Systems pathology attempts to introduce more holistic approaches towards pathology and attempts to integrate clinicopathological information with “-omics” technology. This doctorate researches two examples of a systems approach for pathology: (1) a personalized patient output prediction for ovarian cancer and (2) an analytical approach differentiates between individual and collective tumour invasion. During the personalized patient output prediction for ovarian cancer study, clinicopathological measurements and proteomic biomarkers are analysed with a set of newly engineered bioinformatic tools. These tools are based upon feature selection, survival analysis with Cox proportional hazards regression, and a novel Monte Carlo approach. Clinical and pathological data proves to have highly significant information content, as expected; however, molecular data has little information content alone, and is only significant when selected most-informative variables are placed in the context of the patient's clinical and pathological measures. Furthermore, classifiers based on support vector machines (SVMs) that predict one-year PFS and three-year OS with high accuracy, show how the addition of carefully selected molecular measures to clinical and pathological knowledge can enable personalized prognosis predictions. Finally, the high-performance of these classifiers are validated on an additional data set. A second study, an analytical approach differentiates between individual and collective tumour invasion, analyses a set of morphological measures. These morphological measurements are collected with a newly developed process using automated imaging analysis for data collection in combination with a Bayesian network analysis to probabilistically connect morphological variables with tumour invasion modes. Between an individual and collective invasion mode, cell-cell contact is the most discriminating morphological feature. Smaller invading groups were typified by smoother cellular surfaces than those invading collectively in larger groups. Interestingly, elongation was evident in all invading cell groups and was not a specific feature of single cell invasion as a surrogate of epithelialmesenchymal transition. In conclusion, the combination of automated imaging analysis and Bayesian network analysis provides an insight into morphological variables associated with transition of cancer cells between invasion modes. We show that only two morphologically distinct modes of invasion exist. The two studies performed in this thesis illustrate the potential of a systems approach for pathology and illustrate the need of quantitative approaches in order to reveal the system behind pathology.

by Cheung Kwok Kuen. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 111-130). / Chapter Chapter 1 --- General introduction of human ovarian cancer / Chapter 1.1 --- Epidemiology --- p.1 / Chapter 1.2 --- Symptoms and diagnosis --- p.4 / Chapter 1.3 --- Etiology --- p.5 / Chapter 1.3.1 --- Factors associated with decreased risks --- p.6 / Chapter 1.3.2 --- Factors associated with increased risks --- p.8 / Chapter 1.4 --- Classification of ovarian cancer --- p.12 / Chapter 1.5 --- Molecular basis of ovarian cancer --- p.18 / Chapter 1.6 --- Project aim --- p.29 / Chapter Chaper 2 --- "DOC-2, a differentially expressed gene in human ovarian cancer" / Chapter 2.1 --- Introduction --- p.32 / Chapter 2.2 --- Materials and Methods --- p.35 / Chapter 2.2.1 --- Expression of DOC-2 in human ovarian tissues --- p.35 / Chapter 2.2.1.1 --- Preparation of specimen --- p.35 / Chapter 2.2.1.2 --- Immunohistochemical studies of the expression of DOC-2 protein in human ovarian tissues --- p.35 / Chapter 2.2.1.3 --- Quantitation of immunoreactivity --- p.38 / Chapter 2.2.2 --- Effect of DOC-2 transfection on growth rate of the ovarian cancer cell lineSKOV3 --- p.39 / Chapter 2.2.2.1 --- Cell line --- p.39 / Chapter 2.2.2.2 --- Transfection of DOC-2 to SKOV3 ovarian carcinoma cell line --- p.39 / Chapter 2.2.2.3 --- Growth curve of the transfected ovarian carcinoma cell lines --- p.40 / Chapter 2.2.3 --- In vivo tumorigenicity study --- p.42 / Chapter 2.3 --- Results --- p.44 / Chapter 2.3.1 --- Expression of DOC-2 in human ovarian tissues --- p.44 / Chapter 2.3.2 --- Effects of DOC-2 transfected gene on the growth rate of the human ovarian cancer cell line SKOV3 --- p.46 / Chapter 2.3.2.1 --- Standard curves for calculating cell density from absorbance --- p.46 / Chapter 2.3.2.2 --- The effect of DOC-2 transfection on the growth rate of the human ovarian cancer cell line SKOV3 --- p.47 / Chapter 2.3.3 --- In vivo tumorigenicity --- p.48 / Chapter 2.4 --- Discussion --- p.50 / Chapter Chapter 3 --- DOC-2 expression in mouse embryonic development / Chapter 3.1 --- Introduction --- p.56 / Chapter 3.2 --- Materials and Methods --- p.60 / Chapter 3.2.1 --- Expression of murine homolog of DOC-2 (p96) during mouse embryonic development --- p.60 / Chapter 3.2.1.1 --- Preparation of paraffin-embedded mouse embryo sections --- p.60 / Chapter 3.2.1.2 --- Preparation of OCT-embedded mouse embryo sections --- p.61 / Chapter 3.2.1.3 --- Immunohistochemistry of murine homolog of DOC-2 (p96) on mouse embryos --- p.61 / Chapter 3.2.2 --- Effect of antibody blocking for DOC-2 protein on the growth of embryonic kidney in vitro --- p.62 / Chapter 3.3 --- Results --- p.64 / Chapter 3.4 --- Discussion --- p.69 / Chapter Chapter 4 --- Apoptosis / Chapter 4.1 --- Introduction --- p.72 / Chapter 4.1.1 --- Current methods for the detection of apoptosis --- p.74 / Chapter 4.1.1.1 --- Agarose gel electrophoresis --- p.75 / Chapter 4.1.1.2 --- Flow cytometric analysis --- p.76 / Chapter 4.1.1.3 --- 3-OH end labelling --- p.77 / Chapter 4.1.1.4 --- Nuclease assay --- p.78 / Chapter 4.1.2 --- Apoptosis in normal physiology and oncogenesis --- p.78 / Chapter 4.1.3 --- p53 and apoptosis --- p.80 / Chapter 4.1.4 --- bcl-2 and apoptosis --- p.83 / Chapter 4.2 --- Materials and Methods --- p.92 / Chapter 4.2.1 --- Expression of p53 and bcl-2 in human ovarian tissues --- p.92 / Chapter 4.2.1.1 --- Preparation of specimens --- p.92 / Chapter 4.2.1.2 --- Immunohistochemical studies of the expression of p53 and bcl-2 proteins in ovarian tissue --- p.92 / Chapter 4.2.2 --- In stiu terminal transferase-mediated dUTP nick and labelling (TUNEL) --- p.94 / Chapter 4.3 --- Results --- p.96 / Chapter 4.3.1 --- Expression of p53 and bcl-2 in human ovarian tissues --- p.96 / Chapter 4.3.2 --- Apoptosis in human ovarian tissues --- p.99 / Chapter 4.4 --- Discussion --- p.101 / Chapter Chapter 5 --- Concluding Remarks --- p.108 / References --- p.111 / Appendix --- p.131 / Figures and legend --- p.138

Crumbs is a transmembrane protein and apical determinant in Drosophila epithelial cells. Its cytoplasmic tail contains a PDZ and a FERM domain-binding site through which Crumbs interacts with the FERM proteins Yurt, Moesin and Expanded. Recent evidence suggests that Crumbs can also interact with the uncharacterised FERM proteins CG34347 and Cdep. The main objective of my thesis was to generate mutations in CG34347 and Cdep to facilitate the functional analysis of these genes. I generated a mutation for Cdep that remains to be characterised and two mutant lines for CG34347; one lacking the first exon and one lacking the entire gene, using a FRT-based recombination strategy. Both CG34347 mutants cause severe ovarian defects. The most consistent defect is a multilayering of the interfollicular stalk. These defects are also observed when Notch, Hippo, Wingless and Hedgehog signalling pathways are overactive in ovaries suggesting that CG34347 participates in one of those pathways.

