Thesis (Ph.D.)--University of Hong Kong, 2003. / Also available in print.

Thesis (Ph.D.)--University of Hong Kong, 2003. / Also available in print.

No description available.

1) INTRODUCCIÓN El carcinoma pulmonar, en nuestro medio, es la neoplasia de mayor incidencia en varones y la tercera en mujeres, con una elevada letalidad y baja prevalencia, ya que tiene una tasa de mortalidad (49,2 casos/100.000), muy cercana a la de incidencia (55,8 casos/100.000). El factor pronóstico más relevante es el estadio patológico de la enfermedad (pTNM). Otros menos relevantes son los dependientes del propio paciente como el estado funcional, edad, sexo, parámetros biológicos sanguíneos o las mutaciones de oncogenes. Existen además otros factores, relacionados con el propio tumor, como es el grupo histológico, el tamaño tumoral, el grado de diferenciación celular del tumor y el Standerdized Uptatke Values (SUVmax) tumoral medido en la Tomografía de Emisión de Positrones (PET). En un intento de disponer de otros indicadores pronósticos, no evaluados en el TNM, han surgido estudios sobre el valor de los receptores de proliferación celular, concretamente el antígeno Ki-67. Se trata de una proteína nuclear sintetizada por la propia célula tumoral, valorada como un indicador de proliferación celular del carcinoma broncogénico y factor pronóstico del cáncer de pulmón. 2) OBJETIVOS Principal: Determinar la concordancia del antígeno Ki-67, con los factores de mayor valor pronóstico: grupo histológico, pTNM, tamaño, SUVmax, y el grado de diferenciación celular del tumor. Secundario: Determinar la relación entre el antígeno Ki-67 tumoral, la incidencia de la recidiva y mortalidad postquirúrgica. 3) MATERIAL Y MÉTODO Entre agosto de 2006 y junio de 2008, tras la aplicación de los criterios de exclusión, se han seleccionado consecutivamente 61 pacientes intervenidos de una neoplasia pulmonar con un seguimiento de 12 a 34 meses. Criterios de inclusión - Diagnostico de un carcinoma pulmonar. - Estadificación clínica (PET-TC). - Resección pulmonar mínima lobar y linfadenectomía. Criterios de exclusión - Tumores con componente inflamatorio/infeccioso. - Tumores menores de 1 centímetro. - Carcinomas pulmonares de célula pequeña. - Antecedente de neoplasia no tratada. - Resección pulmonar sublobar y/o sin linfadenectomía completa. - Resecciones pulmonares no radicales. - Pacientes con tratamiento neoadyuvante. - Pacientes con mortalidad perioperatoria. - Pacientes sin seguimiento postoperatorio. Variables a estudio - Edad. - Sexo. - Tabaquismo. - Antecedentes oncológicos. - Diagnóstico de otra neoplasia durante el seguimiento. - Localización anatómica del tumor. - Resección pulmonar prevista y realizada. - Índice del antígeno Ki-67. - Histología tumoral. - Grado de diferenciación celular del tumor. - cTNM y pTNM. - SUVmax tumoral y adenopatías. - Tamaño tumoral (PET). - Tamaño tumoral (pieza quirúrgica). - Tratamiento adyuvante. - Recurrencia de la enfermedad. - Supervivencia global. Metodologia estadistica Tras un análisis descriptivo de tendencia central y de dispersión, así como frecuencias, se ha realizado un análisis multivariado del índice Ki-67, incidencia de recidiva y mortalidad. 4) RESULTADOS Y CONCLUSIONES El antígeno Ki-67 tumoral, esta asociado de manera estadísticamente significativa, a los factores de mayor valor pronóstico del carcinoma pulmonar: histología del tumor, tamaño tumoral, SUVmax, grado de diferenciación celular del tumor y estadio patológico. El carcinoma escamoso de tamaño superior a 4 centímetros, pT2, bajo grado de diferenciación celular y SUVmax superior a 7 gr/ml, se asocia a un índice Ki-67 superior al 25%. El antígeno Ki-67, sin asociarse de forma estadísticamente significativa a la incidencia de recidiva, tiempo libre de enfermedad, mortalidad y tiempo de supervivencia, tiene significación clínica, puesto que con un índice Ki-67 superior al 25%, se registra el doble de recidivas y su aparición 6 meses antes, el triple de fallecimientos secundario a la progresión de la enfermedad, así como vivir 4 meses menos que los casos con un índice Ki-67 inferior al 25%. / 1) INTRODUCTION Lung cancer has a high case-fatality rate. Prevalence is low because of the similarity between incidence and mortality rates (55,8 and 49,2 cases/100.000, respectively). Pathological stage (pTNM) is considered the most relevant prognostic factor for survival in this disease, although several other tumor-related factors, including histological group, tumor size, degree of cellular differentiation, and the Standardized Uptake Values (SUVmax) as measured by Positron Emission Tomography (PET), are also important. Attempts to identify new prognostic indicators have led to the discovery of cell proliferation receptors, in particular, the Ki-67 antigen. Ki-67 is a marker of cell proliferation in bronchogenic carcinoma and is considered a prognostic factor. 2) OBJECTIVES Main objectives: To determine the agreement between the Ki-67 antigen and the best prognostic factors: histologic group, pTNM, tumor size, tumor SUVmax, and degree of cellular differentiation. Secondary objectives: To determine the association between the Ki-67 antigen and rates of tumor recurrence and postoperative mortality. 3) MATERIAL AND METHODS Between August 2006 and June 2008, 173 patients with lung cancer underwent surgery at our institution. Of these, 61 fulfilled the inclusion criteria and were included in this study. These patients were followed for a period ranging from 12 to 34 months. Statistical analysis included a descriptive analysis of central tendency and dispersion, as well as frequencies. This was followed by a multivariate analysis of the Ki-67 index, and relapse and mortality rates. 4) RESULTS AND CONCLUSIONS The Ki-67 tumor antigen is significantly associated with the factors that have the greatest prognostic value in lung carcinoma: histology group, tumor size, tumor SUVmax, degree of cellular differentiation, and pathological stage. The Ki-67 antigen is not, however, significantly associated with relapse rates, disease-free interval, mortality, or survival time. Nevertheless, Ki-67 provides clinically relevant information when the index is above 25%; when compared to patients with a Ki-67 < 25%, relapse rates were twice as high, tumor recurrence occurred 6 months earlier, there were 3 times as many deaths secondary to disease progression, and survival was 4 months less.

