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Rice, William G., Jeff Lightfoot, Hongying Zhang, Tiffany Cheng, Avanish Vellanki, Robert Peralta, Stephen B. Howell, Andrea Local, Fannie Chau, and Luis Esquivies. "Clinical Pharmacokinetics of Apto-253 Support Its Use As a Novel Agent for the Treatment of Relapsed or Refractory Hematologic Malignancies." Blood 126, no. 23 (December 3, 2015): 4934. http://dx.doi.org/10.1182/blood.v126.23.4934.4934.
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Abstract APTO-253 is a novel anticancer small molecule currently in a multicenter open-label, Phase I dose escalation study in patients with relapsed or refractory hematologic malignancies. APTO-253 has potent cytotoxic activity against leukemia, lymphoma and myeloma cell lines IC50s of 6.9 - 305 nM. APTO-253 produces significant tumor growth inhibition in the KG-1, THP-1 and Kasumi-1 xenograft models of human acute myeloid leukemia (AML). The anticancer activity of APTO-253 is mediated through induction of Krüppel-like factor 4 (KLF4), a tumor suppressor that is epigenetically silenced in many solid tumors and hematologic cancers. KLF4 expression is often downregulated in AML due to repressive binding of CDX2 to the KLF4 promoter. Increased levels of CDX2 are found in the majority of patients with AML and ALL, as well as in 40% of MDS patients, whereas CDX2 is not expressed in normal hematopoietic cells. Treatment of cultured AML cells with APTO-253 reverses the KLF4 silencing, resulting in induction of p21 and cell death by apoptosis. KG-1 AML cells treated with APTO-253 showed time- and concentration-dependent induction of KLF4 and a concentration-dependent increase in p21 mRNA levels following induction of KLF4. APTO-253 treatment of KG-1 cells for 24 h induced a 14-fold increase in KLF4 mRNA and 16-fold increase in p21 mRNA over basal levels. Following washout of APTO-253, the level of KLF4 mRNA decayed to approximately 50% of maximum induction level over a 24 h period. The potential for APTO-253 as a therapeutic option in AML was further supported by safety and pharmacokinetics data from an earlier Phase I trial of APTO-253 in patients with advanced or metastatic solid tumors during which APTO-253 was administered at doses of 20 - 387 mg/m2 using a dosing schedule of days 1 and 2, and 15 and 16 of a 28 day cycle. APTO-253 showed a dose-dependent increase in Cmax and AUC, and as the dose was escalated from 80 to 176 mg/m2 the Cmax ranged from 1,800 - 4,960 nM on day 1 and 1,600 - 6,100 nM on day 2. These results suggest that exposure levels from these doses of APTO-253 should be sufficient for single agent activity in patients with AML and other hematologic malignancies. APTO-253 demonstrated a favorable safety profile when tested against 5 major cytochrome P450 enzymes (1A2, 2C19, 2C9, 2D6 and 3A4), against a panel of proteins and receptors, and in the hERG tail current density assay. Metabolic profiling of APTO-253 at 50 μM in human liver microsomes showed no glutathione or glucuronide conjugation and only a minor hydroxylated metabolite. Finally, 1 μM APTO-253 did not inhibit kinases in a safety panel (40 kinases) or in a broad oncology panel (98 kinases), demonstrating that APTO-253 activity is not driven by kinase inhibition. Taken together, our results demonstrate that APTO-253 has substantial potential for the treatment of AML and other hematologic malignancies and is of particular interest due to its ability to modulate the expression of the KLF4 master transcription factor that plays a central role in restraining the growth of leukemic cells. Disclosures Howell: Aptose Biosciences: Consultancy, Equity Ownership; Angstrom: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abeoda: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; InhibRx: Equity Ownership.
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Rice, William G., Avanish Vellanki, Yoon Lee, Jeff Lightfoot, Robert Peralta, Mona Jamerlan, Hongnan Jin, Ronnie Lum, and Tiffany Cheng. "APTO-253 Induces KLF4 to Promote Potent in Vitro Pro-Apoptotic Activity in Hematologic Cancer Cell Lines and Antitumor Efficacy As a Single Agent and in Combination with Azacitidine in Animal Models of Acute Myelogenous Leukemia (AML)." Blood 124, no. 21 (December 6, 2014): 4813. http://dx.doi.org/10.1182/blood.v124.21.4813.4813.
