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Differentiating Peripherally-Located Small Cell Lung Cancer From Non-Small Cell Lung Cancer Using A Ct Radiomic Approach, Bihong T. Chen, Zikuan Chen, Ningrong Ye, Isa Mambetsariev, Jeremy Fricke, Ebenezer Daniel, George Wang, Chi Wah Wong, Russell C. Rockne, Rivka R. Colen, Mohd W. Nasser, Surinder K. Batra, Andrei I. Holodny, Sagus Sampath, Ravi Salgia 2020 City of Hope National Medical Center

Differentiating Peripherally-Located Small Cell Lung Cancer From Non-Small Cell Lung Cancer Using A Ct Radiomic Approach, Bihong T. Chen, Zikuan Chen, Ningrong Ye, Isa Mambetsariev, Jeremy Fricke, Ebenezer Daniel, George Wang, Chi Wah Wong, Russell C. Rockne, Rivka R. Colen, Mohd W. Nasser, Surinder K. Batra, Andrei I. Holodny, Sagus Sampath, Ravi Salgia

Journal Articles: Biochemistry & Molecular Biology

Lung cancer can be classified into two main categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are different in treatment strategy and survival probability. The lung CT images of SCLC and NSCLC are similar such that their subtle differences are hardly visually discernible by the human eye through conventional imaging evaluation. We hypothesize that SCLC/NSCLC differentiation could be achieved via computerized image feature analysis and classification in feature space, as termed a radiomic model. The purpose of this study was to use CT radiomics to differentiate SCLC from NSCLC adenocarcinoma. Patients with primary lung ...


Precision Medicine And Actionable Alterations In Lung Cancer: A Single Institution Experience, Isa Mambetsariev, Yingyu Wang, Chen Chen, Sorena Nadaf, Rebecca Pharaon, Jeremy Fricke, Idoroenyi Amanam, Arya Amini, Andrea Bild, Peiguo Chu, Loretta Erhunmwunsee, Jae Kim, Janet Munu, Raju Pillai, Dan Raz, Sagus Sampath, Lalit Vora, Fang Qiu, Lynette M. Smith, Surinder K. Batra, Erminia Massarelli, Marianna Koczywas, Karen Reckamp, Ravi Salgia 2020 City of Hope

Precision Medicine And Actionable Alterations In Lung Cancer: A Single Institution Experience, Isa Mambetsariev, Yingyu Wang, Chen Chen, Sorena Nadaf, Rebecca Pharaon, Jeremy Fricke, Idoroenyi Amanam, Arya Amini, Andrea Bild, Peiguo Chu, Loretta Erhunmwunsee, Jae Kim, Janet Munu, Raju Pillai, Dan Raz, Sagus Sampath, Lalit Vora, Fang Qiu, Lynette M. Smith, Surinder K. Batra, Erminia Massarelli, Marianna Koczywas, Karen Reckamp, Ravi Salgia

Journal Articles: Biochemistry & Molecular Biology

OBJECTIVES: Oncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients.

MATERIALS AND METHODS: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and ...


Micrornas Orchestrate Pathophysiology Of Breast Cancer Brain Metastasis: Advances In Therapy, Ranjana K. Kanchan, Jawed A. Siddiqui, Sidharth Mahapatra, Surinder K. Batra, Mohd W. Nasser 2020 University of Nebraska Medical Center

Micrornas Orchestrate Pathophysiology Of Breast Cancer Brain Metastasis: Advances In Therapy, Ranjana K. Kanchan, Jawed A. Siddiqui, Sidharth Mahapatra, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

Brain metastasis (BM) predominantly occurs in triple-negative (TN) and epidermal growth factor 2 (HER2)-positive breast cancer (BC) patients, and currently, there is an unmet need for the treatment of these patients. BM is a complex process that is regulated by the formation of a metastatic niche. A better understanding of the brain metastatic processes and the crosstalk between cancer cells and brain microenvironment is essential for designing a novel therapeutic approach. In this context, the aberrant expression of miRNA has been shown to be associated with BM. These non-coding RNAs/miRNAs regulate metastasis through modulating the formation of a ...


Molecular Implications Of Muc5ac-Cd44 Axis In Colorectal Cancer Progression And Chemoresistance, Ramesh Pothuraju, Satyanarayana Rachagani, Shiv Ram Krishn, Sanjib Chaudhary, Rama Krishna Nimmakayala, Jawed A. Siddiqui, Koelina Ganguly, Imayavaramban Lakshmanan, Jesse L. Cox, Kavita Mallya, Sukhwinder Kaur, Surinder K. Batra 2020 University of Nebraska Medical Center

Molecular Implications Of Muc5ac-Cd44 Axis In Colorectal Cancer Progression And Chemoresistance, Ramesh Pothuraju, Satyanarayana Rachagani, Shiv Ram Krishn, Sanjib Chaudhary, Rama Krishna Nimmakayala, Jawed A. Siddiqui, Koelina Ganguly, Imayavaramban Lakshmanan, Jesse L. Cox, Kavita Mallya, Sukhwinder Kaur, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure.

METHODS: MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays ...


Examining The Role Of Metabolic Pathways As Therapeutic Modalities For Triple Negative Breast Cancer, Jeremy Andrew Johnson 2020 University of Kentucky

Examining The Role Of Metabolic Pathways As Therapeutic Modalities For Triple Negative Breast Cancer, Jeremy Andrew Johnson

Theses and Dissertations--Toxicology and Cancer Biology

Triple negative breast cancer (TNBC) comprises 15-20% of breast cancers, affects a younger patient population than other subtypes, and is very aggressive. TNBC is comprised of a diverse group of tumors that have proven refractory to targeted therapy and can be difficult to treat. Patients generally receive neoadjuvant chemotherapy (NAC), surgery, and radiotherapy. The standard of care for NAC includes a taxane, an anthracycline, and/or cyclophosphamide, and administration of NAC has resulted in pathological complete response (pCR) in 30-40% of patients. However, a majority of TNBC patients will not reach pCR and instead have residual disease (RD), which is ...


Gasdermins In Apoptosis: New Players In An Old Game., Corey Rogers, Emad S. Alnemri 2019 Thomas Jefferson University

Gasdermins In Apoptosis: New Players In An Old Game., Corey Rogers, Emad S. Alnemri

Department of Biochemistry and Molecular Biology Faculty Papers

Apoptosis is a form of programmed cell death (PCD) that plays critical physiological roles in removing superfluous or dangerous cell populations that are unneeded or threatening to the health of the host organism. Although the molecular pathways leading to activation of the apoptotic program have been extensively studied and characterized starting in the 1970s, new evidence suggests that members of the gasdermin superfamily are novel pore-forming proteins that augment apoptosis by permeabilizing the mitochondria and participate in the final stages of the apoptotic program by inducing secondary necrosis/pyroptosis. These findings may explain outstanding questions in the field such as ...


Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast 2019 Liberty University

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms ...


Identification And Molecular Analysis Of Dna In Exosomes, Jena Tavormina 2019 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Identification And Molecular Analysis Of Dna In Exosomes, Jena Tavormina

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Exosomes are heterogeneous nanoparticles 50-150nm in diameter. Exosomes contain many functional cargo components, such as protein, DNA, and RNA. While protein and RNA exosome content has been extensively studied, very little work has been done to characterize exosomal DNA. Here, we demonstrate that exosomal DNA is heterogeneous and its packaging into exosomes is dependent on the cell of origin. Furthermore, through a rigorous assessment of various isolation methods, we identify Size Exclusion Chromatography (SEC) as the best method for the isolation of exosomal DNA for downstream applications. Additionally, we evaluate the methylation status of exosomal DNA and demonstrate that exosomal ...


It's A Hard Nacht Life: Understanding How Nlrp12 Ticks, Abbigale Julia Brown 2019 Missouri State University

It's A Hard Nacht Life: Understanding How Nlrp12 Ticks, Abbigale Julia Brown

MSU Graduate Theses

The protein NOD- like receptor pyrin domain containing 12 (NLRP12) comes from a family of protein receptors with a wide range of functions including fertility as well as anti-inflammatory properties. The biological role of NLRP12 is poorly understood: research on the mechanisms behind its function and/or activation remains contradictory between different cell models. Current research suggests its involvement in a multi-protein complex named the inflammasome. The alternative hypothesis that has also been proposed is that NLRP12 is not a part of the inflammasome, rather it negatively regulates a transcription factor known as NF-��B down stream of Toll-like receptors ...


#3 - Inhibition Of The Mitochondrial Calcium Uniporter Reduces Oxidative Phosphorylation In Sgk1-Knockout Vsmc Upon Dietinduced Obesity, Bao Tran, Sharon Francis, Wei Zhong 2019 Georgia Gwinnett College

#3 - Inhibition Of The Mitochondrial Calcium Uniporter Reduces Oxidative Phosphorylation In Sgk1-Knockout Vsmc Upon Dietinduced Obesity, Bao Tran, Sharon Francis, Wei Zhong

Georgia Undergraduate Research Conference (GURC)

Obesity is linked to vascular diseases such as atherosclerosis and coronary artery disease which is a major underlying cause of heart attacks. While the mechanism is not fully known, altering mitochondrial respiration which occurs through oxidative phosphorylation (OXPHOS) may influence the development of vascular disease during obesity. Our previous data with diet-induced obese (DIO) mice demonstrated that serum and glucocorticoid-inducible kinase 1 (SGK1), which regulates cell metabolism, was up-regulated in vascular smooth muscle cells (VSMC) from the aorta. Knocking out SGK1 in VSMCs (KOSGK1) was associated with higher OXPHOS and lower vascular disease relative to wildtype VSMCs (WTSGK1) during DIO ...


A Physiologically-Based Pharmacokinetic Model For Targeting Calcitriol-Conjugated Quantum Dots To Inflammatory Breast Cancer Cells., James Forder, Mallory Smith, Margot Wagner, Rachel J. Schaefer, Jonathan Gorky, Kenneth L. van Golen, Anja Nohe, Prasad Dhurjati 2019 University of Delaware

A Physiologically-Based Pharmacokinetic Model For Targeting Calcitriol-Conjugated Quantum Dots To Inflammatory Breast Cancer Cells., James Forder, Mallory Smith, Margot Wagner, Rachel J. Schaefer, Jonathan Gorky, Kenneth L. Van Golen, Anja Nohe, Prasad Dhurjati

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Quantum dots (QDs) conjugated with 1,25 dihydroxyvitamin D3 (calcitriol) and Mucin-1 (MUC-1) antibodies (SM3) have been found to target inflammatory breast cancer (IBC) tumors and reduce proliferation, migration, and differentiation of these tumors in mice. A physiologically-based pharmacokinetic model has been constructed and optimized to match experimental data for multiple QDs: control QDs, QDs conjugated with calcitriol, and QDs conjugated with both calcitriol and SM3 MUC1 antibodies. The model predicts continuous QD concentration for key tissues in mice distinguished by IBC stage (healthy, early-stage, and late-stage). Experimental and clinical efforts in QD treatment of IBC can be augmented by ...


Virally Packaged Rna In Virus-Like Particle Vaccines Enhances Antigenicity And Augments Latency Reversal Of Hiv-1, Chanuka Wijewardhana 2019 The University of Western Ontario

Virally Packaged Rna In Virus-Like Particle Vaccines Enhances Antigenicity And Augments Latency Reversal Of Hiv-1, Chanuka Wijewardhana

Electronic Thesis and Dissertation Repository

Introduction:

Since Human Immunodeficiency Virus (HIV)-1 was determined to be the etiological agent behind acquired immunodeficiency syndrome (AIDS) in 1983, numerous attempts at a cure have been made; however, none have been effective. One of the primary roadblocks in achieving a cure is a transcriptionally-silent latent reservoir of memory CD4+ T cells harboring HIV provirus. Combined antiretroviral therapy (cART) inhibits actively replicating virus by interfering with various stages of the replication cycle. Therefore, non-replicative viruses–like the proviruses found in latently infected cells–are hidden from the actions of continued antiretroviral therapy. As a result, cART discontinuation or treatment ...


