PURPOSE Estrogen receptor (ER)–positive endometrial cancers (ECs) are characterized by phosphatid... more PURPOSE Estrogen receptor (ER)–positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting. METHODS We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormon...
Tratamos neste artigo da trajetória da Biblioteca Pública no Maranhão com destaque para as reivin... more Tratamos neste artigo da trajetória da Biblioteca Pública no Maranhão com destaque para as reivindicações para a construção de um prédio definitivo para alojar o seu acervo e atender seus leitores. Em princípio, tratamos de situar a Biblioteca no período imperial, depois, abordamos os debates estabelecidos na República e, em seguida, a construção da sua edificação permanente. Para tanto, utilizamos fontes documentais diversas com destaque para os relatórios dos seus diretores, analisados a partir da História Cultura. Concluímos que a construção do prédio da instituição se constituiu em um movimento que tem a sua gênese na sua criação e se encerra na década de 1950, quando é edificado e entregue à sociedade maranhense o prédio que a biblioteca desde então ocupa em São Luís.
Objectives: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT ... more Objectives: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. Prior literature has reported an association of CTNNB1 mutations and an aggressive biology and shorter survival in endometrioid endometrial cancer. We previously demonstrated Wnt activating mutations were associated with higher DKK1 tumoral expression in advanced gynecologic malignancies. Methods: Pts with recurrent gynecologic cancers [endometrial (EEC), ovarian (EOC) and carcinosarcoma (MMMT)] were treated with D as monotherapy (mono) or in combination with paclitaxel (pac) in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on the subgroup of pts with Wnt activating mutations (CTNNB1, RNF43, APC). Clopper-Pearson confidence intervals were used to study the association of Wnt activating mutations with clinical benefit (CR, PR or SD); Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PFS) and overall survival (OS). Results: A total of 111 pts enrolled; 52 pts treated with D mono; 59 pts treated with D + pac. Mean number of prior therapies was 3.6 (range 1, 11) and 3.9 (range 1, 10) for D mono and D + pac, respectively. A total of 108 pts (97%) with available genetics; 23 pts (21%) had Wnt activating mutations [CTNNB1 (n=17), RNF43 (n=5), APC (n=3)]. Wnt activating mutations were more common in EEC (n=17/54, 31%) than EOC (n=2/33, 6%) and MMMT (n=4/24, 17%). Median duration of treatment with D was 6 cycles in pts with Wnt activating mutations compared with 3 cycles for pts without Wnt activating mutations. A total of 15 of 23 (65%) evaluable pts with Wnt activating mutations had clinical benefit [1 PR, 14 SD; durable SD (> 4 months) in 11 of 14 pts (48%)] compared with 34 of 76 (45%) evaluable pts [1 CR, 2 PR, 31 SD; durable SD (> 4 months) in 12 of 31 SD pts (16%)] without Wnt activating mutations. All 4 pts with an objective response had a PIK3CA mutation. Pts with Wnt activating mutations had longer PFS [median 5.5 mos; 95% CI (1.8, 6.0)] and OS [median 22.2 mos; 95% CI (7.3, NE)] compared with pts without Wnt activating mutations [median PFS 2.0 mos; 95% CI (1.8, 3.1)] and OS (median 9.9 mos; 95% CI (6.9, 12.5)]. Download : Download high-res image (65KB) Download : Download full-size image Conclusions: D has single agent activity in a subgroup of pts with Wnt activating mutations, historically identified as a poor prognostic group, whereby they experienced greater clinical benefit and longer survival compared with pts without Wnt activating mutations. A notable finding was that all responding pts had PIK3CA mutations. This study is ongoing and updated results will be presented.
