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Brain and central nervous cancer presents a significant clinical burden, accounting for 2.4% of all cancer deaths. High grade glioma is particularly deadly, with 5 year survival times of 35% or less. Traditional treatment includes tumor resection followed by radiation therapy or chemotherapy. Aggressive resection is essential in order to prolong patient life. In fact, several studies have shown that life expectancy increases with increased extent of resection. Extent of resection is burdened by the fact that surgeons must be careful not to remove functional brain tissue. Resection is incomplete more often than not due to lack of visual cues for the surgeon. He must rely on tactile sensation to distinguish tumor from healthy tissue. Methods such as intraoperative MRI and CT exist, but these require expensive equipment and special training that is not available in all surgical environments. Some laboratories have proposed small molecule dyes to solve this problem, but these are insufficient when used in an invasive tumor model. It was the goal of this research to provide an objective cue in the form of a nanoencapsulated visible dye without the need for additional equipment of changes to the surgery process itself other than injection of the dye. We hypothesized that the nanocarrier would allow staining of the tumor through passive targeting by taking advantage of the enhanced permeability and retention effect. Once the nanocarriers have reached the desired target, they would not diffuse out into healthy tissue due to their large size compared to small molecule dyes, which readily diffuse out and stain healthy tissue. To test this hypothesis, we prepared and characterized a liposomal nanocarrier encapsulating Evans blue dye. The nanocarrier was tested for safety in vitro and in vivo, then used to delineate tumor margins in an invasive rat glioma model in vivo. Microscopic analysis was then conducted to ensure only tumor tissue was stained by the nanocarrier. This thesis presents a successful method of tumor border delineation to provide surgeons with positive visual cues without the need for changes in surgical environment or techniques.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

Aim. In this study, we attempted to identify HCC-specific serum glycoproteins by using glycoproteomic technologies. We targeted at finding glycoforms with aberrant alpha-2,6-sialylation and alpha-1,6-fucosylation in sera of HCC patients. These glycoforms may have potentials to be used as tumor marker(s) in the diagnosis of HCC. / Among the validated differential glycoproteins, Hp was the only glycoprotein, glycoforms of which were found to be significantly up-regulated in the HCC group when examining both the sialylated glycoprotein profiles and the fucosylated glycoprotein profiles. This glycoprotein was selected for further investigation. In the independent validation group, increased serum levels of Hp (total), alpha-2,6 sialylated Hp and alpha-1,6 fucosylated Hp was observed in the HCC patients. A unique pattern of Hp glycoforms comprising both hypersialylated fucosylated and hyposialytated fucosylated species was found in the HCC patients. Serum concentrations of these glycoforms were significantly higher in the HCC patients with advanced tumor, suggesting their tumor-specific nature. Besides, we have performed quantitative profiling of N-glycans of serum Hp in the HCC patients, CLD patients and normal subjects, and have attempted to identify HCC-associated N-glycans for HCC diagnosis. Combined used of serum alpha-fetoprotein, serum Hp and its N-glycans, we could achieve 84% sensitivity at 100% and 93% specificities when distinguishing the HCC patients from the CLD patients and from the normal subjects, respectively. / Background. Hepatocellular carcinoma (HCC) often arises in patients with coexisting chronic liver disease (CLD). Since alpha-fetoprotein, a conventional biomarker, may also be raised in patients with uncomplicated CLD, the use of alpha-fetoprotein in early detection of HCC is limited. Identification of additional biomarkers may improve early detection. Previous studies have shown that levels of alpha-2,6-sialyltransferase and alpha-1,6-fucosyltransferase change in liver cancer, leading to aberrant glycosylations on some serum proteins. / Conclusion. By undertaking glycoproteomic approach, we have identified a panel of potential biomarkers for diagnosis of HCC. These biomarkers were useful for classifying among normal healthy subjects, CLD patients, patients with early HCC and patients with advanced HCC. Some of them were validated with the independent cases. Finally, we have identified a unique pattern of Hp glycoforms comprising both hypersialylated fucosylated and hyposialylated fucosylated species in the HCC patients. Serum Hp and its N-glycans have been shown to have potential values for aiding the diagnosis of HCC. / Methodology. There are four parts in this study. The first part is "method development". A method for obtaining quantitative profiles of serum glycoproteins with alpha-2,6-sialylation or alpha-1,6-fucosylation was developed by combined use of lectin affinity chromatography, two-dimensional polyacrylamide gel electrophoresis and enzyme-linked lectin assay. The second part is "biomarker discovery". The quantitative profiles of the serum glycoproteins from 20 HCC patients and 10 CLD patients (control) were compared by bioinformatic approaches to identify potential biomarkers for diagnosis of HCC. The protein identities of the potential targets were obtained by using MALDI-TOF/TOF mass spectrometry. The third part is "validation". An independent set of serum samples from 40 HCC patients, 30 CLD patients and 20 normal subjects was used to evaluate the diagnostic values of the potential biomarkers. The last part of this study was aimed to identify HCC-associated N-glycans on one of potential biomarkers found, and examine their values in diagnosis of HCC. / Result. When analyzing alpha-2,6-sialylated glycoproteins, 53 glycoprotein spots were significantly different between the HCC and CLD groups, of which 44 spots belonged to 13 glycoproteins. Bioinformatic analyses revealed that these differential sialoglycoprotein profiles contained valuable information for differentiating the HCC patients from CLD patients, and classifying between early HCC and advanced HCC patients. When analyzing alpha-1,6-fucosylated proteins, 11 glycoprotein spots were significant different between the two study groups, of which 8 spots belonged to 1 glycoprotein. Majority of the protein identities were successfully obtained by MALDI-TOF/TOF mass spectrometry. Among the differential glycoproteins, we have identified a subgroup with a unique pattern of glycosylation. These glycoproteins were characterized by the presence of hypersialylated and fucosylated glycoforms. The differential patterns and the diagnostic values of some of these serum glycoproteins were confirmed in the independent validation group by measuring their serum levels with immunoassays. The results of the logistic regression analyses suggest that complement factor B and haptoglobin (Hp) can be used in combination with alpha-fetoprotein to improve the diagnosis of HCC. / Ang, Ling. / Adviser: Tereng Chuen Wai Poon. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0947. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 215-238). / 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. / Abstract also in Chinese. / School code: 1307.

