Ergebnisse der gynäkolgischen Descensuschirurgie unter Verwendung des GYNECARE PROLIFT® prolenemesh am Krankenhaus Agatharied Der Descensus genitalis ist eine der häufigsten gutartigen Erkrankungen der Frau, im Jahr 2010 waren mehr als 316 Millionen Frauen weltweit betroffen. Es besteht ein Lebensrisiko von 11,1% für eine chirurgische Intervention für eine 80jährige Frau. Die Gründe liegen v. a. in der Anzahl vaginaler (operativer) Geburten, Adiopsitas, Z.n. Hysterektomie, Überalterung und chronisch erhöhter intraabdominaler Druck. Die klinische Symptomatik besteht aus den typischen Senkungssymptomen wie Fremdkörper- und Druckgefühl, Ulcerationen mit Blutung, Fluor, Infektionen und Schmerzen. Außerdem kann es zu anorectaler Dysfunktion und Störungen der Blasenspeicher- und entleerungsfunktion kommen. Auch werden häufig Störungen der Sexualfunktion beschrieben. Die anatomiegerechte Beckenbodendefektbehebung mittels Polypropylene-Kunststoffnetzen (GYNECARE PROLIFT® prolenemesh) über den vaginalen Zugang wird zunehmend, neben den klassischen Descensusoperationen, zur Rekonstruktion des weiblichen Beckenbodens verwendet. Anhand der prä- und postoperativen Anamnese und Untersuchung nach dem POP-Q Schema einschließlich intra- und postoperativer Veräufe sowie 4 etablierter Fragebögen (PFDI-20, PFIQ-7, PISQ-12 und PGI-C) zu subjektiven Einschränkungen durch den Descensus erfolgt die Evaluation des Erfolges der Netzimplantation und ein Vergleich mit Ergebnissen anderer Methoden der Descensuschirurgie. Ergebnisse: Netzspezifische Komplikationen wie Exposition in die Scheide, Erosion in Nachbarorgane, Schrumpfung der Netze mit Schmerzen, Auftreten einer De Novo Belastungsinkontinenz oder einer Dyspareunie wurden im vorliegenden Kollektiv deutlich seltener als in der Literatur verzeichnet. Die Netzimplantation war in 81,5% (Stadium 0 oder 1) erfolgreich, es kam in 18,5% zu einem Rezidiv. Je nach Literatur und betroffenem Kompartiment liegen die Rezidivraten nach Mesheinlage zwischen 3,5 und 46% und bei 2 bis 42,5% nach klassischen Descensusoperationen. In allen 4 Fragebögen wurde eine Verbesserung der Lebensqualität, der sexuellen Zufriedenheit und der Speicher- und Entleerungsfunktion von Blase und Darm verzeichnet, jedoch war die Netzimplantation gleichwertig mit den klassischen Senkungsoperationen. / Introduction: Descensus genitalis is one of women’s most frequent benign diseases. In 2010, more than 316 Million women world-wide were affected. There’s an 11.1 % risk for an 80 year-old woman to undergo surgery within her life span. Above all, reasons lie in the number of vaginal births (including surgical intervention), hysterectomy, adipositas, high age and elevated intraabdominal pressure. Typical clinical descensus symptoms include foreign body and pressure sensation, ulceration with bleeding, fluor, infections and pain. Furthermore, anorectal dysfunction, bladder storage and emptying problems. Sexual dysfunctions are also frequently described. Apart from the usual descensus operation for the reconstruction of the female pelvic floor, implementing polypropylene mesh (GYNECARE PROLIFT® prolenemesh) through vaginal access has increasingly become an alternative. Material and methods: Success of the mesh implantation was compared with results of other methods of descensus surgery, using pre- and post-operative medical history, examination based on the POP-Q scale including intra- and post-operative developments as well as on four established questionnaires (PFDI-20, PFIQ-7, PISQ-12 and PGI-C) describing subjective restrictions caused by the descensus. Results/discussion: Mesh-specific complications, such as exposition into the vagina, erosion into adjacent organs, painful shrinking of the mesh, de novo stress incontinence or a dyspareunia were detected much less frequently in the current cohort than described in literature. Mesh implantation was successful in 81.5 % (stage 0 or 1), a recrudescence occurred in 18.5 %. Depending on the respective literature and specific cohort, the rates for recrudescence after mesh implementation lie between 3.5 and 46 %, while they range between 2 and 42.5% after usual descensus surgery. Each of the four questionnaires reported improvement of life quality, of sexual satisfaction as well as better bowel and bladder storage and emptying ability. However, results of mesh implantation showed no significant difference to those of the conventional descensus surgery.

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Abstract not available

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Also available online.

Dissertation (Ph.D.)--University of Toledo, 2009. / Typescript. "Submitted as partial fulfillment of the requirements for the degree of Doctor of Philosophy in Physics, special area of interest, Radiation Oncology Medical Physics." Bibliography: leaves 89-97.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 146-173). Also available in print.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 169-185). Available also in a digital version from Dissertation Abstracts.

Cervical cancer is a largely preventable malignancy due to the availability of cytology screening and vaccination against the essential initiation factor of cervical carcinogenesis, human papillomavirus (HPV). However, cervical cancer remains a significant medical burden worldwide, particularly in developing countries where large scale screening or vaccination programs are not financially feasible. Molecular tests such as HPV DNA tests have the potential to improve the speed and sensitivity of cervical cancer screening but suffer from limited specificity. Additional adjunct molecular markers are therefore desirable for enhancing molecular tests. Our previous research has revealed miR-143, a microRNA downregulated in a number of cancers, could be detected in liquid based cytology samples and is significantly reduced in cervical cancer samples and cell lines. Cellular role of miR-143 and mechanism behind its downregulation remain an unknown in cervical carcinogenesis. To explore the cellular roles of miR-143 in cervical cancer, a construct expressing miR-143 was transfected into cervical cancer cell lines HeLa, SiHa and C33A. miR- 143 overexpression was verified by qPCR. The miR-143 overexpressing cell lines were used to conduct a number of cellular function assays. It has been reported that miR-143 is able to suppress cell growth in HPV-positive HeLa. We followed up the findings and revealed miR-143 overexpression in HPV-negative C33A did not suppress cell growth in an MTT cell proliferation assay. ERK5 and KRAS, two targets of miR-143, are downregulated in colon cancer and bladder cancer to suppress cell grwoth. However, mRNA level of ERK5 and KRAS were not altered in all three miR-143 overexpressed cervical cancer cell lines, suggesting that miR-143 may not target ERK5 and KRAS transcriptionally in cervical cancer. Ability of miR-143 in regulating cell differentiation was evaluated by the expression of K10, an early keratinocyte differentiation marker. K10 was upregulated only in miR-143 overexpressed HeLa and SiHa as revealed by qPCR. A parallel increase in hSkn-1a mRNA, a transcription factor of K10, was also observed specifically in the two miR-overexpressed HPV-positive cell lines. miR-143 level is inversely correlated with cytology grading and progression of cervical disease, hinting its role in mediating cell migration and invasion during cancer progression and metastasis. A reduction of cell migration as demonstrated in wound healing assay and in vitro transwell migration assay was observed exclusively in miR-143 overexpressed HeLa and SiHa. miR-143 overexpression in C33A did not introduce any effect in cell migration. A reduction of cell invasion was also observed merely in miR-143 overexpressed HeLa and SiHa as revealed in a transwell invasion assay. Apart from studying the cellular roles of miR-143 in cervical cancer, this study has also explored mechanisms behind miR-143 downregulation in cervical cancer owing to the fact that certain miR-143 mediated cellular functions were observed only in HPV-positive cervical cancer cell lines. We hypothesized that HPV E6 and E7 oncoprotein may downregulate miR-143 in cervical cancer. The hypothesis was supported by our findings where normal cervical epithelial cell line immortalized by E6 and E7 had an undetectable level of endogenous miR-143 level. The same primary cells immortalized by shp16-hTERT expressed residual amounts of miR-143 as revealed by qPCR. Owing to the low miR-143 expression in shp16-hTERTimmortalized normal cervical epithelial cell line, downregulation of miR-143 in cervical cancer cell lines may also be contributed to hTERT overexpression and p16 silencing. Overall, miR-143 plays an important role in suppressing cell proliferation, enhancing keratinocyte differentiation marker expression, reducing migration and invasion in HPV-positive cervical cancer. Downregulation of miR-143 level may be an effect as manifested by E6 and E7 in HPV-positive cervical cancer. Differential cellular effects in miR-143 overexpressed HPV-positive and HPV-negative cervical cancer cell lines suggest that HPV oncoprotein mediates miR-143 cellular functions. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Cervical cancer is the second major cancer among women worldwide and is associated with persistent infection of human papillomaviruses (HPVs). However, exposure to high-risk type HPVs alone is insufficient for tumor formation. Additional factors are required for the HPV-infected cervical cells to become tumorigenic. Activation of ß-catenin/TCF signaling is essential for transformation of HPV-immortalized keratinocyte into cancer. ß-catenin is excessively expressed in cervical cancer. Dysregulation of microRNAs is profoundly observed in various cancers but their roles in cervical cancer are obscure. MicroRNA-135a (miR-135a) regulates one of the negative regulators of ß-catenin signaling, E3 ubiquitin ligase Seven In Absentia Human Homolog 1 (SIAH1). A 39-fold increase in the expression of miR-135a occurs in early stage cervical cancer. This study hypothesized that over-expression of miR-135a transformed HPV-infected cervical cells to cancer by activating ß-catenin/TCF signaling through down-regulation of SIAH1. In this study, miR-135a was confirmed to be specifically up-regulated in cervical cancer tissues when compared with precancerous lesions. Force-expression of miR-135a induced tumorigenic properties (anchorage independent growth and metastatic abilities) in vitro of a non-tumorigenic cervical epithelial cell line NC104 immortalized by HPV-16 E6 and E7 oncoproteins (NC104 E6/E7). The metastatic activities induced by miR-135a required the presence of E6 and E7 proteins as the activities were not observed in another immortalized cervical cell-line from the same parental cells but without the oncoproteins. The observations were confirmed by the observations that miR-135a knockdown did not impair the above tumorigenic properties in a HPV-negative cervical cancer cell line, but suppressed them in HPV-positive cervical cancer cell lines. The mechanism of action of miR-135a in cervical cancer was evaluated. The tumorigenic effects was due to the inhibitory action of miR-135a on SIAH1 leading to up-regulation of ß-catenin/TCF signaling. MiR-135a force-expression enhanced the growth of the cervical cancer cell line HeLa and NC104 E6/E7-derived tumor in vivo. The effect of miR-135a was partially nullified by SIAH1 force-expression. These observations were in line with expression analyses in cervical biopsies, in which SIAH1 immunoreactivities were inversely correlated, whereas ß-catenin was positively correlated with the expression of miR-135a. The data illustrated an oncogenic role of miR-135a/SIAH1/ß-catenin signaling in cervical cancer formation. The role of miR-135a in the formation of cancer stem cells (CSCs) was also elucidated. The number of CD133+ cells was significantly higher in the miR-135a-transformed NC104 E6/E7 cells than the untreated group. The CD133+ cells isolated from the miR-135a-transformed NC104 E6/E7 possessed self-renewal, differentiation and multidrug resistance properties, up-regulation of miR-135a. They also expressed ß-catenin and the stemness genes OCT4, SSEA-4. CD133+ cells were also identified sporadically in fresh cervical tumors. The observations indicate that CD133+ cervical cancer cells possesses CSC properties. In conclusion, this thesis was the first to identify and characterize the functions of miR-135a as an oncomiR in cervical carcinogenesis. MiR-135a played a pivotal role in malignant transformation and cancer progression in HPV-infected cervical cells through miR-135a/SIAH1/ß-catenin signaling. The microRNA also enhanced the proportion of CD133-expressing cervical CSCs. / published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy