The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatmentsPeer ReviewedPostprint (author's final draft

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus

10.1002/acr.23834ARTHRITIS CARE & RESEARCH715579-59

Estudo sobre o conhecimento e uso popular da garra-do-diabo (harpagophytum procumbens) como planta medicinal

The plant Harpagophytum procumbens is native to the Kalahari Desert and Steppes of Namibia, it belongs to the Pedaliaceae family and is popularly known in Brazil as "diabo's claw". The anti-inflammatory properties attributed to this medicinal plant are given by the presence of the prevalent active compound harpagoside, which makes H. procumbens stand out as herbal medicine for the treatment of diseases such as arthritis, osteoarthritis and rheumatism. Despite not being originally from Brazil, the herbal medicine can be found in the National List of Essential Medicines of the SUS, in portuguese the initial letters (RENAME). The present work aims to evaluate the knowledge and acceptance of the population about the use of H. procumbens as herbal medicine for alternative and auxiliary treatment for inflammatory diseases as well as to warn about the indiscriminate use of herbal medicines. The data of this study were obtained through an online questionnaire which was answered by 300 volunteers, over 18 years old, who answered ten questions about herbal medicines and devil's claw. The results demonstrate the level of knowledge of the interviewees about H. procumbens and the acceptance in the use of herbal medicines obtained by this work. Such results contributed to scientific bases on the rational use of herbal medicines, especially the plant H. procumbens, on its anti- inflammatory effect. Also guiding the population on the safe use of herbal medicine, thus contributing to health promotion.A planta Harpagophytum procumbens é originária do deserto de Kalahari e Estepes da Namíbia perpertence à família Pedaliaceae e é conhecida popularmente no Brasil como “garra-do- diabo”. As propriedades anti-inflamatórias atribuídas à esta planta medicinal, são dadas pela presença do composto ativo prevalente o harpagosídeo, o que faz H. procumbens destacar-se como um fitoterápico para o tratamento de doenças como artrite, osteoartrite e reumatismo. Apesar de não ser originária do Brasil, pode-se encontrar o fitoterápico na Relação Nacional de Medicamentos Essenciais do SUS (RENAME). O presente trabalho tem como objetivo avaliar o conhecimento e aceitação da população sobre o uso de H. procumbens como fitoterápico para o tratamento alternativa e auxiliar para doenças inflamatórias assim como alertar sobre o uso indiscriminado de medicamentos fitoterápicos. Os dados deste estudo foram obtidos por meio de questionário online o qual foi respondido por 300 voluntários, maiores de 18 anos, os quais responderam dez perguntas sobre fitoterápicos e garra-do-diabo. Os resultados   demonstram   o   baixo   nível   de   conhecimento   dos entrevistados sobre o H. procumbens, no entanto, mostrou uma boa aceitação no uso de medicamentos fitoterápicos. Tais resultados, contribuiem para bases científicas sobre o uso racional de fitoterápicos, especialmente a planta H. procumbens, sobre seu efeito anti-inflamatório. Ainda orientando a população sobre o uso seguro de fitoterápico, contribuindo assim, para a promoção da saúde

Utility of the PHQ-9 to identify major depressive disorder in adult patients in Spanish primary care centres

Abstract Background The prevalence of major depressive disorder (MDD) in Spanish primary care (PC) centres is high. However, MDD is frequently underdiagnosed and consequently only some patients receive the appropriate treatment. The present study aims to determine the utility of the Patient Health Questionnaire-9 (PHQ-9) to identify MDD in a subset of PC patients participating in the large PsicAP study. Methods A total of 178 patients completed the full PHQ test, including the depression module (PHQ-9). Also, a Spanish version of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) was implemented by clinical psychologists that were blinded to the PHQ-9 results. We evaluated the psychometric properties of the PHQ-9 as a screening tool as compared to the SCID-I as a reference standard. Results The psychometric properties of the PHQ-9 for a cut-off value of 10 points were as follows: sensitivity, 0.95; specificity, 0.67. Using a cut-off of 12 points, the values were: sensitivity, 0.84; specificity, 0.78. Finally, using the diagnostic algorithm for depression (DSM-IV criteria), the sensitivity was 0.88 and the specificity 0.80. Conclusions As a screening instrument, the PHQ-9 performed better with a cut-off value of 12 versus the standard cut-off of 10. However, the best psychometric properties were obtained with the DSM-IV diagnostic algorithm for depression. These findings indicate that the PHQ-9 is a highly satisfactory tool that can be used for screening MDD in the PC setting. Trial registration Current Controlled Trials ISRCTN58437086 . Registered 20 May 2013

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatmentsPeer Reviewe