Antimalarial Activity of Phenazines from Lapachol, β-Lapachone and Its Derivatives Against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. -The synthesis of some benzophenazines by reaction of naturally occurring naphthoquinones, lapachol (Ia) and β-lapachone (IVa), or their derivatives with phenylenediamine and the evaluation of their antimalarial activities in vitro and in vivo are described. (No yields given.) -(DE ANDRADE-NETO, V. F.; GOULART, M. O. F.; DA SILVA FILHO, J. F.; DA SILVA, M. J.; PINTO, M. D. C. F. R.; PINTO, A. V.; ZALIS, M. G.; CARVALHO, L. H.; KRETTLI*, A. U.; Bioorg. Med.

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Background and Objectives: One of the most frequently mutated oncogenes in cancer belongs to the Ras family of proto-oncogenes, which encode distinct key signaling events. RAS gain-of-function mutations are present in ~30% of all human cancers, with KRAS being the most frequently mutated isoform showing alterations in different cancer types including lung cancer. This study aimed to investigate the incidence of KRAS mutations, and concomitant mutations, in advanced non-small cell lung adenocarcinoma patients. Materials and Methods: This was a retrospective study, where genomic DNA extracted from paraffin-embedded tumor tissues from 121 Brazilian advanced non-small cell lung adenocarcinoma patients were analyzed to evaluate via Next Generation Sequencing (NGS) the incidence of KRAS mutations and co-occurring mutations and correlate, when possible, to clinicopathological characteristics. Statistical analyses were performed to calculate the prevalence of mutations and to investigate the association between mutational status, mutation type, and sex. Results: The results showed a prevalence of male (N = 63; 54.8%) compared to female patients (N = 52, 45.2%), and mutant KRAS was present in 20.86% (24/115) of all samples. Interestingly, 33.3% of the mutant KRAS samples showed other mutations simultaneously. Conclusions: This study revealed the presence of rare KRAS concomitant mutations in advanced lung adenocarcinoma patients. Further investigation on the importance of these genomic alterations in patient prognosis and treatment response is warranted.

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To cite this article: Landau MB, Renni MS, Zalis MG, Spector N, Gadelha T. Coagulation factor XIII Tyr204Phe gene variant and the risk of ischemic stroke. J Thromb Haemost 2013; 11: 1426-7.Several genetic variants have been investigated in association with ischemic stroke, with conflicting results or a rather modest effect being seen for each single gene [1]. Genetic variants of factor XIII have been shown to influence the plasma FXIII level and activity, thereby affecting clot structure and thrombotic risk [2]. FXIII acts in the final stages of blood clotting, crosslinking fibrin to plasma proteins, and thereby increasing the mechanical stability of fibrin clots and protecting them from rapid removal during fibrinolysis [3]. The presence of the Phe allele in the Tyr204Phe variant in the A1 subunit of the FXIII gene, FXIII Tyr204Phe (rs3024477), has been investigated as a risk factor for myocardial infarction [4,5] and ischemic stroke [4,6]. A recently published Dutch population-based case-control study [6] examined the risk of ischemic stroke associated with the Tyr204Phe variant in 190 women (20-50 years of age). This genetic variant was identified in 34% of ischemic stroke patients and in 6% of controls, which translated into an odds ratio (OR) of 9.1 with a 95% confidence interval (CI) of 5.5-15 for ischemic stroke in the presence of the Phe allele. This risk was increased to an OR of 20 (95% CI 9.0-46) when associated with oral contraceptive use, and to an OR of 77 (95% CI 7.0-848) for the homozygous form (Phe204Phe) among oral contraceptive users [6]. These surprising results led us to develop the present study, aiming to assess the association of FXIII Tyr204Phe with ischemic stroke in a sample of Brazilian patients.A case-control study was performed, including 220 ischemic stroke patients referred to the hemostasis laboratory for thrombophilic screening from 1991 to 2012, and 220 controls. Patients with major systemic diseases, transient ischemic attack, hemorrhagic stroke, cerebral venous sinus thrombosis or embolic strokes were excluded. The pool of control individuals consisted of healthy individuals brought in by patients and not genetically related to them.The presence of the FXIII Tyr204Tyr, Tyr204Phe and Phe204Phe variants was determined by real time PCR, as previously described [7]. The association of the genetic variants with ischemic stroke was examined with McNemar's chi-square test, and expressed as ORs and CIs, with SPSS (Version 17.0; SPSS, Chicago, IL, USA).The characteristics of patients and controls, the frequencies of the FXIII Tyr204Phe variant and the risk of ischemic stroke are listed in Table 1. The FXIII Tyr204Phe variant was found in the heterozygous form in five (2.0%) patients and in eight (3.6%) controls, with an OR of 0.6 (95% CI 0.2-1.9). The homozygous form (Phe204Phe) was found neither in ischemic stroke patients nor in controls. Subgroup analysis was also performed in an attempt to investigate special populations who could possibly be affected by the presence of this varia...

e15017 Background: KRAS mutation is common event in colorectal cancer occurring in around 40% of the patients. It is well- known that patients harboring the KRAS mutation do not derive benefit from cetuximab. However data available KRAS mutation profile is limited to Caucasian and Asian individuals and there is a lack of data in the population from Latin America. Brazilian population has a heterogeneous genetic background and this may have pharmacogenetic implications (Suarez-Kurtz, 2006). Methods: Between July and November 2008, we analyzed 989 consecutive patient samples sent to our laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exons 1 were amplified by PCR and submitted to automatic sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and 53% of the patients were male and 47% female. The percentage of wild-type and mutated KRAS was 62 and 38%, respectively. Among the 375 mutated cases, 87% were in codon 12 versus 13% in codon 13. Mutation Gly12Asp was the most common being detected in 39% of the mutated cases. Due to the sample size a comparison among patients from different regions of Brazil was possible. However, no significant difference was observed in relation to the type or percentage of patients harboring the KRAS mutation. Interestingly, a significant difference in the percentage of mutated KRAS patients was observed between male and female (41 versus 35%, p= 0.05). Conclusions: The profile of KRAS mutation in the Brazilian population is similar to that reported for Caucasian and Asian populations. This is one of the largest cohorts of KRAS genotyping in colorectal cancer patients ever reported. To the best of our knowledge our data is the first to put forward the issue of a potential difference in the mutation rate according to gender. The observed higher incidence of KRAS-mutation in male than female deserves further investigation. No significant financial relationships to disclose.

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