11 research outputs found
Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma
Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patientsâ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patientsâ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors
Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma
Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67.10(-18)), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors
Messianismos em conflito: interpretação teolĂłgico-polĂtica de os sertĂ”es Messianisms in conflict: teological-political interpretation of os sertĂ”es
O ensaio investiga os fundamentos teolĂłgico-polĂticos da obra seminal de Euclides da Cunha, Os sertĂ”es, dando especial ĂȘnfase Ă relação entre messianismo e potencial construção da nação. Nele, nĂŁo se aplica simplesmente o modelo "teolĂłgico-polĂtico" Ă leitura da obra, para comprovar, uma vez mais, a tese da equivalĂȘncia estrutural entre conceitos teolĂłgicos e polĂticos. Mais do que isso, analisa os conflitos da Ă©poca a partir das exigĂȘncias teolĂłgico-polĂticas e, assim, compreende as oportunidades e as consequĂȘncias de suas ruĂnas (no sentido duplo de destruição causada e de ruĂna da prĂłpria estrutura teolĂłgico-polĂtica). O ensaio contribui para uma nova percepção crĂtica do papel de Os sertĂ”es, no que diz respeito Ă complexa tradição messiĂąnica brasileira.<br>The essay investigates the theological-political grounds of Euclides da Cunha's seminal work, Os sertĂ”es, with special emphasis put on the relation between messianism and potential construction of the nation. This paper does not simply apply the "theological-political" model to the reading of the work, in order to prove once more the structural equivalence between theological and political concepts. More than that, it analyses the conflicts of the period on the basis of theological-political exigencies. It thus understands opportunities and consequences of its ruins (in the double sense of caused destruction and of the ruin of the theological-political structure itself). With regard to the complex Brazilian messianic tradition, this essay contributes to a new critical perception of the Os sertĂ”es role