Human endogenous retroviruses (HERVs) constitute about 8% of the human genome. There are around 4000 pol-containing retroviral integrations in the human genome, which makes it impractical to measure each of them separately. Therefore we developed a set of degenerate real time PCRs to detect major groups bearing sequence similarities to gammaretroviruses, one of the largest groups of human endogenous retrovirus, and betaretroviruses, some of which have integrated into the human genome most recently and which remain the most intact. It was found that, although both gammaretroviral and betaretroviral RNAs were broadly expressed in various healthy tissues including reproductive tissues and brain, a differential expression pattern was observed. My work further revealed that HERVE and HERVW, two gammaretroviral sequences, were ubiquitously and highly expressed in pathologic and normal female reproductive tissues with tissue specific patterns. Expression of HERVE was higher in endometriotic tissue than in normal endometrium. HERVE and HERVW RNAs were higher in normal ovarian tissue than in ovarian cancer. Besides these tissue- and neoplasia-related differences, there were wide differences in HERV expression among individuals. Next, a selective pattern of HERVW upregulation was demonstrated in SK-N-DZ, a neuroblastoma cell line, upon re-oxygenation after a period of hypoxia or with 5-azacytidine, a demethylating agent. Furthermore, broad and high expressions of gammaretrovirus-like transcripts in different brain areas analyzed were identified. The expression levels were variable among different donors. In conclusion a ubiquitous HERV expression was observed in tissues and cell lines, with various patterns. At this stage the data are not sufficient to conclude whether HERV has any physiological or pathological roles in humans. However, their differential expression patterns are compatible with functional roles of HERV in humans.

No description available.

Le but de cette étude est de cerner, à partir de leur propre point de vue, la trajectoire d’adaptation de conjoints dont l’épouse est atteinte d’un cancer de l’ovaire. Une approche qualitative, la théorisation ancrée, a été utilisée dans le cadre de cette recherche. Les données ont été recueillies à l’aide d'entretiens semi-structurés effectués auprès de neuf conjoints qui accompagnaient leur épouse lors de leurs traitements dans une unité montréalaise ultra-spécialisée de soins pour les cancers gynécologiques. Nos résultats font ressortir qu’une fois passé le choc de l’annonce du diagnostic, nos répondants se ressaisissent et élaborent toute une série de stratégies de protection pour leur épouse et eux-mêmes, puis d’attaque de la maladie. Au bilan, pour eux, le cancer se révèle une expérience « transformante» aux plans personnel, conjugal et social. Les contrastes observés entre nos résultats et ceux des études antérieures, qui insistent sur le désarroi de conjoints, peuvent être expliqués par la prise en charge efficace de la femme par le réseau de la santé, qui valorise le rôle du conjoint et qui l’outille pour accompagner son épouse. S’ajoutent à cela la force du lien conjugal, trempé par les épreuves passées, certains traits de personnalité des conjoints et l'action du réseau de soutien personnel. En regard de la pratique infirmière, notre recherche met en évidence le bien-fondé des politiques soutenant l’intégration des familles dans les plans de soins et les retombées positives d’une approche concertée entre tous les intervenants de la santé. Répéter une telle étude dans d'autres institutions du réseau de la santé permettrait de cerner encore plus finement son impact sur l’adaptation de conjoints à la maladie. / This research focuses on how nine men recall their adaptation trajectory to their spouses’ ovarian cancer. The qualitative analysis made use of the grounded theory approach; semistructured interviews were conducted with husbands accompanying their spouses during their treatments in an ultra-specialized unit for gynaecological cancers in a Montreal hospital. Our results show that after the initial shock initiated by the announcement, the respondents develop a set of strategies, first to protect their wives and themselves, and then to attack the illness. Accompanying their wives through the experience of cancer proves to be, for the husbands, a transformative experience at all levels: personal,conjugal, and social. The perceived efficacy of the health network and its preoccupation with the husband’s caretaker role may explain the sharp contrast we observe between results from the literature, insisting on the husbands’ helplessness in such a context, and our data, which underline their fighting spirit. Other factors identified are the strength of the conjugal link, forged in common ordeals, personality traits of both husbands and wives, and support from their personal network. Concerning nursing practice, this research suggests that the importance and the support given by the health professionals to the family caregivers is of utmost importance for the couple’s quality of life throughout this experience. Besides, the coordination of the health professionals, throughout the women’s illness, is crucial in diminishing the anxiety linked to the cancer diagnosis. The duplication of such a study in other cancer care units would allow a finer analysis of the impact the health network can have on the adaptation of both spouses to illness.

Le cancer épithélial des ovaires (CEO) est classifié en sous types histopathologiques identifiés tel que séreux, endométrioide, à cellules claires et mucineux. Une analyse génétique réalisée au niveau moléculaire a suggéré un rôle pour des gènes suppresseurs de tumeur localisés sur le bras court du chromosome 3p21.3 dans la pathogénèse du CEO de type séreux. Notre objectif était d’évaluer le profil d’expression de HYAL-1, localisé dans cette même région, dans les différents sous types du CEO, et de vérifier une éventuelle corrélation avec l’expression des récepteurs d’hormones stéroïdiennes. Pour se faire, nous avons analysé par RT-PCR quantitative l’expression de l’ARNm de HYAL-1, des récepteurs d’estrogène (ER-α et ER-β) et du récepteur de progestérone (PR) dans des échantillons de tissus extraits de tumeurs du CEO provenant de deux cohortes indépendantes et dans des lignées cellulaires. Nous avons également réalisé des analyses bioinformatiques à partir de l’expression de ces gènes en ayant recours à une base de données de microarray disponible en ligne et ouverte au public. Par la suite, nous avons mesuré l’activité enzymatique de HYAL-1 dans des lignées cellulaires du CEO et dans des échantillons de plasma. Nos résultats ont montré que l’expression de l’ARNm de HYAL-1 était élevée dans le type à cellules claires et mucineux mais non dans les types séreux et endométrioides, autant dans les échantillons sains que de ceux provenant de tumeurs bénignes. De façon cohérente, le niveau d’ARNm et l’activité enzymatique de HYAL-1 étaient élevés dans les lignées cellulaires à cellules claires et mucineuses. Nous avons aussi démontré qu’il y avait une corrélation inverse entre les niveaux de l’ARNm de HYAL-1 et ceux d’ER-α et PR dans les échantillons de tissus de CEO du type mucineux et à cellules claires. De façon similaire, nous avons noté que l’activité de HYAL-1 était élevée dans le plasma de ces mêmes patients. En conséquence nos travaux proposent HYAL-1 en tant que biomarqueur potentiel dans le cas des CEO de type à cellules claires et mucineux présentant un faible niveau d’expression d’ER-α et PR. / Epithelial ovarian cancer (EOC) is morphologically heterogeneous being classified as serous, endometrioid, clear cell, or mucinous. Molecular genetic analysis has suggested a role for tumor suppressor genes located on chromosome 3p in the pathogenesis of serous EOC. Our objective was to evaluate the expression of HYAL-1, located at chromosome 3p21.3, in these EOC subtypes, and to verify a possible correlation with the expression of steroid hormone receptors. We analyzed the mRNA expression of HYAL-1, estrogen receptor (ER)-α, ER-β and progesterone receptor (PR) in EOC tumor samples and cell lines using quantitative RT-PCR. We also performed bioinformatics analyses on the expression of these genes using a publicly available microarray dataset. HYAL-1 enzyme activity was measured in EOC cell lines and in plasma samples from patients. We found that HYAL-1 mRNA expression was elevated in clear cell and mucinous EOC tissue samples, but not in serous and endometrioid samples, normal ovaries or benign tumors. Significantly, similar results were obtained by two different techniques and with tissue sample cohorts from two independent institutions. Concordantly, HYAL-1 mRNA levels and enzyme activity were elevated in EOC cell lines derived from clear cell and mucinous subtypes. We also showed that HYAL-1 mRNA was inversely correlated to that of ER-α and PR, but not to that of ER-β, specifically in clear cell and mucinous EOC tissue samples. HYAL-1 activity was also high in the plasma of patients with these EOC subtypes. Our results suggest Hyaluronidase-1 as a potential target/biomarker for clear cell and mucinous EOCs and especially in tumors with low levels of ER-α and PR.

Le cancer épithélial de l’ovaire (EOC) est le plus mortel des cancers gynécologiques. Cette maladie complexe progresse rapidement de façon difficilement décelable aux stades précoces. De plus, malgré une chirurgie cytoréductive et des traitements de chimiothérapie le taux de survie des patientes diagnostiquées aux stades avancées demeurt faible. Dans le but d’étudier l’EOC dans un contexte ex vivo, l’utilisation de modèles cellulaires est indispensable. Les lignées cellulaires d’EOC sont un outil pratique pour la recherche cependant, la façon dont l'expression des gènes est affectée en culture par comparaison à la tumeur d'origine n'est pas encore bien élucidée. Notre objectif était donc de développer et de caractériser de nouveaux modèles de culture in vitro qui réflèteront plus fidèlement la maladie in vivo. Nous avons tout d’abord utiliser des lignées cellulaires disponibles au laboratoire afin de mettre au point un modèle 3D de culture in vitro d’EOC. Des sphéroïdes ont été générés à l’aide de la méthode des gouttelettes inversées, une méthode pionnière pour la culture des cellules tumorales. Nous avons ensuite procédé à une analyse des profils d’expression afin de comparer le modèle sphéroïde au modèle de culture en monocouche et le modèle xénogreffe in vivo. Ainsi, nous avons identifié des gènes stratifiant les modèles tridimensionnels, tant in vivo qu’in vitro, du modèle 2D monocouche. Parmi les meilleurs candidats, nous avons sélectionné S100A6 pour une caractérisation ultérieure. L’expression de ce gène fût modulée afin d’étudier l’impact de son inhibition sur les paramètres de croissance des sphéroïdes. L’inhibition de ce gène a comme effet de réduire la motilité cellulaire mais seulement au niveau du modèle sphéroïde. Finalement, toujours dans l’optique de développer des modèles d’EOC les plus représentatifs de la maladie in vivo, nous avons réussi à développer des lignées cellulaires uniques dérivées de patientes atteintes d’EOC du type séreux, soit le plus commun des EOC. Jusque là, très peu de lignées cellulaires provenant de ce type de cancer et de patientes n’ayant pas reçu de chimiothérapie ont été produites. De plus, nous avons pour la première fois caractérise des lignées d’EOC de type séreux provenant à la fois de l’ascite et de la tumeur solide de la même patiente. / The epithelial ovarian cancer (EOC) is the most lethal of gynecological cancers. This complexe and heterogenous disease progresses rapidly and is almost asymptomatic in early stages. The survival rate of patients with late stage diagnosis remains low albeit cytoreductive surgery and chemotherapy. In order to study the EOC disease in an ex vivo context, the use of different cellular models is necessary. EOC cell lines derived from long-term passages of malignant ovarian cancers are useful tools for molecular and cellular research but it is not clear how culture conditions affect overall gene expression and oncogenic potential as compared to the original tumor. The main goal of this research was to develo and characterize new in vitro model systems that will recapitulate more closely some of the growth conditions encountered by tumor cells in vivo. In order to develop an in vitro tridimensional EOC spheroid model, we have used cell lines previously established in our laboratory. Spheroids were generated using the hanging droplet method, which was innovative for the culture of cancer cells. Comparative gene expression profile analysis of monolayer cultures, 3D spheroids and in vivo xenografts were performed and we have shown that the spheroid transcriptome more closely reflects expression patterns of the in vivo model compared to that of monolayer cultures. Among the best candidates, S100A6 gene over-expressed in the 3D models versus monolayer cultures was chosen for further analysis. To begin to address how S100A6 might affect EOC growth parameters, we have inhibited its expression in our in vitro models. The loss of S100A6 in the spheroid model results in an reduction of cellular migration, which seems to be in line with previous in vivo results published by other researchers. Always with the objective of developing the most relevant to the in vivo disease model systems, we have also succeeded in developing a unique EOC cell lines derived from patients with the most frequently diagnosed serous type of cancer. Very few cell lines derived from this type of cancers and from chemotherapy naïve patients are available. Moreover, we characterize for the first time EOC serous type cell lines derived from the ascites and the solid tumor of the same patient.