Structural And Functional Analysis Of Parameters Governing Tankyrase-1 Interaction With Telomeric Repeat-Binding Factor 1 And Gdp-Mannose 4,6-Dehydratase., Travis Eisemann, Marie-France Langelier, John M. Pascal 2019 Thomas Jefferson University

Structural And Functional Analysis Of Parameters Governing Tankyrase-1 Interaction With Telomeric Repeat-Binding Factor 1 And Gdp-Mannose 4,6-Dehydratase., Travis Eisemann, Marie-France Langelier, John M. Pascal

Department of Biochemistry and Molecular Biology Faculty Papers

Human tankyrase-1 (TNKS) is a member of the poly(ADPribose) polymerase (PARP) superfamily of proteins that posttranslationally modify themselves and target proteins with ADP-ribose (termed PARylation). The TNKS ankyrin repeat domain mediates interactions with a growing number of structurally and functionally diverse binding partners, linking TNKS activity to multiple critical cell processes, including Wnt signaling, Golgi trafficking, and telomere maintenance. However, some binding partners can engage TNKS without being modified, suggesting that separate parameters influence TNKS interaction and PARylation. Here, we present an analysis of the sequence and structural features governing TNKS interactions with two model binding partners: The PARylated ...


Heme And Hemoglobin Utilization By Mycobacterium Tuberculosis., Avishek Mitra, Ying-Hui Ko, Gino Cingolani, Michael Niederweis 2019 University of Alabama at Birmingham

Heme And Hemoglobin Utilization By Mycobacterium Tuberculosis., Avishek Mitra, Ying-Hui Ko, Gino Cingolani, Michael Niederweis

Department of Biochemistry and Molecular Biology Faculty Papers

Iron is essential for growth of Mycobacterium tuberculosis (Mtb), but most iron in the human body is stored in heme within hemoglobin. Here, we demonstrate that the substrate-binding protein DppA of the inner membrane Dpp transporter is required for heme and hemoglobin utilization by Mtb. The 1.27 Å crystal structure of DppA shows a tetrapeptide bound in the protein core and a large solvent-exposed crevice for heme binding. Mutation of arginine 179 in this cleft eliminates heme binding to DppA and prevents heme utilization by Mtb. The outer membrane proteins PPE36 and PPE62 are also required for heme and ...


Slc36a1-Mtorc1 Signaling Drives Acquired Resistance To Cdk4/6 Inhibitors., Akihiro Yoshida, Yiwen Bu, Shuo Qie, John Wrangle, E. Ramsay Camp, E. Starr Hazard, Gary Hardiman, Renée de Leeuw, Karen E. Knudsen, J. Alan Diehl 2019 Medical University of South Carolina; Case Western Reserve University

Slc36a1-Mtorc1 Signaling Drives Acquired Resistance To Cdk4/6 Inhibitors., Akihiro Yoshida, Yiwen Bu, Shuo Qie, John Wrangle, E. Ramsay Camp, E. Starr Hazard, Gary Hardiman, Renée De Leeuw, Karen E. Knudsen, J. Alan Diehl

Department of Cancer Biology Faculty Papers

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of ...


Development Of Substrate Degradation Enzyme Therapy For Mucopolysaccharidosis Iva Murine Model., Kazuki Sawamoto, Shunji Tomatsu 2019 Nemours/Alfred I. duPont Hospital for Children

Development Of Substrate Degradation Enzyme Therapy For Mucopolysaccharidosis Iva Murine Model., Kazuki Sawamoto, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0-7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of ...


The Role Of The Tau N-Terminal Phosphatase-Activating Domain And Phosphorylation At Thr175 In The Formation Of Tau Cytoplasmic Inclusions, Matthew A. Hintermayer 2019 The University of Western Ontario

The Role Of The Tau N-Terminal Phosphatase-Activating Domain And Phosphorylation At Thr175 In The Formation Of Tau Cytoplasmic Inclusions, Matthew A. Hintermayer

Electronic Thesis and Dissertation Repository

Cytoplasmic inclusions and fibrils of the microtubule-associated protein tau (tau protein) are a key neuropathological hallmark in tauopathies, including Alzheimer’s disease, chronic traumatic encephalopathy, and amyotrophic lateral sclerosis with cognitive impairment. Previous research has demonstrated that the phosphorylation of tau protein at Thr175 is sufficient for the initiation of fibril formation both in vitro and in vivo. Here we use mutated tau protein constructs to demonstrate that phosphorylation at Thr175 results in the aberrant exposure of an N-terminal phosphatase-activating domain (PAD). The tau PAD interacts with protein phosphatase 1 (PP1) leading to the activation of glycogen synthase ...


