IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in jak2v617f-positive myeloproliferative neoplasms

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The recurrent V617F mutation in JAK2 (JAK2(V617F)) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2(V617F) HEL cells, but not in the JAK2(WT) U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2(V617F)-positive but not JAK2(WT) specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34(+) cells from essential thrombocythemia patients compared to healthy donors, and in JAK2(V617F) MPN patients when compared to JAK2(WT). Our data indicate that IRS2 is a binding partner of JAK2(V617F) in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2-mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN.The recurrent V617F mutation in JAK2 (JAK2V617F) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indi7669486959sem informaçãoConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)sem informaçã

Adult neurogenesis and pattern separation in rodents:A critical evaluation of data, tasks and interpretation

Item does not contain fulltex

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.Susan Branford, Dennis Dong Hwan Kim, Jane F. Apperley, Christopher A. Eide, Satu Mustjoki, S. Tiong Ong ... et al. (on behalf of the International CML Foundation Genomics Alliance

Imunodiagnóstico da leptospirose humana através do teste ELISA-IgM, empregando-se diferentes preparações antigênicas a partir de sorotipos prevalentes de Leptospira interrogans Immunodiagnostic of human leptospirosis by ELISA-IgM, employing: different antigenic preparations as from prevalent serovars of Leptospira interrogans

Realizou-se estudo comparativo de diferentes sorotipos de Leptospira interrogans utilizados na preparação de antígenos empregados no teste ELISA, para a detecção de anticorpos da classe IgM, em amostras de soro na fase precoce e tardia da leptospirose humana. Foram utilizados dez sorotipos, escolhidos entre os que apresentaram maior reatividade na soroaglutinação microscópica (SAM), na cidade de São Paulo. Os cinco sorotipos que apresentaram melhores resultados individualmente no teste ELISA-IgM (canicola, hebdomadis, icterohaemorrhagiae, cynopteri e brasiliensis), foram também estudados em mistura antigênica. Os antígenos não tratados apresentaram maior reatividade do que os antígenos tratados com Triton X - 100 (4%) à temperatura de 50ºC, durante 4 horas. O teste ELISA-IgM empregando os sorotipos não tratados, isoladamente, e em mistura antigênica, mostrou-se altamente sensível, podendo ser empregado como teste de triagem para o diagnóstico precoce da leptospirose humana. Outra aplicação do teste é permitir a detecção do início de situações epidêmicas ou de surtos, possibilitando acionar medidas de vigilância epidemiológica.<br>A comparative study among different serovars of Leptospira interrogans was performed in order to prepare antigens to detect IgM antibodies by ELISA in early and late phase of human leptospirosis. Ten serovars were chosen among the most prevalent detected by microscopic seroagglutination (SAM) in São Paulo city. Using ELISA-IgM five of them showed better results (canicola, hebdomadis, icterohaemorrhagiae, cynopteri and brasiliensis). These ones were also studied in a pool. The non-treated antigens showed higher reactivity than the Triton X-100 (4%/50ºC/4h). ELISA-IgM using individually or pool of non treated antigens proved to be reliable with high sensitivity and should be used for an earlier diagnosis of leptospirosis, as a trial test. Faster diagnostic elucidation can be useful to detect epidemic situations, so, allowing epidemiological surveillance interventions