KRAS: A Druggable Target in Colon Cancer Patients

Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific drugs challenging. Indeed, KRAS was considered ‘undruggable’. KRASG12C is the most commonly mutated variant of KRAS in non-small cell lung cancer. Currently, the achievements obtained with covalent inhibitors of this variant have given the possibility to assess the best therapeutic approach to KRAS-driven tumors. Mutation-related biochemical assets and the tissue of origin are expected to influence responses to treatment. Further attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising. Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment

The WINPack 1 a novel wearable system for heart rate and vital signs monitoring

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Missense PDSS1 mutations in CoenzymeQ10 synthesis cause optic atrophy and sensorineural deafness

CoenzymeQ10 is one of the main cellular antioxidants and an essential lipid involved in numerous cell reactions, such as energy production and apoptosis modulation. A large number of enzymes are involved in CoQ10 biosynthesis. Mutations in the genes encoding for these enzymes cause a CoQ10 deficiency, characterized by neurological and systemic symptoms. Here we describe two young sisters with sensorineural deafness followed by optic atrophy, due to a novel homozygous pathogenic variant in PDSS1. The visual system seems to be mainly involved when the first steps of CoQ10 synthesis are impaired (PDSS1, PDSS2, and COQ2 deficiency)

IMPACTOS DAS EMPRESAS ESTRANGEIRAS SOBRE O COMÉRCIO EXTERIOR BRASILEIRO: EVIDÊNCIAS DA DÉCADA DE 90

Durante os anos 90, vários autores procuraram avaliar os impactos do processo de internacionalização produtiva da economia brasileira sobre o seu desempenho externo. Este trabalho procura reproduzir e avaliar as evidências levantadas por esses autores durante a década e, por meio de uma análise de dados em painel, acrescentar novos elementos ao debate. A pergunta a ser respondida é se a origem de capital da firma (estrangeira ou nacional) é um determinante importante de suas exportações e importações. Para isso, utilizaram-se microdados das empresas industriais brasileiras no período de 1996 a 2000 e controlaram-se outros fatores capazes de influenciar o desempenho comercial das firmas. Os resultados obtidos apontam para uma maior inserção comercial das empresas estrangeiras instaladas no país em relação às firmas domésticas, sendo esta maior inserção significativa e maior nas importações do que nas exportações. Estes resultados contradizem as expectativas iniciais de alguns autores de que as empresas estrangeiras pudessem estar colaborando para um desempenho comercial mais favorável ao país durante a década. Abstract During the nineties some economists expected that the intense process of productive internationalization of the Brazilian economy would bring gains, particularly regarding to the trade performance of the country. This paper aims at evaluating the importance of the ownership foreign or national as a determinant of trade of the industrial firms in Brazil between 1996 and 2000. The analysis used individual information about more than 50.000 industrial companies in the period into a panel data econometric model. The results show that transnational corporations seem to be more integrated into international trade than locally owned firms. However, this larger integration takes the form, essentially, of stronger import activities more than of larger exports. These results contradict the expectations of some economists: that foreign companies could collaborate for a better Brazilian trade performance during the period

Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers

PURPOSE: The primary aim of the present study was to assess the pharmacokinetic bioequivalence between a generic formulation of meloxicam 15 mg tablets (Meloxicam Hexal) and its respective brand product (Mobic), in order to verify whether the generic product conforms to the regulatory standards of bioequivalence in the postmarketing setting. As a secondary exploratory aim, the pharmacodynamic effects of the two formulations were also evaluated by means of rating scales following hyperalgesia induced by cutaneous freeze injury. SUBJECTS AND METHODS: A single 15 mg dose of generic or branded meloxicam tablets was administered to 24 healthy male volunteers in a crossover fashion. Plasma samples, collected for 24 hours after dosing, were assayed for meloxicam concentration by a validated highperformance liquid chromatography method. RESULTS: THE ANALYSIS OF PHARMACOKINETIC PARAMETERS DID NOT SHOW ANY SIGNIFICANT DIFFERENCE BETWEEN THE TWO MELOXICAM FORMULATIONS: the 90% confidence intervals fell within the acceptance range of 80%-125% (0.84-1.16 for area under the curve [0-24], and 0.89-1.23 for peak concentration). No difference in the pharmacodynamic end point was observed between the two groups. CONCLUSION: The pharmacokinetic profiles of the two meloxicam formulations confirm the regulatory criteria for bioequivalence; pharmacodynamic data indicate a similar antihyperalgesic effect. The two formulations can be used interchangeably in the clinical setting