²Ä¤@³¡¥÷ Nasopharyngeal carcinoma¡]NPC¡^ is a malignant tumor which occurs at high incidence in southern China. Several risk factors have now been recognized, but the molecular mechanism of this disease is not well understood. To investigate the c-myc¡Bcyclin D1¡Bp16¡Bp27 and Rb gene expression in NPC at protein level, 46 cases of nasopharyngeal carcinoma in southern Taiwan were detected by immunohistochemistry. There was no detectable p16 in 31/45 cases¡]69¢M¡^¡F 34/46 cases¡]73.9¢M¡^had intense staining for the Rb protein¡F 29¡]70.7¢M¡^of 41 cases had c-myc protein expression¡Fcyclin D1 was not overexpression in nasopharyngeal carcinoma¡F 32¡]69.6¢M¡^of 46 cases had high level expression of p27, which was inverse correlation with other tumors. No expression of c-myc protein correlated with higher neck metastasis¡]P¡Õ0.05¡^. No correlation was found between other proteins and any of the clinicopathological parameters. ²Ä¤G³¡¥÷ To better understand nasopharyngeal carcinoma¡]NPC¡^, we have newly established two NPC cell lines. Biopsy specimens from NPC patients were collected, primary culture were set up. Two NPC cell lines were established¡GNPCGK 01 was derived from differentiated carcinoma and NPCGK 02 was derived from undifferentiated carcinoma. Two cell lines have been passaged for more than 25 times. Two cell lines had telomerase activity¡Fstrong expression of hTERT gene and keratin-19 gene were also observed. TGF£] RI protein expression of these NPC cell lines is higher than normal epithelial cell.The oncogenes, c-myc¡Bc-fos and cyclin D1 were overexpressed. The Rb protein was expressed stronger than normal epithelial cells. NPCGK 01 that was derived from differentiated carcinoma had p16 down-regulation and p27 gene not expression, but p21 protein had excess expression. In short, two cell lines had cancer cell characteristics, oncoproteins were overexpression and tumor suppressor proteins were abnormal expression. This result may lead to tumorigenesis of nasopharyngeal carcinoma.

