Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Genetic- And Diet-Induced Ω-3 Fatty Acid Enrichment Enhances Trpv4-Mediated Vasodilation In Mice, Rebeca Caires, Tessa A C Garrud, Luis O Romero, Carlos Fernández-Peña, Valeria Vásquez, Jonathan H Jaggar, Julio F Cordero-Morales

Faculty, Staff and Student Publications

TRPV4 channel activation in endothelial cells leads to vasodilation, while impairment of TRPV4 activity is implicated in vascular dysfunction. Strategies that increase TRPV4 activity could enhance vasodilation and ameliorate vascular disorders. Here, we show that supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid known to have beneficial cardiovascular effects, increases TRPV4 activity in human endothelial cells of various vascular beds. Mice carrying the C. elegans FAT-1 enzyme, which converts ω-6 to ω-3 polyunsaturated fatty acids, display higher EPA content and increased TRPV4-mediated vasodilation in mesenteric arteries. Likewise, mice fed an EPA-enriched diet exhibit enhanced and prolonged TRPV4-dependent vasodilation …

Contributions Of Circulating Micrornas For Early Detection Of Lung Cancer, Jody Vykoukal, Johannes F Fahrmann, Nikul Patel, Masayoshi Shimizu, Edwin J Ostrin, Jennifer B Dennison, Cristina Ivan, Gary E Goodman, Mark D Thornquist, Matt J Barnett, Ziding Feng, George A Calin, Samir M Hanash

Faculty, Staff and Student Publications

There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) …

Genetic Impairment Of Succinate Metabolism Disrupts Bioenergetic Sensing In Adrenal Neuroendocrine Cancer, Priyanka Gupta, Keehn Strange, Rahul Telange, Ailan Guo, Heather Hatch, Amin Sobh, Jonathan Elie, Angela M Carter, John Totenhagen, Chunfeng Tan, Yogesh A Sonawane, Jiri Neuzil, Amarnath Natarajan, Ashley J Ovens, Jonathan S Oakhill, Thorsten Wiederhold, Karel Pacak, Hans K Ghayee, Laurent Meijer, Sushanth Reddy, James A Bibb

Faculty, Staff and Student Publications

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP …

Defining The Cooperation Between Mhc-I And Mhc-Ii Neoantigen-Driven T Cell Responses To Develop Effective Personalized Immunotherapies, Charmelle Williams

Dissertations and Theses (Open Access)

Immune checkpoint therapy (ICT) (e.g. anti-CTLA-4 (α-CTLA-4), anti-PD-1 (α-PD-1)) enables durable T cell-dependent anti-tumor immunity in certain cancer patients. Since a subset of patients respond to ICT, this work aims at developing a more in-depth understanding of T-cell responses to MHC class I (MHC-I) and MHC class II (MHC-II) tumor antigens that are derived from aberrant expression of non-mutant antigens or driver and passenger somatic alterations that can function as tumor neoantigens. We used a poorly immunogenic Braf^v600e Pten^-/- Cdkn2a^-/- YUMM1.7 (Y1.7) murine melanoma line with a paucity of endogenous neoantigens that is unresponsive to ICT, and …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Alyref, A Novel Factor Involved In Breast Carcinogenesis, Acts Through Transcriptional And Post-Transcriptional Mechanisms Selectively Regulating The Short Neat1 Isoform, Christiane Klec, Erik Knutsen, Daniela Schwarzenbacher, Katharina Jonas, Barbara Pasculli, Ellen Heitzer, Beate Rinner, Katarina Krajina, Felix Prinz, Benjamin Gottschalk, Peter Ulz, Alexander Deutsch, Andreas Prokesch, Stephan W Jahn, S Mohammad Lellahi, Maria Perander, Raffaela Barbano, Wolfgang F Graier, Paola Parrella, George Adrian Calin, Martin Pichler

