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You searched for +publisher:"Rutgers University" +contributor:("Chan, Chang"). Showing records 1 – 2 of 2 total matches.

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Rutgers University

1. Laddha, Saurabh, 1985-. Genomic characterization of human neuroendocrine tumors.

Degree: PhD, Quantitative Biomedicine, 2019, Rutgers University

Neuroendocrine tumors (NETs) are a rare, slow growing and biologically poorly understood presenting unique clinical challenges. The majority of NETs are localized to the gastrointestinal tract (predominately small intestinal and pancreas) and lung. NETs are well differentiated and the majority follows a benign course. However, these benign tumors can transform to malignant disease and results in adverse clinical outcome with few therapeutic options. The WHO classification of NETs has evolved over the last two decades but still lack clinical biomarkers for NETs stratifications. With greater awareness of NETs in clinic and improvement in diagnostic imaging techniques, the incidence rate of NETs has increased. Despite the increased incidence rate, the biological knowledge of these NETs is limited. The central theme of this thesis was to provide greater insights into NET biology including clinically relevant molecular subtypes, tumorigenesis pathways, tumor cell-of-origins and biomarkers for translation research. Specifically, the thesis focuses on genomic characterization of three major NET types: pancreatic NETs, lung carcinoids and small intestine NETs. The projects discussed in chapter 2, 3 and 4 involved the integration of genomics dataset (DNAseq, RNAseq and DNA CpG methylation) accompanied by clinical information. In Chapter 2, I discuss the results for pancreatic NETs (PanNETs). We identified two molecular subtypes of PanNETs with distinct genotype and clinical phenotypes. PanNETs with mutation in ATRX, DAXX or MEN1 gene (A-D-M mutant subtype) have adverse clinical outcome and resemble the gene expression profile of pancreatic alpha cells. We identified novel gene signature and biomarkers that differentiate PanNETs genotypes and gained an enhanced biological understanding of PanNETs from the cell lineage viewpoint. In Chapter 3, I discuss the results for lung carcinoids. We identified three novel molecular subtypes (LC1, LC2, and LC3) with distinct clinical phenotypes. The recurrent mutations we identified were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%) (MEN1, ARID1A, KMT2C and KMT2A) as well as DNA repair (17.2%) pathways. We found two biomarkers, ASCL1 and S100 that can stratify the three subtypes. MEN1 mutations were found to be exclusively enriched in subtype LC2. Subtype LC1 and LC3 is predominately found at peripheral and endobronchial lung respectively. Subtype LC3 is diagnosed on average 10 years earlier than LC1 and LC2. In Chapter 4, I discuss the results for small intestine NETs. We identified two (SINET-A and B) molecular subtypes of SI-NETs using gene expression and genetic dataset with distinct cell-of-origin signature. We identified one copy loss of chromosome 18 (chr18) in 85% (22 of 26) of subtype SINET-B while subtype SINET-A is diploid for chr18. We found that SINET-A subtype may originate from TPH1-/REG4- neuroendocrine cells of the small intestine and SINET-B from EC cells, which are TPH1+/REG4+. Gene expression profile of two potential… Advisors/Committee Members: Chan, Chang S (chair), Verzi, Michael (internal member), Ganesan, Shridar (internal member), White, Eileen (outside member), School of Graduate Studies.

Subjects/Keywords: Neuroendocrine tumors

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

APA (6th Edition):

Laddha, Saurabh, 1. (2019). Genomic characterization of human neuroendocrine tumors. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/60031/

Chicago Manual of Style (16th Edition):

Laddha, Saurabh, 1985-. “Genomic characterization of human neuroendocrine tumors.” 2019. Doctoral Dissertation, Rutgers University. Accessed April 17, 2021. https://rucore.libraries.rutgers.edu/rutgers-lib/60031/.

MLA Handbook (7th Edition):

Laddha, Saurabh, 1985-. “Genomic characterization of human neuroendocrine tumors.” 2019. Web. 17 Apr 2021.

Vancouver:

Laddha, Saurabh 1. Genomic characterization of human neuroendocrine tumors. [Internet] [Doctoral dissertation]. Rutgers University; 2019. [cited 2021 Apr 17]. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/60031/.

