Le cancer de la prostate (CaP) est la pathologie tumorale la plus fréquente chez les hommes dans les pays occidentaux. L’âge avancé, les origines ethno-géographiques et la présence d’antécédents familiaux de CaP sont les principaux facteurs de risque clairement établis. Les expositions aux substances chimiques issues de l’activité humaine, en particuliers ceux présentant des propriétés hormonales (perturbateurs endocriniens), sont suspectées. L’objectif général cette thèse est d’étudier le rôle de certains polluants universels présentant des propriétés hormonales, tels que le DDE (principal métabolite du DDT) et les PCBs, ainsi que celui des polymorphismes de gènes codant pour des enzymes intervenant dans le métabolisme des xénobiotiques (GSTM1, GSTT1) et des œstrogènes (CYP17, CYP19, CYP1B1, COMT, UGT1A1) dans la survenue du CaP ou de sa récidive après traitement par prostatectomie radicale. Ce projet s’appuie sur les données obtenues lors de l’étude cas-témoins en population générale en Guadeloupe (KARUPROSTATE) et de la file active des cas traités par prostatectomie radicale. / Prostate cancer (PCa) is the most frequent type of cancer in Western countries. Advanced age, ethno-geographic origin and the presence of a family history of CaP are the main clearly established risk factors. The effects of exposure to synthetic chemicals with hormonal properties, also called endocrine disruptors (EDCs), on PCa are also are suspected. The main objective of this thesis is to evaluate the relationships between plasma concentration of persistent organochlorine pollutants with hormonal properties, such as DDE (the main metabolite of DDT) and PCBs as well polymorphisms of selected genes involved in xenobiotic (GSTM1, GSTT1) and estrogens (CYP17, CYP19, CYP1B1, COMT, UGT1A1) metabolism, and the occurrence of PCa or its recurrence after treatment with radical prostatectomy. This project is based on data obtained from the population-based case-control study (KARUPROSTATE) in Guadeloupe and from cases treated by radical prostatectomy.

No description available.

The three South African crane species, namely, the Wattled Crane (Bugeranus carunculatus), the Blue Crane (Anthropoides paradisea) and the Grey Crowned Crane (Balearica regulorum regulorum) are all threatened. South African legislation protects the cranes, however eggs and/or fledglings are sometimes illegally collected from the wild. These are then sold, often by registered breeders, who falsely claim them as the offspring of their captive breeding pair. DNA fingerprinting is one method to detect this crime. Fifteen RAPD primers were screened for polymorphism in the three species. Seven primers produced polymorphic profiles in the Blue Crane and eight each in the Grey Crowned Crane and Wattled Crane, with an average of 14.57, 12.38 and 5.88 scorable loci per primer, respectively. The Band Sharing Coefficient for unrelated individuals was found to be 0.665, 0.745 and 0.736 for the Blue, Grey Crowned and Wattled Crane respectively. Five microsatellite primers, originally developed for use in Whooping Cranes (Grus american), had previously been shown to be polymorphic in the Wattled Crane. This was also the case in this study with an average of 3.6 alleles per primer. Although all primers cross amplified, only a single primer each showed polymorphism in the Blue Crane (showing 6 alleles) and the Grey Crowned Crane (showing 5 alleles). The RAPDs were found to be irreproducible, show high numbers of novel bands and had parent: offspring BSC values that were not significantly higher than those of unrelated individuals. Statistics showed that, in the Blue Crane, the probability that misassigned parents would be detected was low whilst there was an almost certainty that true parents would be incorrectly excluded. The five microsatellite primers examined gave exclusionary powers of 0.869 and 0.641 where one or two parents were unknown in the Wattled Crane. The exclusionary powers for the Blue Crane and Grey Crowned Crane calculated at only one locus were much lower. It was concluded that RAPDs were totally inappropriate for parentage analyses, however, microsatellites are a suitable technique and recommendations are made that other microsatellites, developed for other species of crane, should be examined for their potential in this respect. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2004.

