The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), is a key calcium (Ca++) regulatory hormone. It is also associated with functions unrelated to Ca++ homeostasis. Here, special attention is paid towards the anticancer properties of 1,25D. 1,25D strongly inhibits the growth of well-differentiated head and neck squamous cell carcinoma (HNSCC) derived cell lines. However, advanced, less differentiated, HNSCC cell lines (e.g. SCC4) are partially resistant to 1,25D. Resistance to nuclear receptor (NR) agonists is a common event that occurs in other NR-related treatments. For example, some leukemias develop resistance to the usually effective retinoic acid (RA) treatment. However, treating RA-resistant cells with HDAC inhibitors (HDACi) sensitizes them to RA. Thus, this study aims to investigate how treatment with TSA, an HDACi, would affect the response of SCC4 cell lines to 1,25D. We found that TSA had a variety of effects on 1,25D-regulated gene expression. Combined treatment with 1,25D and TSA increased the expression of cell-cycle regulating proteins, but also enhanced the downregulation of key target genes. Given the potential of the 1,25D/HDACi combination in combating cancers, two chimeric compounds, each containing parts of 1,25D and an HDACi, were synthesized in collaboration with Dr. James Gleason (Dept. of Chemistry, McGill). These 1,25D analogs have the HDACi-like structure replacing the 1,25D side chain. Both compounds proved to be agonists of the vitamin D receptor. Moreover, the TSA-substituted compound, called triciferol, effectively induced a-tubulin as well as histones acetylation. This study underlines the potential of combining 1,25D and TSA in cancer treatment, and reveals that bi-functional 1,25D analogs can be produced with potentially enhanced therapeutic activity.

Diss. Linköping : Univ., 2004.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2008.

Dissertation (Ph.D.)--University of South Florida, 2008. / Title from PDF of title page. Document formatted into pages; contains 197 pages. Includes vita. Includes bibliographical references.

Dissertation (Ph.D.)--University of South Florida, 2008. / Title from PDF of title page. Document formatted into pages; contains 187 pages. Includes vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed on June 24, 2009). Includes bibliographical references.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 5 uppsatser. Även tryckt utgåva.

INTRODUÇÃO: No mundo ocidental, a prevalência de adenocarcinoma da junção esofagogástrica vem crescendo nas últimas décadas. Atualmente, é aceito que o adenocarcinoma do esôfago se desenvolve de uma lesão pré-maligna: esôfago de Barrett. Este carcinoma é de difícil diagnóstico nos seus estágios iniciais, o que resulta em uma mortalidade significativa. O estudo da biologia molecular tem demonstrado que grande parte dos tumores malignos tem origem na interação entre o componente hereditário e influências externas, que em indivíduos predispostos podem ocasionar alterações genéticas que influenciem o controle da diferenciação e crescimento celular. O p21 (WAF1/CIP1) tem um papel fundamental na regulação do ciclo celular, e sua expressão imunoistoquímica tem sido estudada em diversos tumores, mostrando influência no prognóstico de várias neoplasias. OBJETIVO: Verificar a prevalência da expressão da proteína p21 em pacientes com adenocarcinoma de esôfago diagnosticados nos últimos cinco anos no Grupo de Cirurgia de Esôfago e Estômago do Hospital de Clínicas de Porto Alegre (GCEE/HCPA). METODOLOGIA: A população em estudo foi constituída de 42 pacientes com adenocarcinoma de esôfago diagnosticados no GCEE/HCPA entre janeiro de 1998 e dezembro de 2002. A expressão da proteína p21 foi realizada por meio de imunoistoquímica, com anticorpo primário, p21, clone SX118, código M7202 da DAKO, e avaliada de acordo com o Sistema de Escore de Imunorreatividade (Immunoreactive scoring system – IRS). RESULTADOS: Foram estudados 42 pacientes. 83,3% eram do sexo masculino, com idade superior a 40 anos. Destes, 56,2% foram submetidos a procedimentos cirúrgicos com intenção curativa: Gastrectomia total e Esofagogastrectomia transiatal. Os demais foram submetidos à cirurgia paliativa ou não sofreram tratamento cirúrgico. Apenas cinco pacientes receberam tratamento adjuvante com quimioterapia e radioterapia, isoladas ou combinadas. Quanto ao estadiamento, 78,6% dos pacientes apresentavam doença avançada, estádios III e IV. Apenas 9 apresentaram positividade para o p21, quando considerado o Sistema de Escore de Imunorreatividade (em que p21+ é ³ 3). CONCLUSÃO: A proteína p21 esteve expressa em 9 dos 42 pacientes (21,4%) com adenocarcinoma de esôfago diagnosticados nos últimos cinco anos no Grupo de Cirurgia de Esôfago e Estômago do Hospital de Clínicas de Porto Alegre. Nessa casuística, o acúmulo de p21 não se mostrou essencial no processo de carcinogênese do adenocarcinoma esofágico. / INTRODUCTION: In western societies, the prevalence of adenocarcinoma of the gastroesophageal junction has increased in recent years. It is commonly accepted today that esophageal adenocarcinoma develops from a premalignant lesion: Barrett’s esophagus. This type of carcinoma is hardly diagnosed at early stages, which results in significant mortality. Molecular biology studies have shown that most malignant tumors originate from the interaction between inherited characteristics and external factors, which may cause genetic changes that interfere with the control over the differentiation and growth of cells in susceptible individuals. p21 (WAF1/CIP1) has a key role in the regulation of the cell cycle, and its immunohistochemical expression has been investigated in several tumors, showing that it influences the prognosis of various neoplasms. OBJECTIVE: To check the prevalence of p21 protein expression in patients with esophageal adenocarcinoma diagnosed in the last five years by the Group for Surgeries of the Esophagus and Stomach of Hospital de Clínicas de Porto Alegre (GCEE/HCPA). METHODS: The study population consisted of 42 patients with esophageal adenocarcinoma diagnosed by the GCEE/HCPA between January 1998 and December 2002. The expression of p21 protein was determined by immunohistochemistry using primary antibody, p21, clone SX118, code M7202 (Dako), and assessed according to the Immunoreactive scoring system (IRS). RESULTS: Of 42 analyzed patients, 83.3% were male and older than 40 years. Among these, 56.2% were submitted to curative resection: total gastrectomy and transhiatal esophagogastrectomy. The remaining patients were submitted to palliative surgery or did not undergo any surgical treatment. Only five patients received adjuvant chemotherapy and radiation therapy, either alone or combined. Advanced disease (stages III and IV) was detected in 78.6% of the patients. Only nine patients were positive for p21, according to the immunoreactive scoring system (p21+ ³ 3). CONCLUSION: p21 was expressed in 9 of 42 patients (21.4%) with esophageal adenocarcinoma diagnosed in the last five years by the Group for Surgeries of the Esophagus and Stomach of Hospital de Clínicas de Porto Alegre. In our patient population, the accumulation of p21 did not play a key role in the carcinogenesis of esophageal adenocarcinoma.

