Bibliography: leaves 214-236. / xviii, 238 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1999

<p>The prediction of chromatin accessibility for cancer and neuron cell lines using genomic sequences is quite challenging. Advances in machine learning and deep learning techniques allow such challenges to be addressed. This thesis investigates the use of both the transfer learning and the multi-task learning techniques. In particular, this research demonstrates the potential of transfer learning and multi-task learning in improving the prediction accu?racy for twenty-three cancer types in human and neuron cell lines. Three different network architectures are used: the Basset network, the network, and the DeepSEA network. In addition, two transfer learning techniques are also used. In the first technique data relevant to the desired prediction task is not used during the pre-training stage while the second technique includes limited data about the desired prediction task in the pre-training phase. The preferred performance evaluation metric used to evaluate the performance of the models was the AUPRC due to the numerous negative samples. Our results demonstrate an average improvement of 4% of the DeepSEA network in predicting all twenty-three cancer cell line types when using the first technique, a decrease of 0.42% when using the second technique, and an increase of 0.40% when using multi-task learning. Also, it had an average improvement of 3.09% when using the first technique, 1.16% when using the second technique and 4.60% for the multi-task learning when predicting chromatin accessibility for the 14 neuron cell line types. The DanQ network had an average improvement of 1.18% using the first transfer learning technique, the second transfer learning technique showed an average decrease of 1.93% and also, a decrease of 0.90% for the multi-task learning technique when predicting for the different cancer cell line types. When predicting for the different neuron cell line types the DanQ had an average improvement of 1.56% using the first technique, 3.21% when using the second technique, and 5.35% for the multi-task learning techniques. The Basset network showed an average improvement of 2.93% using the first transfer learning technique and an average decrease of 0.02%, and 0.63% when using the second technique and multi-task learning technique respectively. Using the Basset network for prediction of chromatin accessibility in the different neuron types showed an average increase of 2.47%, 9 3.80% and 5.50% for the first transfer learning technique, second transfer learning technique and the multi-task learning technique respectively. The results show that the best technique for the cancer cell lines prediction is the first transfer learning model as it showed an improvement for all three network types, while the best technique for predicting chromatin accessibility in the neuron cell lines is the multi-task learning technique which showed the highest average improvement among all networks. The DeepSEA network showed the greatest improvement in performance among all techniques when predicting the different cancer cell line types. Also, it showed the greatest improvement when using the first transfer learning technique for predicting chromatin accessibility for neuron cell lines in the brain. The basset network showed the greatest improvement for the multi-task learning technique and the second transfer learning technique when predicting the accessibility for neuron cell lines. </p>

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

A quasi-experimental design was used in this study to determine if guided practice would result in higher breast cancer knowledge scores, higher breast self-examination (BSE) knowledge scores and higher intent to practice scores then modeling alone or teaching without modeling or guided practice. Fifty-eight women participated in the study. There were 19 women in the guided practice group, 22 in the modeling group and 17 in the control group. A pre-test, post-test format was used. ANCOVA was used to statistically control for the variance in pre-test scores. Descriptive statistics were used to analyze demographic data. The results showed that all methods of teaching resulted in higher breast cancer and BSE knowledge scores and in higher intent to practice scores. There were no statistically significant differences between the groups. Nursing research need to continue in this area to find the most effective method of teaching women breast self-examination.

Endometrial carcinoma is the most common gynaecologic cancer in the United States with about 41,200 new cases projected to occur in 2006. It often presents with abnormal uterine bleeding and spreads to the cervix in 10 to 20% of cases. Whilst early diagnosis is essential for optimal disease treatment, the best investigation for abnormal uterine bleeding remains uncertain. Although hysteroscopy has been reported to have high accuracy in predicting normal or abnormal endometrial histopathology, its accuracy varies with the underlying pathology. The highest accuracy occurs in the diagnosis of intrauterine anatomical pathology such as endometrial polyp whereas it is at its lowest in microscopic histopathology such as endometrial hyperplasia. Hysteroscopy is also potentially useful for detecting tumour spread to the uterine cervix that helps in staging and surgical planning. However, the role of hysteroscopy with guided biopsy in detecting endometrial cancer and the choice of distension medium remain to be determined. As the uterine cavity is a collapsed space, hysteroscopy requires its distension with a gaseous or liquid medium to allow complete visualization of the uterine cavity. The use of such media to rinse the uterine cavity raises the concern that when the endometrium harbours endometrial carcinoma cells, there is a potential risk of retrograde dissemination of these cells into the peritoneal cavity. The work in this thesis has addressed four major issues of diagnostic hysteroscopy in the management of patients with endometrial carcinoma. Firstly, the role of diagnostic hysteroscopy and guided biopsy is limited especially in microscopic tumours. Secondly, the role of diagnostic hysteroscopy to detect cervical invasion in preoperative staging of endometrial carcinoma is proven and the usage of normal saline is more accurate than that which uses carbon dioxide. Thirdly, hysteroscopic dissemination occurs more frequent when using normal saline as opposed to carbon dioxide as the distension medium. Lastly, complete occlusion of both fallopian tubes can effectively prevent the dissemination of endometrial carcinoma cells into the peritoneal cavity during diagnostic hysteroscopy. / Lo, Wing Kit Keith. / "May 2006." / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5873. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (167-193). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Abstract not available. / Pak Wai Martin. / Adviser: Charles Andrew van Hasselt. / Source: Dissertation Abstracts International, Volume: 72-10, Section: B, page: . / Thesis (M.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 245-269). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

在世界範圍內，肝細胞癌(HCC)是其中一種惡性程度很高並且預後很差的疾病。和其他的癌症一樣，肝癌是一种基因疾病，基因異常的積累在肝癌的生成中扮演著重要的角色。近年來，第二代測序技術（NGS）的迅速發展顯現了前所未見的能力揭示癌癥基因組中分子的複雜性，這為癌癥的生物學，診斷和药物治療提供了一個嶄新的思路。 / 非酒精脂肪性肝炎（NASH）是一種與代謝有關的疾病，在發達國家地區例如美國，歐洲，日本和加拿大，這是其中一種越來越常見的HCC 的病因。在本論文的第一部份，三個NASH 相關的HCC 以及其配對的血DNA 進行了全基因組測序（WGS）。另外還有一個來源于這三個NASH 相關的HCC其中之一的細胞株也進行了全基因組測序。在全部樣品中，測序深度範圍介乎29.1X 到102.2X，序列覆蓋度均大於99%。結果顯示發現的新的單核苷酸變異（SNVs）數量介乎于6,898 至17,129，平均值是11,133。根據這些找到的SNV，隨機選出56 個體細胞SNV 進行Sanger 測序，其中92.9%可以被確認。基因突變譜顯示有頻繁的A:T>G:C 和C：G>A:T 體細胞突變，而C：G>T:A 則在CpG 位點頻繁出現。在眾多的非同義體細胞突變基因中，我們選擇了CTNNB1，PNLIP 和MLL2 這三個基因進行進一步研究，此三個基因都在多於一個病例中發現有突變。在額外的一組44 對NASH 相關HCC及50 對HBV 相關的HCC 的癌變組織和其臨近非腫瘤組織中，我們進一步對這三個基因和TP53 的編碼區域進行了測序，而TP53 是在HBV 相關HCC中被報導有高頻率突變的。在NASH 相關的HCC 中，這些基因都只在腫瘤組織中發現重複出現的錯義突變，在臨近的非腫瘤肝組織沒有發現有突變。在NASH 相關的HCC 中，CTNNB1 的突變率（36.4%）明顯高於在HBV相關的HCC 中的突變率（12.0%，P=0.007）。PNLIP 和MLL2 的突變只在NASH相關的HCC 中發現，其突變率分別為12.1%和7.1%，而在HBV 相關的HCC中，則沒有發現突變。然而，TP53 的突變率在NASH 相關的HCC 及HBV相關的HCC 中差別不明顯（P>0.1）。在功能性研究的實驗中，我们发现在HKCI-10（有PNLIP 突變D396N）細胞株中，PNILP 的活性比在正常肝細胞L02 細胞株（野生型PNLIP）中要低。在永生性肝細胞L02 細胞株中，CTNNB1的突變引起了TOPFLASH 活性的提高以及增加了細胞群落形成的能力。HKCI-10 是一條我們實驗室建立的NASH 相關的肝細胞癌細胞株，在HKCI-10細胞株中，抑制CTNNB1 表達引起了細胞生長和增殖的減少。另外，在DEN誘導肝癌的有代謝失衡的db/db 轉基因鼠中，發現了一個CTNNB1 的突變T41A。據報導，CTNNB1 發生的致癌突變會引起蛋白的穩定並且因此激活經典的Wnt/β-catenin 信號通路，從而引致特定基因的轉錄。對於CTNNB1中最常見的突變S45P(在發現的CTNNB1 突變中占31.3%)，我們做了ChIP-array 實驗，結果顯示，在HKCI-10（CTNNB1 有S45P 突變）中，CTNNB1比在Hep3B 中（野生型CTNNB1）有著更緊密的啟動子結合能力（P<0.001）。Gene ontology 分析結果表明，被S45P 富集的生物過程涉及有RNA 代謝調節，轉錄因子活性和凋亡。MYC，E2F1 和ZFX 被ChIP-PCR 證實是與CTNNB1突變子S45P 有著更緊密結合能力的轉錄因子。 / 在本論文的第二部份，爲了進一步闡明致癌性的CTNNB1 突變S45P在HCC 中的角色，我們研究了一個此前未在HCC 報導過的基因ZFX。ZFX是一個在脊椎動物中高度保守，屬於Zfy 家族的zinc finger 蛋白。有報導指出ZFX 對於胚胎和造血幹細胞的自我更新有著重要的作用。另外亦有文獻報導ZFX 在一系列人類癌癥病例中有過度表達，例如食道癌，胃癌，前列腺癌和神經膠質瘤，並且顯現出致癌基因的特性。在本研究中，qRT-PCR結果提示ZFX 在HCC 腫瘤中的表達明顯高於正常肝組織。ZFX 的表達在51.8%的HCC 腫瘤中明顯高於其配對的鄰近非腫瘤肝組織。功能性研究表明，在MTT 實驗中，細胞的生存力在ZFX 缺失的穩定克隆中明顯減弱（P<0.0001）。在細胞群落形成實驗中，ZFX 缺失的穩定克隆顯示出明顯減弱的群落生長能力（P<0.0001）。在單細胞克隆生成實驗中，ZFX 缺失的HCC穩定克隆展示出數量更少，體積更小的細胞群落。另外，ZFX 基因抑制或者cisplatin 單獨處理均顯示細胞生存力的抑制，其抑制效率分別是24.0%和30.9%。當ZFX 基因抑制合併cisplatin 處理時，細胞生存力的抑制效率顯著地提高至65.2%，這個結果提示ZFX 基因抑制和cisplatin 處理兩者有協同增效作用（P<0.0001）。ZFX 基因的缺失會引起兩個為人熟知的胚胎幹細胞（ESCs）標誌物SOX-2 和NANOG 表達的明顯降低。 / 綜上所述，通過進行全基因測序，本論文的研究結果為NASH 相關的HCC 分子層面上的異常提供了一個高解析度的視覺角度。在NASH 相關的HCC 中，一些可能對於肝細胞癌變有重要作用並且重複出現突變的基因被確定，例如CTNNB1 和PNLIP。CTNNB1 的突變體S45P 的其中一個下游目標基因ZFX，在HCC 中被證實有幹細胞和腫瘤啟動細胞特性。闡明在HCC發展過程中的分子改變以及機制，對於為肝癌病人探索新的治療手段有著重要意義。 / Hepatocellular Carcinoma (HCC) is one of the most malignant diseases worldwide with poor prognosis. Like other human cancers, HCC is a genetic disease, where accumulation of genetic aberration plays important role in the liver carcinogenesis. The rapid advances in Next Generation Sequencing (NGS) technology in recent years have allowed unprecedented ability to unravel the molecular complexity of the cancer genome, providing new insights into the cancer biology, diagnosis and therapeutic drug development. / Non-alcoholic steatohepatitis (NASH), which is related to metabolic disorder, is an increasing common etiological factor of HCC, especially in developed countries such as United States, Europe, Japan and Canada. In first part of this thesis, Whole Genome Sequencing (WGS) was performed on three NASH-associated HCCs and their matched lymphocytic DNA. A cell line developed from one of the three NASH-associated HCCs was also subjected to WGS. The sequencing depth ranged from 29.1X to 102.2X with the coverage >99% shown in all samples. Novel SNVs identified ranged from 6,898 to 17,129 with an average of 11,133. Based on the SNVs found, the validation rate was 92.9% in 56 randomly selected somatic SNVs by Sanger sequencing. Mutational spectrum showed frequent somatic substitution of A:T>G:C and C:G>A:T while C:G>T:A transition exhibited a predominant somatic mutation rate in CpG sites. Among the non-synonymous somatic mutated genes, we selected CTNNB1, PNLIP and MLL2 which were mutated in more than one tumor for further study. In additional cohort of 44 NASH-associated and 50 HBV-associated HCC tumors and adjacent non-tumoral tissues, further sequencing all the coding regions of these three genes and TP53, which has been reported to be highly mutated in HBV-associated HCCs, were carried out. In NASH-associated HCCs, all genes harboured recurrent missense mutations exclusive in tumor but none in adjacent ,non-tumoral liver. The prevalence of CTNNB1 mutations was significantly higher in NASH-associated HCCs (36.4%) when compared to HBV-associated HCCs (12.0%, P=0.007). Mutations of PNLIP and MLL2 were detected only in NASH-associated HCCs with rates of 12.1% and 7.1%, respectively, but none in HBV-associated HCCs. The mutation rate of TP53, however, did not differ much between NASH-associated and HBV-associated HCCs (P>0.1). In functional study, for PNLIP, a loss-of-function in PNLIP activity was found in HKCI-10 harbouring D396N mutation as compared to normal liver cell, L02 with wild-type PNLIP. We demonstrated that CTNNB1 mutants conferred elevated TOPFLASH activity and enhanced colony growth in an immortalized hepatocyte cell line L02. Knockdown of CTNNB1 in HKCI-10, which is a NASH-associated HCC in-house cell line, resulted in inhibition of cell growth and proliferation. Also, a CTNNB1 mutation (T41A) was found in DEN-induced liver cancer of db/db transgenic mouse with metabolic disorder. Since oncogenic mutations of CTNNB1 were reported to be contributed to the stabilization of the protein and hence activate the canonical Wnt/β-catenin signaling pathway, inducing transcription of specific gene sets. We performed ChIP-array focusing on the most common CTNNB1 S45P mutation (accounted for 31.3% of all detected CTNNB1 mutants) in NASH-associated HCCs, the result showed more intense promoter binding affinities in HKCI-10 with CTNNB1 S45P mutation than Hep3B with wild-type CTNNB1 (P<0.001). Gene ontology analysis revealed that S45P mutant enriched the process including RNA metabolic regulation, transcription factor activities and apoptosis. Furthermore, we found that CTNNB1 S45P mutant showed more profound binding affinity to the promoter regions of transcription factors MYC, E2F1 and ZFX by ChIP-PCR. / In the second part of the thesis, we aimed to further understand the role of oncogenic CTNNB1 S45P mutant in HCC. Zinc finger protein X-linked (ZFX) gene which is previously undescribed in HCC was studied. ZFX is a zinc finger protein of Zfy family that is highly conserved among vertebrates. It has been reported that ZFX is required for self-renewal of embryonic and hematopoietic stem cells. Also, ZFX is suggested to be overexpressed in a number of human cancers such as esophageal carcinoma, gastric cancer, prostate cancer and glioma, conferring oncogenic characteristics. In this study, qRT-PCR analysis showed a significant higher ZFX expression in HCC tumors compared to normal livers. 51.8% of HCC tumors showed significant up-regulations of ZFX when compared to paired adjacent non-tumoral livers. Functional studies showed significant reduction in in-vitro cell proliferation in HCC by MTT assay (P<0.0001) and colony formation ability by colony formation assay (P<0.0001) in ZFX-deficient stable clones. In single-cell clonogenic assay, ZFX-depleted HCC exhibited fewer and smaller colonies. In addition, while ZFX knockdown or cisplatin treatment alone showed an inhibitory effect on cell viability by 24.0% and 30.9%, respectively, the reduction efficiency of cell viability increased dramatically to 65.2% when combine ZFX-knockdown and cisplatin treatment, indicating a synergistic effect between them (P<0.0001). Also, significant reduced expressions of SOX-2 and NANOG, both well-known embryonic stem cells (ESCs) markers, were observed as a result of ZFX depletion. / In summary, findings from this thesis provided high-resolution insight into the molecular aberrations in NASH-associated HCCs by performing WGS. Recurrent mutated genes which may be of great importance in hepatocellular carcinogenesis induced by NASH were identified, such as CTNNB1 and PNLIP. One of the S45P CTNNB1 downstream targets ZFX was demonstrated to confer stemness and tumor-initiating cells (TICs) characteristics in HCC. The understanding of molecular changes and mechanisms underlying HCC development will thus facilitate the exploration of new therapeutic options in patients with this deadly disease. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chen, Jiawei. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 166-190). / Abstracts also in Chinese.

Abstract not available

published_or_final_version / Surgery / Master / Master of Research in Medicine

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr Virus (EBV).Early diagnosis of NPC will improve the overall survival. However, traditional EBV markers do not perform well in high-risk individuals or for early detection of NPC. Aberrant promoter hypermethylation of tumor suppressor genes (TSGs) is an important epigenetic change in early tumorigenesis. This study identified a promising panel of methylation markers for early detection of NPC and assessed the clinical usefulness of these markers using nasopharyngeal (NP) brushing and blood specimens. Methylation-sensitive high resolution melting (MS-HRM) assays were carried out to assess the methylation status of a selected panel of four TSGs (RASSF1A, WIF1, DAPK1, RAR2)in biopsies, NP brushings and cell-free plasma from NPC patients. NP brushing and blood samples from high-risk and cancer-free groups were used as controls. The DNA methylation panel showed higher sensitivity and specificity than the EBV DNA markerincell-free plasma for early stage (Iand II) NPC (sensitivity: 64.6% vs. 51.2% and specificity: 96.0% vs. 88.0%, respectively). In combination with plasma EBV DNA, testing for DNA methylation in plasma and NP brushings using the four-gene MS-HRM test significantly increased the detection rate for all stages of NPC(94.1% for stages I-II, 98.4% for stages III-IV) as well as recurrence(93.5%). Aberrant activation of the Wnt signaling pathway is a common mechanism for cell transformation and tumor development in a variety of human cancers. A high frequency of promoter hypermethylation of WIF1was observed in NPC cell lines (100%), primary tumor biopsies(89.7%), NP brushings (80.2%), and cell-free plasma (51.8%),with no significant correlation with NPC stage. Simultaneously, expression of WIF1 was completely silenced in NPC cell lines (HONE1, HK1, HNE1, SUNE1, CNE1, CNE2, and C666),but not in immortalized NP epithelial cells (NP460 and NP69). These together suggested an important role of WIF1 in NPC development. In vitro and in vivo functional assays revealed a tumor suppressive role of WIF1in NPC. Restoration of WIF1expression in NPC cells significantly suppressed anchorage-independent growth, in vivo tumorigenicity, invasion, migration, and angiogenesis of NPC cells. A number of important angiogenesis-related genes were down-regulated by WIF1expression, including IL6,IL8,VEGF165,VEGFA, PDGFB, and MCP1. There is inhibition of the Wnt/β-catenin signaling pathway, manifested as decreased β-catenin expression and TCF/LEF Wnt promoter activity. These data indicated the important regulatory role of Wnt signaling pathway in NPC tumorigenicity, invasion, migration, and angiogenesis, by interacting with the complex signaling network in NPC cells. To conclude, the MS-HRM assay on the selected gene panel in combination with the EBV DNA test, increases the sensitivity for NPC detection at an early stage and detection of recurrence and has great potential to become a non-invasive test for early diagnosis and disease monitoring after treatment. Collectively, results from this study reveal that WIF1is not only a sensitive biomarker, but also a tumor suppressor gene in NPC. Understanding the molecular regulatory role ofWIF1in NPC will facilitate the diagnosis of NPC, and development of novel NPC therapeutic strategy. / published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy