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Distinct Mechanisms Control Genome Recognition By P53 At Its Target Genes Linked To Different Cell Fates., Marina Farkas, Hideharu Hashimoto, Yingtao Bi, Ramana V Davuluri, Lois Resnick-Silverman, James J. Manfredi, Erik W. Debler, Steven B. McMahon 2021 Thomas Jefferson University

Distinct Mechanisms Control Genome Recognition By P53 At Its Target Genes Linked To Different Cell Fates., Marina Farkas, Hideharu Hashimoto, Yingtao Bi, Ramana V Davuluri, Lois Resnick-Silverman, James J. Manfredi, Erik W. Debler, Steven B. Mcmahon

Department of Biochemistry and Molecular Biology Faculty Papers

The tumor suppressor p53 integrates stress response pathways by selectively engaging one of several potential transcriptomes, thereby triggering cell fate decisions (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to 20-bp response elements (REs) in the genome (RRRCWWGYYYN0-13RRRCWWGYYY). In general, REs at cell cycle arrest targets (e.g. p21) are of higher affinity than those at apoptosis targets (e.g., BAX). However, the RE sequence code underlying selectivity remains undeciphered. Here, we identify molecular mechanisms mediating p53 binding to high- and low-affinity REs by showing that key determinants of the ...


Tumor Microenvironment: An Evil Nexus Promoting Aggressive Head And Neck Squamous Cell Carcinoma And Avenue For Targeted Therapy, Ajaz A. Bhat, Parvaiz Yousuf, Nissar A. Wani, Arshi Rizwan, Shyam S. Chauhan, Mushtaq A. Siddiqi, Davide Bedognetti, Wael El-Rifai, Michael P. Frenneaux, Surinder K. Batra, Mohammad Haris, Muzafar A. Macha 2021 Sidra Medicine

Tumor Microenvironment: An Evil Nexus Promoting Aggressive Head And Neck Squamous Cell Carcinoma And Avenue For Targeted Therapy, Ajaz A. Bhat, Parvaiz Yousuf, Nissar A. Wani, Arshi Rizwan, Shyam S. Chauhan, Mushtaq A. Siddiqi, Davide Bedognetti, Wael El-Rifai, Michael P. Frenneaux, Surinder K. Batra, Mohammad Haris, Muzafar A. Macha

Journal Articles: Biochemistry & Molecular Biology

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a poor prognosis for advanced-stage tumors. Recent clinical, genomic, and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC. Despite significant advances in multimodal therapeutic interventions, failure to cure and recurrence are common and account for most deaths. It is becoming increasingly apparent that tumor microenvironment (TME) plays a critical role in HNSCC tumorigenesis, promotes the evolution of aggressive tumors and resistance to therapy, and thereby adversely affects the prognosis. A complete understanding of the TME factors, together with the highly complex tumor-stromal interactions ...


Radiation Induces Metabolic Dysregulation In Pulmonary Fibroblasts, Josly Pierre-Louis, Margaret A. T. Freeberg, Jane K. Rebman, Thomas H. Thatcher, Patricia J. Sime 2021 Virginia Commonwealth University

Radiation Induces Metabolic Dysregulation In Pulmonary Fibroblasts, Josly Pierre-Louis, Margaret A. T. Freeberg, Jane K. Rebman, Thomas H. Thatcher, Patricia J. Sime

Graduate Research Posters

Rationale: Exposure of the lung to ionizing radiation, such as during radiotherapy, can result in pulmonary fibrosis (PF), which has few treatment options. PF is characterized by an accumulation of extracellular matrix proteins that form scar tissue, resulting in dyspnea, disruption of gas exchange, and even death. We and others have shown that metabolic reprogramming is a hallmark of idiopathic pulmonary fibrosis (IPF). IPF lung tissue, and lung fibroblasts treated with TGF-β, exhibit increased aerobic glycolysis with increased expression of lactate dehydrogenase A (LDHA) and excess production of lactate, leading to reduced extracellular pH that activates latent TGF-β. Here, we ...


A Biochemical Characterization Of The Fusion Proteins From Enveloped Rna Viruses, Chelsea T. Barrett 2021 University of Kentucky

A Biochemical Characterization Of The Fusion Proteins From Enveloped Rna Viruses, Chelsea T. Barrett

Theses and Dissertations--Molecular and Cellular Biochemistry

Enveloped viruses must bind target cells and then fuse the viral membrane with a cell membrane to enter a host cell. These viruses use one or more surface glycoproteins to carry out these critical functions. The surface glycoprotein that carries out the fusion function, termed a fusion protein, is divided into three classes based on structural similarities. Some of the most studied human viral pathogens, such as human immunodeficiency virus (HIV), Ebola virus, influenza, measles, and the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), possess class I fusion proteins. Following synthesis, class I fusion proteins associate as non-covalently ...


