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Articles 1 - 30 of 172

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Hsp90/Axl/Eif4e-Regulated Unfolded Protein Response As An Acquired Vulnerability In Drug-Resistant Kras-Mutant Lung Cancer, Haitang Yang, Shun-Qing Liang, Duo Xu, Zhang Yang, Thomas M. Marti, Yanyun Gao, Gregor J. Kocher, Heng Zhao, Ralph A. Schmid, Ren-Wang Peng Aug 2019

Hsp90/Axl/Eif4e-Regulated Unfolded Protein Response As An Acquired Vulnerability In Drug-Resistant Kras-Mutant Lung Cancer, Haitang Yang, Shun-Qing Liang, Duo Xu, Zhang Yang, Thomas M. Marti, Yanyun Gao, Gregor J. Kocher, Heng Zhao, Ralph A. Schmid, Ren-Wang Peng

Open Access Articles

Drug resistance and tumor heterogeneity are formidable challenges in cancer medicine, which is particularly relevant for KRAS-mutant cancers, the epitome of malignant tumors recalcitrant to targeted therapy efforts and first-line chemotherapy. In this study, we delineate that KRAS-mutant lung cancer cells resistant to pemetrexed (MTA) and anti-MEK drug trametinib acquire an exquisite dependency on endoplasmic reticulum (ER) stress signaling, rendering resistant cancer cells selectively susceptible to blockage of HSP90, the receptor tyrosine kinase AXL, the eukaryotic translation initiation factor 4E (eIF4E), and the unfolded protein response (UPR). Mechanistically, acquisition of drug resistance enables KRAS-mutant lung cancer cells to bypass canonical ...


Insulin Receptor Substrate-1 (Irs-1) And Irs-2 Expression Levels Are Associated With Prognosis In Non-Small Cell Lung Cancer (Nsclc), Andrew J. Piper, Jennifer L. Clark, Jose R. Mercado-Matos, Asia N. Matthew-Onabanjo, Chung-Cheng Hsieh, Ali Akalin, Leslie M. Shaw Aug 2019

Insulin Receptor Substrate-1 (Irs-1) And Irs-2 Expression Levels Are Associated With Prognosis In Non-Small Cell Lung Cancer (Nsclc), Andrew J. Piper, Jennifer L. Clark, Jose R. Mercado-Matos, Asia N. Matthew-Onabanjo, Chung-Cheng Hsieh, Ali Akalin, Leslie M. Shaw

Open Access Articles

The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma ...


Itch Nuclear Translocation And H1.2 Polyubiquitination Negatively Regulate The Dna Damage Response, Lufen Chang, Lei Shen, Hu Zhou, Jing Gao, Hangyi Pan, Li Zheng, Brian Armstrong, Yang Peng, Guang Peng, Binhua P. Zhou, Steven T. Rosen, Binghui Shen Jan 2019

Itch Nuclear Translocation And H1.2 Polyubiquitination Negatively Regulate The Dna Damage Response, Lufen Chang, Lei Shen, Hu Zhou, Jing Gao, Hangyi Pan, Li Zheng, Brian Armstrong, Yang Peng, Guang Peng, Binhua P. Zhou, Steven T. Rosen, Binghui Shen

Molecular and Cellular Biochemistry Faculty Publications

The downregulation of the DNA damage response (DDR) enables aggressive tumors to achieve uncontrolled proliferation against replication stress, but the mechanisms underlying this process in tumors are relatively complex. Here, we demonstrate a mechanism through which a distinct E3 ubiquitin ligase, ITCH, modulates DDR machinery in triple-negative breast cancer (TNBC). We found that expression of a nuclear form of ITCH was significantly increased in human TNBC cell lines and tumor specimens. Phosphorylation of ITCH at Ser257 by AKT led to the nuclear localization of ITCH and ubiquitination of H1.2. The ITCH-mediated polyubiquitination of H1.2 suppressed RNF8/RNF168-dependent formation ...


Regulation Of The Long Non-Coding Rna Fam83h-As1 By Human Papillomavirus In Cervical Cancer, Jamie Ann Barr Ph.D. Jan 2019

Regulation Of The Long Non-Coding Rna Fam83h-As1 By Human Papillomavirus In Cervical Cancer, Jamie Ann Barr Ph.D.

