MAGE-A protein and MAGE-A10 gene expressions in liver metastasis in patients with stomach cancer

Tumour samples from 71 patients with stomach cancer, 41 patients with liver metastasis (group A) and 15 patients each in stages II–IV (group B) and stage I (group C) without liver metastasis were analysed. MAGE-A protein expression was evaluated by immunohistochemistry using a 6C1 monoclonal antibody and MAGE-A10 mRNA expression was detected by highly sensitive in situ hybridisation using a cRNA probe. Expressions of MAGE-A protein and MAGE-A10 mRNA in group A were detected in 65.9 and 80.5%, respectively. Both protein and gene showed significantly higher expression in group A than those in groups B (6.7, 26.7%) and C (0, 0%) (P=0.0003, P=<0.0001, respectively). MAGE-A10 mRNA expression in liver metastasis was found in eight (88.9%) out of nine patients. The concordant rate between MAGE-A family protein expression and MAGE-A10 mRNA expression in the primary sites was 81.7% (P<0.0001). MAGE-A10 gene expression was associated with reduced survival duration. The results of this study suggest that MAGE-A10 is a possible target in active immunotherapy for advanced stomach cancer

Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training

Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role modulating cardiac function in both health and disease. Here, we determined the effect of chronic CaMKII inhibition during an exercise training program in healthy mice. CaMKII was inhibited by KN-93 injections. Mice were randomized to the following groups: sham sedentary, sham exercise, KN-93 sedentary, and KN-93 exercise. Cardiorespiratory function was evaluated by ergospirometry during treadmill running, echocardiography, and cardiomyocyte fractional shortening and calcium handling. The results revealed that KN-93 alone had no effect on exercise capacity or fractional shortening. In sham animals, exercise training increased maximal oxygen uptake by 8% (p < 0.05) compared to a 22% (p < 0.05) increase after exercise in KN-93 treated mice (group difference p < 0.01). In contrast, in vivo fractional shortening evaluated by echocardiography improved after exercise in sham animals only: from 25 to 32% (p < 0.02). In inactive mice, KN-93 reduced rates of diastolic cardiomyocyte re-lengthening (by 25%, p < 0.05) as well as Ca2+ transient decay (by 16%, p < 0.05), whereas no such effect was observed after exercise training. KN-93 blunted exercise training response on cardiomyocyte fractional shortening (63% sham vs. 18% KN-93; p < 0.01 and p < 0.05, respectively). These effects could not be solely explained by the Ca2+ transient amplitude, as KN-93 reduced it by 20% (p < 0.05) and response to exercise training was equal (64% sham and 47% KN-93; both p < 0.01). We concluded that chronic CaMKII inhibition increased time to 50% re-lengthening which were recovered by exercise training, but paradoxically led to a greater increase in maximal oxygen uptake compared to sham mice. Thus, the effect of chronic CaMKII inhibition is multifaceted and of a complex nature

Myosin binding protein C: implications for signal-transduction

Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure

Role of X11 and ubiquilin as In Vivo Regulators of the Amyloid Precursor Protein in Drosophila

The Amyloid Precursor Protein (APP) undergoes sequential proteolytic cleavages through the action of β- and γ-secretase, which result in the generation of toxic β-amyloid (Aβ) peptides and a C-terminal fragment consisting of the intracellular domain of APP (AICD). Mutations leading to increased APP levels or alterations in APP cleavage cause familial Alzheimer's disease (AD). Thus, identification of factors that regulate APP steady state levels and/or APP cleavage by γ-secretase is likely to provide insight into AD pathogenesis. Here, using transgenic flies that act as reporters for endogenous γ-secretase activity and/or APP levels (GAMAREP), and for the APP intracellular domain (AICDREP), we identified mutations in X11L and ubiquilin (ubqn) as genetic modifiers of APP. Human homologs of both X11L (X11/Mint) and Ubqn (UBQLN1) have been implicated in AD pathogenesis. In contrast to previous reports, we show that overexpression of X11L or human X11 does not alter γ-secretase cleavage of APP or Notch, another γ-secretase substrate. Instead, expression of either X11L or human X11 regulates APP at the level of the AICD, and this activity requires the phosphotyrosine binding (PTB) domain of X11. In contrast, Ubqn regulates the levels of APP: loss of ubqn function leads to a decrease in the steady state levels of APP, while increased ubqn expression results in an increase in APP levels. Ubqn physically binds to APP, an interaction that depends on its ubiquitin-associated (UBA) domain, suggesting that direct physical interactions may underlie Ubqn-dependent regulation of APP. Together, our studies identify X11L and Ubqn as in vivo regulators of APP. Since increased expression of X11 attenuates Aβ production and/or secretion in APP transgenic mice, but does not act on γ-secretase directly, X11 may represent an attractive therapeutic target for AD

Olho vivo: analisando a acuidade visual das crianças e o emprego do lúdico no cuidado de enfermagem

Trata-se de uma pesquisa quantiqualitativa de delineamento transversal, que teve como objetivo detectar precocemente o déficit visual nas crianças em fase escolar e promover a saúde visual por meio de atividades lúdicas. Os resultados mostraram que das 250 crianças que participaram das atividades lúdicas de promoção da saúde ocular, apenas 143 crianças realizaram o teste de acuidade visual; as demais não trouxeram a autorização dos pais. Das crianças submetidas ao teste de acuidade visual, 13 foram encaminhadas ao reteste, e todas estas foram encaminhadas ao serviço de oftalmologia, pois a dificuldade visual permaneceu como resultado do reteste. Referente à aplicação do lúdico, percebemos que tanto a história quanto os personagens do teatro ficaram explícitos nas falas das crianças. Na conclusão, evidenciamos que a visão desempenha papel fundamental no desenvolvimento físico e psicossocial da criança; por isso, a triagem oftalmológica com diagnóstico precoce de alterações visuais é de extrema importância.Se trata de una investigación cuantitativa y cualitativa de carácter transversal que tuvo como objetivo detectar precozmente el déficit visual en niños que se encuentran en fase escolar y promover la salud visual a través de actividades lúdicas. Los resultados demostraron que de los 250 niños que participaron en las actividades lúdicas de promoción de la salud ocular, sólo 143 niños hicieron la prueba de agudeza visual, ya que los demás no habían traído la autorización de sus padres. Del total de niños que hicieron la prueba de agudeza visual trece fueron encaminados a realizar una repetición de la prueba y tras hacerla, los mismos trece fueron remitidos al servicio de oftalmología, ya que la dificultad visual fue confirmada por la contraprueba. En lo referente a la aplicación del juego, percibimos que tanto la historia como los personajes del teatro estaban explícitamente presentes en las historias contadas por los niños. En la conclusión, demostramos que la vista desempeña un papel fundamental en el desarrollo físico y psicosocial del niño, por eso, es extremadamente importante el diagnóstico precoz para la detección oftalmológica de las modificaciones visuales.This is a quantitative and qualitative study of transverse delineation; the purpose is the early detection of visual deficits in school-age children and to promote visual health through playful activities. The results showed that from the 250 children who participated of the eye health promotion fun activities only 143 children took the visual acuity test, since the others had not brought parental authorization. From those who submitted to the visual acuity test, 13 children were sent for retesting; all of them were then sent to the ophthalmology service, since the re-test continued to indicate vision problems. With regards to the use of games and playing, we have noticed that both the story and the characters in the puppet show were explicit in the children's comments. In conclusion, it was observed that vision plays a fundamental role in the physical and psychosocial development of children; therefore, ophthalmologic screening with early diagnosis of visual alterations is of extremely important