Host genetic factors may partially account for the uneven distribution of HIV infection worldwide. In addition to influencing relative susceptibility to HIV, host genetic factors may also affect the rate of disease progression in persons who are already HIV infected. J.L-10 was previously identified as an AIDS restricting gene (ARG), i.e. human genes with polymorphic variants that influence the outcome of HIV-1 exposure or infection. IL-10 is a Th2 cytokine, with anti-inflammatory properties, and plays a significant role in the regulation of immune responses; this cytokine may also directly influence viral replication. This study focused on the role of genetic polymorphisms in the proximal promoter region of the IL-10 gene on HIV-:eptibility and primary HIV-1 pathogenesis in a South African comprising of women at high risk of HIV-1 infection In this study 228 black females from the CAPRISA Acute Infection cohort were genotyped for two polymorphisms that naturally occur within the proximal region of the IL-10 promoter, at positions -.1082 and -592 (tracking -819) relative to the transcription start site. DNA samples from study participants were genotyped using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method, which utilises specifically designed primers to detect single nucleotide polymorphisms. The allele frequencies for the mutant -1082G and -592A variants were 0.3203 and 0.333 respectively.Individuals homozygous for the mutation at the -392 position (AA genotype) were 2.78 times more likely to become HIV infected, compared to those who were homozygous wild type (CC genotype) at the same position (p-value=0.0237). Among those who became HIV infected, we found a hierarchical association between IL-10 promoter variants and HIV-1 plasma viral load or CD4+ T cell counts over the course year of HIV-1 infection. At earlier time points, i.e. 0-3 months post-te -1082GG group had significantly higher median viral loads than the -AA or -1082AG groups (pvalues= <0.0001 and 0.0003 respectively); and the -1082AA group had the highest median CD4'' T cell count compared to the -1082AG or -1082GG groups and this was significant (p-values= 0.0194 and 0.0122 respectively). At 6-12 months post-infection the median viral load of the -1082GG group was lower than -1082AA group, however this was not significant (p-value=0.6767). Analysis of the effect of the -592 polymorphism showed that the -592AA group had a lower median viral load at 0-3 months post-infection compared to the homozygous wild-type group (i.e. -592CC p~value=0.0093); and the median CD4+ T cell count for the -592AA group was significantly higher than the -592CC group (p~ value= 0.0198). At 6-12 months post-infection, the median viral load as well as the median CD4+ T cell count of the -592 A A group were both no longer significantly different to the -592CC group (p-values= 0.644land 0.6461 respectively). Plasma IL-10 expression was not significantly different between the IL-I0 genotypes for any of the polymorphic positions.Overall, these results suggest that polymorphisms within the IL-10 promoter may influence the risk of HIV infection and that they may affect primary HIV-1 pathogenesis. Interestingly, our data suggests that the effect of these polymorphic variants on viral and CD4+ T cell counts may vary according to time post-infection. To our knowledge, this is the first study to suggest that an ARG may have a differential effect on markers of disease progression depending on the phase of infection studied. The mechanisms underlying these observations require further studies and may have important implications for HIV/AIDS pathogenesis and the development of effective vaccine and immunotherapeutic strategies. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2007.