Graduate Theses, Dissertations, and Problem Reports

Non-coding RNAs (NcRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been found to be involved in a variety of critical biological processes, and dysregulation of ncRNAs have been involved with several human diseases including cancer.

High-risk human papillomavirus (HPV) infection is one of the first events in the process of carcinogenesis in cervical and a subset of head and neck cancers. The expression of the viral oncoproteins E6 and E7 is essential in this process by inactivating the tumor suppressor proteins p53 and Rb, respectively, in addition to their interactions with other host proteins and regulation of ...


The Role Of Calcineurin/Nfat Signaling In Fibroblast Homeostasis And Activation, Allyson Elizabeth Lieberman Jan 2019

The Role Of Calcineurin/Nfat Signaling In Fibroblast Homeostasis And Activation, Allyson Elizabeth Lieberman

Publicly Accessible Penn Dissertations

Fibroblast activation is a crucial step in tumor growth and metastatic progression; activated fibroblasts remodel extracellular matrix (ECM) in primary tumor and metastatic microenvironments, exerting both pro- and anti-tumorigenic effects. However, the intrinsic mechanisms that regulate the activation of fibroblasts are not well defined. The signaling axis comprising the calcium-activated Ser/Thr phosphatase calcineurin (CN), and its downstream target nuclear factor of activated T cells (NFAT), has been shown to play important roles in in endothelial and immune cell activation, but its role in fibroblasts is not known. We have shown that deletion of CN in fibroblasts in vitro results ...


Targeting The Brd4/Foxo3a/Cdk6 Axis Sensitizes Akt Inhibition In Luminal Breast Cancer, Jingyi Liu, Weijie Guo, Zhibing Duan, Lei Zeng, Yadi Wu, Yule Chen, Fang Tai, Yifan Wang, Yiwei Lin, Qiang Zhang, Yanling He, Jiong Deng, Rachel L. Stewart, Chi Wang, Pengnian Charles Lin, Saghi Ghaffari, B. Mark Evers, Suling Liu, Ming-Ming Zhou, Binhua P. Zhou, Jian Shi Dec 2018

Targeting The Brd4/Foxo3a/Cdk6 Axis Sensitizes Akt Inhibition In Luminal Breast Cancer, Jingyi Liu, Weijie Guo, Zhibing Duan, Lei Zeng, Yadi Wu, Yule Chen, Fang Tai, Yifan Wang, Yiwei Lin, Qiang Zhang, Yanling He, Jiong Deng, Rachel L. Stewart, Chi Wang, Pengnian Charles Lin, Saghi Ghaffari, B. Mark Evers, Suling Liu, Ming-Ming Zhou, Binhua P. Zhou, Jian Shi

Molecular and Cellular Biochemistry Faculty Publications

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a ...


Development Of A Pd-L1 Pet Imaging Biomarker, Caleb Jack Bridgwater Nov 2018

Development Of A Pd-L1 Pet Imaging Biomarker, Caleb Jack Bridgwater

Posters-at-the-Capitol

Immunotherapy strategies are very promising treatments for cancer patients. Specifically, Immune checkpoint inhibitor therapy focusing on the PD-1/PD-L1 pathway shows long-lasting positive results in many cancer patients. Unfortunately, not all the patients can benefit from this highly effective treatment. Hence, there is a great need for predictive biomarkers. Immunohistochemical (IHC) staining has been used as a way of predicting patient response, yet shows many problems. For example, IHC utilizes an invasive biopsy and sample fixing, which creates an incomplete and delayed picture of the patient’s biochemistry and the tumor microenvironment, consequently ignoring metastases.

The purpose of this study ...


Synthesis And Biological Evaluation Of Phaeosphaeride A Derivatives As Antitumor Agents, Victoria Abzianidze, Petr Beltyukov, Sofya Zakharenkova, Natalia Moiseeva, Jennifer Mejia, Alvin Holder, Yuri Trishin, Alexander Berestetskiy, Victor Kuznetsov Nov 2018

Synthesis And Biological Evaluation Of Phaeosphaeride A Derivatives As Antitumor Agents, Victoria Abzianidze, Petr Beltyukov, Sofya Zakharenkova, Natalia Moiseeva, Jennifer Mejia, Alvin Holder, Yuri Trishin, Alexander Berestetskiy, Victor Kuznetsov

Chemistry & Biochemistry Faculty Publications

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell ...


