Additive Cytotoxic and Colony-Formation Inhibitory Effects of Aspirin and Metformin on PI3KCA-Mutant Colorectal Cancer Cells.

Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer drug development, limited success has been obtained and the average number of FDA approvals per year is declining. So, an increasing interest in drug repurposing exists. Metformin (MET) and aspirin (ASP) possess anticancer properties. This work aims to test the effect of these two drugs in combination on colorectal cancer (CRC) cells in vitro. The effects of MET and/or ASP on cell proliferation, viability, migratory ability, anchorage-independent growth ability (colony formation), and nutrient uptake were determined in two (HT-29 and Caco-2) human CRC cell lines. Individually, MET and ASP possessed antiproliferative, cytotoxic, and antimigratory effects and reduced colony formation in HT-29 cells (BRAF- and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PI3KCA)-mutant), although MET did not affect either 3H-deoxy-D-glucose or 14C-butyrate uptake and lactate production, and ASP caused only a small decrease in 14C-butyrate uptake. Moreover, in these cells, the combination of MET and ASP resulted in a tendency to an increase in the cytotoxic effect and in a potentiation of the inhibitory effect on colony formation, although no additive antiproliferative and antimigratory effects, and no effect on nutrient uptake and lactate production were observed. In contrast, MET and ASP, both individually and in combination, were almost devoid of effects on Caco-2 cells (BRAF- and PI3KCA-wild type). We suggest that inhibition of PI3K is the common mechanism involved in the anti-CRC effect of both MET, ASP and their combination and, therefore, that the combination of MET + ASP may especially benefit PI3KCA-mutant CRC cases, which currently have a poor prognostic.

Gallic acid markedly stimulates GLUT1-mediated glucose uptake by the AsPC-1 pancreatic cancer cell line.

Phenolic acids are recognized as chemopreventive and chemotherapeutic agents. Altered glucose and glutamine metabolism are recognized hallmarks of cancer cells. We aimed to test the influence of phenolic acids on glucose and glutamine cellular uptake by a breast (MCF-7) and a pancreatic (AsPC-1) cancer cell line. Several phenolic acids (caffeic, ferrulic, proctocatechuic, coumaric and gallic acid) affected 3H-glutamine and/or 3H-deoxy-d-glucose (3H-DG) uptake. Gallic acid (100 µM) caused a 3-fold increase in 3H-DG uptake by AsPC-1 cells, associated with a 3.7-fold increase in lactic acid production. Gallic acid stimulated GLUT1-mediated 3H-DG uptake and increased the affinity of this transporter for 3H-DG. We further verified that gallic acid does not change GLUT1 transcription rates and cellular redox state and that its effect does not involve PI3K, mTOR and MAP kinases and is not associated with a proproliferative effect. Gallic acid also increased 3H-DG uptake by MCF-7 cells, although less potently. Further investigation is necessary to elucidate the cellular pathways involved in this effect of gallic acid.

Metabolic effects of atypical antipsychotics: Molecular targets.

Atypical antipsychotics (AAPs) are commonly prescribed drugs in the treatment of schizophrenia, bipolar disorder and other mental diseases with psychotic traits. Although the use of AAPs is associated with beneficial effects in these patients, they are also associated with undesired metabolic side effects, including metabolic syndrome (MetS). MeS is defined by the presence of metabolic abnormalities such as large waist circumference, dyslipidemia, fasting hyperglycemia and elevated blood pressure, which predispose to type 2 diabetes (T2D) and cardiovascular disease. In this review, the molecular and cellular mechanisms involved in these undesired metabolic abnormalities induced by AAPs are described. These mechanisms are complex as AAPs have multiple cellular targets which significantly affect the activities of several hormones and neuromodulators. Additionally, AAPs affect all the relevant metabolic organs, namely the liver, pancreas, adipose tissue, skeletal muscle and intestine, and the central and peripheral nervous system as well. A better understanding of the molecular targets linking AAPs with MetS and of the mechanisms responsible for clinically different side effects of distinct AAPs is needed. This knowledge will help in the development of novel AAPs with less adverse effects as well as of adjuvant therapies to patients receiving AAPs.

Gonococcal Infection: Case Report of Bacteremia and Brief Review of a Series of Cases.

Neisseria (N) gonorrhoeae is the microorganism responsible for the second-most reported sexually transmitted disease in the world, commonly infecting mucosal surfaces such as the endocervix, urethra, and pharynx. Gonococcal disease is generally non-symptomatic or pauci-symptomatic, but if untreated, it can progress to a more serious disease with joint, cardiac, or nervous system involvement. Disseminated gonococcal infection occurs in 0.5 to 3% of patients with gonorrhea and can present with purulent arthritis or a combination of dermatitis, tenosynovitis, and migratory polyarthralgia. This article presents the case of a 45-year-old woman examined in the emergency room for fever and acute pain in her right shoulder and knee. A few days later, the patient developed petechiae and vesiculopustular lesions on her right hand. Blood analysis showed elevated inflammation markers, and cultures yielded gram-negative diplococcus identified as N. gonorrhoeae. The patient was successfully treated with ceftriaxone, with complete remission of signs and symptoms of infection. The article then examines a series of 42 cases of gonococcal disease diagnosed in a tertiary hospital, their microbiologic susceptibilities, and the antibiotics chosen to treat them.

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel.

CONTEXT: The BRAF V600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). In colorectal cancer, BRAF V600E was described to functionally cooperate with RAC1b, a hyperactive splice variant of the small GTPase RAC1, to sustain cell survival. This interplay has never been investigated in PTCs. OBJECTIVE: We aimed to analyze the expression of RAC1b in PTC and correlate its expression with BRAF V600E mutational status, histopathological features, and clinical outcome. PATIENTS AND METHODS: Sixty-one patients and 87 samples (61 PTCs and 26 normal thyroid tissues) were included. Patients were divided into two groups based on longitudinal evolution and final outcome. RAC1b expression levels were determined by quantitative RT-PCR and western blotting. RESULTS: RAC1b was expressed in thyroid and overexpressed in 46% of PTCs. Neither RAC1b overexpression nor V600E mutation correlated with histopathological features classically associated with worse prognosis. RAC1b overexpression was significantly associated with both V600E mutation (P=0.0008) and poor clinical outcome (P=0.0029). Whereas BRAF V600E alone did not associate with patient outcome (P=0.2865), the association of RAC1b overexpression with BRAF V600E was overrepresented in the group with poorer clinical outcome (P=0.0044). CONCLUSIONS: Present results document, for the first time, expression of RAC1b in normal thyroid cells as well as overexpression in a subset of PTCs. Furthermore, they suggest a possible interplay between BRAF V600E and RAC1b contributing to poor clinical outcome. Future studies are needed to clarify the oncogenic potential of RAC1b in thyroid carcinogenesis.

Em busca das bases ontológicas da psicologia de Vygotsky / Searching for the ontological bases of Vygotsky's psychology / En busca de las bases ontológicas de la psicología de Vygotsky

O estudo busca estabelecer os fundamentos ontológicos do pensamento de Vygotsky, indicando que a construção teórica erigida pelo e autor está centrada no trabalho, como o complexo que deu origem ao homem como ser social. Tal postulado seria consistente com os princípios do marxismo recuperado por Lukács como uma ontologia do ser social, superadora da tradição metafísica e idealista, firmando, nesse sentido, o caráter radicalmente histórico da essência humana. Apontam-se os equívocos fundamentais operado pelo neovygotskianismo, o qual, tratando as categorias vygotskianas da linguagem, cultura e interação apartadas do princípio marxiano do trabalho, acaba por isolar Vygotsky do campo ontológico e, por extensão, do projeto socialista. Reafirma-se, por fim, que, não obstante a explícita relevância atribuída à dimensão metodológica do marxismo, está pressuposto na obra de Vygotsky, o substrato ontológico sobre o qual se funda o método de Marx.(AU)

The study seeks to establish the ontological foundation of Vygotsky's thought, indicating that his theoretical construct is centered upon labor, as the complex which originated man as a social being. This postulate would be consistent with the principles of Marxism, recoveved by Lukács as an ontology of the social being that goes far beyond the metaphysical and idealistic tradition, to assert the radically historical character of human essence. It denounces the fundamental mistakes operated by neovygotskianism, which, treating Vygotskian categories of language, culture and interaction, apart from the Marxist principle of work, ends up by isolating Vygotsky from the Marxian ontological realm, and, by extension, from the socialist project. It is finally reassured that, despite the explicit relevance attributed by Vygotsky to the methodological dimension of Marxism, it is presupposed in the context of his work, the ontological core, which founds Marx's method.(AU)

El estudio busca establecer el fundamento ontológico del pensamiento de Vygotsky, indicando que su construcción teórica se centra en el trabajo como el complejo que originó el hombre como un ser social. Este postulado es consistente con los principios del marxismo, recuperado por Lukács como uma ontología del ser social queva mucho más allá de la tradición metafísica e idealista, para afirmar el carácter radicalmente histórico de la esencia humana. Denuncia los errores fundamentales operados por el neovygotskianismo, que, tratando las categorias vygotskianas de la lenguage, cultura e interacción, apartadas del principio marxista del trabajo, termina aislando Vygotsky de la esfera del marxismo ontológico y, por extensión, del proyecto socialista. Finalmente se aseguró que, apesar de la relevância explícita atribuída por Vigotski a la dimensión metodológica del marxismo, se presupone en el contexto de su obra, el núcleo ontológico que funda el método de Marx.(AU)

Em busca das bases ontológicas da psicologia de vygotsky / Searching for the ontological bases of vygotsky's psychology / En busca de las bases ontológicas de la psicología de vygotsky

O estudo busca estabelecer os fundamentos ontológicos do pensamento de Vygotsky, indicando que a construção teórica erigida pelo e autor está centrada no trabalho, como o complexo que deu origem ao homem como ser social. Tal postulado seria consistente com os princípios do marxismo recuperado por Lukács como uma ontologia do ser social, superadora da tradição metafísica e idealista, firmando, nesse sentido, o caráter radicalmente histórico da essência humana. Apontam-se os equívocos fundamentais operado pelo neovygotskianismo, o qual, tratando as categorias vygotskianas da linguagem, cultura e interação apartadas do princípio marxiano do trabalho, acaba por isolar Vygotsky do campo ontológico e, por extensão, do projeto socialista. Reafirma-se, por fim, que, não obstante a explícita relevância atribuída à dimensão metodológica do marxismo, está pressuposto na obra de Vygotsky, o substrato ontológico sobre o qual se funda o método de Marx.

The study seeks to establish the ontological foundation of Vygotsky's thought, indicating that his theoretical construct is centered upon labor, as the complex which originated man as a social being. This postulate would be consistent with the principles of Marxism, recoveved by Lukács as an ontology of the social being that goes far beyond the metaphysical and idealistic tradition, to assert the radically historical character of human essence. It denounces the fundamental mistakes operated by neovygotskianism, which, treating Vygotskian categories of language, culture and interaction, apart from the Marxist principle of work, ends up by isolating Vygotsky from the Marxian ontological realm, and, by extension, from the socialist project. It is finally reassured that, despite the explicit relevance attributed by Vygotsky to the methodological dimension of Marxism, it is presupposed in the context of his work, the ontological core, which founds Marx's method.

El estudio busca establecer el fundamento ontológico del pensamiento de Vygotsky, indicando que su construcción teórica se centra en el trabajo como el complejo que originó el hombre como un ser social. Este postulado es consistente con los principios del marxismo, recuperado por Lukács como uma ontología del ser social queva mucho más allá de la tradición metafísica e idealista, para afirmar el carácter radicalmente histórico de la esencia humana. Denuncia los errores fundamentales operados por el neovygotskianismo, que, tratando las categorias vygotskianas de la lenguage, cultura e interacción, apartadas del principio marxista del trabajo, termina aislando Vygotsky de la esfera del marxismo ontológico y, por extensión, del proyecto socialista. Finalmente se aseguró que, apesar de la relevância explícita atribuída por Vigotski a la dimensión metodológica del marxismo, se presupone en el contexto de su obra, el núcleo ontológico que funda el método de Marx.

Como nós tratamos as crianças no HIAS: rotinas médicas 1 / How we treat the childrens in HIAS

Publicaçäo sobre condultas médicas adotadas para as crianças internas no Hospital Infantil Albert Sabin. Tem como finalidade maior a uniformizaçäo das condutas, intentando contribuir para o melhor atendimento aos pequenos pacientes. É dirigido ao recem nascido e lacente até três meses de idade