The Current Landscape Of Antibody-Based Therapies In Solid Malignancies, Ashu Shah, Sanchita Rauth, Abhijit Aithal, Sukhwinder Kaur, Koelina Ganguly, Catherine Orzechowski, Grish C. Varshney, Maneesh Jain, Surinder K. Batra 2021 University of Nebraska Medical Center

The Current Landscape Of Antibody-Based Therapies In Solid Malignancies, Ashu Shah, Sanchita Rauth, Abhijit Aithal, Sukhwinder Kaur, Koelina Ganguly, Catherine Orzechowski, Grish C. Varshney, Maneesh Jain, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Over the past three decades, monoclonal antibodies (mAbs) have revolutionized the landscape of cancer therapy. Still, this benefit remains restricted to a small proportion of patients due to moderate response rates and resistance emergence. The field has started to embrace better mAb-based formats with advancements in molecular and protein engineering technologies. The development of a therapeutic mAb with long-lasting clinical impact demands a prodigious understanding of target antigen, effective mechanism of action, gene engineering technologies, complex interplay between tumor and host immune system, and biomarkers for prediction of clinical response. This review discusses the various approaches used by mAbs for ...


Comparison Of Circulating Tumour Dna And Extracellular Vesicle Dna By Low-Pass Whole-Genome Sequencing Reveals Molecular Drivers Of Disease In A Breast Cancer Patient, Olivia Ruhen, Bob Mirzai, Michael E. Clark, Bella Nguyen, Carlos Salomon, Wendy Erber, Katie Meehan 2021 Edith Cowan University

Comparison Of Circulating Tumour Dna And Extracellular Vesicle Dna By Low-Pass Whole-Genome Sequencing Reveals Molecular Drivers Of Disease In A Breast Cancer Patient, Olivia Ruhen, Bob Mirzai, Michael E. Clark, Bella Nguyen, Carlos Salomon, Wendy Erber, Katie Meehan

ECU Publications Post 2013

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. There is increasing recognition of circulating tumour DNA (ctDNA) as a non-invasive alternative to tumour tissue for the molecular characterisation and monitoring of disease. Recent evidence suggests that cancer-associated changes can also be detected in the DNA contained within extracellular vesicles (EVs). As yet, there has been limited investigation into the relationship between EV DNA and ctDNA, and no studies have examined the EV DNA of breast cancer patients. The aim of this study was to use low-pass whole-genome sequencing to identify copy number variants (CNVs) in serial samples of both ctDNA ...


Hitting The Bullseye: Are Extracellular Vesicles On Target?, Nicole Noren Hooten, María Yáñez-Mó, Rachel M. DeRita, Ashley Russell, Peter Quesenberry, Bharat Ramratnam, Paul D Robbins, Dolores Di Vizio, Sicheng Wen, Kenneth W Witwer, Lucia R Languino 2020 National Institute on Aging

Hitting The Bullseye: Are Extracellular Vesicles On Target?, Nicole Noren Hooten, María Yáñez-Mó, Rachel M. Derita, Ashley Russell, Peter Quesenberry, Bharat Ramratnam, Paul D Robbins, Dolores Di Vizio, Sicheng Wen, Kenneth W Witwer, Lucia R Languino

Department of Cancer Biology Faculty Papers

No abstract provided.


Clinical Application Of Oncolytic Viruses: A Systematic Review, Mary Cook, Aman Chauhan 2020 University Of Maryland

Clinical Application Of Oncolytic Viruses: A Systematic Review, Mary Cook, Aman Chauhan

Internal Medicine Faculty Publications

Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic ...


Blocking C-Met/Erbb1 Axis Prevents Brain Metastasis In Erbb2+ Breast Cancer, Shailendra K. Gautam, Ranjana K. Kanchan, Jawed A. Siddiqui, Shailendra K. Maurya, Sanchita Rauth, Naveenkumar Perumal, Pranita Atri, Ramakanth C. Venkata, Kavita Mallya, Sameer Mirza, Moorthy P. Ponnusamy, Vimla Band, Sidharth Mahapatra, Maneesh Jain, Surinder K. Batra, Mohd W. Nasser 2020 University of Nebraska Medical Center

Blocking C-Met/Erbb1 Axis Prevents Brain Metastasis In Erbb2+ Breast Cancer, Shailendra K. Gautam, Ranjana K. Kanchan, Jawed A. Siddiqui, Shailendra K. Maurya, Sanchita Rauth, Naveenkumar Perumal, Pranita Atri, Ramakanth C. Venkata, Kavita Mallya, Sameer Mirza, Moorthy P. Ponnusamy, Vimla Band, Sidharth Mahapatra, Maneesh Jain, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo ...