A complex network of protein filaments collectively known as the cytoskeleton carries out several crucial cellular processes. These functions include, but are not limited to, motility, cell shape, mitosis and organelle trafficking. The cytoskeleton is also highly responsive, allowing the cell to alter its shape in response to its immediate needs and environment. One of the major components of the cytoskeleton is the microtubule network. To refer to the array of micro tubules in the cell as a skeleton is a misnomer. Microtubules, by virtue of their structure and nature, are highly dynamic, continuously growing and shrinking. They also bind a variety of accessory molecules that aid in regulating and directing their dynamic activity. In this way they provide a structural basis for integral cell functions that require rapid assembly and disassembly. In some cases, perturbations of the microtubule network results in structural anomalies that lead to undesirable outcomes for the cell, namely chromosomal missegregation events and instability. The accumulation of these events may induce aneuploidy, which has been a fundamental component of tumorigenesis. This dissertation examines the role of the microtubule cytoskeleton within three distinct contexts. The first chapter investigates the association of the anti-apoptotic protein survivin with the microtubule network and its potential impact upon the cell from interphase to cytokinesis. The second chapter of this dissertation explores a little-studied, microtubule-dense organelle, referred to as the midbody, and the highly orchestrated events that take place within it during cytokinesis. The third and final chapter describes a unique experimental condition that may further our understanding of the interaction between the tumor suppressor p53 and the centrosome in cell cycle regulation and tumorigenesis.

The thesis evaluates the results of experimental protocol involving the fertility sparing treatment procedure in early stage cervical carcinoma (LAP I protocol). Sentinel lymph node detection and experimental extirpation of afferent channels using laparoscopy and its technical aspects were analysed in prospective group of 85 women. The oncologic results and early/late morbidity show that established surgical procedures can be considered safe with minimal morbidity, provided that the indication criteria are met. The second part analyses the results of 148 women with no further pregnancy plans suffering from cervical tumors less than 2 cm in size with invasion less than half of the stroma (LAP II protocol). The oncological results in our defined group are very good and comparable to 'standard' procedure of modified radical hysterectomy type B or C with lower morbidity. In the separate section the thesis analyses the possibilities of laparoscopy in endometrial cancer treatment including the potentials of use of sentinel lymph node detection and technical aspects of laparoscopy in obese women. Currently the biggest controversy is the use of laparoscopy in malignant ovarian tumors. Our oncogynaecological study group at FN Motol prefers the laparotomic approach and we chose to include the set of advanced...