Crumbs is a transmembrane protein and apical determinant in Drosophila epithelial cells. Its cytoplasmic tail contains a PDZ and a FERM domain-binding site through which Crumbs interacts with the FERM proteins Yurt, Moesin and Expanded. Recent evidence suggests that Crumbs can also interact with the uncharacterised FERM proteins CG34347 and Cdep. The main objective of my thesis was to generate mutations in CG34347 and Cdep to facilitate the functional analysis of these genes. I generated a mutation for Cdep that remains to be characterised and two mutant lines for CG34347; one lacking the first exon and one lacking the entire gene, using a FRT-based recombination strategy. Both CG34347 mutants cause severe ovarian defects. The most consistent defect is a multilayering of the interfollicular stalk. These defects are also observed when Notch, Hippo, Wingless and Hedgehog signalling pathways are overactive in ovaries suggesting that CG34347 participates in one of those pathways.

Ο καρκίνος εκ του επιθηλίου επιφανείας των ωοθηκών είναι η 5η πιο κοινή αιτία θανάτου σε γυναίκες στο Δυτικό κόσμο και είναι υπεύθυνος για τους περισσότερους θανάτους από ότι όλες οι γυναικολογικές κακοήθειες μαζί. Τόσο ο μηχανισμός του νεοπλαστικού μετασχηματισμού όσο και τα μοριακά μονοπάτια που οδηγούν στο ωοθηκικό επιθηλιακό καρκίνωμα δεν έχουν εξακριβωθεί πλήρως. Ένα πρόσφατα αναγνωρισμένο γονίδιο, η μετατχερίνη (MTDH), γνωστή και ως AEG-1 ή LYRIC ενοχοποιείται ως πιθανός σημαντικός διαμεσολαβητής κατά την καρκινογένεση, την μετάσταση και την αντίσταση στις χημειοθεραπείες. Ωστόσο, η κλινική σημασία και ο βιολογικός ρόλος της μετατχερίνης (MTDH), στο επιθηλιακό καρκίνωμα των ωοθηκών δεν έχουν γίνει αποσαφηνισθεί πλήρως. Η υπερέκφραση της MTDH/AEG-1 μπορεί να ενεργοποιήσει πολλά σηματοδοτικά μονοπάτια, όπως για παράδειγμα το NF-κΒ σηματοδοτικό μονοπάτι σε διάφορους καρκινικούς τύπους. Ο NF-κΒ έχει πρόσφατα συσχετισθεί με την ανάπτυξη και την εξέλιξη των όγκων και επιπλέον τα διμερή του NF-κΒ ενισχύουν την έκφραση ποικίλων γονιδίων που αφορούν την κυτταρική αύξηση, τη διαφοροποίηση, τις φλεγμονώδεις αντιδράσεις και τη ρύθμιση της απόπτωσης. Η παρούσα μελέτη σχεδιάστηκε προκειμένου να διερευνηθεί η έκφραση των πρωτεϊνών MTDH και NF-kB (p65/p50) σε επιθηλιακά ωοθηκικά καρκινώματα (καλοήθεις, οριακής κακοήθειας και διηθητικά καρκινώματα). Για το σκοπό αυτό μελετήθηκαν τμήματα επιθηλιακών νεοπλασμάτων ωοθηκών από 76 ασθενείς (15/46 οριακής κακοήθειας όγκοι, 30/46 διηθητικά αδενοκαρκινώματα και 31/76 κυσταδενώματα), μονιμοποιημένα σε ουδέτερη φορμόλη και εγκλεισμένα σε παραφίνη με τη μέθοδο της ανοσοϊστοχημείας για την έκφραση των πρωτεϊνών MTDH και NF-κB (p50/p65). Επίσης εκτιμήθηκε η σχέση της MTDH/AEG-1 με τον NF-κB και με κλινικοπαθολογοανατομικές παραμέτρους όπως ο βαθμός κακοήθειας του όγκου, το στάδιο, η μέγιστη διάμετρος του όγκου και η ηλικία της ασθενούς. Τα αποτελέσματα της ανοσοϊστοχημείας αναλύθηκαν με τη χρήση του στατιστικού πακέτου SPSS. Ο φυσιολογικός ωοθηκικός ιστός και τα κυσταδενώματα ήταν κυρίως αρνητικά για τις πρωτεΐνες MTDH/AEG-1 και NF-κB (p50, p65). Η έκφραση των MTDH/AEG-1 και NF-kappa B/ p50, πρωτεϊνών ήταν σημαντικά αυξημένες στα αδενοκαρκινώματα σε σχέση με τους οριακής κακοήθειας όγκους. Σε αντίθεση η έκφραση της NF-kappa B/ p65 πρωτεΐνης δεν έδειξε σημαντικές διαφορές μεταξύ των οριακής κακοήθειας όγκων και των αδενοκαρκινωμάτων. Σημαντική στατιστική συσχέτιση