguyen, Akira Kanda, Hanh Hong Chu, Nhi Kieu Thi Le, Yasutaka Yun, Yoshiki Kobayashi, Kensuke Suzuki, Akitoshi Mitani, Akihiro Shimamura, Kenta Fukui, Shunsuke Sawada, David Dombrowicz, Hiroshi Iwai

Faculty, Staff and Student Publications

INTRODUCTION: Eosinophils contribute to the pathogenesis of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. We previously reported that human tissue eosinophils have high CD69 expression compared to blood eosinophils, and its expression is correlated with disease severity and the number of infiltrated eosinophils. However, biological CD69 signaling activity in eosinophils remains unclear.

METHODS: CD69 expression on lung tissue eosinophils obtained from mice with ovalbumin-induced asthma was measured using flow cytometry. CD69 crosslinking was performed on eosinophils purified from the spleen of IL-5 transgenic mice to investigate CD69 signaling and its function in eosinophils. Then, qPCR, Western blot, enzyme-linked …

Cns-Associated Macrophages Contribute To Intracerebral Aneurysm Pathophysiology, Martina Glavan, Ana Jelic, Damien Levard, Juhana Frösen, Sara Keränen, Bart A A Franx, Ana-Rita Bras, Estelle R Louet, Ádám Dénes, Mario Merlini, Denis Vivien, Marina Rubio

Faculty, Staff and Student Publications

Simple Summary

Vestibular schwannoma (VS), benign cranial nerve sheath tumors of the vestibulocochlear nerve, lack efficacious systemic therapies, especially if they develop in a NF2-related schwannomatosis (NF2) background. They cause hearing loss, tinnitus and balance problems. Metastasis associated in colon cancer 1 (MACC1) is a key driver of metastasis. Although MACC1 expression is associated with highly malignant tumors and VS are considered benign, both are attached to the HGF/MET signaling pathway and MACC1 is a candidate gene localized at a hearing loss-related gene locus. Therefore, it was investigated whether MACC1 might be involved in VS pathogenesis. Surprisingly, MACC1 expression …

Oxidized Activated Charcoal Nanozymes: Synthesis, And Optimization For In Vitro And In Vivo Bioactivity For Traumatic Brain Injury, Emily A Mchugh, Anton V Liopo, Kimberly Mendoza, Claudia S Robertson, Gang Wu, Zhe Wang, Weiyin Chen, Jacob L Beckham, Paul J Derry, Thomas A Kent, James M Tour

Faculty, Staff and Student Publications

Carbon-based superoxide dismutase (SOD) mimetic nanozymes have recently been employed as promising antioxidant nanotherapeutics due to their distinct properties. The structural features responsible for the efficacy of these nanomaterials as antioxidants are, however, poorly understood. Here, the process-structure-property-performance properties of coconut-derived oxidized activated charcoal (cOAC) nano-SOD mimetics are studied by analyzing how modifications to the nanomaterial's synthesis impact the size, as well as the elemental and electrochemical properties of the particles. These properties are then correlated to the in vitro antioxidant bioactivity of poly(ethylene glycol)-functionalized cOACs (PEG-cOAC). Chemical oxidative treatment methods that afford smaller, more homogeneous cOAC nanoparticles with higher …

An Atlas Of Epithelial Cell States And Plasticity In Lung Adenocarcinoma, Guangchun Han, Ansam Sinjab, Zahraa Rahal, Anne M Lynch, Warapen Treekitkarnmongkol, Yuejiang Liu, Alejandra G Serrano, Jiping Feng, Ke Liang, Khaja Khan, Wei Lu, Sharia D Hernandez, Yunhe Liu, Xuanye Cao, Enyu Dai, Guangsheng Pei, Jian Hu, Camille Abaya, Lorena I Gomez-Bolanos, Fuduan Peng, Minyue Chen, Edwin R Parra, Tina Cascone, Boris Sepesi, Seyed Javad Moghaddam, Paul Scheet, Marcelo V Negrao, John V Heymach, Mingyao Li, Steven M Dubinett, Christopher S Stevenson, Avrum E Spira, Junya Fujimoto, Luisa M Solis, Ignacio I Wistuba, Jichao Chen, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver …

Gamma Delta T Cells In Acute Myeloid Leukemia: Biology And Emerging Therapeutic Strategies, Adishwar Rao, Akriti Agrawal, Gautam Borthakur, Venkata Lokesh Battula, Abhishek Maiti

Faculty, Staff and Student Publications

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of …

Fluvoxamine Inhibits Th1 And Th17 Polarization And Function By Repressing Glycolysis To Attenuate Autoimmune Progression In Type 1 Diabetes, Yuan Zou, Jing Zhang, Fei Sun, Qianqian Xu, Longmin Chen, Xi Luo, Ting Wang, Qing Zhou, Shu Zhang, Fei Xiong, Wen Kong, Ping Yang, Qilin Yu, Shiwei Liu, Cong-Yi Wang

Faculty, Staff and Student Publications

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed.

METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune …

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization In A Hind Limb Ischemia Model In Diabetic, Hyperlipidemic Rabbits, Eri Takematsu, Miles Massidda, Gretchen Howe, Julia Goldman, Patricia Felli, Lei Mei, Gregory Callahan, Andrew D Sligar, Richard Smalling, Aaron B Baker

Faculty, Staff and Student Publications

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. …

The Yap1/Taz-Tead Transcriptional Network Regulates Gene Expression At Neuromuscular Junctions In Skeletal Muscle Fibers, Lea Gessler, Danyil Huraskin, Yongzhi Jian, Nane Eiber, Zhaoyong Hu, Tomasz J Prószyński, Said Hashemolhosseini

Faculty, Staff and Students Publications

We examined YAP1/TAZ-TEAD signaling pathway activity at neuromuscular junctions (NMJs) of skeletal muscle fibers in adult mice. Our investigations revealed that muscle-specific knockouts of Yap1 or Taz, or both, demonstrate that these transcriptional coactivators regulate synaptic gene expression, the number and morphology of NMJs, and synaptic nuclei. Yap1 or Taz single knockout mice display reduced grip strength, fragmentation of NMJs, and accumulation of synaptic nuclei. Yap1/Taz muscle-specific double knockout mice do not survive beyond birth and possess almost no NMJs, the few detectable show severely impaired morphology and are organized in widened endplate bands; and with motor nerve endings being …