Faculty, Staff and Student Publications

The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 …

Targeting Syndecan-1: New Opportunities In Cancer Therapy, Zecheng Yang, Shuaitong Chen, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Syndecan-1 (SDC1, CD138) is one of the heparan sulfate proteoglycans and is essential for maintaining normal cell morphology, interacting with the extracellular and intracellular protein repertoire, as well as mediating signaling transduction upon environmental stimuli. The critical role of SDC1 in promoting tumorigenesis and metastasis has been increasingly recognized in various cancer types, implying a promising potential of utilizing SDC1 as a novel target for cancer therapy. This review summarizes the current knowledge on SDC1 structure and functions, including its role in tumor biology. We also discuss the highlights and limitations of current SDC1-targeted therapies as well as the obstacles …

Reshaping The Tumor Microenvironment With Oncolytic Viruses, Positive Regulation Of The Immune Synapse, And Blockade Of The Immunosuppressive Oncometabolic Circuitry, Teresa T Nguyen, Dong Ho Shin, Sagar Sohoni, Sanjay K Singh, Yisel Rivera-Molina, Hong Jiang, Xuejun Fan, Joy Gumin, Frederick F Lang, Christopher Alvarez-Breckenridge, Filipa Godoy-Vitorino, Lisha Zhu, W Jim Zheng, Lijie Zhai, Erik Ladomersky, Kristen L Lauing, Marta M Alonso, Derek A Wainwright, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Background: Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy.

Methods: We used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography-mass spectrometry. Aryl hydrocarbon receptor (AhR) activation …

Stat3 Activates The Pentraxin 3 Gene In Chronic Lymphocytic Leukemia Cells, Uri Rozovski, Ivo Veletic, David M Harris, Ping Li, Zhiming Liu, Preetesh Jain, Taghi Manshouri, Alessandra Ferrajoli, Jan A Burger, Prithviraj Bose, Phillip A Thompson, Nitin Jain, William G Wierda, Srdan Verstovsek, Michael J Keating, Zeev Estrov

Faculty, Staff and Student Publications

Pentraxin-related protein 3 (PTX3), commonly produced by myeloid and endothelial cells, is a humoral pattern recognition protein of the innate immune system. Because PTX3 plasma levels of patients with chronic lymphocytic leukemia (CLL) are high and most circulating cells in patients with CLL are CLL cells, we reasoned that CLL cells produce PTX3. Western immunoblotting revealed that low-density cells from seven of seven patients with CLL produce high levels of PTX3, flow cytometry analysis revealed that the PTX3-producing cells are B lymphocytes coexpressing CD19 and CD5, and confocal microscopy showed that PTX3 is present in the cytoplasm of CLL cells. …

Comprehensive Characterization Of Tumor Immune Landscape Following Oncolytic Virotherapy By Single-Cell Rna Sequencing, Divya Ravirala, Guangsheng Pei, Zhongming Zhao, Xiaoliu Zhang

Faculty, Staff and Student Publications

An important mechanism of oncolytic virotherapy in ameliorating cancer immunotherapy is by inducing significant changes in the immune landscape in the tumor microenvironment (TME). Despite this notion and the potential therapeutic implications, a comprehensive analysis of the immune changes in carcinomas induced by virotherapy has not yet been elucidated. We conducted single-cell RNA sequencing analysis on carcinomas treated with an HSV-2-based oncolytic virus to characterize the immunogenic changes in the TME. We specifically analyzed and compared the immune cell composition between viral treated and untreated tumors. We also applied CellChat to analyze the complex interactions among the infiltrated immune cells. …

Maximal Activation Of Apoptosis Signaling By Cotargeting Antiapoptotic Proteins In Bh3 Mimetic-Resistant Aml And Aml Stem Cells, Bing Z Carter, Po Yee Mak, Wenjing Tao, Qi Zhang, Vivian Ruvolo, Vinitha M Kuruvilla, Xiangmeng Wang, Duncan H Mak, Venkata L Battula, Marina Konopleva, Elias J Jabbour, Paul E Hughes, Xiaoyue Chen, Phuong K Morrow, Michael Andreeff

Faculty, Staff and Student Publications

MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Cotargeting BCL-2 and MCL-1 was highly synergistic in AML cell lines …

Dedifferentiation-Mediated Stem Cell Niche Maintenance In Early-Stage Ductal Carcinoma In Situ Progression: Insights From A Multiscale Modeling Study, Joseph D Butner, Prashant Dogra, Caroline Chung, Javier Ruiz-Ramírez, Sara Nizzero, Marija Plodinec, Xiaoxian Li, Ping-Ying Pan, Shu-Hsia Chen, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is …

Modeling Of Cns Cancer With A Focus On The Immune Component, Daniel Zamler

Dissertations and Theses (Open Access)

The knowledge surrounding cancers of the central nervous system remains poorly developed, in particular with regard to the immune component. The works contained in this thesis look at craniopharyngioma, glioblastoma, and several forms of brain metastasis. While some attention is given to the tumor cells themselves, as well as the patient setting which these studies model, the immune component of disease progression and treatment plays a strong role in each and is the primary focus of the works contained.

Craniopharyngioma is a relatively rare tumor in adults. Although histologically benign, it can be locally aggressive and may require additional therapeutic …

Peripheral And Central Kynurenine Pathway Abnormalities In Major Depression, Elisabeth R Paul, Lilly Schwieler, Sophie Erhardt, Sandra Boda, Ada Trepci, Robin Kämpe, Anna Asratian, Lovisa Holm, Adam Yngve, Robert Dantzer, Markus Heilig, J Paul Hamilton, Martin Samuelsson

Faculty, Staff and Student Publications

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro-inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an …

Interplay Between Soluble Cd74 And Macrophage-Migration Inhibitory Factor Drives Tumor Growth And Influences Patient Survival In Melanoma, Yasunari Fukuda, Matias A Bustos, Sung-Nam Cho, Jason Roszik, Suyeon Ryu, Victor M Lopez, Jared K Burks, Jeffrey E Lee, Elizabeth A Grimm, Dave S B Hoon, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Faculty, Staff and Student Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

Serglycin Is Involved In Tgf-Β Induced Epithelial-Mesenchymal Transition And Is Highly Expressed By Immune Cells In Breast Cancer Tissue, Marta Tellez-Gabriel, Xavier Tekpli, Trine M Reine, Beate Hegge, Stephanie R Nielsen, Meng Chen, Line Moi, Lisa Svartdal Normann, Lill-Tove R Busund, George A Calin, Gunhild M Mælandsmo, Maria Perander, Achilleas D Theocharis, Svein O Kolset, Erik Knutsen

Faculty, Staff and Student Publications

Serglycin is a proteoglycan highly expressed by immune cells, in which its functions are linked to storage, secretion, transport, and protection of chemokines, proteases, histamine, growth factors, and other bioactive molecules. In recent years, it has been demonstrated that serglycin is also expressed by several other cell types, such as endothelial cells, muscle cells, and multiple types of cancer cells. Here, we show that serglycin expression is upregulated in transforming growth factor beta (TGF-β) induced epithelial-mesenchymal transition (EMT). Functional studies provide evidence that serglycin plays an important role in the regulation of the transition between the epithelial and mesenchymal phenotypes, …

The Role Of Ifitm3 In The Immune Response Of Brca-Deficient High Grade Serous Ovarian Carcinoma, Han Cun

Dissertations and Theses (Open Access)

Background: Prior studies showed that BRCA-deficient high grade serous ovarian carcinoma (HGSOC) had increased tumor infiltrating lymphocytes (TILs) compared to BRCA-wildtype (WT). To better understand the underlying immune mechanism in these tumors, a preliminary transcriptome analysis was performed on a set of microdissected HGSOC tumor specimens with BRCA1-mutation, BRCA2-mutation, or WT. This demonstrated an upregulation of IFITM3, an essential gene in modulating immune function. Based on these findings, we hypothesized that BRCA-deficient HGSOC have increased DNA damage leading to upregulation of IFITM3 and subsequent increase in antigen presentation and T-cell activation.

Methods: Following IRB approval, preliminary transcriptome analysis was performed …

Harnessing The Power Of Trained Immunity In The Setting Of Pancreatic Cancer: A Novel Mechanism Of Immune Trafficking And Tumor Control., Anne Elena Geller

Electronic Theses and Dissertations

Despite the success of immunotherapy in many types of cancer, pancreatic adenocarcinoma (PDAC) has yet to benefit. Innate immune cells are critical to antitumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Though trained innate immunity has mostly been investigated in the context of infection, the induction of trained innate immunity could also protect against tumors, and specifically pancreatic tumors. Here, we demonstrate that yeast-derived particulate β-glucan, a known inducer of trained immunity, traffics to the pancreas following IP administration. This causes …

[(Wr)8Wkβa]-Doxorubicin Conjugate: A Delivery System To Overcome Multi-Drug Resistance Against Doxorubicin, Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the …

The Epigenetic Effects Of Omega-3 Fatty Acids In Diffuse Large B-Cell Lymphoma, Tanner Jeffrey Bakhshi

Theses, Dissertations and Capstones

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. It is an aggressive cancer, with 50-70% of patients diagnosed at an advanced stage and 30-50% of patients not cured by chemoimmunotherapy. DLBCL is almost always caused by genetic damage sustained during the germinal center (GC) reaction. The mechanisms that govern the GC reaction bear a striking resemblance to those that drive DLBCL. Genomic studies have shown that some of its most common mutations occur in genes that encode epigenetic modifiers, including the lysine (histone) acetyltransferases CREBBP and p300. These mutations prevent the acetylation of multiple histone residues, …

Genetic And Epigenetic Determinants Of Diffuse Large B-Cell Lymphoma, Tanner Bakhshi, Philippe T. Georgel

Biomedical Sciences

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma and is notorious for its heterogeneity, aggressive nature, and the frequent development of resistance and/or relapse after treatment with standard chemotherapy. To address these problems, a strong emphasis has been placed on researching the molecular origins and mechanisms of DLBCL to develop effective treatments. One of the major insights produced by such research is that DLBCL almost always stems from genetic damage that occurs during the germinal center (GC) reaction, which is required for the production of high-affinity antibodies. Indeed, there is significant overlap between the mechanisms that …

Investigation Of The Functional Impact Of Anti-Pd-1 On Tumor-Infiltrating Lymphocytes (Til) And Mapping Of Tumor Genomic Features Relevant For Response To Til Therapy, Caitlin Creasy

Dissertations and Theses (Open Access)

With the growing use of both cellular and antibody-based immunotherapies, it has become more important to uncover biomarkers to predict patient response to therapy and ideally aid in patient selection for specific therapeutics, thereby enhancing treatment outcome. At MD Anderson, we have a 43% response rate to therapy when treating metastatic melanoma patients with adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL), but it is unknown what makes the other 57% of patients not respond to therapy. It is further unknown how particularly early doses of checkpoint inhibitors, like anti-PD-1, attribute to TIL functionality, adding another confounding factor in determining …

Allogeneic Mesenchymal Cell Therapy In Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The Cctrn Seneca Trial, Roberto Bolli, Emerson C Perin, James T Willerson, Phillip C Yang, Jay H Traverse, Timothy D Henry, Carl J Pepine, Raul D Mitrani, Joshua M Hare, Michael P Murphy, Keith L March, Sohail Ikram, David P Lee, Connor O'Brien, Jean-Bernard Durand, Kathy Miller, Joao A Lima, Mohammad R Ostovaneh, Bharath Ambale-Venkatesh, Adrian P Gee, Sara Richman, Doris A Taylor, Shelly L Sayre, Judy Bettencourt, Rachel W Vojvodic, Michelle L Cohen, Lara M Simpson, Dejian Lai, David Aguilar, Catalin Loghin, Lem Moyé, Ray F Ebert, Barry R Davis, Robert D Simari

Faculty, Staff and Student Publications

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment.

OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC.

METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 10

RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the …

Comparative Molecular Transporter Properties Of Cyclic Peptides Containing Tryptophan And Arginine Residues Formed Through Disulfide Cyclization, Eman H. M. Mohammed, Dindyal Mandal, Saghar Mozaffari, Magdy Abdel-Hamied Zahran, Amany Mostafa Osman, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

We have previously reported cyclic cell-penetrating peptides [WR]₅ and [WR]₄ as molecular transporters. To optimize further the utility of our developed peptides for targeted therapy in cancer cells using the redox condition, we designed a new generation of peptides and evaluated their cytotoxicity as well as uptake behavior against different cancer cell lines. Thus, cyclic [C(WR)_xC] and linear counterparts (C(WR)_xC), where x = 4–5, were synthesized using Fmoc/tBu solid-phase peptide synthesis, purified, and characterized. The compounds did not show any significant cytotoxicity (at 25 µM) against ovarian (SK-OV-3), leukemia (CCRF-CEM), gastric adenocarcinoma (CRL-1739), breast …

How Can We Stop Cancer?, Joseph R. Current

The Review: A Journal of Undergraduate Student Research

Cancer is a disease that humans have been struggling to combat for centuries. It originates from the accumulation of several mutations over the life of a cell that causes it to evade cell death and multiply rapidly. It can affect any tissue in the body and can spread to other parts of the body through metastasis. Cancer comes in numerous shapes and sizes with different levels of aggression, growth speeds, and health risks. Many treatments for cancer exist today, three of the most popular being surgery, chemotherapy, and radiation therapy, which can be used in combinations with other treatments to …

Prostate Field Cancerization And Exosomes: Association Between Cd9, Early Growth Response 1 And Fatty Acid Synthase, Farideh Amirrad, Philip A. Pytak, Neda Sadeghiani-Pelar, Julie P. T. Nguyen, Emily L. Cauble, Anna C. Jones

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Intracapsular and well‑defined adenocarcinomas of the prostate are often surrounded by tissue areas that harbor molecular aberrations, including those of genetic, epigenetic and biochemical nature. This is known as field cancerization, or a field effect and denotes a state of pre‑malignancy. Such alterations in histologically normal tumor‑adjacent prostatic tissues have been recognized as clinically important and are potentially exploitable as biomarkers of disease and/or targets for preventative/therapeutic intervention. The authors have previously identified and validated two protein markers of field cancerization: The expressional upregulation of the transcription factor early growth response 1 (EGR‑1) and the lipogenic enzyme fatty acid synthase …

Identification And Molecular Analysis Of Dna In Exosomes, Jena Tavormina

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 …

A Systematic Comparison Of Lipopolymers For Sirna Delivery To Multiple Breast Cancer Cell Lines: In Vitro Studies, Hamidreza Montazeri Aliabadi, Remant Bahadur Kc, Emira Bousoik, Ashley Barbarino, Bindu Thapa, Melissa Coyle, Parvin Mahdipoor, Hasan Uludağ

Pharmacy Faculty Articles and Research

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were …

Cc Chemokine Ccl1 Receptor Ccr8 Mediates Conversion Of Mesenchymal Stem Cells To Embryoid Bodies Expressing Foxp3+Ccr8+ Regulatory T Cells, Nasreen Haque, Tuteja Akaash, Niloufar Haque

Publications and Research

Embryoid bodies (EBs) are three dimensional aggregates of pluripotent stem cells primarily used to investigate morphogenesis and cell toxicity, are also attractive tools in regenerative medicine. While embryonic stem cells (ESCs) and induced pluripotent cells (IPSCs) have been shown to form EBs in mouse, primate and humans, EB formation have not been previously demonstrated in mesenchymal stem cells (MSCs). Here we show that rat MSCs form EBs; which express regulatory T cell (Treg) marker Foxp3 and CC chemokine CCL1 receptor CCR8. We show a novel method for formation of EBs from MSCs under stress and demonstrate that the induction of …