Upregulation Of Cpt1a Is Essential For The Tumor-Promoting Effect Of Adipocytes In Colon Cancer, Xiaopeng Xiong, Yang-An Wen, Rachelle Fairchild, Yekaterina Y. Zaytseva, Heidi L. Weiss, B. Mark Evers, Tianyan Gao 2020 University of Kentucky

Upregulation Of Cpt1a Is Essential For The Tumor-Promoting Effect Of Adipocytes In Colon Cancer, Xiaopeng Xiong, Yang-An Wen, Rachelle Fairchild, Yekaterina Y. Zaytseva, Heidi L. Weiss, B. Mark Evers, Tianyan Gao

Markey Cancer Center Faculty Publications

Colon tumors grow in an adipose tissue-enriched microenvironment. Locally advanced colon cancers often invade into surrounding adipose tissue with a direct contact with adipocytes. We have previously shown that adipocytes promote tumor growth by modulating cellular metabolism. Here we demonstrate that carnitine palmitoyltransferase I (CPT1A), a key enzyme controlling fatty acid oxidation (FAO), was upregulated in colon cancer cells upon exposure to adipocytes or fatty acids. In addition, CPT1A expression was increased in invasive tumor cells within the adipose tissue compared to tumors without direct contact with adipocytes. Silencing CPT1A abolished the protective effect provided by fatty acids against nutrient ...


Acinar Transformed Ductal Cells Exhibit Differential Mucin Expression In A Tamoxifen-Induced Pancreatic Ductal Adenocarcinoma Mouse Model, Kavita Mallya, Dhanya Haridas, Parthasarathy Seshacharyulu, Ramesh Pothuraju, Wade M. Junker, Shiv Ram Krishn, Sakthivel Muniyan, Raghupathy Vengoji, Surinder K. Batra, Satyanarayana Rachagani 2020 University of Nebraska Medical Center

Acinar Transformed Ductal Cells Exhibit Differential Mucin Expression In A Tamoxifen-Induced Pancreatic Ductal Adenocarcinoma Mouse Model, Kavita Mallya, Dhanya Haridas, Parthasarathy Seshacharyulu, Ramesh Pothuraju, Wade M. Junker, Shiv Ram Krishn, Sakthivel Muniyan, Raghupathy Vengoji, Surinder K. Batra, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KrasG12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of KrasG12D in multiple PC cell lines resulted in ...


Hypusination Of Eif5a Regulates Cytoplasmic Tdp-43 Aggregation And Accumulation In A Stress-Induced Cellular Model, Shayna Smeltzer, Zainuddin Quadri, Abraian Miller, Frank Zamudio, Jordan Hunter, Nicholas J.F. Stewart, Sheba Saji, Daniel C. Lee, Dale Chaput, Maj-Linda B. Selenica 2020 University of South Florida

Hypusination Of Eif5a Regulates Cytoplasmic Tdp-43 Aggregation And Accumulation In A Stress-Induced Cellular Model, Shayna Smeltzer, Zainuddin Quadri, Abraian Miller, Frank Zamudio, Jordan Hunter, Nicholas J.F. Stewart, Sheba Saji, Daniel C. Lee, Dale Chaput, Maj-Linda B. Selenica

Sanders-Brown Center on Aging Faculty Publications

TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA/DNA binding protein involved in mRNA metabolism. Aberrant mislocalization to the cytoplasm and formation of phosphorylated/aggregated TDP-43 inclusions remains the hallmark pathology in a spectrum of neurodegenerative diseases, including frontotemporal disorders and Alzheimer's disease. Eukaryotic Translation Initiation Factor 5A undergoes a unique post-translation modification of lysine to hypusine (K50), which determines eIF5A binding partners. We used a sodium arsenite-induced cellular stress model to investigate the role of hypusinated eIF5A (eIF5AHypK50) in governing TDP-43 cytoplasmic mislocalization and accumulation in stress granule. Our proteomics and functional data provide evidence that ...


Cd34+ Ucb Stem Cells Attenuate Tgf-Β Signaling And Inhibit Liver Fibrosis: A New Avenue For Liver Cirrhosis-Carcinogenesis Prevention, Wahyunia Likhayati Septiana, Radiana Dhewayani Antarianto, Melva Louisa, Ahmad Aulia Jusuf, Atikah Chalida Barasila, Jeanne Adiwinata Pawitan, Iqbal Fasha 2020 Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia

Cd34+ Ucb Stem Cells Attenuate Tgf-Β Signaling And Inhibit Liver Fibrosis: A New Avenue For Liver Cirrhosis-Carcinogenesis Prevention, Wahyunia Likhayati Septiana, Radiana Dhewayani Antarianto, Melva Louisa, Ahmad Aulia Jusuf, Atikah Chalida Barasila, Jeanne Adiwinata Pawitan, Iqbal Fasha

Makara Journal of Health Research

Background: The liver microenvironment plays a key role in liver fibrosis and carcinogenesis. This study aimed to fill the gap in knowledge on the interaction between hepatic stellate cells and endothelial progenitor cells with biomarkers of liver fibrosis and/or carcinogenesis, including Col1A1, TGF-β, and tenascin-C.

Methods: CD34+ stem cells were isolated from umbilical-cord-blood mononuclear cells. 2D and 3D co-culture of CD34+ UCB SCs and LX2 was performed. The cells were incubated in a CO2 incubator for three days. Morphological observation, qRT-PCR of TGF-β1 and COL1A1, and immunocytochemistry of tenascin-C were performed.

Results: CD34+ UCB SCs were viable in ...


Dysregulation Of Ryr Calcium Channel Causes The Onset Of Mitochondrial Retrograde Signaling, Anindya Roy Chowdhury, Satish Srinivasan, György Csordás, György Hajnóczky, Narayan G Avadhani 2020 University of Pennsylvania

Dysregulation Of Ryr Calcium Channel Causes The Onset Of Mitochondrial Retrograde Signaling, Anindya Roy Chowdhury, Satish Srinivasan, György Csordás, György Hajnóczky, Narayan G Avadhani

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

This study shows that multiple modes of mitochondrial stress generated by partial mtDNA depletion or cytochrome c oxidase disruption cause ryanodine receptor channel (RyR) dysregulation, which instigates the release of Ca2+ in the cytoplasm of C2C12 myoblasts and HCT116 carcinoma cells. We also observed a reciprocal downregulation of IP3R channel activity and reduced mitochondrial uptake of Ca2+. Ryanodine, an RyR antagonist, abrogated the mitochondrial stress-mediated increase in [Ca2+]c and the entire downstream signaling cascades of mitochondrial retrograde signaling. Interestingly, ryanodine also inhibited mitochondrial stress-induced invasive behavior in mtDNA-depleted C2C12 cells and HCT116 carcinoma cells. In addition, co-immunoprecipitation shows reduced ...


Cancer-Targeting Immunostimulatory Peptides As An Immunotherapeutic Approach To Cancer, Rachel Montel 2020 Seton Hall University

Cancer-Targeting Immunostimulatory Peptides As An Immunotherapeutic Approach To Cancer, Rachel Montel

Seton Hall University Dissertations and Theses (ETDs)

This dissertation reports the synthesis and biological applications of bifunctional trimeric peptides with B7H6-derived NKp30 binding motifs that serve to activate an immunocytotoxic response in natural killer cells and a GRP78-binding motif that can target tumors that express surface GRP78. In this manner the cancer-targeting immunostimulatory peptides are anticipated to directly bind and activate effector NK92-MI cells while also recognizing and binding to target A549 tumor cells to facilitate NK cell-dependent immunocytotoxicity of the targeted tumors. The NKp30 binding peptide motifs are derived from the tumor associated B7H6 antigen that is often downregulated or shed from the surface of tumors ...


Alcohol And Smoking Mediated Modulations In Adaptive Immunity In Pancreatitis, Rakesh Bhatia, Christopher Thompson, Koelina Ganguly, Shailender K. Singh, Surinder K. Batra, Sushil Kumar 2020 University of Nebraska Medical Center

Alcohol And Smoking Mediated Modulations In Adaptive Immunity In Pancreatitis, Rakesh Bhatia, Christopher Thompson, Koelina Ganguly, Shailender K. Singh, Surinder K. Batra, Sushil Kumar

Journal Articles: Biochemistry & Molecular Biology

Pancreatitis is a condition of pancreatic inflammation driven by injury to the pancreatic parenchyma. The extent of acinar insult, intensity, and type of immune response determines the severity of the disease. Smoking, alcohol and autoimmune pancreatitis are some of the predominant risk factors that increase the risk of pancreatitis by differentially influencing the adaptive immune system. The overall decrease in peripheral lymphocyte (T-, B- and (natural killer T-) NKT-cell) count and increased infiltration into the damaged pancreatic tissue highlight the contribution of adaptive immunity in the disease pathology. Smoking and alcohol modulate the responsiveness and apoptosis of T- and B-cells ...


Mg2+-Dependent Methyl Transfer By A Knotted Protein: A Molecular Dynamics Simulation And Quantum Mechanics Study, Agata P Perlinska, Marcin Kalek, Thomas Christian, Ya-Ming Hou, Joanna I Sulkowska 2020 University of Warsaw

Mg2+-Dependent Methyl Transfer By A Knotted Protein: A Molecular Dynamics Simulation And Quantum Mechanics Study, Agata P Perlinska, Marcin Kalek, Thomas Christian, Ya-Ming Hou, Joanna I Sulkowska

Department of Biochemistry and Molecular Biology Faculty Papers

Mg2+ is required for the catalytic activity of TrmD, a bacteria-specific methyltransferase that is made up of a protein topological knot-fold, to synthesize methylated m1G37-tRNA to support life. However, neither the location of Mg2+ in the structure of TrmD nor its role in the catalytic mechanism is known. Using molecular dynamics (MD) simulations, we identify a plausible Mg2+ binding pocket within the active site of the enzyme, wherein the ion is coordinated by two aspartates and a glutamate. In this position, Mg2+ additionally interacts with the carboxylate of a methyl donor cofactor S-adenosylmethionine (SAM). The computational results are validated by ...


Lyssavirus Vaccine With A Chimeric Glycoprotein Protects Across Phylogroups, Christine R Fisher, David E Lowe, Todd G Smith, Yong Yang, Christina L Hutson, Christoph Wirblich, Gino Cingolani, Matthias J. Schnell 2020 Thomas Jefferson University

Lyssavirus Vaccine With A Chimeric Glycoprotein Protects Across Phylogroups, Christine R Fisher, David E Lowe, Todd G Smith, Yong Yang, Christina L Hutson, Christoph Wirblich, Gino Cingolani, Matthias J. Schnell

Department of Biochemistry and Molecular Biology Faculty Papers

Rabies is nearly 100% lethal in the absence of treatment, killing an estimated 59,000 people annually. Vaccines and biologics are highly efficacious when administered properly. Sixteen rabies-related viruses (lyssaviruses) are similarly lethal, but some are divergent enough to evade protection from current vaccines and biologics, which are based only on the classical rabies virus (RABV). Here we present the development and characterization of LyssaVax, a vaccine featuring a structurally designed, functional chimeric glycoprotein (G) containing immunologically important domains from both RABV G and the highly divergent Mokola virus (MOKV) G. LyssaVax elicits high titers of antibodies specific to both ...


Molecular Mechanisms Of Manganese Porphyrin Compounds In The Prevention Of Radiation-Induced Fibrosis, Shashank Shrishrimal 2020 University of Nebraska Medical Center

Molecular Mechanisms Of Manganese Porphyrin Compounds In The Prevention Of Radiation-Induced Fibrosis, Shashank Shrishrimal

Theses & Dissertations

Radiation therapy is frequently used as a treatment strategy for prostate cancer patients, which leads to several side effects due to damage to health tissue around the tumor and the development of radiation-induced fibrosis (RIF). Manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP or T2E or BMX-010) and other similar manganese porphyrin compounds that scavenge superoxide molecules have been demonstrated to be effective radioprotectors and prevent the development of RIF. However, understanding of the radioprotective molecular pathway associated with these compounds remains limited. Recent RNA-sequencing data from our laboratory revealed that MnTE-2-PyP treatment may activate the nuclear factor erythroid 2-related factor 2 ...


The Implementation Of Exercise For Chronic Kidney Disease And Dialysis Patients, Syed Ahmad Rizvi 2020 Wayne State University Division of Kinesiology, Health and Sport Studies & Honors College

The Implementation Of Exercise For Chronic Kidney Disease And Dialysis Patients, Syed Ahmad Rizvi

Honors College Theses

While commonly known to be the organ that helps with urine production within the human body, the kidney plays one of the most crucial roles in maintaining homeostasis. When establishing all of the roles the kidney has on keeping humans healthy, there is the question of how does the body cope when a patient is diagnosed with kidney failure. One of the more common treatment options that allows the body to continue to function without a kidney is by beginning a patient on a form of dialysis. However, as with any treatment, there will always be a list of side ...


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