Digital Commons Network^™

Eus-Guided Hydrogel Injection To Separate Pancreatic Head Carcinoma From Duodenum For Enhanced Radiotherapy: Multi-Site Feasibility Study, Manoop S Bhutani, Amol K Narang, Kai Ding, Brenna Casey, Kumar Krishnan, Eugene J Koay, Theodore S Hong, Joseph M Herman, Kristen H Griffin, Eun Ji Shin

Faculty, Staff and Student Publications

Background and study aims The proximity of a pancreas head tumor to the duodenum often limits delivery of an ablative dose of radiation therapy. This study evaluated the feasibility and safety of using an injectable polyethylene glycol (PEG) hydrogel between the head of the pancreas and duodenum.

Patients and methods In a multi-site feasibility cohort study of patients with localized pancreatic cancer, PEG hydrogel was injected under endoscopic ultrasound guidance to temporarily position the duodenum away from the pancreas. Procedure characteristics were recorded, including hydrogel volume and space created. Patients were monitored for adverse events (AEs) and radiotherapy toxicity.

Results …

Ccr2+ Monocytes Promote White Matter Injury And Cognitive Dysfunction After Myocardial Infarction, Edward B Thorp, Mallory Filipp, Maria Dima, Chunfeng Tan, Matthew Feinstein, Brian Popko, Matthew Deberge

Faculty, Staff and Student Publications

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells …

Behavioral Therapies Targeting Reward Mechanisms In Substance Use Disorders, Margaret C Wardle, Heather E Webber, Jin H Yoon, Angela M Heads, Angela L Stotts, Scott D Lane, Joy M Schmitz

Faculty, Staff and Student Publications

Behavioral therapies are considered best practices in the treatment of substance use disorders (SUD) and used as first-line approaches for SUDs without FDA-approved pharmacotherapies. Decades of research on the neuroscience of drug reward and addiction have informed the development of current leading behavioral therapies that, while differing in focus and technique, have in common the overarching goal of shifting reward responding away from drug and toward natural non-drug rewards. This review begins by describing key neurobiological processes of reward in addiction, followed by a description of how various behavioral therapies address specific reward processes. Based on this review, a conceptual …

Identification Of A Clinically Efficacious Car T Cell Subset In Diffuse Large B Cell Lymphoma By Dynamic Multidimensional Single-Cell Profiling, Ali Rezvan, Gabrielle Romain, Mohsen Fathi, Darren Heeke, Melisa Martinez-Paniagua, Xingyue An, Irfan N Bandey, Melisa J Montalvo, Jay R T Adolacion, Arash Saeedi, Fatemeh Sadeghi, Kristen Fousek, Nahum Puebla-Osorio, Laurence J N Cooper, Chantale Bernatchez, Harjeet Singh, Nabil Ahmed, Mike Mattie, Adrian Bot, Sattva Neelapu, Navin Varadarajan

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) T cells used for the treatment of B cell malignancies can identify T cell subsets with superior clinical activity. Here, using infusion products of individuals with large B cell lymphoma, we integrated functional profiling using timelapse imaging microscopy in nanowell grids with subcellular profiling and single-cell RNA sequencing to identify a signature of multifunctional CD8+ T cells (CD8-fit T cells). CD8-fit T cells are capable of migration and serial killing and harbor balanced mitochondrial and lysosomal volumes. Using independent datasets, we validate that CD8-fit T cells (1) are present premanufacture and are associated with clinical responses …

Cholesterol-Dependent Lxr Transcription Factor Activity Represses Pronociceptive Effects Of Estrogen In Sensory Neurons And Pain Induced By Myelin Basic Protein Fragments, Swathi K Hullugundi, Jennifer Dolkas, Andrei V Chernov, Tony L Yaksh, Kelly A Eddinger, Mila Angert, Glaucilene Ferreira Catroli, Alex Y Strongin, Patrick M Dougherty, Yan Li, Oswal Quehenberger, Aaron Armando, Veronica I Shubayev

Faculty, Staff and Student Publications

Background: A bioactive myelin basic protein (MBP) fragment, comprising MBP84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling.

Methods: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP84-104 interactors …

Cancer Incidence After Diagnosis Of Abdominal Aortic Aneurysm-Brief Report, Lingfeng Luo, Allen M Haas, Caitlin F Bell, Richard A Baylis, Shaunak S Adkar, Changhao Fu, Ivan Angelov, Sharon H Giordano, Derek Klarin, Nicholas J Leeper, Kevin T Nead

Faculty, Staff and Student Publications

Background: Epidemiological and mechanistic data support a potential causal link between cardiovascular disease (CVD) and cancer. Abdominal aortic aneurysms (AAAs) represent a common form of CVD with at least partially distinct genetic and biologic pathogenesis from other forms of CVD. The risk of cancer and how this risk differs compared with other forms of CVD, is unknown among AAA patients. We conducted a retrospective cohort study using the IBM MarketScan Research Database to test whether individuals with AAA have a higher cancer risk independent of traditional shared risk factors.

Methods: All individuals ≥18 years of age with ≥36 months of …

Pten Deficiency Induces An Extrahepatic Cholangitis-Cholangiocarcinoma Continuum Via Aurora Kinase A In Mice, Yan Yang, Jiale Wang, Jianhua Wan, Qianqian Cheng, Zenong Cheng, Xueli Zhou, Oliver Wang, Kelvin Shi, Lingxiang Wang, Bin Wang, Xiaohui Zhu, Jiaxiang Chen, Dongfeng Feng, Yang Liu, Yasmin Jahan-Mihan, Ashley N Haddock, Brandy H Edenfield, Guang Peng, Jessica D Hohenstein, Chantal E Mccabe, Daniel R O'Brien, Chen Wang, Sumera I Ilyas, Liuyan Jiang, Michael S Torbenson, Huamin Wang, Raouf E Nakhleh, Xuemei Shi, Ying Wang, Yan Bi, Gregory J Gores, Tushar Patel, Baoan Ji

Faculty, Staff and Student Publications

Background & aims: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease.

Methods: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the …

Navigating The Critical Translational Questions For Implementing Flash In The Clinic, Billy W Loo, Ioannis I Verginadis, Brita Singers Sørensen, Anthony E Mascia, John P Perentesis, Albert C Koong, Emil Schüler, Erinn B Rankin, Peter G Maxim, Charles L Limoli, Marie-Catherine Vozenin

Faculty, Staff and Student Publications

The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions. Technological questions pertinent to each beam type (eg, electron, proton, photon) also dictate the logical progression of …

The Dynamic Trpv2 Ion Channel Proximity Proteome Reveals Functional Links Of Calcium Flux With Cellular Adhesion Factors Ncam And L1cam In Neurite Outgrowth, Pamela N Gallo, Elaine Mihelc, Robyn Eisert, Gary A Bradshaw, Florian Dimek, Andreas Leffler, Marian Kalocsay, Vera Moiseenkova-Bell

Faculty, Staff and Student Publications

TRPV2 voltage-insensitive, calcium-permeable ion channels play important roles in cancer progression, immune response, and neuronal development. Despite TRPV2's physiological impact, underlying endogenous proteins mediating TRPV2 responses and affected signaling pathways remain elusive. Using quantitative peroxidase-catalyzed (APEX2) proximity proteomics we uncover dynamic changes in the TRPV2-proximal proteome and identify calcium signaling and cell adhesion factors recruited to the molecular channel neighborhood in response to activation. Quantitative TRPV2 proximity proteomics further revealed activation-induced enrichment of protein clusters with biological functions in neural and cellular projection. We demonstrate a functional connection between TRPV2 and the neural immunoglobulin cell adhesion molecules NCAM and L1CAM. …

Plasmacytoid Dendritic Cells Control Homeostasis Of Megakaryopoiesis, Florian Gaertner, Hellen Ishikawa-Ankerhold, Susanne Stutte, Wenwen Fu, Jutta Weitz, Anne Dueck, Bhavishya Nelakuditi, Valeria Fumagalli, Dominic Van Den Heuvel, Larissa Belz, Gulnoza Sobirova, Zhe Zhang, Anna Titova, Alejandro Martinez Navarro, Kami Pekayvaz, Michael Lorenz, Louisa Von Baumgarten, Jan Kranich, Tobias Straub, Bastian Popper, Vanessa Zheden, Walter Anton Kaufmann, Chenglong Guo, Guido Piontek, Saskia Von Stillfried, Peter Boor, Marco Colonna, Sebastian Clauß, Christian Schulz, Thomas Brocker, Barbara Walzog, Christoph Scheiermann, William C Aird, Claus Nerlov, Konstantin Stark, Tobias Petzold, Stefan Engelhardt, Michael Sixt, Robert Hauschild, Martina Rudelius, Robert A J Oostendorp, Matteo Iannacone, Matthias Heinig, Steffen Massberg

Faculty, Staff and Student Publications

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK …

Use Of Ipsc-Derived Smooth Muscle Cells To Model Physiology And Pathology, Callie S Kwartler, Jose Emiliano Esparza Pinelo

Faculty, Staff and Student Publications

The implementation of human induced pluripotent stem cell (hiPSC) models has introduced an additional tool for identifying molecular mechanisms of disease that complement animal models. Patient-derived or CRISPR/Cas9-edited induced pluripotent stem cells differentiated into smooth muscle cells (SMCs) have been leveraged to discover novel mechanisms, screen potential therapeutic strategies, and model in vivo development. The field has evolved over almost 15 years of research using hiPSC-SMCs and has made significant strides toward overcoming initial challenges such as the lineage specificity of SMC phenotypes. However, challenges both specific (eg, the lack of specific markers to thoroughly validate hiPSC-SMCs) and general (eg, …

Spontaneous Repolarization Alternans Causes Vt/Vf Rearrest That Is Suppressed By Preserving Gap Junctions, Kenneth R. Laurita, Joseph S. Piktel, Laken Irish, Michelle Nassal, Aurelia Cheng, Matthew Mccauley, Gary Pawlowski, Adrienne T. Dennis, Yi Suen, Soufian Almahameed, Ohad Ziv, Lance D. Wilson

Faculty Scholarship

Background: Ventricular tachycardia (VT)/ventricular fibrillation (VF) rearrest after successful resuscitation is common, and survival is poor. A mechanism of VT/VF, as demonstrated in ex vivo studies, is when repolarization alternans becomes spatially discordant (DIS ALT), which can be enhanced by impaired gap junctions (GJs). However, in vivo spontaneous DIS ALT–induced VT/VF has never been demonstrated, and the effects of GJ on DIS ALT and VT/VF rearrest are unknown. Objectives: This study aimed to determine whether spontaneous VT/VF rearrest induced by DIS ALT occurs in vivo, and if it can be suppressed by preserving Cx43-mediated GJ coupling and/or connectivity. Methods: We …

Α-Synuclein Seed Amplification Technology For Parkinson's Disease And Related Synucleinopathies, Claudio Soto

Faculty, Staff and Student Publications

Synucleinopathies are a group of neurodegenerative diseases (NDs) associated with cerebral accumulation of α-synuclein (αSyn) misfolded aggregates. At this time, there is no effective treatment to stop or slow down disease progression, which in part is due to the lack of an early and objective biochemical diagnosis. In the past 5 years, the seed amplification technology has emerged for highly sensitive identification of these diseases, even at the preclinical stage of the illness. Much research has been done in multiple laboratories to validate the efficacy and reproducibility of this assay. This article provides a comprehensive review of this technology, including …

Microbiomes In Birds: A Review Of Links To Health And Reproduction, Mary Ann Ottinger, Shailaja Mani, Sonja Krüger, Brent Coverdale, Sandi Willows-Munro, Leigh Combrink

Faculty, Staff and Students Publications

Microbiomes have emerged as a key component essential for maintaining the health of an organism. Additionally, the roles of microbiomes are multifaceted, some unique to specific body areas and organs while others, particularly the gut microbiome, having broader effects on the entire organism. Comparative literature is emerging that compares microbiomes across mammals and birds. Domestic poultry have been the most extensively studied relative to their role in production agriculture. These data have provided a great deal of information about the effects of diet and nutritional requirements relative to the gut microbiome, productivity, and resilience to diseases. Conversely, limited research has …

Epigenetic Regulation Of Heart Failure, Manisha Deogharia, Priyatansh Gurha

Faculty, Staff and Student Publications

Purpose of review: The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding of epigenetics. In this review, we provide an overview of the recent studies on epigenetic mechanisms implicated in heart failure.

Recent findings: We focus on the major mechanisms and the conceptual advances in epigenetics as evidenced by studies in humans and mouse models of heart failure. The significance of epigenetic modifications and the enzymes that catalyze them is also discussed. New findings from the studies of histone lysine demethylases demonstrate their significance in regulating fetal gene expression, as …

Emerging Cell And Molecular Targets For Treating Mucus Hypersecretion In Asthma, Ana M Jaramillo, Eszter K Vladar, Fernando Holguin, Burton F Dickey, Christopher M Evans

Faculty, Staff and Student Publications

Mucus provides a protective barrier that is crucial for host defense in the lungs. However, excessive or abnormal mucus can have pathophysiological consequences in many pulmonary diseases, including asthma. Patients with asthma are treated with agents that relax airway smooth muscle and reduce airway inflammation, but responses are often inadequate. In part, this is due to the inability of existing therapeutic agents to directly target mucus. Accordingly, there is a critical need to better understand how mucus hypersecretion and airway plugging are affected by the epithelial cells that synthesize, secrete, and transport mucus components. This review highlights recent advances in …

Cholesterol-Dependent Lxr Transcription Factor Activity Represses Pronociceptive Effects Of Estrogen In Sensory Neurons And Pain Induced By Myelin Basic Protein Fragments, Swathi K Hullugundi, Jennifer Dolkas, Andrei V Chernov, Tony L Yaksh, Kelly A Eddinger, Mila Angert, Glaucilene Ferreira Catroli, Alex Y Strongin, Patrick M Dougherty, Yan Li, Oswal Quehenberger, Aaron Armando, Veronica I Shubayev

Faculty, Staff and Student Publications

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP

METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP

RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP

CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of …

Valine Aminoacyl-Trna Synthetase Promotes Therapy Resistance In Melanoma, Najla El-Hachem, Marine Leclercq, Miguel Susaeta Ruiz, Raphael Vanleyssem, Kateryna Shostak, Pierre-René Körner, Coralie Capron, Lorena Martin-Morales, Patrick Roncarati, Arnaud Lavergne, Arnaud Blomme, Silvia Turchetto, Eric Goffin, Palaniraja Thandapani, Ivan Tarassov, Laurent Nguyen, Bernard Pirotte, Alain Chariot, Jean-Christophe Marine, Michael Herfs, Francesca Rapino, Reuven Agami, Pierre Close

Faculty, Staff and Student Publications

Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

50-Nm Gas-Filled Protein Nanostructures To Enable The Access Of Lymphatic Cells By Ultrasound Technologies, Qionghua Shen, Zongru Li, Yixian Wang, Matthew D Meyer, Marc T De Guzman, Janie C Lim, Han Xiao, Richard R Bouchard, George J Lu

Faculty, Staff and Student Publications

Ultrasound imaging and ultrasound-mediated gene and drug delivery are rapidly advancing diagnostic and therapeutic methods; however, their use is often limited by the need for microbubbles, which cannot transverse many biological barriers due to their large size. Here, the authors introduce 50-nm gas-filled protein nanostructures derived from genetically engineered gas vesicles(GVs) that are referred to as

Surgical Opportunism For Hand Reconstruction Following A Mutilating Injury: A Case Report., Krishna A Patel, Tuna Özyurekoglu

Trauma and Acute Care Articles

We report our management of a 53-year-old female who suffered a wood planer hand-mutilating injury with significant dorsal soft tissue loss and partial metacarpophalangeal joint (MCPJ) amputations of the thumb, index, and middle fingers. The middle finger was deconstructed for "spare parts" and a vascularized osteochondral graft was utilized to reconstruct the metacarpal articular surface of the index finger proximal phalanx, allowing the pedicled transposition of the index finger to the third metacarpal. The middle finger's distal interphalangeal joint was transplanted non-vascularly to recreate the thumb MCPJ and the elevation of a middle finger fillet flap allowed dorsal wound coverage. …

Dose-Dependent Effects Of Dnmt3a In An Inducible Murine Model Of Krasg12d-Driven Leukemia, Jason H Rogers, Allison Rosen, Jaime M Reyes, Shamika Ketkar, Shannon E Conneely, Rohit Gupta, Luibin Yang, Matthew B Miller, Geraldo Medrano, Rogelio Aguilar, Nneka Uchenda, Margaret A Goodell, Rachel E Rau

Children’s Nutrition Research Center Staff Publications

DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies including acute myeloid leukemia (AML). An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly co-mutated genes in myeloid malignancies such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ER^T2 murine model systems to study the effects of constitutively active Kras^G12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of …

Inhibition Of Cathepsin S In Autoimmune Cd25ko Mouse Improves Sjögren Disease-Like Lacrimal Gland Pathology, Kaitlin K Scholand, Jeremias Galletti, Wolfgang Haap, Tiago Santos-Ferreira, Christoph Ullmer, Cintia S De Paiva

Faculty, Staff and Students Publications

PURPOSE: CD25KO mice are a model of Sjögren disease (SjD) driven by autoreactive T cells. Cathepsin S (CTSS) is a protease crucial for major histocompatibility complex class II presentation that primes T cells. We investigated if a diet containing CTSS inhibitor would improve autoimmune signs in CD25KO mice.

METHODS: Four-week female CD25KO mice were randomly chosen to receive chow containing a CTSS inhibitor (R05461111, 262.5 mg/kg chow) or standard chow for 4 weeks. Cornea sensitivity was measured. Inflammatory score was assessed in lacrimal gland (LG) histologic sections. Flow cytometry of LG and ocular draining lymph nodes (dLNs) investigated expression of …

Genetic Deletion Of Galectin-3 Inhibits Pancreatic Cancer Progression And Enhances The Efficacy Of Immunotherapy, Daowei Yang, Xinlei Sun, Rohan Moniruzzaman, Hua Wang, Citu Citu, Zhongming Zhao, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive.

Methods: We generated a novel transgenic mouse model (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1-Cre;Lgals3-/- [KPPC;Lgals3-/-]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated …

Learning Curve For Endoscopic Submucosal Dissection (Esd) In The United States: Large, Untutored, Single-Operator Experience, Mai A Khalaf, Fares Ayoub, Kristen A Staggers, Johanna W El-Haj, Salmaan Jawaid, Mohamed O Othman

Faculty, Staff and Students Publications

Background and study aims Endoscopic submucosal dissection (ESD) allows removal of tumors en-bloc. Western adoption of ESD has been hindered by its steep learning curve. Western data regarding ESD learning curve are limited. We analyzed the learning curve of a single endoscopist at a tertiary referral center in the United States.

Patients and methods All consecutive ESDs performed by a single endoscopist at a tertiary referral center in the United States from 2015 through 2022 were identified. Descriptive statistics and CUSUM analysis were used to describe the learning curve for en-bloc, R0 resection, and resection speed.\

Results In our study, …

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

Acute Kidney Injury In Patients With Cirrhosis: Acute Disease Quality Initiative (Adqi) And International Club Of Ascites (Ica) Joint Multidisciplinary Consensus Meeting, Mitra K Nadim, John A Kellum, Lui Forni, Claire Francoz, Sumeet K Asrani, Marlies Ostermann, Andrew S Allegretti, Javier A Neyra, Jody C Olson, Salvatore Piano, Lisa B Vanwagner, Elizabeth C Verna, Ayse Akcan-Arikan, Paolo Angeli, Justin M Belcher, Scott W Biggins, Akash Deep, Guadalupe Garcia-Tsao, Yuri S Genyk, Pere Gines, Patrick S Kamath, Sandra L Kane-Gill, Manish Kaushik, Nuttha Lumlertgul, Etienne Macedo, Rakhi Maiwall, Sebastian Marciano, Raimund H Pichler, Claudio Ronco, Puneeta Tandon, Juan-Carlos Q Velez, Ravindra L Mehta, François Durand

Faculty, Staff and Students Publications

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting …

The Multifaceted Life Of Macrophages In White Adipose Tissue: Immune Shift Couples With Metabolic Switch, Qun Wang, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We …

Mechanisms Of Gelofusine Protection In An In Vitro Model Of Polymyxin B-Associated Renal Injury, Cole S Hudson, Anirban Roy, Qingtian Li, Aniket S Joshi, Taijun Yin, Ashok Kumar, David Sheikh-Hamad, Vincent H Tam

Faculty, Staff and Students Publications

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was …

Exome Sequencing Identifies Novel Genes Underlying Primary Congenital Glaucoma In The National Birth Defects Prevention Study, Elizabeth E Blue, Kristin J Moore, Kari E North, Tania A Desrosiers, Suzan L Carmichael, Janson J White, Jessica X Chong, Michael J Bamshad, Mary M Jenkins, Lynn M Almli, Lawrence C Brody, Sharon F Freedman, Jennita Reefhuis, Paul A Romitti, Gary M Shaw, Martha Werler, Denise M Kay, Marilyn L Browne, Marcia L Feldkamp, Richard H Finnell, Wendy N Nembhard, Faith Pangilinan, Andrew F Olshan, National Institutes Of Health Intramural Sequencing Center, University Of Washington Center For Mendelian Genomics, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.

Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention …