Biomarqueurs pronostiques dans le cancer de la prostate : mieux prédire pour mieux traiter

Le cancer de la prostate (CP) est le cancer le plus fréquemment diagnostiqué en Amérique du Nord et est au troisième rang en termes de létalité chez les hommes. Suite aux traitements de première ligne, 20 à 30% des patients diagnostiqués avec un cancer localisé auront une récidive biochimique de la maladie. La déplétion androgénique mène fréquemment au développement du stade de résistance à la castration (RC). Ce dernier est associé avec une augmentation de la morbidité (métastases osseuses) et de la mortalité avec une survie moyenne inférieure à deux ans. L’évolution du CP est très hétérogène dans la population et il n’existe actuellement aucun biomarqueur pronostique permettant d’identifier les patients à risque de récurrence biochimique, de métastases osseuses et de développement d’une résistance à la castration. De nombreuses études ont démontré que les cytokines inflammatoires IL-6 et IL-8 jouent un rôle dans la pathogénèse du CP, notamment dans le développement de la résistance à la castration. Par ailleurs, les niveaux sériques élevés de ces cytokines ont été associés à un mauvais pronostic. Précédemment, notre laboratoire a démontré in vitro que la protéine IKKε entraîne une augmentation de la sécrétion de ces cytokines dans les cellules du CP et qu’elle est exprimée davantage dans les tissus de cancers plus avancés. Le premier objectif du présent mémoire fut d’évaluer dans des tissus humains la corrélation d’IKKε, IL-6 et IL-8 avec des paramètres cliniques. Nos résultats soulignent le potentiel d’IKKε comme biomarqueur tissulaire pronostique de récurrence biochimique et de métastases osseuses. Nous n’avons trouvé aucune association entre IL-6/IL-8 et les paramètres cliniques inclus dans l’étude. Le second objectif de ce projet fut d’évaluer la coexpression de ces trois molécules dans l’épithélium du CP. Nos résultats confirment les observations in vitro en mettant en évidence une forte association entre l’expression d’IKKε, IL-6 et IL-8. Le troisième objectif fut d’évaluer la relation entre les niveaux sériques et tissulaires d’IL-6 et d’IL-8. Aucune relation significative n’a été établie, suggérant que les cytokines sériques ne sont pas uniquement d’origine prostatique. En conclusion, mon projet de maîtrise aura permis de préciser le potentiel d’IKKε comme biomarqueur tissulaire pronostique et de valider pour la première fois dans des tissus humains sa co-expression avec les cytokines IL-6 et IL-8, dont le rôle dans la pathogénèse de la maladie est bien établi. Une étude plus exhaustive des voies de signalisation d’IKKε reste d’intérêt pour élucider notamment les mécanismes par lesquels IKKε stimule la production de cytokines et par quels moyens cette protéine pourrait être impliquée dans le développement d’un état résistant à la castration.

Avaliação da perfusão esplénica em modelo de hemorragia de suíno, após reperfusão com duas soluções fisiológicas distintas

O baço tem importantes funções hematopoiéticas e imunológicas, desempenhando um papel crucial na reposição da hipovolemia e de volume sanguíneo, em situações de hemorragia aguda. A administração de soluções fisiológicas tem grande importância na correção do volume circulante, evitando as complicações de hipovolemia. Este trabalho tem como objetivo avaliar as alterações provocadas no baço, após grave hemorragia dos suínos e reperfusão, utilizando duas soluções fisiológicas distintas, um cristaloide - solução de ringer lactato e um coloide - solução de hidroxietilamido. As lesões histopatológicas encontradas no baço foram congestão, hiperplasia da polpa branca, a notoriedade dos elipsoides e o infiltrado inflamatório, razão pela qual, se procedeu à sua avaliação semi-quantitativa. Relativamente à hiperplasia da polpa branca, foram encontradas diferenças estatisticamente significativas entre o grupo Ringer Lactato e o grupo Hidroxietilamido, verificando-se o aumento da hiperplasia da polpa branca no grupo Ringer Lactato. Quanto à área dos elipsoides, apenas um suíno em cada grupo registava grau 1. Houve uma preponderância do grau 2 no grupo de controlo (n = 5) e no grupo Ringer Lactato (n = 11), enquanto que no grupo Hidroxietilamido se registaram valores idênticos para os graus 2 e 3 (n = 5). A congestão ocorreu em todos os grupos, com predomínio do grau 2 (n = 7) nos grupos Ringer Lactato e Hidroxietilmido. Relativamente ao infiltrado inflamatório, no grupo de controlo predominou o grau 1 (n = 5) e registou-se a prevalência do grau 2 no grupo Ringer Lactato (n = 8) e no grupo Hidroxietilamido (n = 9). A área dos elipsoides variou nos diferentes grupos, não tendo revelado diferenças significativas entre os grupos. Foi observada congestão nos três grupos do estudo, não tendo sido, contudo, registadas diferenças significativas entre os grupos. Quanto ao infiltrado inflamatório, verificou-se que no grupo de controlo predominou o grau 1, enquanto que nos grupos Ringer Lactato e Hidroxietilamido prevaleceu o grau 2, o que se justifica pelo facto dos grupos Ringer Lactato e Hidroxietilamido terem sido submetidos a uma hemorragia. Foi assim possível concluir que a reperfusão volémica com Hidroxietilamido 130/0.4 pode reduzir a hiperreatividade esplénica, quando comparado com o Ringer Lactato, após hemorragia aguda. Verificamos que os elipsoides não sofrem qualquer afetação em situações de alterações hemodinâmicos. Atualizamos um sistema de classificação para avaliação de congestão esplénica, usando o modelo suíno. Aferimos que as situações causadoras de alterações hemodinâmicas ou da perfusão tecidual provocam aumento do infiltrado inflamatório.

Recent insights into the mucosal reactions associated with Giardia lamblia infections.

Giardia lamblia is an intestinal protozoan parasite infecting humans and various other mammalian hosts. The most important clinical signs of giardiasis are diarrhoea and malabsorption. Giardia lamblia is able to undergo continuous antigenic variation of its major surface antigen, named VSP (variant surface protein). While intestinal antibodies, and more specifically anti-VSP IgA antibodies, were proven to be involved in modulating antigenic variation of the parasite the participation of the local antibody response in control of the parasite infection is still controversial. Conversely, previous studies based on experimental infections in mice showed that cellular immune mechanisms are essential for elimination of the parasite from its intestinal habitat. Furthermore, recent data indicated that inflammatory mast cells have a potential to directly, or indirectly, interfere in duodenal growth of G. lamblia trophozoites. However, this finding was challenged by other reports, which did not find a correlation between intestinal inflammation and resistance to infection. Since intestinal infiltration of inflammatory cells and/or CD8+T-cells were demonstrated to coincide with villus-shortening and crypt hyperplasia immunological reactions were considered to be a potential factor of pathogenesis in giardiasis. The contribution of physiological factors to pathogenesis was essentially assessed in vitro by co-cultivation of G. lamblia trophozoites with epithelial cell lines. By using this in vitro model, molecular (through surface lectins) and mechanical (through ventral disk) adhesion of trophozoites to the epithelium was shown to be crucial for increased epithelial permeability. This phenomenon as well as other Giardia-induced intestinal abnormalities such as loss of intestinal brush border surface area, villus flattening, inhibition of disaccharidase activities, and eventually also overgrowth of the enteric bacterial flora seem to be involved in the pathophysiology of giardiasis. However, it remains to be elucidated whether at least part of these pathological effects are causatively linked to the clinical manifestation of the disease.

Assessment of foot health and animal welfare: clinical findings in 229 dairy Mediterranean Buffaloes (Bubalus bubalis) affected by foot disorders.

BACKGROUND Lameness represents the third most important health-related cause of economic loss in the dairy industry after fertility and mastitis. Although, dairy Mediterranean Buffaloes (MB) and dairy cows share similar breeding systems predisposing to similar herd problems, published studies exploring its relevance and role in these ruminants are still rare and incomplete. The aims of this study were to describe the clinical findings of foot disorders (FDs) in dairy MB and their influence on animal welfare, determined by assessment of locomotion score (LS), body condition score (BCS) and cleanliness score (CS). RESULTS Of 1297 multiparous MB submitted to routine trimming procedures, 229 buffaloes showed at least one FD. The prevalence of buffaloes affected by FDs was 17.7 %, while motility and lameness indexes were 84.1 % (1091/1297) and 15.9 % (206/1297), respectively. Overgrowth was present in 17.0 % (220/1297), corkscrew claw in 15.8 % (205/1297), interdigital phlegmon in 0.9 % (12/1297), white line abscess in 0.8 % (11/1297), digital dermatitis in 0.1 % (1/1297) and interdigital hyperplasia in 0.1 % (1/1297). Simultaneous presence of FDs was recorded in 17.0 % of MB (221/1297): overgrowth and corkscrew claw occurred together in 15.8 % of cases (205/1297), overgrowth and interdigital phlegmon in 0.3 % (4/1297), overgrowth and white line abscess in 0.8 % (11/1297), digital dermatitis and interdigital hyperplasia in 0.1 % (1/1297). The presence of FDs was always associated with lameness (LS > 2), except from 23 MB with simultaneous overgrowth and interdigital phlegmon occurrence. The majority of MB within the under-conditioned group (95.5 %, 43/45) and all those with CS > 2 (122/122) had a locomotion score above the threshold of normality (LS > 2). Furthermore, foot diseases such as interdigital hyperplasia, white line abscess and digital dermatitis or interdigital hyperplasia seemed to occur more frequently associated with decreased BCS and increased CS scores. CONCLUSIONS This study describes for the first time the involvement of white line disease, interdigital phlegmona, digital dermatitis and interdigital hyperplasia in foot disorders of dairy Mediterranean buffalo and shows their association with an impairment of animal welfare.

Histological analysis of gallbladder diseases in relation to opisthorchiasis in endemic areas of Thailand

Chronic gallbladder disease frequently accompanies infection with the liver fluke, Opisthorchis viverrini, in Northeast Thailand. However, the pathology and pathogenesis of the gallbladder disease have not been described. Accordingly, gallbladder specimens from 187 consecutive patients who had undergone cholecystectomy at a referral hospital in an endemic area in Thailand were histologically characterized in relation to O. viverrini infection. The infection was assessed by the presence of parasite eggs in the bile and/or antibody response to the liver fluke. The average level of parasite-specific IgG was significantly higher in patients with Opisthorchis eggs in the bile than those without (P < 0.001). The main histopathologic features of the gallbladder included inflammation, mucosal atrophy/or hyperplasia, goblet cell metaplasia, mucous gland hyperplasia, Rokitansky-Aschoff sinus formation, dysplasia and fibrosis. The fibrosis was strongly associated with elevated levels of Opisthorchis-specific antibody (P < 0.001) but not with the presence of parasite eggs. Other pathologic features did not vary in frequency or severity with parasitological status. Our results show that severe fibrosis of the gallbladder is a more common histologic feature of cholecystitis among those with O. viverrini infection compared to those without infection. The close relationship between parasite-specific IgG and severe fibrosis suggests that specific immune response to the parasite play an important role in the pathogenesis of the fibrotic change. (C) 2003 Elsevier B.V. All rights reserved.

Conditional inactivation of the Men1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues

Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause beta-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.

Emerging roles of urotensin-II in cardiovascular disease

Urotensin-II (UII) is a highly potent endogenous peptide within the cardiovascular system. Through stimulation of Galphaq-coupled UT receptors, UII mediates contraction of vascular smooth muscle and endothelial-dependent vasorelaxation, and positive inotropy in human right atrium and ventricle. A pathogenic role of the UT receptor system is emerging in cardiovascular disease states, with evidence for upregulation of the UT receptor system in patients with congestive heart failure (CHF), pulmonary hypertension, cirrhosis and portal hypertension, and chronic renal failure. In vitro and in vivo studies show that under pathophysiological conditions, UII might contribute to cardiomyocyte hypertrophy, extracellular matrix production, enhanced vasoconstriction, vascular smooth muscle cell hyperplasia, and endothelial cell hyper-permeability. Single nucleotide polymorphisms of the UII gene may also impart a genetic predisposition of patients to diabetes. Therefore, the UT receptor system is a potential therapeutic target in the treatment of cardiac, pulmonary, and renal diseases. UT receptor antagonists are currently being developed to prevent and/or reverse the effects of over-activated UT receptors by the endogenous ligand. This review describes UII peptide and converting enzymes, and UT receptors in the cardiovascular system, focusing on pathophysiological roles of UII in the heart and blood vessels. (C) 2004 Elsevier Inc. All rights reserved,