Maize (Zea mays L.) is an important agronomic crop with the maize industry forming an important component of the South African economy. Considerable effort has been directed towards the genetic improvement of maize through both conventional breeding and biotechnology. Genotype identification by DNA fingerprinting is becoming an important activity in plant breeding. A widely used molecular based and relatively inexpensive method for DNA fingerprinting is the randomly amplified polymorphic DNA (RAPD) technique. The RAPD technique was tested in this study for its potential use in maize breeding programmes. Initial results using the technique showed a low degree of reproducibility, therefore both the DNA isolation and RAPD protocols were extensively optimised. DNA quality and quantity, and choice of Taq polymerase buffer were three of the variables found to be influential in ensuring reproducibility. The ability of the RAPD technique to characterise seven maize genotypes was evaluated. Sixty random oligonucleotide primers were screened. Forty two primers scored a total of 233 fragments (an average of 5.5 per primer), but not all primers gave reproducible profiles. Eighteen primers scored a total of 110 loci for the presence (1) and absence (0) of DNA fragments. RAPD markers were able to distinguish between all seven genotypes with five primers producing specific fragments for four genotypes. Genetic similarity matrices were calculated using two software programmes i.e. Genstat 5™ release 4.1 (1993) and PAUP (Phylogenetic Analysis Using Parsimony) 4.0 beta version (Swafford, 1998). Cluster analysis was used to generate dendrograms to visualise the genetic relationships of the seven maize genotypes (only minor differences were observed between the Genstat or PAUP method of analysis). Genetic diversity ranged from 0.62 to 0.96. The estimation of genetic relationship was in accordance with the presumed pedigree of the genotypes showing that the RAPD technique demonstrates potential for genome analysis of maize. The applicability of the technique for marker assisted selection was also evaluated. Near-isogenic lines (NILs) for leaf blight (Helminthosporium spp.) were screened for polymorphisms using a total of 120 primers. Ten primers identified polymorphisms between the NILs. Four primers produced five polymorphic fragments present in the resistant inbred K0315Y and absent in the susceptible inbred D0940Y. A small F2 population of 14 individuals was produced by selfing the F1 of a cross between K0315Y and D0940Y. To speed up the generation time, the F1 and F2 plants were cultured by embryo rescue from 18d old harvested seed. One fragment of 627 base pairs produced by primer OPB-01 (5' GTTTCGCTCC 3') showed a 3: 1 segregation in the small F2 population and was considered putatively linked to the HtN gene for leaf blight resistance. This study shows that the RAPD technique does have application in maize breeding programmes. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2000.

Thesis (M.Sc.). / Written for the Institute of Parasitology. Title from title page of PDF (viewed 2008/07/29). Includes bibliographical references.

Thesis (M.Sc.). / Written for the Institute of Parasitology. Title from title page of PDF (viewed 2008/07/29). Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2005. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 Aug 16.

Le FcRn est le récepteur responsable du recyclage des IgG ainsi que de leur transcytose. Ainsi cette protéine a un rôle majeur dans la pharmacocinétique des anticorps thérapeutiques. Nous nous sommes intéressés à différents aspects de l'expression du FcRn. Premièrement nous avons évalué l'influence sur la pharmacocinétique du cétuximab de 2 polymorphismes génétiques influençant l'expression du FcRn. Nous avons montré qu'un Variable Number Tandem Repeat influence la distribution du cétuximab. Nous avons établi que le gène est rarement soumis à des variations de son nombre de copies. Par ailleurs, nous avons montré par une approche de RT-PCR en multiplex l'absence du transcrit FcRn dans les plaquettes humaines. Enfin, l'analyse du niveau de transcrits de FcRn dans un modèle d'activation cellulaire indique qu'il existe une régulation: ce niveau diminue lorsque des monocytes sont différenciés en cellules dendritiques immatures ainsi que lors de l'évolution en cellules dendritiques matures. Les résultats de cette thèse démontrent l'importance de l'étude de l'expression du FcRn dans la variabilité pharmacocinétique des anticorps thérapeutiques. / The FcRn is the receptor responsible for the recycling of IgG and their transcytosis. Thus, this protein has a major role in the pharmacokinetics of therapeutic antibodies. We focused on different aspects of FcRn expression. First, we evaluated the influence on the pharmacokinetics of cetuximab of 2 genetic polymorphisms influencing FcRn expression. We showed that a Variable Number Tandem Repeat influences the distribution of the cetuximab. We determined that the gene is rarely affected by Copy Number Variations. Furthermore, we showed by an RT-PCR approach that the FcRn transcript is absent in human platelets. Finally, the analysis of FcRn transcript level in a model of cellular activation indicates that a regulation occurs : the level decreases when monocytes differenciate into immature dendritic cells as well as during evolution into mature dendritic cells. Results of this thesis demonstrate the importance of the study of FcRn expression in pharmokinetic variability of therapeutic antibodies.

L'infection par le virus de l'hépatite C implique des processus d'interaction complexe entre l'hôte et le virus. Plusieurs facteurs de l'hôte incluant des polymorphismes génétiques et les réponses immunitaires influent sur l'infection et les réponses au traitement. Aussi, il est important d'identifier en amont les facteurs pour prédire la réponse au traitement. L'objectif de la thèse est d'étudier l'influence de certains polymorphismes génétiques de l'hôte sur la réponse à la bithérapie et sur le statut immunitaire du foie dans l'infection chronique par le VHC. L'étude a porté sur les polymorphismes des gènes de l'interféron lambda 3 et 4, l'interféron gamma, l'interleukine 10, et l'interleukine 17, conjointement à la réponse au traitement avec le peg-IFNα et la RBV et aux réponses immunitaires du foie chez les patients. Nous avons établi une méthode PCR-RFLP simple et fiable pour le typage de deux polymorphismes de l'IFNL3. En utilisant les enzymes de restriction BstUI et BrsDI permet le génotypage de deux variantes de IFNL3 (rs12979860 C/T et rs8099917 T/G, respectivement). Les résultats indiquent que cette méthode PCR-RFLP donne des résultats similaires à ceux des méthodes standard et présente un intérêt pour des analyses de routine en laboratoire clinique car elle est peu coûteuse. Nous avons analysé l'association des polymorphismes avec la réponse au traitement antiviral sur une cohorte de 108 patients infectés par le VHC de génotype 1 traités par la bithérapie. Nous avons ainsi démontré que le génotype de l'IFNL4 TT/TT de ss469415590 et une réponse virologique rapide sont des facteurs prédictifs indépendants pour atteindre un taux de réponse virologique soutenue (OR = 3,93, p = 0,004 et OR = 6,74, p = 0,021). D'autre part, une charge virale initiale haute est associée à l'échec au traitement (OR = 0,34, p = 0,023). Ainsi, ces paramètres sont utiles pour la définition d'un traitement personnalisé. Pour expliquer l'influence de ces polymorphismes dans l'infection chronique par le VHC, nous avons étudié l'association des polymorphismes IFNL3 et 4 avec la réponse immunitaire du foie chez les patients atteints d'une infection chronique par le VHC. En utilisant l'expression de CD107a comme marqueur de l'activité sécrétoires des lymphocytes, nous avons observé une activité de dégranulation des lymphocytes du foie plus importante les patients porteurs des génotypes de IFNL4 favorables en comparaison avec les patients porteurs de l'allèle défavorable. En utilisant des analyses de régression, les taux d'ALT sont en corrélation avec la fréquence des cellules NKT CD107a+ dans le foie. Enfin, chez les patients traités par la bithérapie, une forte activité de dégranulation est observée chez les patients avec les génotypes favorables IFNL3 et 4. Nous suggérons que les polymorphismes des gènes de l'interféron lambda sont associés à l'activité de la dégranulation des lymphocytes intra-hépatiques et contribuent à un mécanisme de clairance du VHC sous la bithérapie. Nous avons également étudié l'impact de plusieurs polymorphismes génétiques sur la gravité de l'hépatite C chronique. Les résultats montrent une association significative observée entre le polymorphisme de l'IFN-γ et la gravité de l'hépatite C chronique. Pour l'analyse de régression logistique, l'allèle T et la présence d'une stéatose sont des facteurs prédictifs indépendants de la sévérité de la maladie hépatique chronique associée au VHC. L'utilisation du génotypage de l'IFN-γ pourrait être utile dans la prise en charge des patients. En conclusion, nous avons montré que les polymorphismes des gènes des IFNL3 et 4 et de l'IFN-γ de l'hôte jouent un rôle important dans l'efficacité du traitement et les réponses immunitaires hépatiques. Ces résultats aident à définir un traitement personnalisé pour le contrôle de l'infection chronique par le VHC, en particulier dans les régions aux ressources limitées où les nouveaux traitements ne sont pas