Council of Science Editors:

Laddha, Saurabh 1. Genomic characterization of human neuroendocrine tumors. [Doctoral Dissertation]. Rutgers University; 2019. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/60031/

2. Mahdi, Amar Hekmat, 1977-. Understanding the role of the PALB2-BRCA1 interaction in tumor suppression.

Degree: PhD, Physiology and Integrative Biology, 2017, Rutgers University

Homologous recombination (HR) is the only error-free pathway for the repair of DNA double strand breaks (DSBs). BRCA1 and BRCA2, the two major breast cancer suppressor proteins, play essential roles in HR-mediated repair of DSBs by promoting the recruitment of RAD51, the recombination enzyme, to DNA damage sites for the initiation of HR. PALB2 (partner and localizer of BRCA2) plays a key role in this pathway by acting as a chromatin adaptor for BRCA2 and a linker between BRCA1 and BRCA2. Like BRCA1 and BRCA2, PALB2 is a tumor suppressor gene itself. Germline, heterozygous mutations in the gene increase the risk of breast, ovarian and pancreatic cancers. However, its mechanism is not fully understood. To investigate the in vivo role of the PALB2-BRCA1 interaction, we previously generated a Palb2 knockin mouse strain that contains a mutation that disrupts BRCA1 binding. This mouse model also allows us to bypass the embryonic lethality of the Palb2 KO mice. In this study, we hypothesized that the direct communication between the two proteins is critical for proper DNA damage repair and response in vivo and for suppression of tumorigenesis. Indeed, both immunohistochemistry (IHC) and immunofluorescence (IF) demonstrated that different tissues of the Palb2 mutant mice have higher levels of endogenous DSBs (gamma H2AX foci) and slower DSB repair kinetics after ionizing radiation (IR). Yet, mutant cells were more resistant to cell death. When aged under normal conditions, mutant mice showed increased tumor incidence in multiple tissues, particularly in the liver. Upon challenging of these mutant mice with carcinogen administration or gamma irradiation, they showed accelerated tumor development as compared with wild-type (wt) mice. When crossed with Trp53 mutant mice, the compound mutant mice showed greatly accelerated development of tumors typically associated with mutations in p53, i.e. thymic lymphoma, osteosarcoma and soft tissue sarcoma, etc. Whole exome sequencing (WES) of the tumors arising from Palb2m/m;Trp53+/- mice revealed loss of the wt allele of Trp53 in the majority of tumors, with at least some tumors showing focal deletions of the wt gene, suggesting that disruption of BRCA1-PALB2/BRCA2 axis promotes regional genomic deletions that may lead to loss of other tumor suppressors such as p53. These results underscore the importance of the BRCA1-PALB2/BRCA2 pathway for tumor suppression and suggest a potentially novel mechanism for BRCA/PALB2-mediated tumor suppression, which is by preventing Trp53/TP53 loss of heterozygosity (LOH), which would allow for tumor development. Finally, we also found constitutively elevated levels of reactive oxygen species (ROS) and activation of NF-kB, a redox sensitive transcription factor, in tissues and cells from the mutant mice. Given its established pro-survival function, NF-kB activation could explain why cells in the mutant mice are resistant to apoptosis upon irradiation despite having increased and prolonged DNA damage. This finding also suggests that the NF-kB pathway… Advisors/Committee Members: Bunting, Samuel (chair), Fan, Huizhou (internal member), Xia, Bing (internal member), Chan, Chang (outside member).

Subjects/Keywords: Cancer – Prevention; Breast – Cancer

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

APA (6th Edition):

Mahdi, Amar Hekmat, 1. (2017). Understanding the role of the PALB2-BRCA1 interaction in tumor suppression. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/53735/

Chicago Manual of Style (16th Edition):

Mahdi, Amar Hekmat, 1977-. “Understanding the role of the PALB2-BRCA1 interaction in tumor suppression.” 2017. Doctoral Dissertation, Rutgers University. Accessed April 17, 2021. https://rucore.libraries.rutgers.edu/rutgers-lib/53735/.

MLA Handbook (7th Edition):

Mahdi, Amar Hekmat, 1977-. “Understanding the role of the PALB2-BRCA1 interaction in tumor suppression.” 2017. Web. 17 Apr 2021.

Vancouver:

Mahdi, Amar Hekmat 1. Understanding the role of the PALB2-BRCA1 interaction in tumor suppression. [Internet] [Doctoral dissertation]. Rutgers University; 2017. [cited 2021 Apr 17]. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/53735/.

Council of Science Editors:

Mahdi, Amar Hekmat 1. Understanding the role of the PALB2-BRCA1 interaction in tumor suppression. [Doctoral Dissertation]. Rutgers University; 2017. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/53735/

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