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Abstract APTO-253, a small molecule that mediates anticancer activity through induction of the Krüppel-like factor 4 (KLF4) tumor suppressor, is being developed clinically for the treatment of acute myelogenous leukemia (AML) and high risk myelodysplastic syndromes (MDS). APTO-253 was well tolerated in a Phase I study in patients with solid tumors using a dosing schedule of days 1, 2, 15, 16 of a 28 day cycle (2T-12B-2T-12B), but recent scientific observations guided APTO-253 toward AML and high risk MDS. Indeed, suppression of KLF4 was reported as a key driver in the leukemogenesis of AML and subsets of other hematologic diseases. The vast majority (~90%) of patients with AML aberrantly express the transcription factor CDX2 in human bone marrow stem and progenitor cells (HSPC) (Scholl et al., J Clin Invest. 2007, 117(4):1037-48). The CDX2 protein binds to CDX2 consensus sequences within the KLF4 promoter, thereby suppressing KLF4 expression in HSPC (Faber et al., J Clin Invest. 2013, 123(1):299-314). Based on these observations, the anticancer activity of APTO-253 was examined in AML and other hematological cancers. APTO-253 showed potent antiproliferative activity in vitro against a panel of blood cancer cell lines, with ηM IC50values in AML (6.9 - 305 ηM), acute lymphoblastic leukemia and chronic myeloid leukemia (39 – 250 ηM), non-Hodgkin’s lymphoma (11 – 190 ηM) and multiple myeloma (72 – 180 ηM). To explore in vivo efficacy, dose scheduling studies were initially conducted in the H226 xenograft model in mice. In the H226 model, APTO-253 showed improved antitumor activity when administered for two consecutive days followed by a five day break from dosing (2T-5B) each week, i.e. on days 1,2, 8,9, 15,16, 22,23, compared to the 2T-12B-2T-12B schedule. The 2T-5B schedule was used to evaluate antitumor activity of APTO-253 in several AML xenograft models in mice. In Kasumi-1 AML and KG-1 AML xenograft models, APTO-253 showed significant antitumor activity (p = 0.028 and p=0.0004, respectively) as a single agent when administered using the 2T-5B schedule each week for four weeks compared to control animals. Mice treated with APTO-253 had no overt toxicity based on clinical observations and body weight measurements. Mice bearing HL-60 AML xenograft tumors were treated with APTO-253 for one day or two consecutive days per week for three weeks, either as a single agent or combined with azacitidine, or with azacitidine alone twice per week (on days 1,4, 8, 11, 15 and 18). APTO-253 as a single agent inhibited growth of HL-60 tumors to approximately the same extent as azacitidine. Furthermore, both once weekly and twice weekly dosing of APTO-253 in combination with azacitidine resulted in significantly enhanced antitumor activity relative to either single agent alone (p = 0.0002 and p = 0.0006 for 1X and 2X weekly APTO-253 treatment, respectively, compared to control). Likewise, using a THP-1 AML xenograft model, APTO-253 administered as a single agent using the 2T-5B per week schedule showed significant efficacy, similar to that of azacitidine, while the combination of APTO-253 and azacitidine demonstrated greatly improved antitumor effects relative to either drug alone. APTO-253 was effective and well tolerated as a single agent or in combination with azacitidine in multiple AML xenograft models, plus APTO-253 does not cause bone marrow suppression in animal models or humans. Taken together, our results indicate that APTO-253 may serve as a targeted agent for single agent use and may provide enhanced efficacy to standard of care chemotherapeutics for AML and other hematological malignancies. Disclosures Rice: Lorus Therapeutics Inc.: Employment. Vellanki:Lorus Therapeutics Inc.: Employment. Lee:Lorus Therapeutics Inc.: Employment. Lightfoot:Lorus Therapeutics Inc.: Employment. Peralta:Lorus Therapeutics Inc.: Employment. Jamerlan:Lorus Therapeutics Inc.: Employment. Jin:Lorus Therapeutics Inc.: Employment. Lum:Lorus Therapeutics Inc.: Employment. Cheng:Lorus Therapeutics Inc.: Employment.
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Antonelli, Patrick J., Kristen M. Lloyd, and James C. Lee. "Gastric Reflux is Uncommon in Acute Post-Tympanostomy Otorrhea." Otolaryngology–Head and Neck Surgery 132, no. 4 (April 2005): 523–26. http://dx.doi.org/10.1016/j.otohns.2004.12.004.
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OBJECTIVE: Acute post-tympanostomy otorrhea (APTO) is a common complication of tympanostomy tube placement. APTO has been related primarily to viral upper respiratory infections and external ear contamination. Elevated levels of gastric enzymes have been found in a large proportion of chronic middle ear effusions, implicating gastric reflux (GR) in its pathogenesis. Thus, our objective was to determine whether GR may be a contributing factor in the development of APTO. STUDY DESIGN AND SETTING: Prospective, nonrandomized design. Otorrhea samples were collected from children with APTO. Total pepsinogen concentrations were measured with a commercial ELISA, using a pepsinogen I–specific capture antibody and horseradish peroxidase detection antibody. RESULTS: Twenty-six samples from 24 patients were collected and analyzed. Eight samples demonstrated measurable pepsinogen I, but the measured concentrations, 2-17 mg/L, were below the normal serum reference ranges. CONCLUSIONS: GR does not play a major role in the development of APTO in children.
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Zhang, Hongying, Andrea Local, Khalid Benbatoul, Peter Folger, Susan Sheng, Luis Esquivies, Jeff Lightfoot, Avanish Vellanki, and William G. Rice. "Inhibition of c-Myc By Apto-253 As an Innovative Therapeutic Approach to Induce Cell Cycle Arrest and Apoptosis in Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 1716. http://dx.doi.org/10.1182/blood.v128.22.1716.1716.
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Abstract The c-Myc multifunctional transcription factor protein, a product on the c-myc proto-oncogene, contributes to the pathogenesis of many types of human cancers through mechanisms of proliferation, apoptosis, cell cycle progression and cellular senescence. c-Myc is frequently overexpressed in acute myeloid leukemia, yet strategies to effectively modulate c-Myc function do not exist. We evaluated inhibition of c-myc gene expression by APTO-253, a small molecule anticancer agent that is being developed clinically for the treatment of acute myelogenous (myeloid) leukemia (AML) and high risk myelodysplastic syndromes (MDS). We first confirmed that c-Myc mRNA level were significantly higher in AML cell lines as compared to peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors. However, the c-Myc expression in AML cells was inhibited by APTO-253 in dose-dependent and time-dependent manners at both the mRNA and protein levels. Likewise, APTO-253 was found to induce AML cell apoptosis in dose-dependent and time-dependent manners as demonstrated by positive Annexin-V staining and increases in cleaved poly (ADP-ribose) polymerase (c-PARP). APTO-253 induced AML cells arrest at G1/G0 phase of cell cycle by increasing p21 expression and decreasing expression of cyclin D3 and cyclin-dependent kinases 4/6 (CDK4/6). For the p53 positive cell lines MV4-11 and EOL-1, p53 was also increased by APTO-253 at early time points (less than 6-hour treatment), suggesting that p53-dependent cell cycle arrest and apoptosis is mechanistically operative as a consequence of treatment with APTO-253. Importantly, we demonstrated that APTO-253 selectively targeted tumor cells but not normal healthy cells, with MV4-11 AML cells and normal PBMCs having IC50s of 0.25±0.03µM and more than 100µM, respectively. Our previous studies (56th ASH abstract #4813) showed that APTO-253 induces the Krüppel-like Factor 4 (KLF4) transcription factor and was effective and well tolerated as a single agent in multiple AML xenograft models without causing bone marrow suppression. Taken together, our results suggested that APTO-253 may serve as an effective and safe agent for AML chemotherapy, and that APTO-253 mechanistically inhibits c-Myc expression in AML cells and subsequently induces cell cycle arrest and apoptosis. Disclosures No relevant conflicts of interest to declare.
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Tsai, Cheng-Yu, Hongying Zhang, William G. Rice, and Stephen B. Howell. "Synthetic Lethal Interaction between Apto-253 and IDH1/2 Mutations." Blood 134, Supplement_1 (November 13, 2019): 5755. http://dx.doi.org/10.1182/blood-2019-123571.
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APTO-253 is a small molecule with a novel mechanism of action and potent antiproliferative activity against cell lines derived from a wide range of human malignancies. A Phase 1 study of APTO-253 was completed in patients with advanced solid tumors. It was well tolerated and produced evidence of antitumor activity in patients but did not cause myelosuppression even at the maximum tested dose. A phase 1a/b trial of APTO-253 in patients with relapsed/refractory acute leukemias (including AML) and high-risk MDS (NCT02267863) is currently underway. We previously reported that APTO-253 was converted intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]. Both APTO-253 and Fe(253)3 stabilized DNA quadruplex (G4) structures in the Myc promotor region to reduce the expression of Myc (Figure 1). Stabilization of G4 structures has been reported to stall replication forks and produce DNA strand breaks. Treatment of cancer cells with APTO-253 produced time and concentration-dependent γH2AX foci formation and DNA double strand breaks that have to be repaired by homologous recombination. Loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 whose magnitude was similar to the effects of PARP inhibitors, olaparib. Thus, APTO-253 is a member of the limited repertoire of drugs which can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression. The goal of this project was to identify synthetic lethal interactions in addition to BRCA1/2 deficiency that can guide combination drug studies. The normal function of the isocitrate dehydrogenase (IDH) enzymes is to catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the citric acid cycle. IDH1 mutations occur in more than 70% of low-grade gliomas, 20% of high-grade glioblastomas and with a frequency of about 10% in AML, cholangiocarcinomas, melanomas and chondrosarcomas. Additionally, mutations are also identified in IDH2 in about 4% of gliomas and 10% of AMLs. IDH1/2 alterations are heterozygous missense mutations that confer a neomorphic activity on the encoded enzyme such that they covert αKG to (R)-2-hydroxyglutarate [(R)-2HG]. (R)-2HG is an oncometabolite with pleiotropic effects on cell biology including chromatin methylation and cellular differentiation. It was reported that IDH1/2 mutations induce a homologous recombination defect that renders tumor cells exquisitely sensitive to PARP inhibitors. We used 2 pairs of isogenic IDH1 wild type and mutant cell lines to test the hypothesis that cells carrying IDH1/2 mutations are hypersensitive to APTO-253. Induction of the expression of IDH1 R132H in THP-1 AML cells increased the 2-HG concentration ~150-fold whereas induction of wild-type IDH1 expression increased it only 2-fold (doi: 10.1038/nm.3788). THP-1 cells expressing the mutant IDH1 R132H were hypersensitive the treatment of APTO-253 compared to cells expressing the wild-type IDH1 (Figure 2). Comparison of wild-type and isogenic IDH1 R132H HCT116 cells disclosed a ~100-fold higher level of (R)-2-HG in the mutant cells (doi: 10.1126/scitranslmed.aal2463), and an increase in sensitivity to the cytotoxic effect of APTO-253 (Figure 3). These results are consistent with the observation that both APTO-253 and increased levels of 2-HG cause DNA damage that depends on homologous recombination for repair and that this favors a synthetic lethal interaction. We surmise that the ability of APTO-253 to markedly reduce the expression of Myc further contributes to the favorable interaction. This data further supports the conclusion that defects in homologous DNA repair can enhance the potency of APTO-253 and suggest the use of this non-myelosuppressive drug in both IDH1/2 mutant AML and solid tumors. Disclosures Zhang: Aptose Biosciences, Inc: Employment. Rice:Aptose Biosciences, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Howell:Aptose Biosciences, Inc: Consultancy, Research Funding.
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Tsai, Cheng-Yu, Hongying Zhang, Andrea Local, William G. Rice, and Stephen B. Howell. "Mechanisms of Resistance to Apto-253." Blood 128, no. 22 (December 2, 2016): 5247. http://dx.doi.org/10.1182/blood.v128.22.5247.5247.
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Abstract APTO-253 is a small molecule indolyl-phenanthroline-imidazole that exerts potent cytotoxicity against human acute myeloid leukemia and lymphoma cells but not normal PBMC or bone marrow cells. The goal of this project was to provide fundamental information on the mechanism of resistance of APTO-253 so as to identify synthetic lethal interactions that can guide combination drug studies. The human Burkitt's lymphoma cell line Raji was exposed to progressively increasing concentrations of APTO-253 over a period of 6 months to generate the resistant subline Raji/253R. Raji/253R cells were 16.7 ± 3.9-fold resistant to a 120 h exposure to APTO-253 (IC50: Raji IC50 91.9 ± 22.3 nm; Raji /253R IC50 1387.7 ± 98.5 nm). The level of resistance remained stable for at least 3 month during culture in drug-free media. Exposure of the parental Raji cells to 500 nM APTO-253 for 24 h produced: a) G1 arrest accompanied by up-regulation of proapoptotic proteins BIK and BAD and down-regulation of anti-apoptotic protein MCL-1; b) cleavage of PARP; and, c) time-dependent up-regulation of γH2AX. None of these changes were detected in the Raji/253R cells subjected to the same exposure. RNA-seq analysis of the parental and resistant cells in the absence of drug exposure demonstrated marked up-regulation of ATP-binding cassette sub-family G member 2 (ABCG2) in the Raji/253R cells that was confirmed by qRT-PCR and Western blot analysis. Ko143 is a specific inhibitor of ABCG2 that was not toxic to either Raji or Raji/253R when used as a single agent. When Raji/253R cells were concurrently treated with either 5 nM or 50 nM Ko143 and APTO-253, resistance to APTO-253 was reversed by 1.6- and 6.8-fold, respectively, confirming that overexpression of ABCG2 is one mechanism of resistance to APTO-253. The overexpression of ABCG2 in Raji/253R resulted in 2.2-fold less intracellular APTO-253 in Raji/253R cells relative to the Raji cells after a 6 h exposure to 500 nM APTO-253. Raji/253R was found to be cross-resistant to topotecan, a known ABCG2 substrate, and Ko143 also reverses topotecan resistance in Raji/253R. Etoposide is also an ABCG2 substrate but, surprisingly, Raji/253R cells were found to be hypersensitive to etoposide. Etoposide is a non-intercalating topoisomerase II inhibitor and a potent inducer double strand breaks. The hypersensitivity to etoposide in Raji/253R suggests that DNA repair pathways are aberrant in the Raji/253R cells. The second major finding in the Raji/253R cells is that they express only a truncated 45 kDa form of c-Myc in which 159 nucleotides (53 amino acids) are missing from exon 2. Sanger sequencing disclosed microhomologies at each end of the deletion suggesting that microhomology mediated end-joining (MMEJ) repair of a double strand break produced as a result of APTO-253 exposure was responsible for the deletion. BRCA1 plays crucial roles in both homologous recombination (HR) and non-homologous end joining (NHEJ) repair. The RNA-seq RPKM (reads per kilobase exon per million) data revealed that there was less BRCA1 in Raji/253R suggesting that the two classic DNA repair mechanisms (HR and NHEJ) may be impaired in the Raji/253R cells. We conclude that high level resistance to APTO-253 is mediated in part by ABCG2, and that adaption to the drug has resulted in expression of an altered form of c-Myc whose link to the resistant phenotype is not yet established. Disclosures No relevant conflicts of interest to declare.
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Dantas Amaral, Gabriella, and Raquel Naiara Fernandes Silva. "Análise pericial de aterros industriais no município de Uberlândia (MG) com o uso de geotecnologias." Revista de Geociências do Nordeste 8, no. 1 (April 14, 2022): 103–17. http://dx.doi.org/10.21680/2447-3359.2022v8n1id25950.
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O monitoramento de aterros sanitários industriais se destaca pela sua importância diante do contexto de disposição final de resíduos, pois permite o controle operacional desses sistemas e contribui para a minimização dos impactos ambientais provocados por essas unidades. Diante disso, esta pesquisa visa estudar e praticar o uso de geotecnologias na realização de análises periciais nos aterros industriais de Uberlândia-MG e tem como apoio à decisão através da lógica booleana. A investigação criteriosa desses locais é de suma importância, pois, garante a minimização dos impactos oriundos deste empreendimento. A metodologia deste trabalho visou a estipulação de critérios de restrição, seguindo as diretrizes normativas vigentes, analisando os aterros que admitem resíduos industriais quanto a sua localização através de mapas booleanos com classificação de apto ounão apto. O resultado do mapa final de aptidão revelou que os aterros industriais no município de Uberlândia não estão em uma região apta. Por fim, caracterizou-se as técnicas de geoprocessamento como uma ferramenta prática e confiável. Apesar dos objetivos estabelecidos terem sido atingidos, análises in loco são de extrema importância a fim de corroborar o presente trabalho.
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Lombardero, Martín. "Apto Físico Pre Competitivo en Mayores De 35 Años: Paradojas, Falacias y Misterios de un Falso Seguro De Vida." Revista de Ecocardiografía Práctica y Otras Técnicas de Imagen Cardíaca 5, no. 3 (December 19, 2022): 1–4. http://dx.doi.org/10.37615/retic.v5n3a1.
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En la creencia popular el apto fisico precompetitivo se lo interpreta como una poliza de seguro de vida. La comunidad medica sabe que no es asi. Existes variables inmanejables cuando el deportista compite. La tasa de muerte subita (MS) es muy baja en menores de 35 años (la mayoria de la causas de MS son congenitas), pero es mayor en mayores de 35 años. Esta poblacion, ademas de estar en constante crecimiento, es la mas compleja de evaluar porque la mayor parte de las MS ocurren por enfermedad coronaria, impredecible e indetectable con test funcionales mientras transcurre la variante subclinica. Y los aptos fisicos precompetitivos en mayores de 35 años tienen vigencia por un año. Si bien son utiles para evaluar su estado actual con reevaluacion de factores de riesgo, no pueden asegurar que ante un esfuerzo intenso y en otras condiciones metabolicas y psicologicas, no se genere un evento coronario. Evaluamos el rol del apto fisico precompetitivo en esta poblacion y el rol de la calcificacion coronaria en el deporte.
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Carrión Gordón, Hugo. "Redes sociales: ¿ambiente apto para menores?" Hachetetepé. Revista científica de Educación y Comunicación 2, no. 1 (2010): 105–10. http://dx.doi.org/10.25267/hachetetepe.2010.v2.i1.11.
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Hernández Sánchez, Tania, and Dumá Méndez Esteban. "Elaboración de pan apto para celiacos." Boletín Científico de las Ciencias Económico Administrativas del ICEA 11, no. 21 (December 5, 2022): 68–69. http://dx.doi.org/10.29057/icea.v11i21.9683.
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La enfermedad celíaca, es una enfermedad inflamatoria de origen autoinmune desencadenada por la ingesta de gluten, la cual es una proteína compuesta por los glucoprotéinas, la gliadiana y la glutenina. El gluten se encuentra en cereales como el trigo, cebada y centeno, por lo que el tratamiento para esta enfermedad es eliminar de la dieta estos cereales, así como cualquier alimento que los contenga. En la panificación el principal ingrediente utilizado es la harina de trigo, por lo que resulta complicado consumir alimentos panificados para las personas con celiaquía. Es así como se han buscado formulaciones de harinas de otros cereales o leguminosas que permitan conferir las características de calidad que ofrece la harina de trigo, por lo cual se detalla la elaboración de un pan libre de gluten.
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Kurtz, Stephen E., Daniel Bottomly, Beth Wilmot, Shannon K. McWeeney, William Rice, Stephen B. Howell, Avanish Vellanki, Brian J. Druker, and Jeffrey W. Tyner. "Broad Activity of Apto-253 in AML and Other Hematologic Malignancies Correlates with KLF4 Expression Level." Blood 126, no. 23 (December 3, 2015): 1358. http://dx.doi.org/10.1182/blood.v126.23.1358.1358.
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Abstract Introduction: Aberrant expression of the homeodomain transcription factor CDX2 has recently been reported in a large proportion of AML cases. One consequence of CDX2 deregulation appears to be repressed expression of the transcription factor KLF4. Repression of KLF4 was shown to be critical for CDX2-mediated tumorigenesis, and forced genetic de-repression of KLF4 led to apoptosis of AML cells. APTO-253 is a novel small molecule that induces the expression of KLF4 and is cytotoxic to AML cell lines at low-nanomolar concentrations. We evaluated the activity of APTO-253 against a broad panel of primary specimens from patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). APTO-253 was tested both as a single agent and in combinations with 2 other emerging targeted therapies, the BET bromodomain inhibitor JQ1 and the FLT3 inhibitor quizartinib. Methods: We used an ex vivo drug sensitivity assay to determine the activity of APTO-253, JQ1, and quizartinib across increasing concentrations of each agent up to 10 μM. Combinations were tested at fixed, equimolar ratios over the same concentration range. After a 3-day ex vivo culture, cell viability was assessed using a colorimetric tetrazolium-based MTS assay, and IC50 values were calculated. RNA-Seq was performed on AML specimens to permit investigation of correlations of drug sensitivity with gene expression levels. Results: We evaluated specimens from 177 patients with a variety of hematologic malignancy diagnoses (80 AML, 72 CLL, 25 MDS/MPN). The highest frequency of APTO-253 sensitivity occurred in AML, with 43/80 (54%) samples exhibiting an IC50 <1 μM. At this cutoff, 25/72 (35%) CLL samples and 3/25 (12%) MDS/MPN samples were sensitive to APTO-253. The average expression of KLF4 mRNA was 2-fold lower among AML samples with an IC50 <1 µM compared to those with IC50 >1 µM (p=0.07). Approximately 65% (56/87) of cases tested with a combination of APTO-253 and JQ1 showed the combination IC50 to be at least 2-fold lower than the IC50 of either agent alone. This enhanced efficacy of APTO-253 with JQ1 was observed across all 3 hematologic malignancies tested, whereas quizartinib enhancement of APTO-253 sensitivity was confined to AML (14/38, or 37% showed reduced IC50). Conclusions: These results support the potential of KLF4 as an important and frequently dysregulated master transcription factor in AML and suggest that the KLF4 inducer APTO-253 is effective at killing tumor cells in a majority of AML samples. The data also indicate activity of APTO-253 in other hematologic malignancies, namely CLL. Expression level of KLF4 may be one component of a biomarker for prediction of APTO-253 efficacy; a more extensive global gene expression signature analysis is under way. Finally, these data have identified prominent interaction of APTO-253 with the BET bromodomain inhibitor JQ1, as well as AML-restricted interaction of APTO-253 with the FLT3 inhibitor quizartinib, suggesting these classes of drugs as potential combination partners for APTO-253. Disclosures Rice: Aptose Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Howell:Aptose Biosciences: Consultancy, Equity Ownership; Angstrom: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abeoda: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; InhibRx: Equity Ownership. Vellanki:Aptose Biosciences: Employment, Equity Ownership. Druker:Oncotide Pharmaceuticals: Research Funding; Sage Bionetworks: Research Funding; Fred Hutchinson Cancer Research Center: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis Pharmaceuticals: Research Funding; Henry Stewart Talks: Patents & Royalties; McGraw Hill: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; AstraZeneca: Consultancy; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Tyner:Incyte: Research Funding; Janssen Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding.
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Howell, Stephen B., Hongying Zhang, and William G. Rice. "A Phase 1a/b Dose Escalation Study of Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS." Blood 134, Supplement_1 (November 13, 2019): 5148. http://dx.doi.org/10.1182/blood-2019-129685.
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INTRODUCTION: APTO-253 has captured attention because of its distinguishing mechanism of action as the only known a small molecule in clinical development to target a conserved structure in the promoter of the MYC oncogene and interrupt MYC gene expression. In preclinical studies of acute myeloid leukemia (AML) cell lines, APTO-253 was discovered to potently down-regulate MYC gene expression, reduce MYC mRNA and protein level, induce apoptosis, and deplete cells of the MYC oncoprotein. APTO-253 demonstrated broad killing of primary mononuclear cells isolated from the bone marrow of patients with AML, MDS or MPN and enhanced AML cell killing when combined with BET bromodomain inhibitors or FLT3 inhibitors (Kurtz, Blood 2017 126:1358). Because dysregulated MYC is considered a major oncogenic operator in AML and myelodysplasias and because APTO-253 has such a distinct mechanism to kill such cells, APTO-253 has been granted orphan drug designation for the treatment of AML by the US FDA and is currently in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS). METHODS: APTO-253 is being evaluate in an ongoing clinical trial, entitled "A Phase I a/b Dose Escalation and Expansion, Multicenter, Open-label, Safety, Pharmacokinetic and Pharmacodynamic Study of APTO-253 in Patients with Relapsed or Refractory Acute Myelogenous Leukemia or High-Risk Myelodysplasia (NCT02267863)". The protocol provides for patients to be dosed once weekly on days 1, 8, 15, and 22 of each 28-day cycle with the intended dose levels of 20, 40, 66, 100, 140, 180 or 220 mg/m2. Eligible patients must be ≥18 years old, have a life expectancy of at least 2 months, and have acceptable hematologic, renal and liver functions and coagulation status parameters. Primary objectives are to determine the safety and tolerability of APTO-253, to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT), and to establish the recommended Phase 2 dose for patients with specific types of hematologic malignancies. Key secondary objectives are to seek evidence of antitumor activity by hematologic and bone marrow evaluations and to assess the impact of APTO-253 on the expression of pharmacodynamic biomarkers (including MYC and p21 gene expression). RESULTS: To date, R/R AML and high-risk MDS patients have been enrolled and treated at dose levels of 20, 40 and 66 mg/m2 APTO-253. As specified by the protocol, only one patient was required at each of the 20 and 40 mg/m2 doses. The AML patient on the lowest dose level completed the 28-day cycle and demonstrated approximately a 72% reduction in MYC expression levels in peripheral white blood cells during the cycle. The high-risk MDS patient who received 40 mg/m2 demonstrated a 79% reduction in MYC expression during the first cycle. To date (as of July 2019), no drug related TEAEs, SAEs or dose limiting toxicities have been reported. Two patients are receiving treatment with 66 mg/m2, and samples are being analyzed for a series of pharmacodynamic markers. CONCLUSIONS: APTO-253 is a potent molecule with a particularly interesting and novel mechanism of action that results in robust suppression of MYC expression. The Phase 1 a/b trial has successfully enrolled R/R-AML and HR-MDS patients into the first three cohorts at 20, 40 and 66 mg/m2. Clinical data to date suggest APTO-253 is generally well tolerated at the doses tested, and target engagement has been evidenced by the reduction in cellular MYC gene expression in whole blood samples from R/R AML and high-risk MDS patients. Recruitment and enrollment are continuing, and updated safety, PK and biomarker data will be presented at the meeting. Disclosures Howell: Aptose Biosciences, Inc: Consultancy, Research Funding. Zhang:Aptose Biosciences, Inc: Employment. Rice:Aptose Biosciences, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Lopes, Renata Costa, and Raquel Naiara Fernandes Silva. "Uso de lógica booleana na triagem de áreas aptas para a implantação de aterro sanitário no Município de Campina Verde, Minas Gerais, Brasil." Revista Brasileira de Gestão Ambiental e Sustentabilidade 7, no. 16 (2020): 487–99. http://dx.doi.org/10.21438/rbgas(2020)071603.
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A redução das milhões de toneladas de lixo que a civilização produz todos os dias é um dos maiores desafios da atualidade. No Brasil, dar destinação correta a esse lixo é uma meta ainda distante. Em Minas Gerais, cerca de 25,29% da população urbana reside em áreas que não possuem meios de descarte de seus resíduos sólidos em aterros sanitários, destinando-os em lixões e/ou aterros controlados. Neste contexto, este estudo tem como objetivo avaliar a aptidão de áreas para a instalação de aterros sanitários no Município de Campina Verde-MG, com o uso de SIG e apoio à decisão através da lógica booleana. Uma análise criteriosa destes espaços territoriais é importante para garantir a minimização dos impactos ambientais provenientes desse tipo de empreendimento. A metodologia deste estudo consistiu no estabelecimento dos critérios de restrição, originando mapas booleanos com classificação de apto/não apto. O resultado foi o mapa de aptidão para a instalação de aterro sanitário, que revelou 1.924,64 km² de área apta à instalação de aterro sanitário. A conclusão do estudo caracteriza as técnicas de geoprocessamento como uma ferramenta eficaz, rápida e de baixo custo, que podem vir a ser aplicadas em outros municípios, facilitando desta maneira a disposição final adequada dos resíduos sólidos urbanos.
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Burchill-Limb, K. Y., and John Oldfield. "‘De pulchro et apto’ de san Agustín." Augustinus 48, no. 188 (2003): 27–33. http://dx.doi.org/10.5840/augustinus200348188/1914.
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Arenson-Pandikow, Helena M., Ronaldo Bordin, Jane Maria Reos Wolff, and Maria Carlota Borba Brum. "ESTÁGIO URGÊNCIA E EMERGÊNCIA: PROJETO INTEGRADO DE AVALIAÇÃO DO ENSINO MÉDICO." Revista Brasileira de Educação Médica 18, no. 3 (December 1994): 116–20. http://dx.doi.org/10.1590/1981-5271v18.3-004.
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Resumo: Este trabalho descreve o nível referido de aquisição de habilidades psicomotoras na área de urgência e emergência, obtidas por estudantes de Medicina do 11º semestre, durante um mês de treinamento no Hospital Municipal de Pronto Socorro de Porto Alegre (HPS-PoA). Questionários contendo uma listagem de habilidades técnicas inquiriam, antes do treinamento e imediatamente após, se os alunos consideravam-se aptos ao desempenho dessas habilidades. Na análise, as habilidades foram agrupadas de acordo com áreas de treinamento: clínica médica, politraumatizados, sutura, traumatologia e hemoterapia. Houve incremento significativo de respondentes que se consideraram aptos em 23 das 32 habilidades listadas. Quanto ao desempenho não houve diferença significativa em 15 das habilidades estudadas. Estes resultados sugerem que o fato do aluno julgar-se apto à execução de uma habilidade não significa que ele a lenha desempenhado durante seu período de treinamento.
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Bejar, Rafael, Hongying Zhang, Nasrin Rastgoo, Khalid Benbatoul, Yuying Jin, Matthew Thayer, Susan Sheng, et al. "A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS." Blood 136, Supplement 1 (November 5, 2020): 45–46. http://dx.doi.org/10.1182/blood-2020-141409.
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INTRODUCTION: APTO-253 is the only known small molecule in clinical development to target a conserved G-quadruplex structure in the promoter of the MYC oncogene and interrupt MYC gene expression. In preclinical studies of acute myeloid leukemia (AML) cell lines, APTO-253 potently down-regulates MYC gene expression, reduces MYC mRNA and protein level, depletes cells of the MYC oncoprotein and induces apoptosis (Local et al., 2018). APTO-253 demonstrated broad killing of primary mononuclear cells isolated from the bone marrow of patients with AML, MDS, or MPN and enhanced AML cell killing when combined with BET bromodomain inhibitors or FLT3 inhibitors (Kurtz, et al., 2017). Fe(253)3, a ferrous complex formed from parental APTO-253 when it chelates iron, exhibits similar in vitro anti-tumor potency as its monomeric form (Tsai, et al., 2018). Because dysregulated MYC is considered a major oncogenic operator in AML and myelodysplasias, and because APTO-253 has such a distinct cytotoxic mechanism, APTO-253 has been granted orphan drug designation for the treatment of AML by the US FDA and is currently in a Phase 1a/b clinical trial (NCT02267863) in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, to determine the maximum tolerated dose and the dose limiting toxicities (DLT), and to establish the recommended Phase 2 dose for future clinical trials in patients with R/R AML or high-risk MDS. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients are those with R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts will enroll at a starting dose of 20 mg/m2 with planned escalating to 403 mg/m2. RESULTS: As of July 28, 2020, a total of 10 patients (age 66.1 ± 13.58 years, male 50%, female 50%, 8 AML and 2 MDS) have been treated with APTO-253 in this clinical trial at doses of 20 mg/m2 (n=1), 40 mg/m2 (n=1), 66 mg/m2 (n=4), and 100 mg/m2 (n=4). All 8 AML patients and 1 MDS patient were RBC and platelet transfusion dependent; 1 MDS patient was RBC transfusion dependent. No DLTs or drug-related serious adverse events have been reported. Possible drug related grade 2 TEAEs included fatigue, increased alkaline phosphatase, decreased appetite, hematoma, hypokalemia, thrombophlebitis, upper respiratory tract in 1 (10%) patient each. Only 1 TEAE of grade 3 or greater (fatigue, considered possibly drug-related) has occurred to date. Preliminary PK analysis showed plasma levels of APTO-253 were dose proportional. Cmax and AUC0-24h on cycle 1 day 1 (C1D1) were 0.18, 0.07, 0.28 ± 0.15 and 0.77 ± 0.63 µM and 0.08, 0.13, 1.14 ± 0.57, 1.84 ± 0.41 µM*h for dose levels of 20 mg/m2, 40 mg/m2, 66 mg/m2, and 100 mg/m2, respectively. Not surprisingly, Fe(253)3 was detected in the patients' plasma immediately after dosing and at a significantly higher concentration than the APTO-253 monomer. For example, Cmax and AUC0-24h of Fe(253)3 on C1D1 of patients in Cohort 66 mg/m2 were 3- and 8-fold higher than the monomer at 0.92 ± 0.29 µM and 20.61 ± 9.01 µM*h, respectively. The levels of MYC mRNA in the whole blood, a PD biomarker of APTO-253 and Fe(253)3 measured by RT-qPCR, were reduced 20-48% at 24 h post-dose as compared to pre-dose in the first 3 cohorts (other samples of Cohort 100 mg/m2 in process), suggesting target engagement by the drug. CONCLUSIONS: APTO-253 has been well-tolerated in patients treated with 20, 40, 66, and 100 mg/m2 over multiple cycles. PK analysis revealed APTO-253 monomer rapidly transformed to and co-existed with the Fe(253)3 complex in peripheral blood and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m2 dose level is underway and updated clinical data will be presented at the meeting. Disclosures Bejar: Aptose Biosciences, Inc: Current Employment, Current equity holder in publicly-traded company. Zhang:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rastgoo:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Benbatoul:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Jin:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Thayer:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Sheng:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Chow:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Montalvo-Lugo:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Marango:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell:Aptose Biosciences, Inc.: Current equity holder in publicly-traded company. Rice:Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company.
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Trunckle, Yuri Franco, Cristina Akemi Okamoto, Caroline Machado Daitx, Diego Toniolo do Prado, Juliana Takitane, and Daniel Romero Muñoz. "Avaliação de Parâmetros Físicos para Direção Veicular: Força, Audição e Visão." Saúde Ética & Justiça 25, no. 2 (January 6, 2020): 63–72. http://dx.doi.org/10.11606/issn.2317-2770.v25i2p63-72.
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De acordo com o Código de Trânsito Brasileiro (CTB), todo candidato à Carteira Nacional de Habilitação (CNH) deve submeter-se ao exame de aptidão física e mental. Essa avaliação, a ser realizada por médicos especialistas em Medicina de Tráfego, é constituída por anamnese, exame físico geral, exames específicos e exames complementares, a critério médico. A avaliação específica envolve diversos aparelhos e sistemas, sendo composta pela avaliação oftalmológica, otorrinolaringológica, cardiorrespiratória, neurológica, do aparelho locomotor e avaliação dos distúrbios do sono. A partir do resultado do exame, o médico perito examinador de trânsito pode considerar o candidato como apto, apto com restrições, inapto temporário e inapto. Objetivos: avaliar os parâmetros de saúde (força da mão, visão e audição) em funcionários e alunos da Faculdade de Medicina da Universidade de São Paulo (FMUSP) com base na resolução 425 do Conselho Nacional de Trânsito (CONTRAN), que determina as normas para obtenção da CNH. Método: foi aplicado questionário padronizado, seguido por exame clínico direcionado, utilizando o equipamento Raizamed®. Resultados: dos 70 participantes, 47 encontravam-se aptos para a direção veicular. Dos 23 que apresentavam alguma alteração ao exame, que os tornou temporariamente ou permanentemente inaptos, 2 tiveram problemas ao teste de campo visual; 15, por força manual; 2, por tempo de reação ao ofuscamento; 2, por combinação de campo visual com força manual; 1, por alterações de acuidade visual e auditiva; e 1, por alteração de força manual, campo visual, acuidade visual e tempo de reação ao ofuscamento. Conclusão: os condutores em exame de direção veicular devem ser avaliados de forma cuidadosa e individual para que cada caso tenha suas peculiaridades observadas a contento.