accessibles. / Hepatitis C virus (HCV) infection is a complex interaction process between the host and viral factors. The host immune responses and genetic polymorphisms have been shown to be associated with the outcome of HCV infections and the responses to treatments. Thus, it is very important to identify pre-treament factors to predict treatment outcomes. The overall aim of the thesis study is to investigate the role of host genetic polymorphisms on response to combination therapy and immune response in the liver in chronic HCV infection. The study has focused on polymorphisms in the interferon lambda (IFNL) genes, interferon gamma, interleukin 10, and interleukin 17 in relation to response to therapy with peg-IFNα and Ribavirin (RBV) and liver immune responses in patients with chronic HCV infection.First, we have established a simple and reliable method for genotyping of the IFNL3 polymorphisms. We designed primers and selected restriction enzymes BstUI and BrsDI for genotyping 2 variants rs12979860 C/T and rs8099917 T/G, respectively. The results indicate that this PCR-RFLP method yields to identical data than standard sequencing method and commercial kit. We suggest that PCR-RFLP method could be used routinely in conventionally clinical laboratory for genotyping of IFNL3 polymorphisms. Next, we analysed the association of these variants with response in combination therapy of peg-IFNα and RBV. Among 108 treated patients infected with HCV genotype 1, by using logistic regression model analyses, we showed that patients who had favorable IFNL4 genotype (genotype TT/TT of ss469415590) and presented a rapid virological response (RVR) were independent predictors of achieving sustained virological response rate (OR = 3.93, CI = 1.53 -10.08, p = 0.004 and OR = 6.74, CI = 1.33 - 34.06, p= 0.021), whereas patients with high baseline viral load level were associated with failure to treatment (OR = 0.34, CI = 0.13 - 0.87, p = 0.023). We suggest that patients had favorable IFNL4 genotype and achieved RVR should benefit an individualized treatment of combination therapy of peg-IFNα and RBV. To explain the influence of these polymorphisms in chronic HCV infection, we investigated the association of IFNL4 polymorphisms with immune response in the liver in patients with chronic HCV infection. By using marker CD107a, a marker expressing degranulation activity of cytotoxic lymphocytes, we indicated that degranulation process was found in liver lymphocytes in patients carrying favourable IFNL4 genotypes compared with patients with unfavourable genotypes. By using multiple regression analyses, we demonstrated that ALT levels correlate with frequency of CD107a+ NKT cells in the liver. Finally, in patients treated by peg-IFNα and RBV, high degranulation activity observed in patients with favourable genotypes of IFNL3 and IFNL4 (CC of rs12979860 and TT/TT of ss469415590). We suggest that polymorphisms in the interferon lambda genes associated with intrahepatic lymphocyte degranulation activity and contribute to clearance mechanism of HCV under combination treatment of peg-IFNα and RBV.We investigated the impact of several genetic polymorphisms on the severity of chronic hepatitis C. We showed a significant association observed between polymorphism of IFN-γ and the severity of chronic hepatitis C. By using logistic regression analysis, T allele of IFN-γ and the presence of steatosis are independent predictive factors of severity of HCV-1 - related liver disease. This suggests we can use genetic variant of IFN-γ in classification and management of chronic hepatitis C. In conclusion, we indicated that host genetic polymorphisms play critical roles both in responses to treatment and in the immunopathogenesis of chronic HCV infection. This study can help to reach a closer step to individualized medicine for the control of chronic HCV infection in resource-limited regions when new treatment regimens are not available.