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Cornell University

1. McElwee, John. Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target.

Degree: PhD, Veterinary Medicine, 2014, Cornell University

Breast cancer is the most frequently diagnosed cancer in women, with over 1 million new cases in the world each year. Recently, in addition to genetic mutations, numerous studies have found that epigenetics plays a direct role in the etiology of breast cancer. The PADIs are a family of epigenetic enzymes that catalyze citrullination, with previous work in our lab showing that PADIs can convert both protein and histone arginine to citrulline, leading to the disruption of protein-protein interactions, as well as direct transcriptional downregulation. Previous research has suggested a potential oncogenic role for PADI2 in breast cancer, though no formal analysis existed. The studies herein investigate the potential role of PADI2 as a novel oncogene and therapeutic target in the treatment of breast cancer in vitro and in vivo. First, using an in vitro model of breast cancer progression (MCF10AT), we show that PADI2 is upregulated upon the malignant transformation of cells, especially in MCF10DCIS cells, which recapitulate the highly invasive comedo-like ductal carcinoma in situ (DCIS) tumors seen in humans. Secondly, using RNA-seq, we show that PADI2 is highly correlated with HER2/ERBB2 overexpression across 57 breast cancer cell lines. We concluded this study by validating the use of our first-generation PADI inhibitor, Cl-amidine, as a therapeutic agent for the treatment of breast cancer both in vitro and in vivo. Following this, we further investigated the functional relationship between PADI2 and HER2 expression. Interestingly, PADI2 appears to function both upstream and downstream of HER2, potentially indicating a role in an oncogenic positivefeedback loop with HER2. Previous evidence from our lab established that PADI2 functions as an ER co-activator via the citrullination of histone H3 arginine 26 (H3R26) at ER-target gene promoters. We show here that PADI2 can bind to the HER2 promoter and downstream ERE; thus, suggesting that the epigenetic regulation of HER2 gene expression by PADI2 occurs via similar mechanisms to ER-target genes. Moreover, we were able to validate our highly potent next-generation PADI inhibitor, BB-Cl-amidine, in the treatment of breast cancer cells in vitro. Lastly, using a mouse model of PADI2 overexpression (MMTV-FLAGPADI2), we found that 20% of mice developed skin lesions after five months. These tumors express high levels of transgenic human PADI2 and display markers of increased inflammation and invasiveness-EMT. Furthermore, a subset of these tumors showed via histopathological analysis to have undergone malignant progression to highly invasive squamous cell carcinomas. Collectively, these studies provide functional and mechanistic evidence establishing PADI2 as a potential novel oncogene and target for cancer therapy. Advisors/Committee Members: Coonrod, Scott A. (chair), Soloway, Paul (committee member), Schimenti, John C. (committee member), Lin, David M. (committee member).

Subjects/Keywords: Peptidylarginine deiminase; Cl-amidine; PADI2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

McElwee, J. (2014). Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36093

Chicago Manual of Style (16th Edition):

McElwee, John. “Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target.” 2014. Doctoral Dissertation, Cornell University. Accessed March 08, 2021. http://hdl.handle.net/1813/36093.

MLA Handbook (7th Edition):

McElwee, John. “Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target.” 2014. Web. 08 Mar 2021.

Vancouver:

McElwee J. Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/1813/36093.

Council of Science Editors:

McElwee J. Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36093

2. Papadaki, Garyfalia. Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as rheumatoid arthritis and its subtypes like Still’s disease.

Degree: 2016, University of Crete (UOC); Πανεπιστήμιο Κρήτης

Rheumatoid arthritis (RA) is a chronic immune inflammatory disease characterized by synovial hyperplasia, joint destruction and extra-articular manifestations with a significant impact on both morbidity and mortality. Disease severity correlates with the presence of citrullinated proteins and immune complexes containing various citrullinated antigens which exhibit increased immunogenicity and arthritogenicity. The source of these proteins and immune complexes remains unknown. RA presents local inflammation in the joints, which subsequently develops into a systemic disorder as a result of the loss of immune tolerance. Pathogenic T cells not only help B cells produce auto-Abs (rheumatoid factor (RF) and anti-citrullinated protein, anti-CCPs), but also actively mediate tissue destruction by secreting proinflammatory cytokines (IL-17, IL-6, and TNF-a) thus creating an inflammatory microenvironment that favors macrophage and neutrophil recruitment and osteoclast activation.Dendritic cells (DCs) as professional antigen presenting cells (APCs), migrate to the lymph nodes where they process and present acquired antigens to naïve T cells and secrete cytokines resulting in skewing of naïve T cells toward T helper (Th1, Th17). Emerging data have revealed that the Th1 and Th17 are of the major T cell subsets during the course of RA but what drives their polarization and expansion is unknown. In the clinical setting, neutrophils are present in high numbers in the synovial tissue during the initial stages of RA and persist in the synovial fluid during the perpetuation of the disease. A novel feature of neutrophils, recently described, is their ability to form neutrophil extracellular traps (NETs), a cell death mechanism that is referred as NETosis. NETs are composed of chromatin decorated with a variety of granular proteins. NETs may promote differential cell activation and cytokine release. Aberrant formation of neutrophil extracellular traps (NETs) is a key feature in Rheumatoid arthritis (RA) and has been demonstrated to play a pivotal role in disease pathogenesis. However, the mechanism through which NETs shape the autoimmune response in RA remains elusive. Our aims were: (a) to delineate the role of NETs in shaping the RA autoimmune response, (b) to explore the mechanism involved in the NETs-mediated regulation of the autoimmune response. In this study, we demonstrate that inhibition of peptidylarginine deiminases (PADs) activity in collagen-induced arthritis (CIA) mouse model significantly reduced NET formation, attenuated clinical disease activity and inhibited joint destruction. Importantly, blocking of PADs markedly reduced the frequency of collagen-specific IFN-γ producing Th1 cells in the draining lymph nodes (dLNs) of immunized animals whereas the levels of Th17 cells remained unaffected. Mechanistically, we showed that exposure of DCs to CIA-derived NETs induced DC maturation characterized by significant up-regulation of CD80 and CD86 costimulatory molecules as well as elevated secretion of the inflammatory cytokine…

Subjects/Keywords: Αυτοανοσία; Ρευματοειδής αρθρίτιδα; Εξωκυττάριες παγίδες ουδετεροφίλων; αρθρίτιδα επαγώμενη από κολλαγόνο; Δενδριτικά κύτταρα; πολυμορφοπύρηνα-ουδετερόφιλα; Autoimmunity; Rheumatoid arthritis; Neutrophil extracellular traps; Collagen-induced arthritis; Cl-amidine; Dendritic cells; PMNs

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Papadaki, G. (2016). Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as rheumatoid arthritis and its subtypes like Still’s disease. (Thesis). University of Crete (UOC); Πανεπιστήμιο Κρήτης. Retrieved from http://hdl.handle.net/10442/hedi/39273

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Papadaki, Garyfalia. “Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as rheumatoid arthritis and its subtypes like Still’s disease.” 2016. Thesis, University of Crete (UOC); Πανεπιστήμιο Κρήτης. Accessed March 08, 2021. http://hdl.handle.net/10442/hedi/39273.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Papadaki, Garyfalia. “Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as rheumatoid arthritis and its subtypes like Still’s disease.” 2016. Web. 08 Mar 2021.

Vancouver:

Papadaki G. Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as rheumatoid arthritis and its subtypes like Still’s disease. [Internet] [Thesis]. University of Crete (UOC); Πανεπιστήμιο Κρήτης; 2016. [cited 2021 Mar 08]. Available from: http://hdl.handle.net/10442/hedi/39273.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Papadaki G. Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as rheumatoid arthritis and its subtypes like Still’s disease. [Thesis]. University of Crete (UOC); Πανεπιστήμιο Κρήτης; 2016. Available from: http://hdl.handle.net/10442/hedi/39273

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.