Rare Gene Fusion Rearrangement Sptnb1-Pdgfrb In An Atypical Myeloproliferative Neoplasm, Vanessa Fiorini Furtado, Neeraj Y. Saini, William V. Walsh, Venu G. Bathini, Patricia M. Miron Oct 2018

Rare Gene Fusion Rearrangement Sptnb1-Pdgfrb In An Atypical Myeloproliferative Neoplasm, Vanessa Fiorini Furtado, Neeraj Y. Saini, William V. Walsh, Venu G. Bathini, Patricia M. Miron

Open Access Articles

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia recognizes a distinct class of myeloid and lymphoid tumors with eosinophilia-related proliferations associated with specific gene rearrangements, one of which involves rearrangements of platelet-derived growth factor receptor B (PDGFRB) gene. We report a case of a rare PDGFRB rearrangement with SPTNB1 (spectrin beta, nonerythrocytic 1) that presented as atypical myeloproliferative neoplasm.


Proteomic Profiling Of Serum Derived Exosomes From Prostate Cancer Patients, David Turay Oct 2018

Proteomic Profiling Of Serum Derived Exosomes From Prostate Cancer Patients, David Turay

David Turay, MD

Touted among the major achievements in the diagnosis and management of Prostate cancer (PCa) in the past few decades has been, the dramatic decline of men with advanced/metastatic PCa at diagnosis coupled with a significant improvement ( >90%) in the five and ten year survival rates of the disease. Non-palpable PCa (potentially clinically treatable disease) now accounts for 70-80% of all newly diagnosed cases of PCa. Preceding these changes by about a decade was the introduction of Prostatic Specific Antigen (PSA) into clinical practice; first as biomarker for monitoring response to therapy and subsequently as a complementary screening tool. It ...


Experiences Of The Breast Cancer Patients Undergoing Radiotherapy At A Public Hospital Peshawar Pakistan, Gulzar Habibullah, Raisa Raisa, Shanaz Hussein Cassum Sc, Rehana Elahi Apr 2018

Experiences Of The Breast Cancer Patients Undergoing Radiotherapy At A Public Hospital Peshawar Pakistan, Gulzar Habibullah, Raisa Raisa, Shanaz Hussein Cassum Sc, Rehana Elahi

School of Nursing & Midwifery

Objective: This study aimed to explore the experiences of female breast cancer patients undergoing radiotherapy (RT) in a public hospital in Peshawar, Pakistan.
Methods: This study employed a descriptive exploratory method. A purposive sample of 14 breast cancer women undergoing RT was selected for this study. Data were collected over the period of 5 months, using a semi-structured interview guide and conducting in-depth face-to-face interviews. These interviews were audio taped and transcribed by a bilingual transcriber. The translated version of the interview was coded, and the analysis was done manually.
Results: Four main categories emerged from data analysis, which were ...


Peptide Density Targets And Impedes Triple Negative Breast Cancer Metastasis, Daxing Liu, Peng Guo, Craig Mccarthy, Biran Wang, Yu Tao, Debra Auguste Jan 2018

Peptide Density Targets And Impedes Triple Negative Breast Cancer Metastasis, Daxing Liu, Peng Guo, Craig Mccarthy, Biran Wang, Yu Tao, Debra Auguste

Publications and Research

The C-X-C chemokine receptor type 4 (CXCR4, CD184) pathway is a key regulator of cancer metastasis. Existing therapeutics that block CXCR4 signaling are dependent on single molecule-receptor interactions or silencing CXCR4 expression. CXCR4 localizes in lipid rafts and forms dimers therefore CXCR4 targeting and signaling may depend on ligand density. Herein, we report liposomes presenting a CXCR4 binding peptide (DV1) as a threedimensional molecular array, ranging from 9k to 74k molecules μm−2, target triple negative breast cancer (TNBC). TNBC cells exhibit a maxima in binding and uptake of DV1functionalized liposomes (L-DV1) in vitro at a specific density, which yields ...


Targeting Ovarian Cancer And Endothelium With An Allosteric Ptp4a3 Phosphatase Inhibitor, Kelley E. Mcqueeney, Joseph M. Salamoun, James C. Burnett, Nektarios Barabutis, Paula Pekic, Sophie L. Lewandowski, Danielle C. Llaneza, Robert Cornelison, Yunpeng Bai, Zhong-Yin Zhang, John D. Catravas Jan 2018

Targeting Ovarian Cancer And Endothelium With An Allosteric Ptp4a3 Phosphatase Inhibitor, Kelley E. Mcqueeney, Joseph M. Salamoun, James C. Burnett, Nektarios Barabutis, Paula Pekic, Sophie L. Lewandowski, Danielle C. Llaneza, Robert Cornelison, Yunpeng Bai, Zhong-Yin Zhang, John D. Catravas

Bioelectrics Publications

Overexpression of protein tyrosine phosphatase PTP4A oncoproteins is common in many human cancers and is associated with poor patient prognosis and survival. We observed elevated levels of PTP4A3 phosphatase in 79% of human ovarian tumor samples, with significant overexpression in tumor endothelium and pericytes. Furthermore, PTP4A phosphatases appear to regulate several key malignant processes, such as invasion, migration, and angiogenesis, suggesting a pivotal regulatory role in cancer and endothelial signaling pathways. While phosphatases are attractive therapeutic targets, they have been poorly investigated because of a lack of potent and selective chemical probes. In this study, we disclose that a potent ...


Esope-Equivalent Pulsing Protocols For Calcium Electroporation: An In Vitro Optimization Study On 2 Cancer Cell Models, Stefania Romeo, Anna Sannino, Maria Rosaria Scarfi, P. Thomas Vernier, Ruggero Cadossi, Julie Gehl, Olga Zeni Jan 2018

Esope-Equivalent Pulsing Protocols For Calcium Electroporation: An In Vitro Optimization Study On 2 Cancer Cell Models, Stefania Romeo, Anna Sannino, Maria Rosaria Scarfi, P. Thomas Vernier, Ruggero Cadossi, Julie Gehl, Olga Zeni

Bioelectrics Publications

Reversible electroporation is used to increase the uptake of chemotherapeutic drugs in local tumor treatment (electrochemotherapy) by applying the pulsing protocol (8 rectangular pulses, 1000 V/cm, 100 µs) standardized in the framework of the European Standard Operating Procedure on Electrochemotherapy multicenter trial. Currently, new electrochemotherapy strategies are under development to extend its applicability to tumors with different histology. Electrical parameters and drug type are critical factors. A possible approach is to test pulse parameters different from European Standard Operating Procedure on Electrochemotherapy but with comparable electroporation yield (European Standard Operating Procedure on Electrochemotherapy-equivalent protocols). Moreover, the use of non-toxic ...


Cold Atmospheric Plasma As A Potential Tool For Multiple Myeloma Treatment, Dehui Xu, Yujing Xu, Qingjie Cui, Dingxin Liu, Zhijie Liu, Xiaohua Wang, Yanjie Yang, Niaojuan Feng, Rong Liang, Hailan Chen, Kai Ye, Michael G. Kong Jan 2018

Cold Atmospheric Plasma As A Potential Tool For Multiple Myeloma Treatment, Dehui Xu, Yujing Xu, Qingjie Cui, Dingxin Liu, Zhijie Liu, Xiaohua Wang, Yanjie Yang, Niaojuan Feng, Rong Liang, Hailan Chen, Kai Ye, Michael G. Kong

Bioelectrics Publications

Multiple myeloma (MM) is a fatal and incurable hematological malignancy thus new therapy need to be developed. Cold atmospheric plasma, a new technology that could generate various active species, could efficiently induce various tumor cells apoptosis. More details about the interaction of plasma and tumor cells need to be addressed before the application of gas plasma in clinical cancer treatment. In this study, we demonstrate that He+O2 plasma could efficiently induce myeloma cell apoptosis through the activation of CD95 and downstream caspase cascades. Extracellular and intracellular reactive oxygen species (ROS) accumulation is essential for CD95-mediated cell apoptosis in ...


Wnt5a Signaling Induced Phosphorylation Increases Acyl Protein Thioesterase Activity And Promotes Melanoma Metastatic Behavior, Rochelle Shirin Sadeghi Jan 2018

Wnt5a Signaling Induced Phosphorylation Increases Acyl Protein Thioesterase Activity And Promotes Melanoma Metastatic Behavior, Rochelle Shirin Sadeghi

Publicly Accessible Penn Dissertations

Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remains unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity. We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization ...


Association Of Two Foxp3 Polymorphisms With Breast Cancer In Chinese Han Women, Wenge Zhu, +Several Additional Authors Jan 2018

Association Of Two Foxp3 Polymorphisms With Breast Cancer In Chinese Han Women, Wenge Zhu, +Several Additional Authors

Biochemistry and Molecular Medicine Faculty Publications

Background

Forkhead box P3 (FOXP3) is a key gene in the immune system which also plays a role in tumor development. This study aims to explore the association of two FOXP3 polymorphisms (rs3761548 and rs3761549) with susceptibility to breast cancer (BC).

Method

A case–control study was conducted, involving 560 patients and 583 healthy individuals from the Chinese Han population. The genotypes of FOXP3 polymorphisms were detected using the Sequenom MassARRAY method. The association between FOXP3 polymorphisms and BC risk was evaluated using a χ2 test with an odds ratio (OR) and 95% confidence intervals (95% CIs) under six genetic ...


Evaluation Of Extracellular Matrix Composition And Rheology As Determinants Of Growth, Invasion, And Response To Photodynamic Therapy In 3d Cell Culture Models Of Pancreatic Ductal Adenocarcinoma, Gwendolyn M. Cramer Dec 2017

Evaluation Of Extracellular Matrix Composition And Rheology As Determinants Of Growth, Invasion, And Response To Photodynamic Therapy In 3d Cell Culture Models Of Pancreatic Ductal Adenocarcinoma, Gwendolyn M. Cramer

Graduate Doctoral Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is a notoriously lethal disease characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich stroma has been implicated as a barrier to drug penetration, although stromal depletion strategies have had mixed clinical success. It remains less clear how biophysical interactions with the ECM regulate invasive progression and susceptibilities to specific therapies. Here, an integrative approach combining 3D cell culture and quantitative imaging techniques is used to evaluate invasive behavior and motility as determinants of response to classical chemotherapy and photodynamic therapy (PDT), in which ...


Role Of Heat Shock Transcription Factor 1 In Ovarian Cancer Epithelial-Mesenchymal Transition And Drug Sensitivity, Chase David Powell Nov 2017

Role Of Heat Shock Transcription Factor 1 In Ovarian Cancer Epithelial-Mesenchymal Transition And Drug Sensitivity, Chase David Powell

Graduate Theses and Dissertations

The heat shock response (HSR) is a robust cellular reaction to mitigate protein damage from heat and other challenges to the proteome. This protective molecular program in humans is controlled by heat shock transcription factor 1 (HSF1). Activation of HSF1 leads to the induction of an array of cytoprotective genes, many of which code for chaperones. These chaperones, known as heat shock proteins (HSPs), are responsible for maintaining the functional integrity of the proteome. HSPs achieve this by promoting proper folding and assembly of nascent proteins, refolding denatured proteins, and processing for degradation proteins and aggregates which cannot be returned ...


Effect Of Extracellular Survivin And Lymphoma Exosomes On Natural Killer Cells, Heather R. Ferguson Bennit Sep 2017

Effect Of Extracellular Survivin And Lymphoma Exosomes On Natural Killer Cells, Heather R. Ferguson Bennit

Loma Linda University Electronic Theses, Dissertations & Projects

Tumors alter their microenvironment to promote survival using methods such as angiogenesis promotion, growth signals, and immune suppression. The immune system becomes unresponsive to transformed neoplastic cells through a variety of methods including T cell suppression, increased myeloid-derived suppressor cells (MDSCs), and reduced natural killer (NK) cell activity. NK cells have inherent killing capabilities and thus are among the first responders in recognizing and destroying abnormal cells. However, many types of cancers inhibit the surveillance and cytotoxic abilities of NK cells by releasing exosomes, vesicles that can modulate the tumor microenvironment (TME) and intercellular communication for the purpose of enhancing ...


Chloroformate Derivatization For Tracing The Fate Of Amino Acids In Cells And Tissues By Multiple Stable Isotope Resolved Metabolomics (Msirm), Ye Yang, Teresa W. -M. Fan, Andrew N. Lane, Richard M. Higashi Jul 2017

Chloroformate Derivatization For Tracing The Fate Of Amino Acids In Cells And Tissues By Multiple Stable Isotope Resolved Metabolomics (Msirm), Ye Yang, Teresa W. -M. Fan, Andrew N. Lane, Richard M. Higashi

Center for Environmental and Systems Biochemistry Faculty Publications

Amino acids have crucial roles in central metabolism, both anabolic and catabolic. To elucidate these roles, steady-state concentrations of amino acids alone are insufficient, as each amino acid participates in multiple pathways and functions in a complex network, which can also be compartmentalized. Stable Isotope-Resolved Metabolomics (SIRM) is an approach that uses atom-resolved tracking of metabolites through biochemical transformations in cells, tissues, or whole organisms. Using different elemental stable isotopes to label multiple metabolite precursors makes it possible to resolve simultaneously the utilization of these precursors in a single experiment. Conversely, a single precursor labeled with two (or more) different ...


Investigating The Synergistic Effects Of Cisplatin And Two Curcuminoid Compounds On Cancer, Denis Hodzic Jun 2017

Investigating The Synergistic Effects Of Cisplatin And Two Curcuminoid Compounds On Cancer, Denis Hodzic

Honors College Capstone Experience/Thesis Projects

Cisplatin is an anti-cancer drug effective against several cancers which can produce the serious side-effect of hearing loss. Curcumin, a natural plant compound, can increase the activity of cisplatin against cancer and counteract cisplatin’s effect against hearing. Because curcumin exhibits poor bioavailability, there is considerable interest in developing synthetic curcumin analogs (curcuminoids) that are more soluble and which retain anti-cancer activity and otoprotective function. This study investigated whether two curcuminoids, EF-24 and CLEFMA, increase the cytotoxic and ototoxic effects of cisplatin against the lung cancer cell line, A549, and the colorectal cancer cell line, Caco2. Cytotoxicity was measured by ...


Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), Ronald C. Bruntz, Andrew N. Lane, Richard M. Higashi, Teresa W. -M. Fan Jun 2017

Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), Ronald C. Bruntz, Andrew N. Lane, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.


Functional Roles Of Matrix Metalloproteinases In Bone Metastatic Prostate Cancer, Jeremy S. Frieling May 2017

Functional Roles Of Matrix Metalloproteinases In Bone Metastatic Prostate Cancer, Jeremy S. Frieling

Graduate Theses and Dissertations

Skeletal metastasis is a lethal component of many advanced cancers including prostate, the second most common cancer among men. Patients whose prostate cancer is localized and detected early benefit from multiple treatment options ranging from active surveillance to radiation and surgery, resulting in a 5-year survival rate of nearly 100%. Unfortunately, the prognosis and survival for patients with advanced metastatic disease is much worse due to the highly aggressive nature of the disease and a paucity of treatment options. Understanding the mechanisms and interactions that occur between metastatic cancer cells and the bone will enable the future treatment landscape for ...


Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition Of Exosome And Microvesicle Release And Enhanced Efficacy Of Cancer Chemotherapy, Uchini S. Kosgodage, Rita P. Trindade, Paul R. Thompson, Jameel M. Inal, Sigrun Lange May 2017

Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition Of Exosome And Microvesicle Release And Enhanced Efficacy Of Cancer Chemotherapy, Uchini S. Kosgodage, Rita P. Trindade, Paul R. Thompson, Jameel M. Inal, Sigrun Lange

Open Access Articles

Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increase drug retention within cancer cells and allow for lower doses of chemotherapeutic drugs. The contribution of exosomes to drug retention still remains unknown. Potential exosome and MV (EMV) biogenesis inhibitors, tested on human prostate cancer (PC3) cells for their capacity to inhibit EMV release, were also tested on PC3 and MCF-7 (breast cancer) cells for improving chemotherapy. Agents inhibiting EMV release most significantly, whilst maintaining cell viability, were chloramidine (Cl-amidine; 50 microM) and bisindolylmaleimide-I (10 microM). Apoptosis mediated by the ...


A Review Of The Signal Transduction Pathways Involved In Epithelial Mesenchymal Transition Induced In Breast Cancer Metastasis And Their Cross-Talks, Kasey Cervantes '17 May 2017

A Review Of The Signal Transduction Pathways Involved In Epithelial Mesenchymal Transition Induced In Breast Cancer Metastasis And Their Cross-Talks, Kasey Cervantes '17

Independent Study

Epithelial-Mesenchymal Transition (EMT) is a biological process utilized by epithelial cells to transform into motile mesenchymal cells, initiating metastasis in cancer. EMT is also utilized during development and wound healing [10]. This process allows for cancerous cells to detach themselves from their primary tumor and invade normal tissue in preferred organ sites, forming secondary tumors called metastases. Metastasis is very important in the progression of cancer in patients as it the process responsible for the mortality of patients through the collection of metastases that effect vital organs like the brain, lung, or immune system. The most common metastases for malignant ...


Metastasis-Associated Protein 1 Is An Upstream Regulator Of Dnmt3a And Stimulator Of Insulin-Growth Factor Binding Protein-3 In Breast Cancer., S Deivendran, Hezlin Marzook, T R Santhoshkumar, Rakesh Kumar, M Radhakrishna Pillai Apr 2017

Metastasis-Associated Protein 1 Is An Upstream Regulator Of Dnmt3a And Stimulator Of Insulin-Growth Factor Binding Protein-3 In Breast Cancer., S Deivendran, Hezlin Marzook, T R Santhoshkumar, Rakesh Kumar, M Radhakrishna Pillai

Biochemistry and Molecular Medicine Faculty Publications

Despite a recognized role of DNA methyltransferase 3a (DNMT3a) in human cancer, the nature of its upstream regulator(s) and relationship with the master chromatin remodeling factor MTA1, continues to be poorly understood. Here, we found an inverse relationship between the levels of MTA1 and DNMT3a in human cancer and that high levels of MTA1 in combination of low DNMT3a status correlates well with poor survival of breast cancer patients. We discovered that MTA1 represses DNMT3a expression via HDAC1/YY1 transcription factor complex. Because IGFBP3 is an established target of DNMT3a, we investigated the effect of MTA1 upon IGFBP3 expression ...


Mammalian Swi/Snf Enzymes And The Epigenetics Of Tumor Cell Metabolic Reprogramming, Jeffrey A. Nickerson, Qiong Wu, Anthony N. Imbalzano Apr 2017

Mammalian Swi/Snf Enzymes And The Epigenetics Of Tumor Cell Metabolic Reprogramming, Jeffrey A. Nickerson, Qiong Wu, Anthony N. Imbalzano

UMass Metabolic Network Publications

Tumor cells reprogram their metabolism to survive and grow in a challenging microenvironment. Some of this reprogramming is performed by epigenetic mechanisms. Epigenetics is in turn affected by metabolism; chromatin modifying enzymes are dependent on substrates that are also key metabolic intermediates. We have shown that the chromatin remodeling enzyme Brahma-related gene 1 (BRG1), an epigenetic regulator, is necessary for rapid breast cancer cell proliferation. The mechanism for this requirement is the BRG1-dependent transcription of key lipogenic enzymes and regulators. Reduction in lipid synthesis lowers proliferation rates, which can be restored by palmitate supplementation. This work has established BRG1 as ...


A Novel Microrna-1207-3p/Fndc1/Fn1/Ar Regulatory Pathway In Prostate Cancer, Dibash K. Das, Olorunseun O. Ogunwobi Feb 2017

A Novel Microrna-1207-3p/Fndc1/Fn1/Ar Regulatory Pathway In Prostate Cancer, Dibash K. Das, Olorunseun O. Ogunwobi

Publications and Research

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells ...


Intrathecal Aav9.Trastuzumab Tumor Prophylaxis And Treatment In A Murine Xenograft Model Of Her2+ Breast Cancer Brain Metastases, William Thomas Rothwell Jan 2017

Intrathecal Aav9.Trastuzumab Tumor Prophylaxis And Treatment In A Murine Xenograft Model Of Her2+ Breast Cancer Brain Metastases, William Thomas Rothwell

Publicly Accessible Penn Dissertations

Breast cancer brain metastases (BCBM) are a deadly sequela of breast tumors that overexpress human epidermal growth factor receptor 2 (HER2). HER2+ BCBM affects approximately 17,000 women in the US every year. Median survival is 10-13 months from the time of diagnosis of central nervous system (CNS) disease. Current therapeutic interventions are invasive, toxic, and largely ineffective, leaving a clear, unmet need for targeted HER2+ BCBM treatments. Trastuzumab(Herceptin®) is a monoclonal antibody used to treat HER2+ breast cancer successfully, but systemic trastuzumab cannot bypass the blood-brain barrier (BBB). To solve this problem, we have developed an adeno-associated virus ...