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<p>Loss of chromosome 17p is frequently observed in various cancers. One of the most commonly mutated targets p53 is on chromosome 17p13.1. However, studies have also reported loss of the 17p13.2 region in breast and medulloblastoma, thereby suggesting the residence of potential tumour suppressors in 17p13.2. Cytochrome b5 domain containing 2 (CYB5D2) is located on 17p13.2 implying CYB5D2 being a candidate tumour suppressor. CYB5D2 (neuferricin) belongs to the family of membrane associated progesterone receptors (MAPR). The archetypal member of the family, progesterone receptor membrane component 1 (PGRMC1), has been shown to play a role in domains independently of its function in mediating progesterone signalling. Consistent with this, CYB5D2 was reported to promote neurogenesis and inhibit the proliferation of Neuro2a cells. However, its role in tumorigenesis remains unknown.</p> <p>To investigate the role of CYB5D2 in tumorigenesis, western blot analysis was performed on 20 matched clear cell renal cell carcinomas (ccRCC) and the adjacent non-tumour kidney (ANK) tissues; significant down-regulation of CYB5D2 was demonstrated in ccRCC in comparison to ANK tissues, an observation that was confirmed by immunohistochemistry (IHC) analysis of 9 pairs of ccRCC-ANK tissues. Ectopic expression of CYB5D2 inhibited the proliferation and the invasion of A498 ccRCC along with the inhibition of AKT activation. Collectively, the above results support the possibility of CYB5D2 being a potential tumour suppressor.</p> <p>In support of the results obtained in ccRCC, we were able to show a significant reduction of CYB5D2 in cervical squamous carcinoma compared to normal cervical tissues in our analysis of CYB5D2 expression in 35 cervical squamous tumours. In vitro, overexpression and knockdown of CYB5D2 inhibited and enhanced the invasion of HeLa cells, respectively. As a member of the MAPR family, CYB5D2 contains the signature motif of the family, the cytochrome b5 (cyt-b5) like heme/steroid binding domain. This domain is known for heme binding and research in our laboratory has shown the residue D86 being critical for heme association. Ssubstitution of D86 with G (D86G) abolished not only CYB5D2's ability to bind heme but also its capacity of inhibiting HeLa cell invasion. Taken together, we provide evidence that CYB5D2 possesses activities in suppressing tumorigenesis, at least for the tumorigenesis of ccRCC and cervical squamous carcinoma.</p> / Master of Science (MSc)

Human papillomaviruses (HPV) have been implicated as etiologic agents in the genesis of cervical carcinoma and certain other benign lesions of the cervix. Clinical and epidemiological data, and the demonstration of HPV 16 viral DNA sequences in cervical cancer biopsies lend support to the etiologic association of HPV type 16 and cervical carcinoma. Interpretation of the association between HPV 16 and cervical cancer is limited by methods of detection. Different methods of detection of viral DNA sequences have been used based on DNA-DNA hybridization. Recently, a method based upon the in vitro enzymatic amplification of specific viral DNA sequences or polymerase chain reaction (PCR) has been used. The purpose of this study was to compare PCR with DNA-DNA hybridization methods in clinical specimens obtained from invasive cervical cancer. The in vitro enzymatic amplification or PCR was carried out on three specific regions of HPV 16. E6, E7 and L1 regions of HPV 16 were chosen as the target sequences of amplification and primers were synthesized specific to these regions. PCR was performed on 163 cervical cancer specimens using primers specific for E6 and E7 regions of HPV 16. 112 of these specimens were also analyzed using L1 primers of HPV 16. Estimates of sensitivity and specificity of the different methods to see if PCR is a better, more sensitive method compared to the other methods were computed. The results suggest that although percent positivity by PCR method increases significantly, thereby improving sensitivity of detection, the specificity suffers compared to the other methods. However the advantages of using PCR as a diagnostic tool are attractive, as it requires only picogram quantities of DNA, is rapid and easy to perform, and is amenable to automation. / Thesis / Master of Science (MS)

Yes / Non-communicable diseases (NCDs) affect a growing share of the population in Kosovo. The country faces challenges with NCDs management, specifically detecting, screening, and treating people with NCDs. To assess the management of NCDs, including the inputs that influence the provision of NCDs and outcomes of NCD management. Eligibility criteria: Studies had to report NCD management in Kosovo. Sources of evidence: We systematically searched Google Scholar, PubMed, Scopus, and Web of Science. Charting methods: The data were charted by two researchers. We extracted data on general study details and design and information on the management and outcomes of NCDs in Kosovo. Synthesis of results: For the mix of studies that were included in the review, thematic narrative synthesis was used. We developed a conceptual framework based on health production core components to analyze the data. Results: Kosovo's health care system is available to provide basic care for patients with NCDs. However, there are serious limitations in the availability of key inputs providing care, i.e., funding, medicines, supplies, and medical staff. Additionally, in terms of the management of NCDs, there are areas for improvement, such as limited application of clinical pathways and guidelines and issues with referrals of patients among levels and sectors of care. Finally, it is worth noting that there is overall limited information on NCD management and outcomes. Conclusions: Kosovo provides only basic services and treatment of NCDs. The data reporting the existing situation on NCD management are limited. The inputs from this review are helpful for existing policy efforts by the government aimed to enhance NCD care in Kosovo. / This study is part of the research done for a World Bank review of the state of NCDs in Kosovo and APC was funded through the Access Accelerated Trust Fund (P170638).

Objetivo: Avaliar a acurácia da colposcopia utilizando a Classificação Colposcópica Internacional de 2002. Métodos: 3040 pacientes de população geral foram rastreadas para patologia cervical através de exame citopatológico, captura híbrida para HPV de alto risco e inspeção cervical. As colposcopias que resultaram em biópsia (n=468) executadas no rastreamento e acompanhamento destas pacientes foram gravadas, revistas por dois colposcopistas cegados e incluídas para análise. Resultados: Os observadores apresentaram excelente concordância (Kappa=0.843) no relato dos achados pela nova nomenclatura. A colposcopia apresentou sensibilidade de 86% e especificidade de 30.3% em diferenciar colo normal de colo anormal (LSIL, HSIL ou carcinoma); quando a colposcopia objetivava diferenciar colo normal ou LSIL de HSIL ou carcinoma, apresentou sensibilidade de 61.1% e especificidade de 94.4%. Os achados colposcópicos classificados como “maiores” pela nova classificação apresentaram valores preditivos positivos elevados para HSIL. Presença do achado colposcópico na zona de transformação e tamanho da lesão estavam associados a HSIL. Bordas externas definidas, associação de múltiplos achados distintos e presença de zona iodo negativa não estavam relacionados à gravidade das lesões. Conclusão: A colposcopia utilizando a Classificação Internacional de 2002 mostra-se um bom método de rastreamento, mas como método diagnóstico apresenta falhas, não podendo substituir a avaliação histológica. A categorização em achados colposcópicos “maiores” e “menores” apresentada pela nova classificação é adequada. Na realização da colposcopia, é importante também que a lesão seja situada em relação à zona de transformação e que seu tamanho seja indicado, já que estes foram fatores associados a lesões de alto grau. / Objectives: To evaluate the colposcopic accuracy according to 2002 International Colposcopic Classification. Methods: 3,040 women from the general population were screened for cervical pathology by Pap smear, high risk HPV Hybrid Capture and naked eye visual inspection. All colposcopic exams that needed biopsy (n=468) performed during screening or follow-up were recorded, reviewed by two blinded colposcopists and included for analysis. Results: The two observers showed excellent agreement (Kappa=0.843) on reporting colposcopic findings according to the new classification. Colposcopy had sensitivity of 86% and specificity of 30.3% when the objective was to distinguish normal cervix from abnormal (LSIL, HSIL or carcinoma); for distinguishing normal cervix or LSIL from HSIL or carcinoma, colposcopy had sensitivity of 61.1% and specificity of 94.4%. Colposcopic findings graded as “major changes” had the highest predictive positive values for detecting HSIL or carcinoma. Colposcopic findings at transformation zone and size of lesion were related to HSIL. Sharp outer border, multiple colposcopic findings and iodine negativity were not statically related to severe lesions. Conclusion: Colposcopy using the new International Classification is a considerable screening method, but its value for diagnoses is restricted and it is not possible to substitute histological sampling. Categorization in “major changes” and “minor changes” according to the new classification is appropriate. When performing colposcopy, it is important to describe where is the colposcopic finding, in or outside the transformation zone, and its size, whereas these characteristics were related to high grade lesions.

Objetivo: Avaliar a acurácia da colposcopia utilizando a Classificação Colposcópica Internacional de 2002. Métodos: 3040 pacientes de população geral foram rastreadas para patologia cervical através de exame citopatológico, captura híbrida para HPV de alto risco e inspeção cervical. As colposcopias que resultaram em biópsia (n=468) executadas no rastreamento e acompanhamento destas pacientes foram gravadas, revistas por dois colposcopistas cegados e incluídas para análise. Resultados: Os observadores apresentaram excelente concordância (Kappa=0.843) no relato dos achados pela nova nomenclatura. A colposcopia apresentou sensibilidade de 86% e especificidade de 30.3% em diferenciar colo normal de colo anormal (LSIL, HSIL ou carcinoma); quando a colposcopia objetivava diferenciar colo normal ou LSIL de HSIL ou carcinoma, apresentou sensibilidade de 61.1% e especificidade de 94.4%. Os achados colposcópicos classificados como “maiores” pela nova classificação apresentaram valores preditivos positivos elevados para HSIL. Presença do achado colposcópico na zona de transformação e tamanho da lesão estavam associados a HSIL. Bordas externas definidas, associação de múltiplos achados distintos e presença de zona iodo negativa não estavam relacionados à gravidade das lesões. Conclusão: A colposcopia utilizando a Classificação Internacional de 2002 mostra-se um bom método de rastreamento, mas como método diagnóstico apresenta falhas, não podendo substituir a avaliação histológica. A categorização em achados colposcópicos “maiores” e “menores” apresentada pela nova classificação é adequada. Na realização da colposcopia, é importante também que a lesão seja situada em relação à zona de transformação e que seu tamanho seja indicado, já que estes foram fatores associados a lesões de alto grau. / Objectives: To evaluate the colposcopic accuracy according to 2002 International Colposcopic Classification. Methods: 3,040 women from the general population were screened for cervical pathology by Pap smear, high risk HPV Hybrid Capture and naked eye visual inspection. All colposcopic exams that needed biopsy (n=468) performed during screening or follow-up were recorded, reviewed by two blinded colposcopists and included for analysis. Results: The two observers showed excellent agreement (Kappa=0.843) on reporting colposcopic findings according to the new classification. Colposcopy had sensitivity of 86% and specificity of 30.3% when the objective was to distinguish normal cervix from abnormal (LSIL, HSIL or carcinoma); for distinguishing normal cervix or LSIL from HSIL or carcinoma, colposcopy had sensitivity of 61.1% and specificity of 94.4%. Colposcopic findings graded as “major changes” had the highest predictive positive values for detecting HSIL or carcinoma. Colposcopic findings at transformation zone and size of lesion were related to HSIL. Sharp outer border, multiple colposcopic findings and iodine negativity were not statically related to severe lesions. Conclusion: Colposcopy using the new International Classification is a considerable screening method, but its value for diagnoses is restricted and it is not possible to substitute histological sampling. Categorization in “major changes” and “minor changes” according to the new classification is appropriate. When performing colposcopy, it is important to describe where is the colposcopic finding, in or outside the transformation zone, and its size, whereas these characteristics were related to high grade lesions.

Objetivo: Avaliar a acurácia da colposcopia utilizando a Classificação Colposcópica Internacional de 2002. Métodos: 3040 pacientes de população geral foram rastreadas para patologia cervical através de exame citopatológico, captura híbrida para HPV de alto risco e inspeção cervical. As colposcopias que resultaram em biópsia (n=468) executadas no rastreamento e acompanhamento destas pacientes foram gravadas, revistas por dois colposcopistas cegados e incluídas para análise. Resultados: Os observadores apresentaram excelente concordância (Kappa=0.843) no relato dos achados pela nova nomenclatura. A colposcopia apresentou sensibilidade de 86% e especificidade de 30.3% em diferenciar colo normal de colo anormal (LSIL, HSIL ou carcinoma); quando a colposcopia objetivava diferenciar colo normal ou LSIL de HSIL ou carcinoma, apresentou sensibilidade de 61.1% e especificidade de 94.4%. Os achados colposcópicos classificados como “maiores” pela nova classificação apresentaram valores preditivos positivos elevados para HSIL. Presença do achado colposcópico na zona de transformação e tamanho da lesão estavam associados a HSIL. Bordas externas definidas, associação de múltiplos achados distintos e presença de zona iodo negativa não estavam relacionados à gravidade das lesões. Conclusão: A colposcopia utilizando a Classificação Internacional de 2002 mostra-se um bom método de rastreamento, mas como método diagnóstico apresenta falhas, não podendo substituir a avaliação histológica. A categorização em achados colposcópicos “maiores” e “menores” apresentada pela nova classificação é adequada. Na realização da colposcopia, é importante também que a lesão seja situada em relação à zona de transformação e que seu tamanho seja indicado, já que estes foram fatores associados a lesões de alto grau. / Objectives: To evaluate the colposcopic accuracy according to 2002 International Colposcopic Classification. Methods: 3,040 women from the general population were screened for cervical pathology by Pap smear, high risk HPV Hybrid Capture and naked eye visual inspection. All colposcopic exams that needed biopsy (n=468) performed during screening or follow-up were recorded, reviewed by two blinded colposcopists and included for analysis. Results: The two observers showed excellent agreement (Kappa=0.843) on reporting colposcopic findings according to the new classification. Colposcopy had sensitivity of 86% and specificity of 30.3% when the objective was to distinguish normal cervix from abnormal (LSIL, HSIL or carcinoma); for distinguishing normal cervix or LSIL from HSIL or carcinoma, colposcopy had sensitivity of 61.1% and specificity of 94.4%. Colposcopic findings graded as “major changes” had the highest predictive positive values for detecting HSIL or carcinoma. Colposcopic findings at transformation zone and size of lesion were related to HSIL. Sharp outer border, multiple colposcopic findings and iodine negativity were not statically related to severe lesions. Conclusion: Colposcopy using the new International Classification is a considerable screening method, but its value for diagnoses is restricted and it is not possible to substitute histological sampling. Categorization in “major changes” and “minor changes” according to the new classification is appropriate. When performing colposcopy, it is important to describe where is the colposcopic finding, in or outside the transformation zone, and its size, whereas these characteristics were related to high grade lesions.