Pathology Commons^™

Cells And Networks In Flux: Rethinking Ontogenesis And Pathogenesis, Mark L. Tykocinski

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Organ and tissue functions emerge from the coordinated activity of cell networks. Therapeutics that act on pathogenic cell networks, modulating their cellular interplay, follow naturally. Over several decades, our laboratory has developed a series of approaches for rewiring cell networks, culminating in a class of cell surface-directed signal converter proteins (SCPs) that do so by modulating juxtacrine and autocrine signaling in and among their nodal cells. A first such SCP has now produced encouraging clinical data for cancer immunotherapy. Yet, these early network-directed fusion proteins rest on a deliberately simplified picture: discrete end-cell types plugged into graphically tractable networks. That …

Intermembrane Coupling Between Bcl-Xl And The Ip3 Receptor Supports Local Ca2+ Transfer At Er-Mitochondrial Contacts, Arijita Ghosh, David Weaver, Chi Li, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP₃ receptor Ca²⁺ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca²⁺ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca²⁺ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca²⁺ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy …

An Inf2-Dependent Actin-Mediated Step In Inositol 1,4,5-Trisphosphate Receptor Cluster Formation And Activity, Maite R. Zavala, Amrapali Ghosh, Suresh K. Joseph, Rajarshi Chakrabarti

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Intracellular calcium signaling plays a vital role in regulating various cellular processes including gene regulation, motility, metabolism, and cell death. Inositol 1,4,5-trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER) are a major cation channel that regulates stimulus-induced calcium release from the ER. While several molecular players regulate the activity of IP3R, its regulation by actin filaments was uncharacterized. Here, we show that actin filaments polymerized by the specific actin nucleator INF2 facilitate agonist-induced IP3R activity. Our results demonstrate that INF2-mediated actin filaments regulate the formation and/or stability of IP3R clusters on the ER that have been previously shown to be …

Intrathecal (G4c2)149 Delivery In C9orf72-Deficient Mice Yields Mild Motor Dysfunction And Als/Ftd Pathological Hallmarks, Katelyn Russell, Amelia Shahrabi, Suleyman Akerman, Matthew D. Byrne, Jeffrey Rothstein, Davide Trotti, Brigid Jensen, Aaron Haeusler

Farber Institute for Neuroscience Faculty Papers

A repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity …

Disease-Causing Mfn2 Mutants Impair Mitochondrial Fission Dynamics By Distinct Drp1 Dysregulation, Daniel Lagos, Pamela R. De Santiago, Nicolás Pérez-Bravo, Benjamín Cartes-Saavedra, Josefa Vial-Brizzi, Diego Troncoso-Chandía, Oliver Podmanicky, Rita Horvath, Verónica Eisner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular …

Routine Transfusion Of Rh(D)-Positive Rbcs To Rh(D)-Negative Patients Designated As Do Not Resuscitate Conserves Rh(D)-Negative Red Blood Cell Inventory, Julie Katz Karp, Jovanna Everetts, Juliana Guarente, Angelica Vivero, Tiffany Bohr, Mary Harach

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: A minority of blood donors are Rh(D)-negative, and Rh(D)-negative red blood cell (RBC) products are often overutilized. As such, Rh(D)-negative RBCs may be difficult to maintain in blood bank inventory.

Study design and methods: We changed our blood bank laboratory policy to approve non-alloimmunized Rh(D)-negative patients to receive Rh(D)-positive RBCs for routine transfusion under defined criteria. Those criteria included Rh(D)-negative males (all ages) and females (aged >50 years) who were designated as do not resuscitate (DNR), either with or without intubation, in the electronic medical record.

Results: From August 15, 2024 through August 15, 2025, a total of 204 …

Inhibition Of Cyclophilin D Rescues Cardiac Function And Bioenergetic Defects Caused By Neonatal Hypoxia, Jonathan R. Burris, Gisela Beutner, Min Yee, Bartholomew V. Simon, Michael F. Swartz, Kathryn B. Boudreau, Ethan D. Cohen, Chaitanya A. Kulkarni, Prottoy Hasan, Hongyue Wang, Karen L. De Mesy Bentley, György Hajnóczky, George M. Alfieris, Eric M. Small, Paul S. Brookes, Michael A. O'Reilly, George A. Porter

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Increased oxygen levels at birth regulate myocyte bioenergetic and structural maturation controlled by mitochondrial cyclophilin D (CypD). We evaluated mechanisms of neonatal hypoxic cardiac dysfunction by exposing neonatal mice to 12% oxygen and studied cardiac bioenergetics, myocyte maturation, and function. Hypoxia decreased the activity/assembly of electron transport chain complex I, uncoupled oxidative phosphorylation, increased proliferation, decreased differentiation, increased ventricular mass, and decreased cardiac function. CypD inhibition rescued most hypoxia-mediated effects and increased cardiac function. In conclusion, neonatal hypoxia alters cardiac bioenergetics, myocyte maturation, and cardiac function through CypD-dependent pathways, providing potential therapeutic targets for neonatal cardiac dysfunction.

Hydatid Cyst In The Right Ventricle Leading To Tricuspid Stenosis And Heart Failure: A Case Report, Muhammad Sheraz Hameed, Syed Rafay Hussain Zaidi, Shafaq Saleem, Muhammad Ahsan, Sarah Rahman, Azeen Razzaq, Ali Iqbal, Muhammad Sohaib Alvi, Muhammad Usama Naveed

Department of Medicine Faculty Papers

BACKGROUND: Cystic hydatid infection is a parasitic disease caused by the larval stages of Echinococcus granulosus, most commonly involving the liver and lungs. Cardiac involvement is rare, accounting for less than 2% of cases, with the left ventricle being the most commonly affected site. Involvement of the right ventricle is extremely uncommon and may lead to life-threatening complications such as tricuspid valve obstruction and hemodynamic compromise.

CASE PRESENTATION: We report a rare case of a 42-year-old patient who presented to the emergency department with exertional dyspnea, hemoptysis, chest pain, syncope, peripheral edema, and signs of right-sided heart failure. The patient …

Ms-Gator: Multi-Scale Graph Attention With Topological Reasoning For Segmentation And Classification Of Prostate Cancer Based On Gleason Scores Using Histopathology Images, Sujata Patil, Mahadeva Swamy, Kavitha Sooda, Rajanikanth Vadigepalli, Khalid Nazim Abdul Sattar, Md Rafeeq

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Prostate cancer is one of the prevalent and potentially fatal malignancies, affecting men globally. Accurate segmentation and classification of prostate cancer in histopathology images remain challenging due to complex tissue architecture, staining variability, and high inter-observer differences in manual diagnosis. To address these challenges, this research proposes a Multi-Scale Graph Attention with Topological Reasoning (MS-GATOR) for segmentation and classification of prostate cancer based on Gleason Scores (GS). The MS-GATOR incorporates topological reasoning with hierarchical biological structures by constructing a graph-based representation among three spatial scales such as nuclei, glands, and tissues using Delaunay triangulation to capture both geometric and photometric …

Tumor Biology And Access To Care And Metastatic Breast Cancer Outcomes, Matthew R. Dunn, Sarah C. Van Alsten, Marc A. Emerson, Katherine Reeder-Hayes, Terry Hyslop, Melissa A. Troester

Kimmel Cancer Center Faculty Papers

PURPOSE: To understand how access to care influences metastatic breast cancer burden (MBC) while accounting for molecular tumor characteristics, and identify interventions to reduce metastatic disease burden.

METHODS: The Carolina Breast Cancer Study is a population-based cohort with invasive breast cancer (diagnosed 2008-2013). Both de novo metastasis (stage IV at diagnosis) and distant recurrence were evaluated (12 years of follow-up. Tumor data were from medical records, pathology reports, and RNA expression data. Social variables and access to care were from participant surveys. Generalized linear models were used to estimate associations of biological and access characteristics with MBC; Cox models were …

A Tissue Renewal-Based Mechanism Drives Colon Tumorigenesis, Ryan M. Boman, Gilberto Schleiniger, Christopher Raymond, Juan P. Palazzo, Anne Shehab, Bruce M. Boman

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Our Goal is to identify how colorectal cancer (CRC) arises in the single-layered cell epithelium (simple columnar epithelium) that lines the luminal surface of the large intestine. Background: We recently reported that the dynamic organization of cells in colonic epithelium is encoded by five biological rules and conjectured that colon tumorigenesis involves an autocatalytic tissue renewal reaction. Introduction Our objective was to define how altered crypt turnover explains tissue disorganization that leads to adenoma morphogenesis and CRC. Hypothesis: Changes in rate of tissue renewal-based cell polymerization leads to epithelial expansion and tissue disorganization during adenoma histogenesis. Methods: Accordingly, we created …

Correction: Amino Acid Transporter Lat1 (Slc7a5) Promotes Metabolic Rewiring In Tnbc Progression Through The L-Trp/Qprt/Nad+ Pathway, Margot Y. Fedoroff, Lei Zhao, Shaomin Wang, Leili Saeednejad Zanjani, Alok Bhushan, Haifeng Yang, Karen M. Bussard, Stephen C Peiper, Jun He

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Correction: J Exp Clin Cancer Res 44, 190 (2025) Following publication of the original article [1], the authors found that Dr. Leila Saeednejad Zanjani was not included in the final author list despite her contributions. The details are provided below: Current authors: Margot Y. Fedoroff1†, Lei Zhao1†, Shaomin Wang1, Alok Bhushan2, Haifeng Yang1, Karen M. Bussard3, Stephen C. Peiper1 and Jun He1*. Updated author list: Margot Y. Fedoroff1†, Lei Zhao1†, Shaomin Wang1, Leili Saeednejad Zanjani1, Alok Bhushan2, Haifeng Yang1, Karen M Bussard3, Stephen C Peiper1, Jun He1*. The correction does not compromise the validity of the conclusions and the overall …

Sex-Specific Angiogenic Responses In Endothelial Cells-Role Of The Pluripotency Factor Oct4, Junchul Shin, Junyoung Hong, Iuliia Molokotina, Irene Krukovets, Ellin Kim, Svyatoslav Tkachenko, Eugene Podrez, Tatiana V Byzova, Olga A Cherepanova

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The study investigates the sex-specific effects of the pluripotency factor OCT4 deficiency in endothelial cells (ECs) on angiogenesis. OCT4 is known for its role in embryonic stem cells, but we recently found that it plays a protective role in ECs during atherosclerosis. Herein, we utilized cultured mouse aortic ECs (MAECs) and several in vivo models, including skin wounding, melanoma tumor implantation, and hindlimb ischemia, to explore the role of OCT4 in angiogenesis in both male and female mice. Our findings revealed significant sexual dimorphism in wild type mice, along with sex differences in responses to OCT4 deficiency across all three …

Discovery Of A Small Molecule Tlr3 Agonist Adjuvant, Branden Lee, Danica Dong, Etsuro Nanishi, John Mark Awad, Kimia Abedi, Yoshine Saito, Francesco Borriello, Soumik Barman, Byron Brook, Aisling Kelly, Manisha Menon, Constance Marques-Mourlet, Maansi Gupta, Ida Lister, Chiwoo Oh, Kevin Lyskawa, Morgan Goetz, Kristina Walker, Wing Ki Cheng, Spencer Brightman, Pankaj Sharma, Timothy O'Meara, Katherine Chew, Daniel Vieira, Kevin Ryff, Cali Sweitzer, Sanya Thomas, Simon Van Haren, Matthew Pettengill, Hyuk-Soo Seo, Sirano Dhe-Paganon, Wei Zhang, Ofer Levy, David Dowling

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pattern-recognition receptor (PRR) agonists are valuable agents across multiple medical applications, from vaccinology to immune-oncology. However, well-defined and potent small molecule agonists for many PRRs still await discovery and development. Screening of chemical libraries of ~200,000 small molecules for maturation of human monocytic cells by quantifying NF-κB activation and cell adherence was completed. From this screen, we selected a thiazole benzamide derivative, PVP-057, for its robust immunomodulatory properties, low toxicity profile, and concentration-dependent activity. In vitro investigation of pathway and receptor activation reveals that PVP-057 is a Toll-like receptor 3 (TLR3) agonist. As a single-component adjuvant, administered intramuscularly or intradermally …

Short-Term Preeclampsia Prediction: Cutoff Variations For Sflt-1/Plgf In U.S. Patients With Or Without Hypertensive Disorders, Yaxin Li, Kristen Cagino, Jim Yee, Caroline Andy, Dajana Borova, Ayush Shah, Isla Racine, Tracy Grossman, Zhen Zhao

Student Papers, Posters & Projects

BACKGROUND: Preeclampsia (PE) is a complex disorder with significant maternal and fetal risks. The soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio shows promise as a diagnostic tool, but its adoption in the U.S. remains limited due to the lack of accessible testing platforms, U.S.-based studies, and evidence-based implementation guidelines.

PATIENTS/MATERIALS AND METHODS: We conducted a cohort study to evaluate the sFlt-1/PlGF ratio for predicting PE within two weeks among pregnant individuals ≥18 years, ≥20 weeks gestation. Serum samples were obtained from routine prenatal visits or triage evaluations. sFlt-1/PlGF ratios were measured using Roche Elecsys assays, and …

Decorin Deficiency Promotes D-Galactose-Induced Skeletal Muscle Atrophy And Fibrosis By Regulating Itgb1/Akt/Mtor Signalling Pathway, Xiaoqin Luo, Mengxue Zhang, Lili Chen, Ruichang Wang, Jiabing Lian, Zhe Yang, Renato V. Iozzo, Jin Wang, Yan Zhang, Xiuli Bi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Primary sarcopenia is an age-associated disorder with progressive and generalised loss of skeletal muscle strength and mass. Skeletal muscle fibrosis is one of the significant pathological manifestations of age-associated sarcopenia. Decorin, a small dermatan-sulfate proteoglycan, participates in extracellular matrix assembly. In numerous studies, the involvement of decorin is not restricted to matrix structural proteins, and it also affects a diverse variety of biological functions like cell growth, adhesion, migration, proliferation and differentiation. Additionally, it modulates the process of inflammation and fibrillogenesis. Based on these preclinical evidences, we hypothesised that decorin may potentially play an important role in skeletal muscles …

Perceived Gaps In Preparation For Pathology Residency And Opportunities For Improvement, Barbara Knollmann-Ritschel, Julie Karp, Stephanie Barak, John Childs, Kristen Johnson, Amanda Lofgreen, Mary Berg, Satyapal Chahar, Hailey Gosnell, Cindy Mccloskey, Balaram Puligandla, Kristie White, Bronwyn Bryant

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The transition from medical school to residency is both a transformative and a challenging process. International literature suggests that there are known or perceived gaps in preparation for residency training in many areas of medicine. However, in the current published literature, there is no discussion of perceived gaps existing in pathology residency preparation. This study surveyed both pathology residency program directors and first-year pathology residents about the knowledge of pathology and basic medical skills residents received in medical school, perceptions about readiness for pathology residency, and perceived gaps in preparation for pathology residency that could be addressed. This survey found …

Role Of M6a Mrna Methylation In Plant Defense, Rakesh Srivastava, Niraj Lodhi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

N6-methyladenosine (m⁶A) is the most abundant and dynamic RNA modification in eukaryotic messenger and non-coding RNAs, playing a pivotal role in the post-transcriptional regulation of gene expression. The coordinated actions of m⁶A writers, erasers, and readers influence transcript stability, immune activation, and pathogen suppression. Growing evidence indicates that m⁶A fine-tunes the expression of defense-related genes, modulates RNA processing events, and is frequently hijacked by pathogens and pests to promote virulence. Notably, the dual role of m⁶A in enhancing plant defense and facilitating pathogen adaptation highlights its significance in the host–pathogen arms race. …

Decorin Evokes A Pro-Lysosomal Pathway In Lymphatic Endothelial Cells, Gabriel J. Pascal, Dipon K. Mondal, Sadie Kim, Christopher Xie, Devanarayanan Siva Sankar, Jörn Dengjel, Renato V. Iozzo

Kimmel Cancer Center Faculty Papers

The lymphatic system is critical to the body's immune and circulatory system, and lymphangiogenesis, the development of new lymphatic vessels from pre-existing ones is a significant process capitalized upon by cancer during tumorigenesis. Decorin is a small leucine-rich proteoglycan which we have previously shown to be anti-tumorigenic and a suppressor of lymphangiogenesis. We have also shown that decorin exercises its anticancer properties through its ability to evoke autophagy. Through a comprehensive and unbiased proteomic analysis, we explored the implications of decorin exposure on protein expression within mouse lymphatic endothelial cells. We discovered that decorin enriches several protein pathways, notably proteasomal …

Decorin Evokes A Pro-Lysosomal Pathway In Lymphatic Endothelial Cells, Gabriel J. Pascal, Dipon K. Mondal, Sadie Kim, Christopher Xie, Devanarayanan Siva Sankar, Jörn Dengjel, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The lymphatic system is critical to the body's immune and circulatory system, and lymphangiogenesis, the development of new lymphatic vessels from pre-existing ones, is a significant process capitalized upon by cancer during tumorigenesis. Decorin is a small leucine-rich proteoglycan which we have previously shown to be anti-tumorigenic and a suppressor of lymphangiogenesis. We have also shown that decorin exercises its anticancer properties through its ability to evoke autophagy. Through a comprehensive and unbiased proteomic analysis, we explored the implications of decorin exposure on protein expression within mouse lymphatic endothelial cells. We discovered that decorin enriches several protein pathways, notably proteasomal …

Distinct Transcriptional Regulation Of The Wnt And Tgfβ Signaling Families Associated With Wound Healing And Fibrotic Outcomes To Lens Injury, Catherine Lalman, Kylie R. Stabler, Joshua Disatham, Lisa A. Brennan, Marc Kantorow, Janice L. Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Posterior capsule opacification (PCO) is a fibrotic complication of cataract surgery caused by aberrant repair of residual lens cells. It remains unclear how the lens injury response shifts toward a pathological repair process. Here, we performed a transcriptional analysis of two major pro-fibrotic pathways, the TGF-β superfamily and Wnt signaling pathways to determine how they are differentially regulated during regenerative wound healing versus fibrosis in a lens injury model. For these studies, RNA sequencing was performed on an ex vivo lens explant system that models post-surgical healing within regenerative and fibrotic microenvironments, from 0 to 3 days post-injury. Fibrotic conditions …

Dynamics And Malleability Of Plant Dna Methylation During Abiotic Stresses, Niraj Lodhi, Rakesh Srivastava

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Epigenetic regulation, particularly DNA methylation, plays a crucial role in plant adaptation to environmental stresses by modulating gene expression without altering the underlying DNA sequence. In response to major abiotic stresses such as salinity, drought, heat, cold, and heavy metal toxicity, plants undergo dynamic changes in DNA methylation patterns. These modifications are orchestrated by DNA methyltransferases and demethylases with variations depending on plant species, genetic background, and ontogenic phase. DNA methylation affects the expression of key genes involved in cellular, physiological, and metabolic processes essential for stress tolerance. Furthermore, it contributes to the establishment of stress memory, which can be …

Astrocytes Expressing Mutant Hnrnpa1 Induce Non-Cell-Autonomous Motor Neuron Death, Qinxue Wu, Xionghao Liu, Tingting Zhang, Shiquan Cui, Bo Huang, Cao Huang, Qilin Cao, Xu-Gang Xia, Hongxia Zhou

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pathogenic mutation of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is causative to amyotrophic lateral sclerosis (ALS). Neuron death resulting from pathogenic hnRNPA1 may not require its presence across all pertinent cells types, including neurons, glia, and muscles. Rather, the exclusive presence of pathogenic hnRNPA1 in a specific cell type, such as astrocytes, may suffice to substantially alter cellular functions. Consequently, this alteration initiates abnormal interaction within intricate neuron-glia networks, culminating in non-cell-autonomous motor neuron death. To investigate the pivotal role of non-cell-autonomous neuron death in hnRNPA1-associated ALS, we developed transgenic rats overexpressing mutant hnRNPA1 in specifically astrocytes. The confined overexpression of …

Matrix Molecules Associated With Both Regulation Of Inflammation And Pathogenic Outcomes Associated With The Surface Of The Lens In The Eyes Of Eau Mice, Phuong M. Le, Jodirae Dedreu, Mary J Mattapallil, Rachel R Caspi, Ryan Tomlinson, Mary Ann Stepp, A. Sue Menko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Immune cells with immunoregulatory properties are recruited to the surface of the lens in the Experimental Autoimmune Uveitis (EAU) mouse and remain linked through resolution of EAU inflammation. Since protein components of the extracellular matrix provide biochemical and mechanical signals that regulate immune cell migration and phenotype, we investigated whether EAU inflammation caused matrix molecules to become associated with the lens surface. We focused on matrix proteins known to influence leukocyte phenotype and behavior, and/or lead to pathological outcomes in uveitis. We found that fibrinogen became associated with the lens capsule surface by the peak of EAU inflammation and increased …

Amino Acid Transporter Lat1 (Slc7a5) Promotes Metabolic Rewiring In Tnbc Progression Through The L-Trp/Qprt/Nad+ Pathway, Margot Y. Fedoroff, Lei Zhao, Shaomin Wang, Alok Bhushan, Haifeng Yang, Karen M. Bussard, Stephen C. Peiper, Jun He

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Cancer cells uptake excessive nutrients by expressing higher levels of glucose and/or amino acid transporters to meet their increased energy demands. L-type amino acid transporter 1 (LAT1), is regarded as a cancer-specific transporter for the uptake of large neutral amino acids such as L-tryptophan. However, the mechanism by which LAT1 rewires cellular metabolism to promote cancer progression and chemoresistance have not yet been investigated.