Hepatocellular carcinoma (HCC) is one of deadliest cancers worldwide and ranking the third among all cancer-related mortalities. Current effective therapeutic approaches for HCC include surgical resection and trans-arterial embolization (TAE). Chemotherapy remains largely ineffective, and most popular used agents are epirubicin, doxorubicin, cisplatin and 5-FU. Besides, these chemotherapic drugs had potential serious side-effects such as low blood count, hair loss, vomiting, and they rarely present good anti-HCC effect in clinical practice. Our previous studies found that epirubicin injection attenuated the tumor burden of orthotopic Novikoff hepatoma, but caused serious side effects to hosts including reduction in spleen weight, white count, and body weight and high GOT level. Therefore, we aimed to evaluate possible alternative treatment such as COX-2 inhibitor for HCC. Celecoxib is a highly selective COX-2 inhibitor and less toxic than the traditional non-selective NSAIDs. Celecoxib showed relatively low cytotoxicity in Novikoff N1-S1 hepatoma cells and Clone 9 normal hepatocytes with an IC50 of up to 100 microM. Expression analysis revealed that COX-2 expression is very low in N1-S1 cells at protein and mRNA levels. Thus, N1-S1 is a kind of hepatoma cell line with low COX-II level. Interestingly, celecoxib upregulated PTEN expression and decreased AKT phosphorylation in vitro by COX-2 independent pathway, and then oral administration of celecoxib (30 mg/kg) for 7 days showed tendency of tumor suppression of Novikoff hepatoma in rats revealed by ultrasound and computed tomography (CT) scan. Histological analysis revealed that CD31-positive neo-vascularization¡BKi-67-positive cell-proliferation and FOXP3-positive regulatory T cells were found to reduce in celecoxib-treated rats, and then TUNEL-positive apoptotic cells were found to increase in celecoxib-treated rats. Besides, celecoxib-treated rats exhibited no significant side effect. Therefore, oral celecoxib may be a suitable chose of adjuvant therapy in combination with epirubicin or other chemotherapeutic agents for the treatment of HCC.

Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 143-163).

The RET proto-oncogene encodes a receptor tyrosine kinase (RTK) that is widely expressed in neuroendocrine tissues and is essential for embryonic development of the kidney and enteric nervous system. Mutations leading to constitutive activation of the RET protein underlie various tumours of endocrine tissues. Conversely, loss-of-function mutations of RET lead to Hirschsprung disease, a congenital disorder characterized by a loss of enteric neurons throughout the colon and small intestine. Intracellular trafficking of RTKs through multiple cellular compartments has been shown to impact on downstream signalling. To date, the intracellular trafficking of RET has not been investigated. Here, we show that RET is rapidly internalized after activation and that trafficking to cytoplasmic endosomes plays an important role in downstream signalling. RET is alternatively spliced into multiple isoforms that are co-expressed in cells; therefore, we further investigated RET internalization in an isoform-specific context. This study revealed a number of differences between RET isoforms including differences in sub-cellular localization pre-activation, rate of internalization, and ability to recycle to the plasma membrane. Differential trafficking of RET isoforms alter their downstream signalling properties, providing an additional mechanism to explain the distinct contributions of RET isoforms to cellular processes. Finally, we investigated the impact of altered sub-cellular localization in the context of thyroid carcinoma. Activation of RET has been implicated in a number of thyroid tumours that differ in their inherent oncogenicity. We observed that altered subcellular localization of oncogenic forms of RET, RET/PTCs, enhance their oncogenicity. Interestingly, RET/PTC tumours are indolent and rarely metastasize compared to other RET-mediated forms of cancer. Further investigation revealed that RET/PTC oncogenes are expressed off relatively weak promoters, resulting in quantitatively less RET/PTC oncoprotein expression in these tumours compared to mutant RET expression in more aggressive cancers. Together, our results represent the first in-depth study of the trafficking properties of RET and indicate the importance of proper sub-cellular localization and trafficking in the maintenance of normal cell metabolism. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2009-11-19 22:51:47.38

