Medical Pathology Commons^™

Investigation On The Effects Of Hypoxia-Mimicking Agents In Cancer Progression And Oxidative Stress In Hepatocellular Carcinoma, June Wong Xin Ni

Student Works (2020-2029)

Hypoxia, or oxygen deprivation, is a common pathological feature found in hepatocellular carcinoma (HCC). Hypoxia-inducible factor (HIF) is the master transcription factor of oxygen homeostasis, eliciting a wide range of cellular adaptive responses to either enhance oxygen delivery or reduce oxygen consumption. HIF is primarily regulated by two types of oxygen sensors, the prolyl hydroxylase domain-containing proteins (PHDs) and factor-inhibiting HIF (FIH). In tumours, HIF functions as a double-edged sword whereby it could either promote or hinder tumour progression. This is mainly contributed by the pleiotropic nature of hypoxia and tumour heterogeneity. Recently, there is a growing interest in the …

The Non-Coding Rna Journal Club: Highlights On Recent Papers-14, El Cheima Mhamedi, Florent Hubé, Suresh K. Alahari, Francisco J. Enguita, Barbara Pardini, Mark W. Feinberg, Laura Poliseno, Beshoy Armanios, Jing Jin, Xiao-Bo Zhong, Nikolaos Sideris, Salih Bayraktar, Leandro Castellano, Gaetano Santulli, Stanislovas S. Jankauskas, Will S. Plewa, Simon J. Conn, Ling Yang, Patrick K. Shiu, Abhishek Kaushik, Alexander Serganov, Gentile, Giuseppe Viglietto, Nicola Amodio, Tijana Mitić, Andrea Caporali

School of Graduate Studies Faculty Publications

The field of non-coding RNA research is advancing at a breathtaking pace, continually uncovering new layers of regulatory complexity and functional diversity [...].

Pseudomonas Aeruginosa Exoenzyme Y Enzymatic Activity Inhibits Exoenzyme S-Induced Caspase Activation But Not Cytotoxicity In Pulmonary Microvascular Endothelial Cells, Connor Holm

Honors Theses

Pseudomonas aeruginosa (P. aeruginosa) is the most common cause of ventilator-associated pneumonia in intensive care unit patients. P. aeruginosa utilizes a type III secretion system that injects exoenzymes U, S, T, and/or Y into the host cell cytosol. A majority of clinically isolated P. aeruginosa strains express ExoY often in combination with ExoU and ExoT, or ExoS and ExoT. Host signaling mechanisms in response to intoxication with individual exoenzymes have been extensively studied, yet little is known about host cell response to co-intoxication. In this study, pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains expressing different combinations …

Mechanisms Of Familial And Uv-Induced Melanoma, Jeri D. Hughes

Pursuit - The Journal of Undergraduate Research at The University of Tennessee

Melanoma is the most common form of skin cancer in the United States. Melanoma is a disease where cancerous cells derive from melanocytes. Common melanoma susceptibility genes induce dysregulation in the mitogen-activated protein kinase (MAPK) pathway, phosphatase and tensin homolog (PTEN),and AKT expression. Melanoma can be induced through prolonged UV-radiation or familial diagnosis. This article aims to discuss the mechanisms of both familial and UV-induced melanomagenesis

Coronary Artery Disease – Future Tools For Optimizing Primary Prevention, Nick Makosiej

Capstone Showcase

Coronary artery disease (CAD) is a progressive, obstructive, and inflammatory process affecting the endothelial lining of the coronary arteries, which ultimately compromises the perfusion of the myocardium and can lead to ischemic infarction. This narrowing of vasculature which supplies the myocardial tissue leads to a spectrum of anginal syndromes and inevitably, catastrophic consequences. This article is focused on understanding the pathophysiology of this disease process and educating providers on emerging clinical tools that can be utilized to prevent progression, and ultimately reduce morbidity and mortality of this insidious disease process.

Hif Expression In Clear-Cell Renal Cell Carcinoma (Ccrcc) Tumors Of Adults With And Without Obstructive Sleep Apnea (Osa), Olivia Heppell, Carlos Guerra Londono, Nilesh Gupta

Medical Student Research Symposium

Introduction: Upregulation of hypoxia-inducible factors (HIF) is an important pathological feature shared by clear cell renal cell carcinoma (ccRCC) and obstructive sleep apnea (OSA). However, it is unclear whether OSA alters the pathogenesis of ccRCC via HIF expression.