METHODS: The protein levels of LAT1, p-PKM2, and p-LDHA were determined in breast cancer tissue arrays by immunohistochemistry staining followed by survival analysis. The orthotopic breast cancer models in mice, syngeneic breast cancer models, and …

Developmental Lead Exposure And Aggression In Male Rats: Influences Of Maternal Care And Environmental Enrichment, Shamaila Zafar, Courtney K. Williams, Jaehyun Joo, Blanca E. Himes, Jay S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Developmental lead (Pb) exposure results in a variety of cognitive deficits and behavioral issues including increased antisocial behavior and aggression. This study investigated the effect of developmental Pb exposure on aggression and violent behavior in male rats and the potential modulatory influences of quality of maternal care and enriched/non-enriched housing conditions. Long-Evans male rats with or without Pb exposure (perinatal or early postnatal) from low or high maternal care mothers (based on amounts of licking/grooming and arched- back nursing) were randomly assigned to live in enriched or non-enriched environments at weaning. At post- natal day 120–190, offensive aggression was assessed …

Neovascular Pruning By Ido1 Inhibitors Can Potentiate Immunogenic Cytotoxicity Of Ischemia-Targeted Agents To Synergistically Enhance Anti-Pd-1 Responsiveness, Shih-Chun Shen, Souvik Dey, James B. Duhadaway, Erika Sutanto-Ward, Maurice T. Hampton, Serguei V. Kozlov, George C. Prendergast, Alexander J. Muller

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Strategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1's role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-γ that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.

METHODS: Pulmonary metastases …

Rescue Of The First Mitochondrial Membrane Carrier, The Mpic, By Tat-Mediated Protein Replacement Treatment, Samar Zabit, Orly Melloul, Michal Lichtenstein, Erin L. Seifert, Haya Lorberboum-Galski

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The mitochondrial phosphate carrier (mPiC), encoded by the nuclear gene SLC25A3, is synthesized with an N-terminus mitochondrial targeting sequence (MTS), enabling its import into the mitochondria. mPiC imports inorganic phosphate (P_i) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca²⁺ uptake and buffering of matrix Ca²⁺. PiC also imports copper (Cu), crucial to COX subunit holoenzyme assembly. Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first …

Targeting Bard1 Suppresses A Myc-Dependent Transcriptional Program And Tumor Growth In Pancreatic Ductal Adenocarcinoma, Sohum Patel, Eleanor Jenkins, Rutuj P. Kusurkar, Sherry Lee, Wei Jiang, Avinoam Nevler, Matthew Mccoy, Michael J. Pishvaian, Rosalie C. Sears, Jonathan R. Brody, Charles J. Yeo, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin-proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. …

Case Report: Myeloid Neoplasms With The T(3;12)(Q26.2;P13.1)/ Mecom-Etv6 Translocation: Report Of Two New Cases And Review Of The Literature, Soumya Mikkilineni, Juan Pablo Pineda-Reyes, Lindsay Wilde, Andres Ferber, Zi-Xuan Wang, Stephen Peiper, Guldeep Uppal, Md, Jerald Gong, Jinglan Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The MECOM (MDS1 and EVI1 complex locus) gene, located at 3q26.2, encodes an oncogenic transcription factor implicated in multiple signaling pathways. Rearrangements involving MECOM/3q26.2, including inversions, translocations, insertions and cryptic chromosomal changes, are observed in myeloid neoplasms and are associated with high-risk disease features and poor clinical outcomes. The translocation t(3;12)(q26.2;p13.1) is a rare genetic event, resulting in a fusion of the MECOM gene at 3q26.2 with the ETV6 gene at 12p13.1. To date, only 78 cases of hematologic neoplasms harboring t(3;12) have been reported in the English literature, primarily as case reports or case series. T(3;12) has …