Ovarian cancer (OC) is the fifth most common cancer among women and has the highest mortality of any cancer of the female reproductive system. The majority (61%) of OC cases are diagnosed at a distant stage. Because diagnoses occur most commonly at a late-stage and prognosis for advanced disease is poor, research focusing on the development of effective OC screening methods to facilitate early detection in high-risk, asymptomatic women is fundamental in reducing OC-specific mortality. Presently, there is no screening modality proven efficacious in reducing OC-mortality. However, transvaginal ultrasonography (TVS) has shown value in early detection of OC. TVS presents with the possibility of false positive results which occur when a women receives an abnormal TVS screening test result that is deemed benign following repeat testing (about 7% of the time). The purpose of this dissertation was to evaluate the impact of false positive TVS screening test results on a variety of psychological and behavioral outcomes using mixed and trajectory statistical modeling. The three specific aims of this dissertation were to 1) compare psychological and behavioral outcomes between women receiving normal and false positive results, 2) identify characteristics of women receiving false positive results associated with increased OC-specific distress and 3) characterize distress trajectories following receipt of false positive results. Analyses included a subset of women participating in an experimental study conducted through the University of Kentucky Ovarian Cancer Screening Program. 750 women completed longitudinal assessments: 375 false positive and 375 normal results. Mixed and group-based trajectory modeling were used to evaluate the specific aims. Results suggest women receiving false positive TVS result experience increased OC-specific distress compared to women receiving normal results. Among those receiving false positives, less education, no history of an abnormal screening test result, less optimism and more social constraint were associated with increased OC-specific distress. Family history was associated with increased distress among women with monitoring informational coping styles. Three distinct trajectories characterize the trajectory of distress over a four-month study period. Although decreasing over time, a notable proportion of women experience sustained high levels of OC-specific distress.

Introduction Tumour-infiltrating lymphocytes (TIL) are an important prognostic indicator in high-grade serous ovarian carcinoma (HGSC). Certain types of TIL (in particular CD8+ effector T cells) predict better outcomes, whereas others (most notably CD4+CD25+FoxP3+ regulatory T cells; Tregs) predict worse outcomes. An unconventional subset of CD8+FoxP3+ T cells has been reported to be involved in autoimmunity and in immune response to several cancers. While the functional significance of CD8+FoxP3+ TIL remains poorly understood, they were associated with effective anti-tumour responses in a murine tumour model. Hypothesis CD8+FoxP3+ TIL are present in a subset of cases of HGSC and correlate with a strong immune response and increased patient survival. Experimental Design Multi-colour immunohistochemistry (IHC) was performed on a cohort of 44 primary HGSC specimens to enumerate and locate CD8+FoxP3+ TIL in comparison to CD8+FoxP3- and CD8-FoxP3+ TIL. Triple-colour IHC methodology was developed to further assess the phenotype of CD8+FoxP3+ TIL, including the measurement of additional markers CD4 and CD25 (classical markers of Tregs), Ki-67 (a marker of proliferation), and TIA-1 (a marker of cytotoxic potential). Intraepithelial versus stromal location was determined by staining adjacent sections for the epithelial marker pan-cytokeratin. Survival analysis was performed using a cohort of 188 cases of HGSC. Multi-colour staining was resolved using the Nuance™ multispectral imaging system in conjunction with Metamorph™ software. Survival analysis was performed using Kaplan-Meier and log rank tests. Results CD8+FoxP3+ cells were found in 60% of 44 cases of HGSC, in variable proportions ranging from 0.2 - 7.9% of CD8+ TIL and 0.5 – 12.7% of FoxP3+ TIL. CD8+FoxP3+ TIL were found to be either CD4+ (38.8%) or CD4- (61.2%). The majority of CD8+FoxP3+ TIL were also found to be CD25-TIA-1+Ki-67-, more closely resembling their CD8+FoxP3- counterparts. CD8+FoxP3+ TIL were found mainly in intraepithelial regions and were positively associated with patient survival (progression free survival; P = 0.0396). Conclusions CD8+FoxP3+ TIL are a component of the host immune response to HGSC. They appear to have a non-proliferative effector phenotype, consistent with an active role in the anti-tumour response. CD8+FoxP3+ TIL are associated with increased patient survival. An improved understanding of this new TIL subset may inform future immunotherapeutic strategies for this challenging malignancy. / Graduate / 0982 / sarakost@hotmail.com

The statin family of hydroxymethylglutaryl coenzyme A reductase (HMGCR) inhibitors, used to control hypercholesterolemia, triggers apoptosis of various human tumour cells. HMGCR is the rate-limiting enzyme of the mevalonate (MVA) pathway, a fundamental metabolic pathway required for the generation of a number of biochemical end-products including cholesterol and isoprenoids, but the contribution of the MVA pathway to human cancer remains largely unexplored. Furthermore, as only a subset of tumour cells has been shown to be highly responsive to statins, the identification of appropriate subsets of patients will be required to successfully advance these agents as anticancer therapeutics. To this end, there were two major aims to this work: 1) Elucidate a molecular rationale for the observed therapeutic index of statin-induced apoptosis in normal and tumour cells; 2) Identify molecular determinants of sensitivity for statin-induced apoptosis in human tumour cells. To address the first aim we demonstrated that dysregulation of the MVA pathway, achieved by ectopic expression of either full length HMGCR (HMGCR-FL) or its novel splice variant lacking exon 13 (HMGCR-D13), increases transformation. Ectopic HMGCR promotes growth of transformed and non-transformed cells under anchorage-independent conditions or as xenografts in immunocompromised mice. We also show that high mRNA levels of HMGCR and four out of five other MVA pathway genes correlate with poor prognosis in primary breast cancer, suggesting the MVA pathway may play a role in the etiology of human cancers. To address the second aim, we show that dysregulation of the MVA pathway is a key determinant of sensitivity to statin-induced apoptosis in multiple myeloma. In a panel of 17 distinct myeloma cell lines, half were sensitive to statin-induced apoptosis and the remainder were insensitive. Interestingly, in sensitive cells, the classic feedback response to statin exposure is lost, a feature we demonstrated could distinguish a subset of statin-sensitive primary myeloma cells. We further illustrated that statins are highly effective and well tolerated in an orthotopic model of myeloma using cells harboring a dysregulated MVA pathway. Taken together, this work provides a molecular rationale and determinants of sensitivity for statin-induced apoptosis of human tumour cells.

In this study, we have explored the combination of a novel Purine Nucleoside Phosphorylase mediated Gene-Directed Enzyme Prodrug Therapy (PNP-GDEPT) with chemotherapeutics, Taxotere and/or Carboplatin to target prostate and ovarian cancer (PC & OC). PNP converts the prodrug (Fludarabine-phosphate) to a toxic purine, 2-fluoroadenine (2FA) that inhibits RNA/DNA synthesis. Taxotere is active against late stage PC whilst carboplatin is first line therapy for OC. Neither modality is adequately effective. We expect that a combination will target heterogeneity via cytotoxicity to diverse cancer cell populations leading to effective synergies, which may improve efficacy and quality of life. For PC, Synergy between Ad-PNP-GDEPT and Taxotere were assessed in vitro and in vivo. Cell killing effects of combination led to significant synergistic killing of human PC-3 & murine RM1 PC cells accompanied by enhanced apoptosis. A lower individual dose (by up to 8 fold) led to enhanced efficacy. In vivo, the combination regimen given at the suboptimal doses led to reduction in local tumour (PC-3 & RM1) growth in nude and in C57BL/6 mice, respectively. A significant reduction in lung RM1 colony numbers indicated enhanced systemic efficacy. Combination treated mice also displayed significantly improved survival (25 days vs 15 days for control mice). Importantly, the condition of combination treated mice (e.g. weight loss) was better than those given individual treatments. The possible involvement of the immune system in this enhanced effect is under investigation. For OC, three-way synergy between Ad-PNP-GDEPT, Taxotere and carboplatin was effectively demonstrated in SKOV-3 and OVCAR-3 cells. This was significantly greater than bimodal or individual treatments. A 10-50 fold dose reduction of individual treatments was effective when combined, accompanied by enhanced apoptosis. Western-blotting analyses revealed a shift in the expression of anti-apoptotic and proapoptotic proteins upon treatment with various combinations. This is the first demonstration of synergy between these modalities.

Prostate cancer is a significant public health concern due to its high incidence and mortality, and that no consensus exists regarding the best form of treatment for any stage of the disease. Prostate cancer mortality can be reduced by the early prostate cancer detection. The earlier the detection the more effective the treatment would be. Prostate cancer screening or early detection has been accomplished applying the digital rectal examination (DRE) , the measurement of serum the prostate specific antigen (PSA), transrectal ultrasonography and combinations of these tests. MS based proteomics and particularly MS-SEDLI-TOF technology have assisted in discovering prostate cancer biomarkers. On the other hand, a major cause of mortality for women is the ovarian cancer. Malignant ovarian tumors are heterogeneous in their biological and clinical behaviour and a greater understanding of how they develop and progress is a prerequisite to successful early detection, screening programs, and treatment modalities. Accordingly, the aims of the present thesis are: (i) To develop a reliable pattern recognition system for the discrimination of healthy from patients with prostate cancer as well as controls from patients with ovarian cancer ,(ii) To develop efficient algorithms in order to handle the large number of features that are extracted from proteomic spectra, (iii) To develop a methodology to facilitate the investigation of the low intensity peaks which are the peaks in which biologists are mostly interested in, (iv) To propose potential biomarkers for discriminating healthy from prostate cancer cases and healthy from ovarian cancer cases . To cope with the above issues and in search of efficient methods for handling proteomic spectra a novel multi classifier pattern recognition methodology has been designed, developed and implemented, for the analysis of prostate and ovarian proteomic data. Furthermore, a novel method for splitting and grouping peaks according to their intensities has been developed to be consistent with biologist interest in investigating low intensity peaks. / Τα δεδομένα πρωτεομικής τα οποία εξάγονται από φασματογράφο μάζας έχουν ως αποτέλεσμα την δημιουργία ενός μονοδιάστατου σήματος το οποίο στον οριζόντιο άξονα έχει τιμές μάζας/φορτίο και στον κατακόρυφο άξονα έχει τις αντίστοιχες τιμές έντασης. Οι τιμές στον οριζόντιο άξονα (μάζα/φορτίο) οι οποίες αντιπροσωπεύουν πεπτίδια ή πρωτεΐνες έχουν ένα εύρος από 0 έως δεκάδες χιλιάδες. Επομένως τα πρωτεομικά φάσματα θεωρούνται ιδιαίτερα πολύπλοκα. Η διαχείριση της πληροφορίας των πρωτεομικών φασμάτων καθώς και η εξαγωγή διαγνωστικών συμπερασμάτων είναι ένα πεδίο ανοιχτό προς έρευνα. Ο καρκίνος του προστάτη αποτελεί την δεύτερη πιο σημαντική αιτία θανάτου στην Ηνωμένες Πολιτείες Αμερικής και τον Καναδά. Η θνησιμότητα που οφείλεται στον καρκίνο του προστάτη μπορεί να μειωθεί από την έγκαιρη πρόγνωσή του. Όσο ποιο έγκαιρη είναι η πρόγνωσή του τόσο ποιο αποτελεσματική είναι η θεραπεία του. Ο προστάτης είναι ένας αδένας που βρίσκεται στο εσωτερικό του σώματος, κάτω από την ουροδόχο κύστη του άνδρα και περιβάλλει την ουρήθρα. Τον αδένα αυτό τον έχει ένας άνδρας ήδη από την στιγμή που γεννιέται. Με την λειτουργία του συμβάλει, στον έλεγχο της ούρησης, το οποίο το πετυχαίνει λόγω της ανατομικής του θέσης, στον εμπλουτισμό του σπέρματος με χρήσιμα και απαραίτητα συστατικά και στη λειτουργία της εκσπερμάτισης. Ο καρκίνος του προστάτη είναι η ανάπτυξη καρκινικών κυττάρων στον αδένα αυτόν. Τα καρκινικά κύτταρα πολλαπλασιάζονται πολύ πιο γρήγορα από τα φυσιολογικά κύτταρα, και έτσι, η ολοένα αυξανόμενη συγκέντρωσή τους δημιουργεί όγκους. Επιπλέον, τα καρκινικά κύτταρα έχουν την δυνατότητα να μεταφέρονται σε άλλα σημεία του σώματος (κάνουν μετάσταση) και να καταστρέφουν τα υγιή κύτταρα. Η πρωτεομική με την εφαρμογή της φασματογραφίας μάζας έχει βοηθήσει σημαντικά στην πρόγνωση του καρκίνου του προστάτη και στην ανακάλυψη γνωστών βιοδεικτών του καρκίνου του προστάτη όπως είναι το ειδικό αντιγόνο του προστάτη (PSA), η προστατική όξινη φωσφατάση (PAP), το ειδικό πεπτίδιο του προστάτη (PSP) και το ειδικό αντιγόνο μεμβράνης του προστάτη (PSMA). Ο καρκίνος των ωοθηκών είναι μια συνήθεις γυναικολογική κακοήθεια με ποικίλα ιστολογικά χαρακτηριστικά. Είναι η κύρια αιτία θανάτου από καρκίνου ανάμεσα σε όλες τις γυναικολογικές κακοήθειες, καθώς και ο πέμπτος πιο συχνός τύπος καρκίνου μεταξύ γυναικών του δυτικού κόσμου. Η πλειοψηφία των κακοηθών όγκων των ωοθηκών εμφανίζεται σε γυναίκες ηλικίας άνω των 65 χρόνων, ενώ οι καλοήθεις όγκοι είναι συνηθέστεροι σε νεότερης ηλικίας γυναίκες μεταξύ 25 και 45 χρόνων. Λόγω της πολυπαραγοντικής φύσης του καρκίνου, είναι πολύ πιθανό, μια ομάδα βιοδεικτών να είναι πιο ενδεικτικοί για την πρόβλεψη της βιολογικής συμπεριφοράς διαφόρων όγκων, από την χρήση ενός μόνο βιοδείκτη. Το CA-125 είναι ένας δείκτης ο οποίος χρησιμοποιείται για την διάγνωσης και συγκεκριμένα στην πρόγνωση του καρκίνου των ωοθηκών. Η επιβεβαίωση του και αξιοπιστία του βιοδείκτη CA-125 οδήγησε στην ευρέως χρήση του, ως βιοδείκτης για τον καρκίνο των ωοθηκών, καθώς και στην κλινική διάγνωση της ανταπόκρισης του ασθενούς κατά την θεραπεία του καρκίνου. Πρόσφατες προσπάθειες επικεντρώθηκαν στην βελτίωση της διαγνωστικής ακρίβειας του CA-125, είτε χρησιμοποιώντας μόνο τον συγκεκριμένο βιοδείκτη (CA-125), είτε χρησιμοποιώντας τον με νέους βιοδείκτες που έχουν συσχετιστεί με τον καρκίνο των ωοθηκών. Ο βιοδείκτης CA-125 βρίσκεται στο μητρικό γάλα και στο αμνιακό υγρό στις υγιείς γυναίκες. Παρόλα αυτά υπάρχει επίσης σε γυναίκες με γυναικολογικά προβλήματα όπως μητρικό λειομύωμα και ενδομητρίωση μειώνοντας έτσι την ειδικότητα του βιοδείκτη. Επιπροσθέτως άλλοι βιοδείκτες οι οποίοι έχουν βρεθεί είναι οι prostasin, OVX1, CA-15.3, CA-72.4, και inhibin. Έτσι οι στόχοι της παρούσας διατριβής είναι: (i) ο κατάλληλος συνδυασμός των βημάτων, προεπεξεργασίας, εξαγωγής χαρακτηριστικών, επιλογής χαρακτηριστικών και επιλογής ταξινομητή ώστε η διάγνωση να είναι ακριβέστερη από τις υπάρχουσες μεθόδους. (ii) να προταθούν βιοδείκτες (biomarkers) και συγκεκριμένα τιμές φάσματος (μάζας/φορτίου) οι οποίες ενδεχομένως να σχετίζονται με τις ασθένειες προς μελέτη (Καρκίνου του προστάτη και των ωοθηκών). Για την εκπλήρωση των ανωτέρω στόχων σχεδιάστηκαν και αναπτύχθηκαν μεθοδολογίες με στόχο την ακριβή διάκριση των υγειών από ασθενείς με καρκίνο του προστάτη και ωοθηκών. Προτείνονται τιμές μάζας/φορτίο οι οποίες ενδεχομένως να αποτελέσουν χρήσιμους βιοδείκτες για τον καρκίνο του προστάτη και για τον καρκίνο των ωοθηκών. Επίσης υλοποιήθηκε μεθοδολογία για να μπορέσουμε να ερευνήσουμε την διαγνωστική αξία των κορυφών, των πρωτεομικών φασμάτων, με διάφορες τιμές έντασης και κυρίως των χαμηλών, οι οποίες θεωρούνται ως πλούσιες σε πληροφορία από τους βιολόγους.