Cleavage And Sub-Cellular Redistribution Of Nuclear Pore Protein 98 By Coxsackievirus B3 Protease 2a Impairs Cardioprotection., Paul J. Hanson, Al Rohet Hossain, Ye Qiu, Huifang M. Zhang, Guangze Zhao, Cheng Li, Veena Lin, Saheedat Sulaimon, Marli Vlok, Gabriel Fung, Victoria H. Chen, Eric Jan, Bruce M. McManus, David J. Granville, Decheng Yang 2019 University of British Columbia; St. Paul's Hospital

Cleavage And Sub-Cellular Redistribution Of Nuclear Pore Protein 98 By Coxsackievirus B3 Protease 2a Impairs Cardioprotection., Paul J. Hanson, Al Rohet Hossain, Ye Qiu, Huifang M. Zhang, Guangze Zhao, Cheng Li, Veena Lin, Saheedat Sulaimon, Marli Vlok, Gabriel Fung, Victoria H. Chen, Eric Jan, Bruce M. Mcmanus, David J. Granville, Decheng Yang

College of Population Health Faculty Papers

Myocarditis, inflammation of the heart muscle, affects all demographics and is a major cause of sudden and unexpected death in young people. It is most commonly caused by viral infections of the heart, with coxsackievirus B3 (CVB3) being among the most prevalent pathogens. To understand the molecular pathogenesis of CVB3 infection and provide strategies for developing treatments, we examined the role of a key nuclear pore protein 98 (NUP98) in the setting of viral myocarditis. NUP98 was cleaved as early as 2 h post-CVB3 infection. This cleavage was further verified through both the ectopic expression of viral proteases and in ...


Modulation Of Inflammation Driven Wound Healing After Glaucoma Surgery, James J. Armstrong 2019 The University of Western Ontario

Modulation Of Inflammation Driven Wound Healing After Glaucoma Surgery, James J. Armstrong

Electronic Thesis and Dissertation Repository

Dysregulated wound healing contributes to most currently unanswered ophthalmological morbidity. Opacification and structure altering contractures compromise the delicate ocular anatomy upon which ocular function and healthy vision are reliant. Glaucoma filtration surgery, corneal stromal injury, proliferative vitreoretinopathy and age-related macular degeneration are major contributors to ocular morbidity – all with myofibroblast transdifferentiation and pathognomonic scarring activity at their core.

This thesis aims to revaluate the means by which dysregulated ocular wound healing is combated with evidence describing a novel strategy to mitigate its effects. A translational approach was used. An initial retrospective analysis of over ten thousand glaucoma surgeries found that ...


Structural Basis For The Homotypic Fusion Of Chlamydial Inclusions By The Snare-Like Protein Inca., Gino Cingolani, Michael McCauley, Anna Lobley, Alexander J Bryer, Jordan Wesolowski, Deanna L Greco, Ravi K Lokareddy, Erik Ronzone, Juan R Perilla, Fabienne Paumet 2019 Thomas Jefferson University, Department of Biochemistry and Molecular Biology, Philadelphia, PA 19107, United States; Institute of Biomembranes and Bioenergetics, National Research Council, Via Amendola 165/A, Bari, 70126, Italy

Structural Basis For The Homotypic Fusion Of Chlamydial Inclusions By The Snare-Like Protein Inca., Gino Cingolani, Michael Mccauley, Anna Lobley, Alexander J Bryer, Jordan Wesolowski, Deanna L Greco, Ravi K Lokareddy, Erik Ronzone, Juan R Perilla, Fabienne Paumet

Department of Biochemistry and Molecular Biology Faculty Papers

Many intracellular bacteria, including Chlamydia, establish a parasitic membrane-bound organelle inside the host cell that is essential for the bacteria's survival. Chlamydia trachomatis forms inclusions that are decorated with poorly characterized membrane proteins known as Incs. The prototypical Inc, called IncA, enhances Chlamydia pathogenicity by promoting the homotypic fusion of inclusions and shares structural and functional similarity to eukaryotic SNAREs. Here, we present the atomic structure of the cytoplasmic domain of IncA, which reveals a non-canonical four-helix bundle. Structure-based mutagenesis, molecular dynamics simulation, and functional cellular assays identify an intramolecular clamp that is essential for IncA-mediated homotypic membrane fusion ...


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