παρατηρήθηκε στην έκφραση των πρωτεϊνών MTDH/AEG-1, NF-kappa B/p50 και NF-kappaB/p65 στα αδενοκαρκινώματα. Καμία στατιστική συσχέτιση δεν παρατηρήθηκε στην έκφραση μεταξύ του NF-κB, της MTDH πρωτεΐνης και κλινικοπαθολογοανατομικών παραμέτρων. Συμπερασματικά, τα αποτελέσματα μας υποδεικνύουν ότι η MTDH/AEG-1 ίσως παίζει ένα σημαντικό ρόλο στην παθογένεια του ανθρώπινου ωοθηκικού καρκίνου, πιθανώς μέσω της ενεργοποίησης του σηματοδοτικού μονοπατιού του πυρηνικού μεταγραφικού παράγοντα NF-κB. Επειδή η MTDH συσχετίζεται σημαντικά με την αντίσταση στη χημειοθεραπεία, θα μπορούσε ενδεχομένως να αποτελέσει σημαντικό στόχο για θεραπεία, ενισχύοντας την αποτελεσματικότητα της χημειοθεραπείας στον επιθηλιακό ωοθηκικό καρκίνο. / Epithelial ovarian cancer is the fifth most common cause of cancer death in women in the Western world and the leading cause of death from gynaecological malignancies. Little is known about the mechanism of neoplastic transformation and the molecular events leading to epithelial ovarian cancer are poorly understood. A recently discovered gene, metadherin (MTDH, also known as AEG-1 or LYRIC) has emerged as a potentially crucial mediator of tumor progression, metastasis, and resistance to chemotherapies. The clinical significance and biological role of metadherin (MTDH), in epithelial ovarian carcinoma however, remains unclear. Overexpression of MTDH/AEG-1 can activate several downstream pathways, including the NFκB pathway in various types of cancer cells. Recently, NF-kB has been related to cancer development and progression and NF-kB dimers (p50/p65) could induce the expression of various genes regarding cell growth, differentiation, inflammatory responses and the regulation of apoptosis. This study was designed in order to determine the expression of the MTDH and NF-kB (p65/p50) proteins in epithelial ovarian tumors (benign, borderline and malignant). Formalin-fixed and paraffin embedded tissue blocks from 76 patients with epithelial ovarian neoplasms (15/46 borderline tumors, 30/46 invasive adenocarcinomas and 31/76 cystadenomas) were studied. Expressions of MTDH/AEG-1, NF-κB (p50, p65) were investigated immunohistochemically. The relationship of MTDH/AEG-1 with NF-κB and clinicopathological parameters such as tumor grade, stage, tumor maximal diameter and patient age were evaluated. The results of immunohistochemistry were analyzed with the SPSS statistic analyze protocol. Normal ovarian tissue and benign ovarian cystadenomas were mostly MTDH/AEG-1, NF-κB (p50, p65) negative. The expression of MTDH/AEG-1 and NF-kappaB p50, proteins were significantly higher in adenocarcinoma tissue in comparison with borderline tumors. In contast NF-kappaB p65 expession shows no significant differences between borderline tumors and adenocarcinomas. A statistical significant correlation was observed between MTDH/AEG-1 and NF-kappaB p50, p65 protein expression in adenocarcinomas. No statistical correlation was observed between the NF-Kb and MTDH protein expression and clinicopathological parameters. In conclusion our data indicate that the upregulation of MTDH/AEG-1 may play an important role in the pathogenesis of human ovarian cancer possibly through activation of Nuclear factor-κB signalling pathway. Since MTDH has also a significant correlation with chemoresistance could be an important therapeutic target enhancing chemotherapy efficacy in ovarian epithelial cancer.

The theoretical part of diploma thesis is aimed at breeding, growth and molting events in crayfish. Thesis is also aimed at life cycle and reproduction of three indigenous crayfish species (Astacus astacus, Austropotamobius torrentium, Pontastacus leptodactylus) and two introduced crayfish species (Faxonius limosus, Pacifastacus leniusculus). The results show apparent linear dependence between female size (POCL), abdomen surface (1M: y = -1061,2 + 65,4*x; r2 = 0,9829; p10-5; 2M: y = -1160,4 + 68,7*x; r2 = 0,8732; p < 10-5) and fertility (1M: y = -194,4 + 12,8*x; r2 = 0,4104 p = 0,0042; y = -330.9 + 15,9*x; r2 = 0.4372; p < 10-4) in once (1M) and twice (2M) molted females. As the length of carapax increase, the area of the abdomen increase and fertility increase in both groups of females. Furthermore, the differences in fertility, carapax length, abdomen surface, and weights in once and twice molted females of signal crayfish. In group of once molted females fertility (t-test, t = -3.12, p = 0.003), carapax length (t-test, t = -3.17, p = 0.003) = -3.24; p = 0.002) and the weight (t-test, t = -3.35; p = 0.002) was higher than in twice molted group of female. Consequentially evaluation of egg size of females. The size of the eggs did not differ between groups of females (1M and 2M) (t-test, t = -0.975, p = 0.335). The mean egg size for both groups of females was 2.71 ? 0.18 mm. Evaluation of post-ovulation conditions of the ovary, including visible signs of females that resorbed unovulated oocytes. Evaluating how much unovulated oocytes were found in the ovaries. Only in 46.4% of the total number of females were ovaries completely empty. In once and twice molted females were found in average 2.2 ? 3.8 and 1.9 ? 2.6. unovulated oocytes, respectively. In once molted, three females didn't lay eggs, two females lost the clutch of eggs. In twice molted females, six females did not lay the eggs and four females lost the clutch.

Le cancer de l’ovaire est la cinquième cause de décès par cancer chez la femme en France. La prolifération tumorale dans ce cancer est liée principalement à la dérégulation de l’apoptose. Cette dérégulation joue un rôle clé principalement dans la pathogénèse et la progression tumorale mais aussi dans le développement des résistances aux chimiothérapies existantes. La croissance accrue des cellules tumorales dans le cas du cancer de l’ovaire est liée à une surexpression des protéinesanti-apoptotiques de la famille Bcl-2, en particulier les protéines MCL-1 et Bcl-xL. L’inhibition concomitante de ces deux protéines conduit à la mort des cellules chimiorésistances. A ce jour, seuls les inhibiteurs de Bcl-xL ont démontré une efficacité en clinique, et l’inhibition de MCL-1 reste problématique dans un contexte clinique. Dans ce contexte, l’objectif principal de ces travaux de thèse consiste à caractériser, par RMN et modélisation moléculaire, l’interaction entre la protéine MCL-1 et le Pyridoclax, foldamère oligopyridinique très prometteur, synthétisé au CERMN. La spectroscopie RMN nous a permis de définir le site d’interaction, d’estimer la constante d’affinité et de guider le Docking pour obtenir une structure tridimensionnelle du complexe MCL-1:Pyridoclax. Afin de conforter notre étude sur l’implication du Pyridoclax dans l’interaction, des fragments dérivés de ce dernier ont été utilisés. La caractérisation de l’interaction entre ces fragments et la protéine MCL-1 a permis de relever l’importance du groupement styryle du Pyridoclax dans l’interaction avec la protéine MCL-1. Par ailleurs, nous avons élargi notre étude à d’autres inhibiteurs potentiels de MCL-1 tels que certains médicaments existant sur le marché. La spectroscopie RMN a permis de mettre en évidence et de caractériser l’interaction entre deux de ces médicaments (le Torsémide et le Déférasirox) et la protéine MCL-1. Pour finir, afin d’améliorer l’affinité de ces médicaments pour la protéine MCL-1, des modifications structurales ont été proposés en se basant sur la littérature. Les dérivés proposés semblent avoir une affinité très importante pour la protéine MCL-1. / Ovarian cancer is the fifth leading cause of cancer death of women in France. Tumor proliferation in this cancer is mainly related to the deregulation of apoptosis. This one plays a main role in pathogenesis and tumor progression but also on the term of development of resistance to existing chemotherapies. The increased growth of tumor cells in ovarian cancer is linked to an overexpression of the anti-apoptotic proteins of the Bcl-2 family, in particular the MCL-1 and Bcl-xL proteins. The concomitant inhibition of these two proteins leads to the death of chemoresistance cells. To date, only Bcl-xL inhibitors have demonstrated clinical efficacy andinhibition of MCL-1 remains problematic in a clinical context. In this context, the aim of this thesis is to characterize, by NMR and molecular modeling, the interaction between MCL-1 protein and potential inhibitors including Pyridoclax, an oligopyridine foldamer. NMR spectroscopy allowed us to define the interaction site, estimate the affinity constant and guide Docking to obtain a three-dimensional structure of the MCL-1:Pyridoclax complex. In order to obtain more information on the involvement of Pyridoclax in this interaction, fragmentsderived from it has been used. The characterization of the interaction between these fragments and MCL-1 protein revealed the importance of the styryl group of Pyridoclax in the interaction with MCL-1 protein. Furthermore, we expanded the scope of our study to include some existing drugs able to interact with MCL-1. NMR spectroscopy allowed us to identify and characterize the interaction between two of these drugs (Torsemide and Deferasirox) and the MCL-1 protein. Finally, in order to improve the affinity of these drugs for MCL-1 protein, structural modifications had been proposed based on the literature. The proposed derivatives appear to have a very high affinity for MCL-1 protein.

Indiana University-Purdue University Indianapolis (IUPUI) / Menopausal symptoms, primarily hot flashes, are a pressing clinical problem for both naturally menopausal women and breast and ovarian cancer patients, with a high societal and personal cost. Hot flashes are poorly understood, and animal modeling has been scarce, which has substantially hindered the development of non-hormonal treatments. An emerging factor in the hot flash experience is the role of anxiety and stress-related stimuli, which have repeatedly been shown to influence the bother, frequency, and severity of hot flashes. Causal relationships are difficult to determine in a clinical setting, and the use of animal models offers the ability to elucidate causality and mechanisms. The first part of this work details the development and validation of novel animal models of hot flashes using clinically relevant triggers (i.e., compounds or stimuli that cause hot flashes in clinical settings), which also increase anxiety symptoms. These studies revealed that these triggers elicited strong (7-9 °C) and rapid hot flash-associated increases in tail skin temperature in rats. In a surgical ovariectomy rat model of menopause, which typically exhibit anxiety-like behavior, hot flash provocation revealed an ovariectomy-dependent vulnerability, which was attenuated by estrogen replacement in tested models. An examination of the neural circuitry in response to the most robust flushing compound revealed increased cellular activity in key thermoregulatory and emotionally relevant areas. The orexin neuropeptide system was hyperactive and presented as a novel target; pretreatment with selective and dual orexin receptor antagonists significantly diminished or eliminated, respectively, the response to a hot flash provocation in ovariectomized rats. The insertion/deletion polymorphism of the serotonin transporter has been linked to increased anxiety-associated traits in humans, and subsequent studies prolonged hot flashes in SERT+/- rats, which also caused hot flashes in highly symptomatic women. These studies indicate the orexin system may be a novel non-hormonal treatment target, and future studies will determine the therapeutic importance of orexin receptor antagonists for menopausal symptoms.

Conura torvina (Cresson) (Hymenoptera: Chalcididae) is a solitary pupal endoparasite of numerous insect species. In Brassica crops it acts as a parasite of Plutella xylostella (L.) (Lepidoptera: Plutellidae) and was found as a hyperparasite of Cotesia rubecula (Marshall) (Hymenoptera: Braconidae) and several other parasitoid species. Cotesia rubecula was introduced into Virginia in 1987 as a biological control agent for Pieris rapae (L.) (Lepidoptera: Pieridae), and because C. torvina was thought to have eliminated this population of C. rubecula, studies of C. torvina's reproductive biology and behavior were initiated. A study using plants laden with "trap hosts" to detect C. torvina activity in the spring indicated no activity until late June, but proved trap host sampling to be an efficient and effective method of monitoring C. torvina activity. Studies of C. torvina's ability to reproduce in C. rubecula pupae of different ages indicated that C. torvina can successfully parasitize pupae at all stages of development, but was most successful in young to middle aged pupae. Studies of C. torvina's host species preference indicated the larger host species such as P. xylostella were preferred. Equal numbers of P. xylostella and C. rubecula were parasitized, but a greater proportion of fertile eggs were laid in P. xylostella. Smaller host species were often ignored. Host dissection studies indicated that caged C. torvina were inefficient at host finding and oviposition. Superparasitism was common, but declined as the females gained oviposition experience. Experienced C. torvina produced an average of 8.25 progenies per day for a period of 12 days when provided with 13 P. xylostella hosts each day. Conura torvina produced up to 14 progenies a day when provided 3 26 hosts. Dissection of C. torvina ovaries indicated three ovarioles per ovary with a mean of 9.2 and maximum of 15 mature eggs per female. Host dissection indicated that a mean of 18 and maximum of 30 eggs could be laid per day. New eggs were produced as oviposition occurred. Significantly larger eggs were laid in P. xylostella than in C. rubecula, and significantly more eggs were laid in C. rubecula than in P. xylostella. From these data and data from earlier studies I concluded that C. torvina has a poor reproductive ability and its impact as a hyperparasite is limited to the summer months. This makes C. torvina an unlikely cause of C. rubecula's disappearance. / Ph. D.

Ongoing research in the fields of genetics and biotechnology hold the promise of improved diagnosis and treatment of genetic diseases, and potentially the development of individually tailored pharmaceuticals and gene therapies. Difficulty, however, arises in determining how these services are to be evaluated and integrated equitably into public health care systems such as Canada's. The current context is one of increasing fiscal restraint on the part of governments, limited financial resources being dedicated to health care, and rising costs for new health care services and technologies. This has led to increasing public debate in the last few years about how to reform public health care, and whether we should prohibit, permit or perhaps even encourage private purchase of health care services. In Canada, some of these concerns have crystallized around the issue of gene patents and commercial genetic testing, in particular as illustrated by the case of Myriad Genetics' patented BRACAnalysis test for hereditary breast and ovarian cancer. While most Canadians who currently access genetic services do so through the public health care system, for those with the means, private purchase is becoming an option. This situation raises serious concerns - about justice in access to health care; about continued access to safe and reliable genetic testing supported by unbiased patient information; and about the broader effects of commercialization for ongoing research and the Canadian public health care system. Commercial genetic testing presents a challenge to health care professionals, policy analysts, and academics concerned with the social, ethical and policy implications of new genetic technologies. Using the Myriad case as an exemplar, tools from moral philosophy, the social sciences, and health policy and law will be brought to bear on the larger issues of how as a society we should regulate commercial research and product development, and more coherently decide which services to cover under public health insurance and which to leave to private purchase. Generally, the thesis is concerned with the question of "how best to bring capital, morality, and knowledge into a productive and ethical relationship" (Rabinow 1999, 20).