O presente artigo teve por objetivo analisar a producao, a circulacao e os metodos de ensino, pre... more O presente artigo teve por objetivo analisar a producao, a circulacao e os metodos de ensino, presentes nas mobilias escolares para os jovens e adultos das escolas radiofonicas na Amazonia Bragantina, no periodo de 1961-1968. A metodologia utilizada foi a abordagem da Nova Historia Cultural. As imagens contidas nos Livros de Tombo do Tribunal de Contas da Diocese de Braganca, o uso dos decretos e as leis foram as principais fontes deste estudo. Foi constatado que as mobilias eram produzidas na oficina anexada ao Escritorio do Sistema Educativo Radiofonico de Braganca (SERB) e enviadas apenas para tres municipios. As outras localidades fabricavam suas mobilias com a ajuda dos marceneiros de suas respectivas comunidades. Foram identificadas, nas imagens, o uso de dois tipos de mobilias escolares nas escolas radiofonicas: a de mesas rusticas com cadeiras de assento e apoio para as costas, encontradas numa escola municipal. Elas variavam de tamanho, visto que eram produzidas para o ensi...
Background: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT ... more Background: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01, a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. We report response and survival outcomes in EEC patients (pts) treated with DKN-01 monotherapy by tumor genetics (Wnt signaling alterations and PI3K/AKT mutations). Methods: Pts with recurrent EEC were treated with DKN-01 as monotherapy (mono) or in combination with paclitaxel in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on EEC mono group only. Clopper-Pearson confidence intervals and logistic regression were used to study the association of Wnt signaling alterations with clinical benefit (CR, PR or SD) following DKN-01 monotherapy; Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PF...
Extracellular vesicles (EVs) are recognized cancer biomarkers, however, clinical analysis has bee... more Extracellular vesicles (EVs) are recognized cancer biomarkers, however, clinical analysis has been difficult due to a lack of simple and sensitive assays. Here, we describe a bead-enhanced flow cytometry method, BEAD flow, using biotinylated EVs captured on streptavidin particles. With this method, we show analysis of patient-derived EVs using a panel of pancreatic cancer biomarkers. BEAD flow is easily translatable to any biomarker or cancer type and can be run with conventional flow cytometers, making it highly flexible and adaptable to diverse research and clinical needs.
PURPOSE Estrogen receptor (ER)–positive endometrial cancers (ECs) are characterized by phosphatid... more PURPOSE Estrogen receptor (ER)–positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting. METHODS We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormon...
Tratamos neste artigo da trajetória da Biblioteca Pública no Maranhão com destaque para as reivin... more Tratamos neste artigo da trajetória da Biblioteca Pública no Maranhão com destaque para as reivindicações para a construção de um prédio definitivo para alojar o seu acervo e atender seus leitores. Em princípio, tratamos de situar a Biblioteca no período imperial, depois, abordamos os debates estabelecidos na República e, em seguida, a construção da sua edificação permanente. Para tanto, utilizamos fontes documentais diversas com destaque para os relatórios dos seus diretores, analisados a partir da História Cultura. Concluímos que a construção do prédio da instituição se constituiu em um movimento que tem a sua gênese na sua criação e se encerra na década de 1950, quando é edificado e entregue à sociedade maranhense o prédio que a biblioteca desde então ocupa em São Luís.
Objectives: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT ... more Objectives: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. Prior literature has reported an association of CTNNB1 mutations and an aggressive biology and shorter survival in endometrioid endometrial cancer. We previously demonstrated Wnt activating mutations were associated with higher DKK1 tumoral expression in advanced gynecologic malignancies. Methods: Pts with recurrent gynecologic cancers [endometrial (EEC), ovarian (EOC) and carcinosarcoma (MMMT)] were treated with D as monotherapy (mono) or in combination with paclitaxel (pac) in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on the subgroup of pts with Wnt activating mutations (CTNNB1, RNF43, APC). Clopper-Pearson confidence intervals were used to study the association of Wnt activating mutations with clinical benefit (CR, PR or SD); Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PFS) and overall survival (OS). Results: A total of 111 pts enrolled; 52 pts treated with D mono; 59 pts treated with D + pac. Mean number of prior therapies was 3.6 (range 1, 11) and 3.9 (range 1, 10) for D mono and D + pac, respectively. A total of 108 pts (97%) with available genetics; 23 pts (21%) had Wnt activating mutations [CTNNB1 (n=17), RNF43 (n=5), APC (n=3)]. Wnt activating mutations were more common in EEC (n=17/54, 31%) than EOC (n=2/33, 6%) and MMMT (n=4/24, 17%). Median duration of treatment with D was 6 cycles in pts with Wnt activating mutations compared with 3 cycles for pts without Wnt activating mutations. A total of 15 of 23 (65%) evaluable pts with Wnt activating mutations had clinical benefit [1 PR, 14 SD; durable SD (> 4 months) in 11 of 14 pts (48%)] compared with 34 of 76 (45%) evaluable pts [1 CR, 2 PR, 31 SD; durable SD (> 4 months) in 12 of 31 SD pts (16%)] without Wnt activating mutations. All 4 pts with an objective response had a PIK3CA mutation. Pts with Wnt activating mutations had longer PFS [median 5.5 mos; 95% CI (1.8, 6.0)] and OS [median 22.2 mos; 95% CI (7.3, NE)] compared with pts without Wnt activating mutations [median PFS 2.0 mos; 95% CI (1.8, 3.1)] and OS (median 9.9 mos; 95% CI (6.9, 12.5)]. Download : Download high-res image (65KB) Download : Download full-size image Conclusions: D has single agent activity in a subgroup of pts with Wnt activating mutations, historically identified as a poor prognostic group, whereby they experienced greater clinical benefit and longer survival compared with pts without Wnt activating mutations. A notable finding was that all responding pts had PIK3CA mutations. This study is ongoing and updated results will be presented.
O presente artigo teve por objetivo analisar a producao, a circulacao e os metodos de ensino, pre... more O presente artigo teve por objetivo analisar a producao, a circulacao e os metodos de ensino, presentes nas mobilias escolares para os jovens e adultos das escolas radiofonicas na Amazonia Bragantina, no periodo de 1961-1968. A metodologia utilizada foi a abordagem da Nova Historia Cultural. As imagens contidas nos Livros de Tombo do Tribunal de Contas da Diocese de Braganca, o uso dos decretos e as leis foram as principais fontes deste estudo. Foi constatado que as mobilias eram produzidas na oficina anexada ao Escritorio do Sistema Educativo Radiofonico de Braganca (SERB) e enviadas apenas para tres municipios. As outras localidades fabricavam suas mobilias com a ajuda dos marceneiros de suas respectivas comunidades. Foram identificadas, nas imagens, o uso de dois tipos de mobilias escolares nas escolas radiofonicas: a de mesas rusticas com cadeiras de assento e apoio para as costas, encontradas numa escola municipal. Elas variavam de tamanho, visto que eram produzidas para o ensi...
Background: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT ... more Background: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01, a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. We report response and survival outcomes in EEC patients (pts) treated with DKN-01 monotherapy by tumor genetics (Wnt signaling alterations and PI3K/AKT mutations). Methods: Pts with recurrent EEC were treated with DKN-01 as monotherapy (mono) or in combination with paclitaxel in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on EEC mono group only. Clopper-Pearson confidence intervals and logistic regression were used to study the association of Wnt signaling alterations with clinical benefit (CR, PR or SD) following DKN-01 monotherapy; Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PF...
Extracellular vesicles (EVs) are recognized cancer biomarkers, however, clinical analysis has bee... more Extracellular vesicles (EVs) are recognized cancer biomarkers, however, clinical analysis has been difficult due to a lack of simple and sensitive assays. Here, we describe a bead-enhanced flow cytometry method, BEAD flow, using biotinylated EVs captured on streptavidin particles. With this method, we show analysis of patient-derived EVs using a panel of pancreatic cancer biomarkers. BEAD flow is easily translatable to any biomarker or cancer type and can be run with conventional flow cytometers, making it highly flexible and adaptable to diverse research and clinical needs.
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