Methods: A retrospective cohort of adults undergoing nephrectomy for ccRCC was identified electronically (IRB#16040-1). The diagnosis of OSA was established with preoperative STOP-BANG scores or polysomnography. A consecutive sample of 20 individuals with and 20 without OSA was selected. Clinical characteristics and pathology results were reviewed. Resected tumor sections were immunohistochemically stained for HIF-1& HIF-2 at antibody dilutions of 1:150. Intensity and …

Preclinical Repurposing Of Sitagliptin As A Drug Candidate For Colorectal Cancer By Targeting Cd24/Ctnnb1/Sox4-Centered Signaling Hub, Jing-Wen Shih, Alexander T H Wu, Ntlotlang Mokgautsi, Po-Li Wei, Yan-Jiun Huang

Faculty, Staff and Student Publications

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also …

Pdgfra And B Copositive Fibroblasts Drive Fibrosis In Mouse Salivary Glands Through Tgfβ Signaling, Renae Williams Atkinson

Electronic Theses & Dissertations (2024 - present)

Fibrosis is of significant concern to the medical community as numerous disease processes are characterized by progressive fibrosis leading to organ damage. We begin the process of examining the mechanism of fibrosis to salivary gland hypofunction and briefly consider Sjögren’s Disease (SjD). Method: We employed single-cell RNA sequencing data from a reversible mouse salivary gland injury model and from NOD/ShiLtJ mice, a model of secondary SjD. We performed treatment comparisons with the help of Seurat dotplots and UMAPS. Using differential gene expression analysis and the publicly available R packages: clusterProfiler, WikiPathways and Cytoscape, we identified the processes and pathways …

Pathobiology Of Myocardial Ischemia And Reperfusion Injury: Models, Modes, Molecular Mechanisms, Modulation, And Clinical Applications, L Maximilian Buja

Faculty, Staff and Student Publications

This review presents an integrated approach to the analysis of myocardial ischemia and reperfusion injury and the modulating influence of myocardial conditioning during the evolution of acute myocardial infarction (AMI) and other clinical settings. Experimental studies have involved a spectrum of in vitro, ex vivo, and in vivo models, and guidelines have been developed for the conduct of rigorous preclinical studies and for the identification of various forms of cell injury and death in evolving AMI. AMI in vivo is dominated by oncosis (cell injury with swelling) leading to necroptosis and final necrosis of ischemic cardiomyocytes (CMCs), without or with …

Role Of Phosphorylated Dicer1 In Tumor Progression, Raisa Reyes-Castro

Dissertations and Theses (Open Access)

DICER1 is a multidomain enzyme discovered and widely recognized for its function in small non-coding microRNA (miRNA) synthesis. In cancer development, DICER1 functions as a haploinsufficient tumor suppressor which regulates miRNAs and Epithelial-to-Mesenchymal Transition (EMT). The Arur laboratory discovered that DICER1 is phosphorylated by active ERK and that ERK-mediated phosphorylation triggers DICER1 to translocate from the cytoplasm to the nucleus of cells in worms, mice and humans. Further, a heterozygous allele of a genetically engineered mouse model of phosphomimetic Dicer1 when combined with heterozygous Kras oncogenic background contributes to lung tumor progression in vivo. Mechanisms through which phosphomimetic Dicer1 …

Sindrom Respons Inflamasi Sistemik, Yefta Moenadjat

Department of Surgery Teaching Materials and Monographs

Materi perkuliahan memuat uraian respons inflamasi pascatrauma yang berkembang menjadi sindrom respons inflamasi sistemik, berakhir dengan kegagalan organ multipel ditinjau dari aspek biomolekuler.

Buku ini merupakan bagian pertama dari seri inflamasi yang disusun dalam bentuk digital dan dipublikasi menurut konsep lisensi Commons Attribution-NonCommercial 4.0 International License untuk tujuan diseminasi.

Identity, Structure, And Function Of The Mitochondrial Permeability Transition Pore: Controversies, Consensus, Recent Advances, And Future Directions, Paolo Bernardi, Christoph Gerle, Andrew P. Halestrap, Elizabeth A. Jonas, Jason Karch, Nelli Mnatsakanyan, Evgeny Pavlov, Shey-Shing Sheu, Alexander A. Soukas

Center for Translational Medicine Faculty Papers

The mitochondrial permeability transition (mPT) describes a Ca2+-dependent and cyclophilin D (CypD)-facilitated increase of inner mitochondrial membrane permeability that allows diffusion of molecules up to 1.5 kDa in size. It is mediated by a non-selective channel, the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening causes mitochondrial swelling, which ruptures the outer mitochondrial membrane leading to subsequent apoptotic and necrotic cell death, and is implicated in a range of pathologies. However, transient mPTP opening at various sub-conductance states may contribute several physiological roles such as alterations in mitochondrial bioenergetics and rapid Ca2+ efflux. Since its discovery decades ago, intensive efforts …

Changes In Nascent Chromatin Structure Regulate Activation Of The Pro-Fibrotic Transcriptome And Myofibroblast Emergence In Organ Fibrosis, Morgan D. Basta, Svetlana Petruk, Ross Summer, Joel Rosenbloom, Peter J. Wermuth, Edward J. Macarak, Alex V. Levin, Alexander Mazo, Janice L. Walker

Department of Biochemistry and Molecular Biology Faculty Papers

Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. …

Acute Kidney Injury In The Elderly, Zachary Palanza

Honors Scholar Theses

Acute kidney injury (AKI) is a significant clinical concern in the elderly, marked by heightened incidence rates, increased morbidity and mortality, and impaired kidney repair mechanisms. AKI often has severe consequences, including extended hospital stays, heightened rates of chronic kidney disease, and elevated healthcare costs. The vulnerability of elderly individuals to AKI is amplified by age-related structural and functional changes in the kidneys, reduced physiological reserve, and increased exposure to nephrotoxic agents. The impaired kidney repair mechanisms observed in the elderly pose further complexities in AKI management. With age, the regenerative capacity of the kidneys diminishes, resulting in incomplete recovery …

Acute Acat1/Soat1 Blockade Increases Mam Cholesterol And Strengthens Er-Mitochondria Connectivity., Taylor C Harned, Radu V Stan, Ze Cao, Rajarshi Chakrabarti, Henry N Higgs, Catherine C Y Chang, Ta Yuan Chang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). The genetic and pharmacological blockade of acyl-CoA:cholesterol acyltransferase 1/sterol O-acyltransferase 1 (ACAT1/SOAT1), a cholesterol storage enzyme found on the endoplasmic reticulum (ER) and enriched at the mitochondria-associated ER membrane (MAM), has been shown to reduce amyloid pathology and rescue cognitive deficits in mouse models of AD. Additionally, blocking ACAT1/SOAT1 activity stimulates autophagy and lysosomal biogenesis; however, the exact molecular connection between the ACAT1/SOAT1 blockade and these observed benefits remain …

Epstein-Barr Virus-Associated Lymphoepithelial Carcinoma Arising In The Parotid Gland: A Case Report And Literature Review, Akinobu Kubota, Nobuyuki Bandoh, Takashi Goto, Ken-Ichi Matsumoto, Tomomi Yamaguchi-Ishochi, Yasutaka Kato, Hiroshi Nishihara, Hidehiro Takei

Faculty, Staff and Student Publications

A 60-year-old woman presented with a 3-year history of a slow-growing, painless mass in their left parotid gland. Ultrasonography revealed a well-circumscribed, lobulated, hypoechoic mass measuring 19x12x10 mm in the left parotid gland. Computed tomography revealed a well-circumscribed, solid mass with homogeneous enhancement. Fluorodeoxyglucose-positron emission tomography revealed uptake by the tumor but no uptake in other organs, including the nasopharynx. The patient underwent superficial parotidectomy with adequate safety margins and selective neck dissection followed by radiotherapy. No facial paralysis or recurrence of the tumor had been observed as of 20 months post-operation. Histologically, the tumor was composed of sheets of …

Molecular Mechanisms Of Prdm16 As A Tumor Suppressor In Pancreatic Ductal Adenocarcinoma, Eric Hurwitz

Theses and Dissertations

The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-b) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the Kras^G12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation …

Healthy Exosomes And Their Effects On Diabetic Cardiomyocytes, Miguel A. Garza, Genaro A. Ramírez-Correa, Maria Lourdes Garza-Rodríguez, Andres J. Medina

MEDI 9331 Scholarly Activities Clinical Years

Extracellular Vesicles, and more specifically, exosomes, are essential for effective cell-to-cell communication in a wide variety of tissues. In the last couple of decades, these nanovesicles have been proven to be active participants and regulators in many disease processes; therefore, their therapeutic effects have been widely studied and proven in various cardiovascular diseases both, in vitro and in vivo. Thus, this study aims at assessing the effects of running healthy mice exosomes on cardiomyocyte and cardiac tissue samples obtained from diabetic mice. Here, we successfully extract exosomes from mice plasma and detect their presence through the use of anti-CD9 and …

Anthracyclines Attenuate The Nrf1-Mediated Bounce-Back Response, Bader Albalawi

Theses and Dissertations

Proteasome inhibitors, such as carfilzomib, are FDA-approved to treat multiple myeloma and mantle cell lymphoma. Unfortunately, proteasome inhibitors have only produced clinically significant results in patients with hematologic cancers, despite their predicted pan-cancer utility, and even hematologic cancer types frequently show intrinsic and acquired resistance.

One proposed mechanism responsible for the proteasome inhibitors' shortcomings is the NRF1-mediated bounce-back response. Identification of drugs that can potentiate the action of proteasome inhibitors could overcome resistance in patients with hematologic cancers and expand proteasome inhibitors' use to treat solid tumors. Our previous studies have identified anthracyclines as potential compounds that interfere with the …

Platelet Micrornas Inhibit Primary Tumor Growth Via Broad Modulation Of Tumor Cell Mrna Expression In Ectopic Pancreatic Cancer In Mice, Jeremy G.T. Wurtzel, Sophia Lazar, Sonali Sikder, Kathy Q Cai, Igor Astsaturov, Andrew S Weyrich, Jesse W Rowley, Lawrence E. Goldfinger

Department of Medicine Faculty Papers

We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls …

Hypercalcemia Of Malignancy Attributed To Cosecretion Of Pth And Pthrp In Lung Adenocarcinoma, Jeffrey Kroopnick, Ubaldo E. Martinez-Outshoorn, Madalina Tuluc, Caroline S Kim

Department of Medical Oncology Faculty Papers

Introduction: Hypercalcemia of malignancy (HCM) portends a very poor prognosis, and no established guidelines exist regarding its management. Most instances of HCM are due to local osteolysis or secretion of parathyroid hormone related-peptide, while less than 1% of all cases are due to ectopic secretion of parathyroid hormone.

Case report: We present an unusual case of HCM due to proposed cosecretion of both parathyroid hormone and parathyroid hormone-related protein in a 36-year-old man with a poorly differentiated lung adenocarcinoma. The patient's hypercalcemia was refractory to conventional measures, including intravenous bisphosphonate therapy (zoledronic acid), and was improved with administration of denosumab. …

Bispecific Human Il2-Ccr4 Immunotoxin Targets Human Cutaneous T-Cell Lymphoma, Haoyu Wang, Zhaohui Wang, Huiping Zhang, Zeng Qi, Ariel C Johnson, David Mathes, Elizabeth A Pomfret, Erin Rubin, Christene A Huang, Zhirui Wang

Faculty, Staff and Student Publications

The majority of clinically diagnosed cutaneous T‐cell lymphomas (CTCL) highly express the cell‐surface markers CC chemokine receptor 4 (CCR4) and/or CD25. Recently, we have developed diphtheria toxin‐based recombinant Ontak®‐like human IL2 fusion toxin (IL2 fusion toxin) and anti‐human CCR4 immunotoxin (CCR4 IT). In this study, we first compared the efficacy of the CCR4 IT vs IL2 fusion toxin for targeting human CD25+CCR4+ CTCL. We demonstrated that CCR4 IT was more effective than IL2 fusion toxin. We further constructed an IL2‐CCR4 bispecific IT. The bispecific IT was significantly more effective than either IL2 fusion toxin or CCR4 IT alone. The bispecific …

Educational Needs Of Newly Diagnosed Cancer Patients In Learning About Cancer: A Qualitative Study In The Malaysian Urban Setting, Munisamy Murallitharan

Student Works (2020-2029)

Patients with chronic diseases such as cancer are able to have better outcomes if they understand about all aspects of the disease, develop the correct attitude to manage themselves and their disease better; and engage in preventive practices that can help them prevent worsening of disease or recurrence. Patient education is an intervention that has proven to be effective in different settings for this. However in the Malaysian cancer setting, the educational needs of patients are poorly understood. The aim of this study was to explore and understand the educational needs of newly diagnosed cancer patients in learning about cancer …

Identifying Exosomes In Oral Squamous Cell Carcinoma With Efirm, Bram Holladay

Student Scholarship

Oral Squamous Cell Carcinoma (OSCC) affects 53,000 Americans each year making it the sixth most common cancer in the United States. The incidence rate may be even higher since current screening methods are underutilized and physical examinations can misdiagnose malignant oral tumors as benign inflammatory lesions. Recent advances in genetic, protein, and extracellular vesicle biomarker detection techniques can monitor the transformation of healthy cells into tumors before terminal stages arise. Biomarkers can be easily extracted from biofluids such as saliva making them less invasive than traditional tissue biopsies. One biomarker prevalent in OSCC is exosomes, which are extracellular vesicles that …

Supervised Dimension Reduction For Large-Scale "Omics" Data With Censored Survival Outcomes Under Possible Non-Proportional Hazards, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

The past two decades have witnessed significant advances in high-throughput ``omics" technologies such as genomics, proteomics, metabolomics, transcriptomics and radiomics. These technologies have enabled simultaneous measurement of the expression levels of tens of thousands of features from individual patient samples and have generated enormous amounts of data that require analysis and interpretation. One specific area of interest has been in studying the relationship between these features and patient outcomes, such as overall and recurrence-free survival, with the goal of developing a predictive ``omics" profile. Large-scale studies often suffer from the presence of a large fraction of censored observations and potential …

Characterization Of Different Molecular Markers For Identification Of Salmonella Enterica Serovar Typhi In Pakistani Population, Faizan Muttiullah, Fida Muhammad Khan, Fakhar-I- Abbas, Sabiha Shamim

Journal of Bioresource Management

Typhoid is caused by Salmonella enterica serovar Typhi that is usually diagnosed by using serologic and immuno-chromatographic techniques in developing counties including Pakistan, which is thought to be an unreliable diagnostic method. For accurate diagnosis we used molecular techniques to amplify 204 bp StyR-36 and 498 bp flagellin gene for the identification of Salmonella enterica serovar Typhi. This study was done on 58 individuals diagnosed positive of typhoid via serologic tests and 50 healthy individuals as a control group. Success rate of amplification for flagellin gene was 77.58% while that for StyR-36 gene was 68.97% showing that flagellin gene primer …

Telomerase Reverse Transcriptase In Atherosclerosis, Hua Qing

Theses and Dissertations--Pharmacology and Nutritional Sciences

Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase and the limiting factor for the enzyme activity. The expression of TERT and telomerase activity is increased in atherosclerotic plaques. However, the role of TERT dysregulation during atherosclerosis formation remains unknown.

The work herein first identified a multi-tiered regulation of TERT expression in smooth muscle cells (SMC) through histone deacetylase (HDAC) inhibition. HDAC inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Furthermore, during vascular remodeling in vivo, TERT protein …

The Pathogenesis Of Natural Killer/T Cell Lymphoma, Bei Jiang

Theses & Dissertations

Extranodal natural killer/T-cell lymphomas (NKTCL) are uncommon lymphomas with poor prognosis. In order to gain a better understanding of the molecular pathogenesis of NKTCL, we obtained and compared the global gene expression profile, global somatic mutation profile, and global methylation profile of normal NK cells, malignant NK cell lines, and NKTCL patient samples. We showed that the JAK-STAT pathway was constitutively activated in NKTCL through the cooperation between activation of signal transducer and activator of transcription proteins (STATs) via activating mutations and inactivation of STAT suppressor protein suppressor of cytokine signaling 6 (SOCS6) through promoter hypermethylation. Activating STAT3 and STAT5B …

Human Neural Progenitor Cells Are Productively Infected By R5-Tropic Hiv-1: Opiate Interactions On Infection And Function Involve Cdk5 Signaling, Joyce Magat Balinang

Theses and Dissertations

Human immunodeficiency virus type 1 (HIV-1) is known to cause a spectrum of neurological, behavioral and motor deficits collectively termed as HIV-1 associated neurocognitive impairments (HAND). Opiates augment HIV-related CNS complications through both direct and indirect mechanisms that disrupt glial and neuronal function. All CNS macroglia and neurons derive from neural progenitor cells (NPCs) during development, and NPCs in the adult brain contribute to repair processes. Since disruptions in NPC function are known to impact CNS populations and brain function in a number of disease/injury conditions, we determined whether HIV ± opiate exposure affected the maturation and fate of human …

Analysis Of Differential Mrna And Mirna Expression In An Alzheimer’S Disease Mouse Model, Amanda Hazy, Matthew Dalton

Other Undergraduate Scholarship

Research has shown that changes in gene expression play a critical role in the development of Alzheimer’s Disease (AD). Our project will evaluate genome-wide RNA expression patterns from brain and blood in an AD mouse model. This analysis will provide insight regarding the mechanisms of AD pathology as well as determine a possible diagnostic tool utilizing RNA expression patterns found in the blood as biomarkers for AD.