Karzinome des Oropharynx zählen zu Karzinomen des Kopf-Hals-Bereichs und zeigen in den letzten Jahrzehnten weltweit eine ansteigende Inzidenz. Die Hauptrisikofaktoren, die zur Entstehung von Oropharynxkarzinomen führen sind Alkohol- und Tabakkonsum. In den letzten Jahren wurde zunehmend über eine Infektion der Rachenschleimhaut mit Hochrisiko-HPV als weiterer Risikofaktor diskutiert. Durch die Einführung multimodaler Therapiekonzepte konnte das Überleben von Patienten, die an einem Oropharynxkarzinom erkranken deutlich verbessert werden. Trotzdem sind die Therapieerfolge insbesondere bei lokal fortgeschrittenen Karzinomen noch unbefriedigt, so dass auch im Hinblick auf die posttherapeutische Lebensqualität nach weiteren Therapiestrategien gesucht wird. Bei der folgenden Arbeit handelt es sich um eine retrospektive Untersuchung der im Zeitraum von 1993 bis 2009 an der Universitätsklinik für Hals-Nasen-Ohrenheilkunde Leipzig behandelten Oropharynxkarzinome. Die klinischen Daten wurden durch Analyse der Patientenakten gewonnen und in eine klinikinterne Access-Datenbank eingepflegt. Die statistische Auswertung erfolgte mittels SPSS. Ziel der Arbeit war die Beurteilung der Entwicklung von Prävalenz, Risikofaktoren, Therapiemodalitäten und der Ergebnisse der Behandlung. Über den untersuchten Zeitraum kam es zu einem kontinuierlichen Anstieg der Prävalenz der Oropharynxkarzinome, wie er laut Literatur auch weltweit festzustellen ist. Im hier untersuchten Patientenkollektiv lassen sich über den untersuchten Zeitraum hinsichtlich der Risikofaktoren Alkohol und Tabak keine Veränderungen im Konsum feststellen. Dies lässt eine Zunahme der HPV-induzierten Oropharynxkarzinome vermuten. Allerdings lässt sich diese Vermutung mit den zugrundeliegenden Daten nicht sicher beweisen, da bis 2010 keine routinemäßige HPV-Diagnostik durchgeführt wurde. Weiterhin zeigt sich etwa ab dem Jahre 2002 eine Veränderung in den angewandten Therapien mit einer Zunahme multimodaler Therapieansätze insbesondere in der postoperativen adjuvanten Situation. Diese Veränderung führt insbesondere bei den fortgeschrittenen Oropharynxkarzinomen zu einer Verbesserung der Überlebensraten ab dem Jahr 2005. Einen weiteren prognostischen Faktor stellt der Alkohol- und Tabakkonsum zum Zeitpunkt der Diagnose dar. So zeigen Patienten mit starkem Alkohol- und Tabakkonsum zum Diagnosezeitpunkt ein schlechteres Überleben als Patienten ohne oder mit geringem Alkohol- oder Tabakkonsum. Inwieweit eine Tabak- bzw. Alkoholkarenz ab dem Zeitpunkt der Diagnose das Überleben der Patienten beeinflusst, kann mit den untersuchten Daten nicht belegt werden. Auch eine Aussage über die posttherapeutische Lebensqualität ist auf Grundlage der untersuchten Daten nicht möglich. Insgesamt konnten in der Arbeit verschiedene Änderungen des therapeutischen Standardvorgehens in Hinblick auf die Ergebnisqualität herausgearbeitet werden. Als zentrale Erkenntnis stellte sich die Hinzuziehung der additiven Cisplatingabe zur postoperativen Radiotherapie als wesentlicher Erfolgsfaktor in der verbesserten Therapie des Oropharynxkarzinoms heraus.

Hepatitis C virus (HCV) infects an estimated 200,000 people in Canada, and is the leading cause of liver transplants in North America. Viral infection usually leads to chronic infection, and complications include liver fibrosis, steatosis and hepatocellular carcinoma (HCC). The HCV non-structural proteins 3 and 4A (NS3/4A), is a multifunctional protein complex with roles in RNA replication and polyprotein processing. Additionally, the NS3 protease has been shown to induce advanced cellular transformation in vivo and tumour formation in nude mice. However, the mechanism by which transformation occurs remains unknown. The objective of this study was to determine if the naturally occurring NS3/4A protein complex, rather than the NS3 protease domain on its own, could also induce cellular transformation and to determine the changes that NS3/4A expression had on the host cell proteome.