MOLECULAR GENETICS OF GYNECOLOGIC CANCERS

The thesis is focused on the molecular genetics of gynecologic cancers, specifically uterine serous carcinoma (USC) and ovarian clear cell carcinoma (OCCC), two relatively uncommon cancer types with aggressive clinical behavior. In the first project, we sequenced 10 exomes of USCs and validated the most frequent somatic mutations in 66 additional USCs. In addition, gene copy number was characterized by single-nucleotide polymorphism (SNP) arrays in 23 USCs. Frequent somatic mutations were identified in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%) in USCs. Concordant PIK3CA, PPP2R1A, and TP53 mutation status between USC and the its precursor lesion, serous endometrial intraepithelial carcinoma (SEIC), were recognized in all SEICs examined. DNA copy number analysis revealed frequent genomic amplification of the CCNE1 locus and deletion of the FBXW7 locus. Among 23 uterine serous carcinomas that were subjected to SNP array analysis, seven tumors with FBXW7 mutations did not have CCNE1 amplification, and 13 (57%) tumors had either a molecular genetic alteration in FBXW7 or CCNE1 amplification. Nearly half of these uterine serous carcinomas harbored PIK3CA mutation and/or PIK3CA amplification. This study implicated genetic aberrations of the p53, cyclin E–FBXW7, and PI3K pathways as major mechanisms in the development of USC. In the second project, I evaluated in 525 gynecologic cancers the prevalence of gain-of-function TERT promoter mutations, which have been shown to promote transcriptional activation of TERT and likely play a key role in immortalization of some cancer types. With the exception of ovarian clear cell carcinomas (OCCC), of which 15.9% harbored the mutations, the majority of gynecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with OCCC. OCCC cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences. TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression and PIK3CA mutation in ovarian clear cell carcinomas. These results suggest that aberrations in telomere biology may play an important role in the pathogenesis of OCCC

A Collaborative Relevance Feedback Approach to Task-driven Recommendation

Abstract Managing knowledge is an important issue for organizations to gai

Identification of PBX1 Target Genes in Cancer Cells by Global Mapping of PBX1 Binding Sites

PBX1 is a TALE homeodomain transcription factor involved in organogenesis and tumorigenesis. Although it has been shown that ovarian, breast, and melanoma cancer cells depend on PBX1 for cell growth and survival, the molecular mechanism of how PBX1 promotes tumorigenesis remains unclear. Here, we applied an integrated approach by overlapping PBX1 ChIP-chip targets with the PBX1-regulated transcriptome in ovarian cancer cells to identify genes whose transcription was directly regulated by PBX1. We further determined if PBX1 target genes identified in ovarian cancer cells were co-overexpressed with PBX1 in carcinoma tissues. By analyzing TCGA gene expression microarray datasets from ovarian serous carcinomas, we found co-upregulation of PBX1 and a significant number of its direct target genes. Among the PBX1 target genes, a homeodomain protein MEOX1 whose DNA binding motif was enriched in PBX1-immunoprecipicated DNA sequences was selected for functional analysis. We demonstrated that MEOX1 protein interacts with PBX1 protein and inhibition of MEOX1 yields a similar growth inhibitory phenotype as PBX1 suppression. Furthermore, ectopically expressed MEOX1 functionally rescued the PBX1-withdrawn effect, suggesting MEOX1 mediates the cellular growth signal of PBX1. These results demonstrate that MEOX1 is a critical target gene and cofactor of PBX1 in ovarian cancers

Clinicopathologic features and outcomes following surgery for pancreatic adenosquamous carcinoma

<p>Abstract</p> <p>Background</p> <p>Pancreatic adenosquamous carcinoma (ASC) is a rare pancreatic malignancy subtype. We investigated the clinicopathological features and outcome of pancreatic ASC patients after surgery.</p> <p>Methods</p> <p>The medical records of 12 patients with pancreatic ASC undergoing surgical treatment (1993 to 2006) were retrospectively reviewed. Survival data of patients with stage IIB pancreatic adenocarcinoma and ASC undergoing surgical resection were compared.</p> <p>Results</p> <p>Symptoms included abdominal pain (91.7%), body weight loss (83.3%), anorexia (41.7%) and jaundice (25.0%). Tumors were located at pancreatic head in 5 (41.7%) patients, tail in 5 (41.7%), and body in 4 (33.3%). Median tumor size was 6.3 cm. Surgical resection was performed on 7 patients, bypass surgery on 3, and exploratory laparotomy with biopsy on 2. No surgical mortality was identified. Seven (58.3%) and 11 (91.7%) patients died within 6 and 12 months of operation, respectively. Median survival of 12 patients was 4.41 months. Seven patients receiving surgical resection had median survival of 6.51 months. Patients with stage IIB pancreatic ASC had shorter median survival compared to those with adenocarcinoma.</p> <p>Conclusion</p> <p>Aggressive surgical management does not appear effective in treating pancreatic ASC patients. Strategies involving non-surgical treatment such as chemotherapy, radiotherapy or target agents should be tested.</p

Isolated pancreatic metastasis from rectal cancer: a case report and review of literature

Isolated pancreatic metastases from a non-pancreatic primary malignancy are very rare. Studies have shown that resection of metastases is of proven benefit in some types of tumors. We report a case of 76-year-old Taiwanese woman with rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy and abdominoperineal resection 2 years ago presenting with an asymptomatic mass at the pancreatic tail on a routine follow up abdominal computed tomography scan. The patient underwent distal pancreatectomy and splenectomy under the preoperative impression of a primary pancreatic malignancy. Histological examination of the surgical specimen showed metastatic adenocarcinoma. Immunohistochemical studies confirmed the diagnosis of pancreatic metastasis from rectal adenocarcinoma. Postoperative chemotherapy in the form of oral capecitabine was given. The patient is alive and disease free 12 months after the surgery. In a patient presenting with a pancreatic mass with history of a non-pancreatic malignancy, a differential diagnosis of pancreatic metastasis should be considered. Surgical resection of a solitary pancreatic mass is justified not only to get the definitive diagnosis but also to improve the survival

Development, test and comparison of two Multiple Criteria Decision Analysis(MCDA) models: A case of healthcare infrastructure location

When planning a new development, location decisions have always been a major issue. This paper examines and compares two modelling methods used to inform a healthcare infrastructure location decision. Two Multiple Criteria Decision Analysis (MCDA) models were developed to support the optimisation of this decision-making process, within a National Health Service (NHS) organisation, in the UK. The proposed model structure is based on seven criteria (environment and safety, size, total cost, accessibility, design, risks and population profile) and 28 sub-criteria. First, Evidential Reasoning (ER) was used to solve the model, then, the processes and results were compared with the Analytical Hierarchy Process (AHP). It was established that using ER or AHP led to the same solutions. However, the scores between the alternatives were significantly different; which impacted the stakeholders‟ decision-making. As the processes differ according to the model selected, ER or AHP, it is relevant to establish the practical and managerial implications for selecting one model or the other and providing evidence of which models best fit this specific environment. To achieve an optimum operational decision it is argued, in this study, that the most transparent and robust framework is achieved by merging ER process with the pair-wise comparison, an element of AHP. This paper makes a defined contribution by developing and examining the use of MCDA models, to rationalise new healthcare infrastructure location, with the proposed model to be used for future decision. Moreover, very few studies comparing different MCDA techniques were found, this study results enable practitioners to consider even further the modelling characteristics to ensure the development of a reliable framework, even if this means applying a hybrid approach

Antimicrobial Drug Resistance in Pathogens Causing Nosocomial Infections at a University Hospital in Taiwan, 1981-1999

To determine the distribution and antimicrobial drug resistance in bacterial pathogens causing nosocomial infections, surveillance data on nosocomial infections documented from 1981 to 1999 at National Taiwan University Hospital were analyzed. During this period, 35,580 bacterial pathogens causing nosocomial infections were identified. Candida species increased considerably, ranking first by 1999 in the incidence of pathogens causing all nosocomial infections, followed by Staphylococcus aureus and Pseudomonas aeruginosa. Candida species also increased in importance as bloodstream infection isolates, from 1.0% in 1981-1986 to 16.2% in 1999. The most frequent isolates from urinary tract infections were Candida species (23.6%), followed by Escherichia coli (18.6%) and P. aeruginosa (11.0%). P. aeruginosa remained the most frequent isolates for respiratory tract and surgical site infections in the past 13 years. A remarkable increase in incidence was found in methicillin-resistant S. aureus (from 4.3% in 1981-1986 to 58.9% in 1993-1998), cefotaxime-resistant E. coli (from 0% in 1981-1986 to 6.1% in 1993-1998), and cefotaxime-resistant Klebsiella pneumoniae (from 4.0% in 1981-1986 to 25.8% in 1993-1998). Etiologic shifts in nosocomial infections and an upsurge of antimicrobial resistance among these pathogens, particularly those isolated from intensive care units, are impressive and alarming

Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis

SummaryCancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer