Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

The role of EphB6 and ephrinbs in blood pressure regulation

L’hypertension artérielle est le facteur de risque le plus important dans les maladies cardiovasculaires (MCV) et les accidents vasculaires cérébraux (AVC). L’hypertension artérielle essentielle est une maladie complexe, multifactorielle et polygénique. Même si on a identifié de nombreux facteurs de risque de l’hypertension artérielle, on ne comprend pas encore clairement les mécanismes qui la régissent. Les kinases hépatocytes produisant l’érythropoïétine (Eph) constituent la plus grande famille des récepteurs tyrosine kinase qui se lient à des ligands de surface cellulaire appelés éphrines sur les cellules avoisinantes. On sait que les interactions de Eph et des éphrines sont essentielles aussi bien dans les processus de développement que dans le fonctionnement des organes et des tissus adultes. Cependant on n’a pas encore étudié la relation entre Eph/éphrines et l’hypertension artérielle. Nous avons créé des modèles de souris knockout (K.O.) Ephb6-/-, Efnb1-/- et Efnb3-/- pour cette étude. Dans le modèle EphB6-/-, nous avons observé que les souris K.O. Ephb6 castrées, mais pas les femelles, ainsi que les souris mâles non castrées présentaient une tension artérielle élevée (TA) par rapport à leurs homologues de type sauvage (TS). Ceci suggère que Ephb6 doit agir de concert avec l’hormone sexuelle mâle pour réguler la TA. Les petites artères des mâles castrés Ephb6-/- présentaient une augmentation de la contractilité, une activation de RhoA et une phosphorylation constitutive de la chaîne légère de la myosine (CLM) lorsque comparées à celles de leurs homologues TS. Ces deux derniers résultats indiquent que la phosphorylation de CLM et de RhoA passe par la voie de signalisation de Ephb6 dans les cellules du muscle lisse de la paroi vasculaire (CMLV). Nous avons démontré que la réticulation de Efnbs mais non celle de Ephb6 aboutit à une réduction de la contractilité des CMLV. Ceci montre que l’effet de Ephb6 passe par la signalisation inversée à travers Efnb. Dans le modèle Efnb1-/- conditionnel spécifique au muscle lisse, nous n’avons observé aucune différence entre Efnb1-/- et les souris de TS concernant la mesure de la TA dans des conditions normales. Cependant, la TA des souris K.O. Efnb1 lors d’un stress d’immobilisation est supérieure à celle des souris de TS. Dans les petites artères des souris K.O. Efnb1, le rétrécissement et la phosphorylation de CLM étaient élevés. In vitro, la contractilité et l’activation RhoA de la CMLV des souris TS étaient augmentées quand leur Efnb1 était réticulé. Ces résultats corroborent ceux des souris KO Ephb6 et prouvent que l’effet de Ephb6 dans le contrôle de la TA se produit au moins par l’intermédiaire d’un de ses ligands Efnb1 dans les CMLV. Dans le modèle Efnb3-/-, on a observé une augmentation de la TA et du rétrécissement des vaisseaux chez les femelles Efnb3-/-, mais non chez les mâles; l’échographie a aussi révélé une résistance accrue au débit sanguin des souris K.O. femelles. Cependant la mutation de Efnb3 ne modifie pas la phosphorylation de la CLM ou l’activation de RhoA in vivo. Dans l’expérience in vitro, les CMLV des souris femelles Efnb3-/- ont présenté une augmentation de la contractilité mais pas celle des souris mâles Efnb3-/-. La réticulation des CMLV chez les mâles ou les femelles de TS avec solide anti-Efnb3 Ab peut réduire leur contractilité. Notre étude est la première à évaluer le rôle de Eph/éphrines dans la régulation de la TA. Elle montre que les signalisations Eph/éphrines sont impliquées dans le contrôle de la TA. La signalisation inverse est principalement responsable du phénotype élevé de la TA. Bien que les Efnb1, Efnb3 appartiennent à la même famille, leur fonction et leur efficacité dans la régulation de la TA pourraient être différentes. La découverte de Eph/Efnb nous permet d’explorer plus avant les mécanismes qui gouvernent la TA.

Lymphatic vessel function in atherosclerosis

L'athérosclérose est une maladie inflammatoire chronique caractérisée par l'accumulation de cholestérol dans la paroi artérielle et associée à une réponse immunitaire anormale dans laquelle les macrophages jouent un rôle important. Récemment, il a été démontré que les vaisseaux lymphatiques jouent un rôle primordial dans le transport inverse du cholestérol (Martel et al. JCI 2013). L’objectif global de mon stage de maîtrise a été de mieux caractériser la dysfonction lymphatique associée à l’athérosclérose, en étudiant de plus près l’origine physiologique et temporelle de ce mauvais fonctionnement. Notre approche a été d’étudier, depuis l’initiation de l’athérosclérose jusqu’à la progression d’une lésion athérosclérotique tardive, la physiologie des deux constituants principaux qui forment les vaisseaux lymphatiques : les capillaires et collecteurs lymphatiques. En utilisant comme modèle principal des souris Ldlr-/-; hApoB100+/+, nous avons pu démontrer que la dysfonction lymphatique est présente avant même l’apparition de l’athérosclérose, et que cette dysfonction est principalement associée avec un défaut au niveau des vaisseaux collecteurs, limitant ainsi le transport de la lymphe des tissus périphériques vers le sang. De plus, nous avons démontré pour la première fois l’expression du récepteur au LDL par les cellules endothéliales lymphatiques. Nos travaux subséquents démontrent que ce défaut de propulsion de la lymphe pourrait être attribuable à l’absence du récepteur au LDL, et que la dysfonction lymphatique observée précocement dans l’athérosclérose peut être limitée par des injections systémiques de VEGF (vascular endothelial growth factor) –C. Ces résultats suggèrent que la caractérisation fonctionnelle de la capacité de pompage des vaisseaux collecteurs serait une condition préalable à la compréhension de l'interaction entre la fonction du système lymphatique et la progression de l'athérosclérose. Ultimement, nos travaux nous ont amené à considérer de nouvelles cibles thérapeutiques potentielles dans la prévention et le traitement de l’athérosclérose.

A "Trojan horse" strategy to reverse drug-resistance in brain tumors

Los gliomas malignos representan una de las formas más agresivas de los tumores del sistema nervioso central (SNC). De acuerdo con la clasificación de los tumores cerebrales de la Organización Mundial de la Salud (OMS), los astrocitomas han sido categorizados en cuatro grados, determinados por la patología subyacente. Es así como los gliomas malignos (o de alto grado) incluyen el glioma anaplásico (grado III) así como el glioblastoma multiforme (GBM, grado IV),estos últimos los más agresivos con el peor pronóstico (1). El manejo terapéutico de los tumores del SNC se basa en la cirugía, la radioterapia y la quimioterapia, dependiendo de las características del tumor, el estadio clínico y la edad (2),(3), sin embargo ninguno de los tratamientos estándar es completamente seguro y compatible con una calidad de vida aceptable (3), (4). En general, la quimioterapia es la primera opción en los tumores diseminados, como el glioblastoma invasivo y el meduloblastoma de alto riesgo o con metástasis múltiple, pero el pronóstico en estos pacientes es muy pobre (2),(3). Solamente nuevas terapias dirigidas (2) como las terapias anti-angiogénicas (4); o terapias génicas muestran un beneficio real en grupos limitados de pacientes con defectos moleculares específicos conocidos (4). De este modo, se hace necesario el desarrollo de nuevas terapias farmacológicas para atacar los tumores cerebrales. Frente a las terapias los gliomas malignos son con frecuencia quimioresistentes, y esta resistencia parece depender de al menos dos mecanismos: en primer lugar, la pobre penetración de muchas drogas anticáncer a través de la barrera hematoencefálica (BBB: Blood Brain Barrier), la barrera del fluido sangre-cerebroespinal (BCSFB: Blood-cerebrospinal fluid barrier) y la barrera sangre-tumor (BTB: blood-tumor barrier). Dicha resistencia se debe a la interacción de la droga con varios transportadores o bombas de eflujo de droga ABC (ABC: ATP-binding cassette) que se sobre expresan en las células endoteliales o epiteliales de estas barreras. En segundo lugar, estos transportadores de eflujo de drogas ABC propios de las células tumorales confieren un fenotipo conocido como resistencia a multidrogas (MDR: multidrug resistance), el cual es característico de varios tumores sólidos. Este fenotipo también está presente en los tumores del SNC y su papel en gliomas es objeto de investigación (5). Por consiguiente el suministro de medicamentos a través de la BBB es uno de los problemas vitales en los tratamientos de terapia dirigida. Estudios recientes han demostrado que algunas moléculas pequeñas utilizadas en estas terapias son sustratos de la glicoproteína P (Pgp: P-gycoprotein), así como también de otras bombas de eflujo como las proteínas relacionadas con la resistencia a multidrogas (MRPs: multidrug resistance-related proteins (MRPs) o la proteína relacionada con cáncer de seno (BCRP: breast-cancer resistance related protein)) que no permiten que las drogas de este tipo alcancen el tumor (1). Un sustrato de Pgp y BCRP es la DOXOrubicina (DOXO), un fármaco utilizado en la terapia anti cáncer, el cual es muy eficaz para atacar las células del tumor cerebral in vitro, pero con un uso clínico limitado por la poca entrega a través de la barrera hematoencefálica (BBB) y por la resistencia propia de los tumores. Por otra parte las células de BBB y las células del tumor cerebral tienen también proteínas superficiales, como el receptor de la lipoproteína de baja densidad (LDLR), que podría utilizarse como blanco terapéutico en BBB y tumores cerebrales. Es asi como la importancia de este estudio se basa en la generación de estrategias terapéuticas que promuevan el paso de las drogas a través de la barrera hematoencefalica y tumoral, y a su vez, se reconozcan mecanismos celulares que induzcan el incremento en la expresión de los transportadores ABC, de manera que puedan ser utilizados como blancos terapéuticos.Este estudio demostró que el uso de una nueva estrategia basada en el “Caballo de Troya”, donde se combina la droga DOXOrubicina, la cual es introducida dentro de un liposoma, salvaguarda la droga de manera que se evita su reconocimiento por parte de los transportadores ABC tanto de la BBB como de las células del tumor. La construcción del liposoma permitió utilizar el receptor LDLR de las células asegurando la entrada a través de la BBB y hacia las células tumorales a través de un proceso de endocitosis. Este mecanismo fue asociado al uso de estatinas o drogas anticolesterol las cuales favorecieron la expresión de LDLR y disminuyeron la actividad de los transportadores ABC por nitración de los mismos, incrementando la eficiencia de nuestro Caballo de Troya. Por consiguiente demostramos que el uso de una nueva estrategia o formulación denominada ApolipoDOXO más el uso de estatinas favorece la administración de fármacos a través de la BBB, venciendo la resistencia del tumor y reduciendo los efectos colaterales dosis dependiente de la DOXOrubicina. Además esta estrategia del "Caballo de Troya", es un nuevo enfoque terapéutico que puede ser considerado como una nueva estrategia para aumentar la eficacia de diferentes fármacos en varios tumores cerebrales y garantiza una alta eficiencia incluso en un medio hipóxico,característico de las células cancerosas, donde la expresión del transportador Pgp se vió aumentada. Teniendo en cuenta la relación entre algunas vías de señalización reconocidas como moduladores de la actividad de Pgp, este estudio presenta no solo la estrategia del Caballo de Troya, sino también otra propuesta terapéutica relacionada con el uso de Temozolomide más DOXOrubicina. Esta estrategia demostró que el temozolomide logra penetrar la BBB por que interviene en la via de señalización de la Wnt/GSK3/β-catenina, la cual modula la expresión del transportador Pgp. Se demostró que el TMZ disminuye la proteína y el mRNA de Wnt3 permitiendo plantear la hipótesis de que la droga al disminuir la transcripción del gen Wnt3 en células de BBB, incrementa la activación de la vía fosforilando la β-catenina y conduciendo a disminuir la β-catenina nuclear y por tanto su unión al promotor del gen mdr1. Con base en los resultados este estudio permitió el reconocimiento de tres mecanismos básicos relacionados con la expresión de los transportadores ABC y asociados a las estrategias empleadas: el primero fue el uso de las estatinas, el cual condujo a la nitración de los transportadores disminuyendo su actividad por la via del factor de transcripción NFκB; el segundo a partir del uso del temozolomide, el cual metila el gen de Wnt3 reduciendo la actividad de la via de señalización de la la β-catenina, disminuyendo la expresión del transportador Pgp. El tercero consistió en la determinación de la relación entre el eje RhoA/RhoA quinasa como un modulador de la via (no canónica) GSK3/β-catenina. Se demostró que la proteína quinasa RhoA promovió la activación de la proteína PTB1, la cual al fosforilar a GSK3 indujo la fosforilación de la β-catenina, lo cual dio lugar a su destrucción por el proteosoma, evitando su unión al promotor del gen mdr1 y por tanto reduciendo su expresión. En conclusión las estrategias propuestas en este trabajo incrementaron la citotoxicidad de las células tumorales al aumentar la permeabilidad no solo de la barrera hematoencefálica, sino también de la propia barrera tumoral. Igualmente, la estrategia del “Caballo de Troya” podría ser útil para la terapia de otras enfermedades asociadas al sistema nervioso central. Por otra parte estos estudios indican que el reconocimiento de mecanismos asociados a la expresión de los transportadores ABC podría constituir una herramienta clave en el desarrollo de nuevas terapias anticáncer.

The impact of the catechol-O-methyltransferase genotype on vascular function and blood pressure after acute green tea ingestion

SCOPE: Evidence for the benefits of green tea catechins on vascular function is inconsistent, with genotype potentially contributing to the heterogeneity in response. Here, the impact of the catechol-O-methyltransferase (COMT) genotype on vascular function and blood pressure (BP) after green tea extract ingestion are reported. METHODS AND RESULTS: Fifty subjects (n = 25 of the proposed low-activity [AA] and of the high-activity [GG] COMT rs4680 genotype), completed a randomized, double-blind, crossover study. Peripheral arterial tonometry, digital volume pulse (DVP), and BP were assessed at baseline and 90 min after 1.06 g of green tea extract or placebo. A 5.5 h and subsequent 18.5 h urine collection was performed to assess green tea catechin excretion. A genotype × treatment interaction was observed for DVP reflection index (p = 0.014), with green tea extract in the AA COMT group attenuating the increase observed with placebo. A tendency for a greater increase in diastolic BP was evident at 90 min after the green tea extract compared to placebo (p = 0.07). A genotypic effect was observed for urinary methylated epigallocatechin during the first 5.5 h, with the GG COMT group demonstrating a greater concentration (p = 0.049). CONCLUSION: Differences in small vessel tone according to COMT genotype were evident after acute green tea extract.

A time-invariant visco-elastic windkessel model relating blood flow and blood volume

The difference between the rate of change of cerebral blood volume (CBV) and cerebral blood flow (CBF) following stimulation is thought to be due to circumferential stress relaxation in veins (Mandeville, J.B., Marota, J.J.A., Ayata, C., Zaharchuk, G., Moskowitz, M.A., Rosen, B.R., Weisskoff, R.M., 1999. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J. Cereb. Blood Flow Metab. 19, 679–689). In this paper we explore the visco-elastic properties of blood vessels, and present a dynamic model relating changes in CBF to changes in CBV. We refer to this model as the visco-elastic windkessel (VW) model. A novel feature of this model is that the parameter characterising the pressure–volume relationship of blood vessels is treated as a state variable dependent on the rate of change of CBV, producing hysteresis in the pressure–volume space during vessel dilation and contraction. The VW model is nonlinear time-invariant, and is able to predict the observed differences between the time series of CBV and that of CBF measurements following changes in neural activity. Like the windkessel model derived by Mandeville, J.B., Marota, J.J.A., Ayata, C., Zaharchuk, G., Moskowitz, M.A., Rosen, B.R., Weisskoff, R.M., 1999. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J. Cereb. Blood Flow Metab. 19, 679–689, the VW model is primarily a model of haemodynamic changes in the venous compartment. The VW model is demonstrated to have the following characteristics typical of visco-elastic materials: (1) hysteresis, (2) creep, and (3) stress relaxation, hence it provides a unified model of the visco-elastic properties of the vasculature. The model will not only contribute to the interpretation of the Blood Oxygen Level Dependent (BOLD) signals from functional Magnetic Resonance Imaging (fMRI) experiments, but also find applications in the study and modelling of the brain vasculature and the haemodynamics of circulatory and cardiovascular systems.

Fractal structures in stenoses and aneurysms in blood vessels

Recent advances in the field of chaotic advection provide the impetus to revisit the dynamics of particles transported by blood flow in the presence of vessel wall irregularities. The irregularity, being either a narrowing or expansion of the vessel, mimicking stenoses or aneurysms, generates abnormal flow patterns that lead to a peculiar filamentary distribution of advected particles, which, in the blood, would include platelets. Using a simple model, we show how the filamentary distribution depends on the size of the vessel wall irregularity, and how it varies under resting or exercise conditions. The particles transported by blood flow that spend a long time around a disturbance either stick to the vessel wall or reside on fractal filaments. We show that the faster flow associated with exercise creates widespread filaments where particles can get trapped for a longer time, thus allowing for the possible activation of such particles. We argue, based on previous results in the field of active processes in flows, that the non-trivial long-time distribution of transported particles has the potential to have major effects on biochemical processes occurring in blood flow, including the activation and deposition of platelets. One aspect of the generality of our approach is that it also applies to other relevant biological processes, an example being the coexistence of plankton species investigated previously.

Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model

Background: The expression levels of the clotting initiator protein Tissue Factor (TF) correlate with vessel density and the histological malignancy grade of glioma patients. Increased procoagulant tonus in high grade tumors (glioblastomas) also indicates a potential role for TF in progression of this disease, and suggests that anticoagulants could be used as adjuvants for its treatment. Objectives: We hypothesized that blocking of TF activity with the tick anticoagulant Ixolaris might interfere with glioblastoma progression. Methods and results: TF was identified in U87-MG cells by flow-cytometric and functional assays (extrinsic tenase). In addition, flow-cytometric analysis demonstrated the exposure of phosphatidylserine in the surface of U87-MG cells, which supported the assembly of intrinsic tenase (FIXa/FVIIIa/FX) and prothrombinase (FVa/FXa/prothrombin) complexes, accounting for the production of FXa and thrombin, respectively. Ixolaris effectively blocked the in vitro TF-dependent procoagulant activity of the U87-MG human glioblastoma cell line and attenuated multimolecular coagulation complexes assembly. Notably, Ixolaris inhibited the in vivo tumorigenic potential of U87-MG cells in nude mice, without observable bleeding. This inhibitory effect of Ixolaris on tumor growth was associated with downregulation of VEGF and reduced tumor vascularization. Conclusion: Our results suggest that Ixolaris might be a promising agent for anti-tumor therapy in humans.

Effects of ginger (Zingiber officinale Roscoe) on DNA damage and development of urothelial tumors in a mouse bladder carcinogenesis model

Extracts of the spice ginger (Zingiber officinale Roscoe) are rich in gingerols and shogaols, which exhibit antioxidant, anti-inflammatory, antifungal, anti mycobacterial, and anticarcinogenic proprieties. The present study evaluated the chemoprotective effects of a ginger extract on the DNA damage and the development of bladder cancer induced by N-butyl-N-(4-hydroxibutyl) nitrosamine (BBN)/N-methyl-N-nitrosourea (MNU) in male Swiss mice. Groups G1-G3 were given 0.05% BBN in drinking water for 18 weeks and four i.p. injections of 30 mg/kg body weight MNU at 1, 3, 10, and 18 weeks. Group G4 and G5 received only the BBN or MNU treatments, respectively, and groups G6 and G7 were not treated with BBN or MNU. Additionally, Groups G2, G3, and G6 were fed diets containing 1, 2, and 2% ginger extract, respectively, while Groups G1, G4, G5, and G7 were fed basal diet. Samples of peripheral blood were collected during the experiment for genotoxicity analysis; blood collected 4 hr after each MNU dose was used for the analysis of DNA damage with the Comet assay (assay performed on leukocytes from all groups), while reficulocytes collected 24 hr after the last MNU treatment of Groups G5-G7 were used for the micronucleus assay. At the end of the experiment, the urinary bladder was removed, fixed, and prepared for histopathological, cell proliferation, and apoptosis evaluations. Ginger by itself was not genotoxic, and it did not alter the DNA damage levels induced by the BBN/MNU treatment during the course of the exposure. The incidence and multiplicity of simple and nodular hyperplasia and transitional cell carcinoma (TCC) were increased by the BBN/MNU treatment, but dietary ginger had no significant effect on these responses. However, in Group G2 (BBN/MNU/2% ginger-treated group), there was an increased incidence of Grade 2 TCC. The results suggest that ginger extract does not inhibit the development of BBN-induced mouse bladder tumors.

About the arterial blood vessels pelvic opossum's (Didelphis albiventris) behaviour

The work consists of the study of 20 opossums (Didelphis albiventris); 7 females and 13 males, adults, natives of Jaboticabal county proceeding to a canulation and injection of the arterial system with neoprene latex-650 in the aorta artery (full-blooded). Right away the preparations were fixed by a 10% formaldehyde aqueous solution and afterwards dissected and formed a scheme. The analysis of the pieces showed that in the opossum, the end of the aorta always divides in the common iliac artery, right and left sides, both originating the external and internal iliac artery, on the right and left sides. The medium sacral artery results, medianly, from the aorta division's angle in 2 common iliac arteries in 8 cases (40% - 6 males and 2 females); this vessel comes from the left common iliac artery in 7 animals (35% - 5 males and 2 females) or comes from the right common iliac artery, in 5 preparations (25% - 3 females and 2 males). The deep iliac circumflex artery is born by the common iliac artery from the right side in 10 preparations (50% - 6 males and 4 females), can appear as well, concomitantly with the external and internal iliac artery, from the right side in 9 pieces (45% - 6 males and 3 females) and further from the right this vessels can emerge from the external iliac artery, in 1 case only (5% - 1 male).

Immunological alterations in patients with primary tumors in central nervous system

Natural killer (NK) cells play an important role in immune surveillance against tumors. The present work aimed to study the cytotoxic activity of NK cells and T cell subsets in peripheral blood of 13 patients with primary tumors in central nervous system (CNS). As controls 29 healthy subjects with the age range equivalent to the patients were studied. The methods employed were: a) determination of cytotoxic activity of NK cells towards K562 target cells, evaluated by single cell-assay; b) enumeration of CD3+ lymphocytes and their CD4+ and CD8+ subsets defined by monoclonal antibodies; c) the identification of tumors were done by histologic and immunochemistry studies. The results indicated that adults and children with tumor in CNS display reduced percentage of total T cells, helper/inducer subset and low helper/suppressor ratio. The cytotoxic activity of NK cells was decreased in patients with CNS tumors due mainly to a decrease in the proportion of target-binding lymphocytes. These results suggest that cytotoxic activity of NK cells may be affected by the immunoregulatory disturbances observed in patients with primary tumors in CNS.

Cellular localization of androgen synthesis in equine granulosa-theca cell tumors: Immunohistochemical expression of 17α-hydroxylase/17,20-lyase cytochrome P450

Elevated blood testosterone concentrations, often accompanied by male-typical behaviors, is a common signalment of mares with granulosa-theca cell tumors (GCTCs), but no definitive information exists regarding the cellular differentiation of tumors associated with androgen secretion. This study was conducted to localize and thereby define the cellular expression of 17α-hydroxylase/17,20-lyase cytochrome P450 (P450c17), the enzyme most directly responsible for androgen synthesis, in 30 GTCTs and control tissues (gonads and adrenal glands) using immuno-histochemistry (IHC). Immuno-reactivity for P450c17 was evident in approximately half of 30 specimens examined, was most consistent in the interstitial cells surrounding existing or developing cysts, and was less intense in cells within cysts in the smaller proportion of specimens where this was observed. In control tissues, the expression of P450c17 was localized primarily in theca interna of normal ovarian follicles, in theca-lutein cells of some corpora lutea, but not in granulosa-lutein cells. Testicular interstitial cells and islands of adreno-cortical cells located in the adrenal medulla of the adrenal cortex further established the specificity of the antisera used. These data provided the first substantive evidence that polyhedral cells identified previously in GTCTs by histopathology have the potential to synthesize and secrete androgens, similar to theca interna and theca lutein cells in normal equine ovaries. © 2010 Elsevier Inc.

Genetic and modifying factors that determine the risk of brain tumors

Some modifying factors may determine the risk of brain tumors. Until now, it could not be attempted to identify people at risk and also to improve significantly disease progression. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. Despite of these treatments, the prognosis for patients is poor. In this review, we highlight general aspects concerning genetic alterations in brain tumors, namely astrocytomas, glioblastomas, oligodendrogliomas, medulloblastomas and ependymomas. The influence of these genetic alterations in patients' prognosis is discussed. Mutagen sensivity is associated with cancer risk. The convincing studies that linked DNA damages and DNA repair alterations with brain tumors are also described. Another important modifying factor is immunity. General immune response against cancer, tumor microenvironment and immune response, mechanisms of tumor escape, CNS tumor immunology, immune defects that impair anti-tumor systemic immunity in brain tumor patients and local immunosuppressive factors within CNS are also reviewed. New hope to treatment perspectives, as dendritic-cell-based vaccines is summarized too. Concluding, it seems well established that there is association between brain tumor risk and mutagen sensivity, which is highly heritable. Primary brain tumors cause depression in systemic host immunity; local immunosuppressive factors and immunological characteristics of tumor cells may explain the poor prognosis and DNA damages responses can alert immune system. However, it is necessary to clarify if individuals with both constitutional defects in immune functions and genetic instability have higher risk of developing brain tumors. Cytogenetic prospective studies and gene copy number variations analysis also must be performed in peripheral lymphocytes from brain tumor patients. © 2011 Bentham Science Publishers Ltd.

Genomic screening of testicular germ cell tumors from monozygotic twins

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)