Foram analisados 50 casos de osteossarcoma não metastáticos das extremidades tratados no Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo entre 1986 e 2006 no que se refere à expressão de VEGF. Dezenove pacientes do sexo feminino e 31 do sexo masculino foram a casuística do trabalho. A idade variou de 5 a 28 anos (média de 16 anos) e o seguimento dos pacientes variou de 25 a 167 meses (média de 60,6 meses). As variáveis estudadas foram idade, sexo, localização anatômica, tipo de cirurgia, margens cirúrgicas, tamanho do tumor, necrose pós QT, recidiva local, metástase pulmonar e óbito. Trinta e seis pacientes apresentaram expressão de VEGF menor ou igual a 30% das células tumorais (baixa expressão), ao passo que os 14 restantes apresentaram expressão acima de 30% das células (alta expressão). Dos 36 pacientes com baixa expressão de VEGF, nove evoluíram com metástases pulmonares, dos quais quatro foram a óbito (11,1%). Dentre os 14 casos com alta expressão de VEGF, seis evoluíram com metástases pulmonares e três foram a óbito (21,4%). Porém, não houve correlação estatisticamente significante entre a expressão de VEGF e qualquer das variáveis estudadas / Fifty cases of nonmetastatic osteosarcoma of the extremities treated between 1986 and 2006 at the Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo were evaluated regarding the expression of VEGF. There were 19 females and 31 males. The mean age was 16 years (528) and the mean followup was 60,6 months (25 167). The variables studied were age, gender, anatomic location, type of surgery, surgical margins, tumor size, post chemotherapy necrosis, local recurrence, pulmonary metastasis and death. Thirtysix patients showed VEGF expression equal or under 30% of the cells (low expression), as the remaining 14 cases had VEGF expression above 30% (high expression). Among the 36 patients with low VEGF expression, nine developed pulmonary metastasis and four died (11,1%). Among the 14 patients with high VEGF expression, six developed pulmonary metastasis and three died (21,4%). There was no statistical significant correlation between the VEGF expression and any of the variables studied

Includes bibliographies. / [xvii], 173, [38] leaves, [18] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis presents the development of an assay for reverse transcription-polymerase chain reaction (RT-PCR) to be applied to the immunomagnetic isolation of carcinoma cells, as a possible means of detecting small numbers of breast cancer cells in a haemopoietic environment. The messenger RNA expression of two different genes, CD44 and the cytokeratin K19, is assessed for suitability as tumour markers for the Immunobead RT-PCR method, and clinical results using K19 are presented. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1977?

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 5 uppsatser.

Theoretical studies focusing on the nature of landscapes that correlate molecular sequences to molecular function have mainly been carried out in silico due to the vast amounts of data that are needed for analysis. In vitro selections of aptamers are a good model system to study theoretical questions at a experimental level. With the introduction of robotic platforms that conduct in vitro selections, it is now capable of producing significant amounts of data in a short time, making theoretical modeling with real experimental data attainable. I will be using a Biomek 2000 Laboratory Automation Workstation to carry out multiple in vitro nucleic acid selections in parallel. I will explore the sequence space to examine whether existing in vitro selection systems are optimal at isolating the best winning species. New methods will be introduced that will allow for the selection of identical targets with identical pools free of cross contamination on the open robotic system. This will open the doors to further conduct selections against other identical or highly similar targets, such as complex cellular targets. Finally, I will investigate the methods to improve the effectiveness at isolating aptamers against the highly complex lung cancer cell lines. These targets are highly challenging for isolating specific aptamers because of the great diversity of biomarkers found among them. Moreover, their highly morphological similarity of the cultured cells makes selections for specific aptamers very difficult. I explore the different methods that will allow for the generation of aptamers that can distinguish between non-small cell lung cancer and small cell lung cancer, and between non-small cell lung cancer and normal lung cells. Fine-tuning of this process is essential at transferring this process to automated platforms for large-scale generation of biosensors against tumor biomarkers.

published_or_final_version / abstract / toc / Surgery / Doctoral / Doctor of Philosophy

The aim of this research was to study the correlation between tissue tumor marker expression and HR-HPV infection, smoking, hormonal contraceptive use and sex steroids in women with cervical intraepithelial neoplasia or normal epithelium. The study investigated the expression of 11 tumor markers in cervical biopsies obtained from 228 women with different diagnoses ranging from normal cervical epithelium to various stages of CIN. 188 women were recruited at our colposcopy clinic (out-patient surgery, Department of Obstetrics and Gynecology, Falun Hospital) for laser cervical conization or a directed punch biopsy, either because of a vaginal smear (Pap smear) that showed cytological findings suggesting CIN, or because of repeated findings showing atypical squamous cells of undetermined significance (ASCUS). For 40 volunteers, punch biopsies were taken from the normal cervical epithelium. The time period for this study was 2005-2007. Study I :  228 women, of whom 116 were tested, 64 were positive to HR-HPV. The results showed that Ki67 tumor cell proliferation index was the only marker that independently correlated to both the presence of HR-HPV and the severity of cervical lesions. Study II:  228 women, of whom 83 were smokers (36, 9%). Smokers showed lower expression of p53, FHIT (tumor suppressor markers) and interleukin-10 .Higher expression of Cox-2 and Ki-67 (tumor proliferation markers). Study III:  195 women who were premenopausal. There was increased p53 expression (tumor suppressor) in the progestin-IUD users compared to non-users. Decreased IL-10 expression (immunological marker) was observed in both COC users and any progestin-only users. Study IV: Serum from 80 premenopausal women was available. The main finding was that the increased levels of serum progesterone and estradiol were associated with increased Cox-2 expression (proliferation marker). Serum progesterone and estradiol levels influence cellular and extracellular proteins which have been associated with neoplastic development in normal epithelium and CIN. Conclusion: The results of these studies support previous epidemiological findings on the role of smoking, contraceptive use and sex steroids as co-factors in development of CIN and that tumor marker expression varies in different grades of CIN.