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Rodríguez Reartes, Sabrina, P. Bima, and M. Jacqueline Joseau. "Desarrollo de una técnica para la obtención de material vegetativo de Eucalyptus dunnii apto para la multiplicación in vitro = Development of a technique to obtain vegetative material of Eucalyptus dunnii suitable." Ciencia & Investigación Forestal 14, no. 3 (July 11, 2008): 539–47. http://dx.doi.org/10.52904/0718-4646.2008.307.
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Ohanian, Maro, Martha L. Arellano, Moshe Y. Levy, Kristen O'Dwyer, Hani Babiker, Daruka Mahadevan, Hongying Zhang, et al. "A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS." Blood 138, Supplement 1 (November 5, 2021): 3411. http://dx.doi.org/10.1182/blood-2021-150049.
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Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.
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Chiaretto, Marcelo. "O nativismo crítico e germanista de Sílvio Romero." O Eixo e a Roda: Revista de Literatura Brasileira 21, no. 2 (December 31, 2012): 145–60. http://dx.doi.org/10.17851/2358-9787.21.2.145-160.
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O artigo busca estudar certas noções críticas de Sílvio Romero eidentificar a posteriori a conformação de um pensamento germanista apto adefender uma concepção bem particular de nativismo crítico na literaturabrasileira.
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Santos, Silvia Evangelista, and Matheus Carvalho Viana. "TECNOLOGIA RENOVADORA DAS VANTAGENS E DESVANTAGENS DO PRONTUÁRIO ELETRÔNICO DO PACIENTE NA ÁREA DA SAÚDE: ESPECIALIZAÇÃO EM INFORMÁTICA EM SAÚDE." Revista Ibero-Americana de Humanidades, Ciências e Educação 7, no. 10 (October 31, 2021): 300–306. http://dx.doi.org/10.51891/rease.v7i10.2413.
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Objetivo: Descrever as vantagens e desvantagens da utilização do prontuário eletrônico do paciente na área da saúde. Método: Trata-se de uma pesquisa de referencial bibliográfico, com artigos publicados no período de 2013 a 2018, coletados nas seguintes bases de dados da LILACS e SCIELO. Resultados: Foram selecionados sete artigos, segundo os critérios de inclusão e exclusão para a leitura completa. Evidenciou-se que os profissionais reconhecem a importância do PEP na área hospitalar e a utilizam em diversos aspectos, contudo ainda encontram limitações quando á seu uso. Conclusão: Verificou-se o reconhecimento da importância do uso do PEP por parte dos profissionais da saúde em unidades hospitalares, porém destaca-se quem nem sempre o profissional está apto a sua utilização ou a instituição está apta a colocá-lo em prática, sendo necessário um árduo trabalho por parte das instituições de ensino e do departamento de educação continuada das instituições.
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Rodríguez, Milagros Elena. "ENFOQUES RIZOMÁTICOS DE LA BIOPOLÍTICA-EDUCACIÓN MATEMÁTICA." Imagens da Educação 11, no. 2 (July 17, 2021): 256–76. http://dx.doi.org/10.4025/imagenseduc.v11i2.54933.
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Con la deconstrucción rizomática como transmétodo, el transparadigma transcomplejo bajo el proyecto transmoderno se analizan enfoques rizomáticos de la diada biopolítica-Educación Matemática. Enmarcada en la línea de investigación: Educación Matemática Decolonial Transcompleja. La escuela y la disciplina son artefactos coloniales de conocer-poder regularizado en la biopolítica conveniente de hacer Educación Matemática. Bajo el develar de la soslayación y las consecuencias en la psique de los actores del proceso educativo en el desarrollo de su personalidad y en la clasificación de apto y no aptos incurren mesetas de salidas: El proceso de enseñanza de la matemática entonces debería aprovecharse para que posibilite el desarrollo humano del individuo, clarificando decolonialmente ¿Qué es dicho desarrollo humano? La necesidad de la decolonialidad del ser y del hacer matemática. La insurrección de los saberes sometidos, la disminución de la pereza febril y el pensamiento abismal entre las matemáticas escolares y no escolares.
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Huang, Beibei, Xiaojun Liu, Xinglong Wang, Yan Pi, Hainian zeng, Juan Lin, Jiong Fei, Xiaofen Sun, and Kexuan Tang. "Genomic cloning and characterization of aPto-like geneSsPto-2fromSolanum surattense." DNA Sequence 16, no. 4 (January 2005): 277–87. http://dx.doi.org/10.1080/10425170500158115.
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Pati Limachi, Alberto, and Mario E. Ramos Flores. "Análisis multicriterio para la identificación de áreas agroecológicas para el Centro Experimental Cota Cota, ciudad de La Paz-Bolivia." Revista de Investigación e Innovación Agropecuaria y de Recursos Naturales 8, no. 2 (August 28, 2021): 102–12. http://dx.doi.org/10.53287/ehoi6370fd86e.
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La presente investigación se llevó a cabo en el Centro Experimental Cota Cota perteneciente a la Facultad de Agronomía de la Universidad Mayor de San Andrés, con el objetivo de identificar: zonas agroecológicas, de uso forestal y de conservación, a través del análisis multicriterio. Es así que, para el trabajo de investigación se tomó seis muestras de suelo extraídas de calicatas con la profundidad de un metro, previamente elaboradas dentro del perímetro del Centro Experimental bajo los criterios de pendiente, proximidad al río y plan del uso del suelo; dichas muestras se llevaron a laboratorio y el resultado del análisis físico y químico fue mapeado a través de un software que aplique Sistemas de Información Geográfica (SIG), haciendo uso de las herramientas de interpolación espacial de datos Kriging e IDW. Los suelos más aptos para el uso agroecológico, son aquellos ubicados según el centroide generado por computadora en la siguiente coordenada: latitud 16° 32' 10.7'' Sur y longitud 68° 3' 51.2'' W. Indicando un suelo con 10-30 % de pendiente, pH neutro (6.54-7.14), un NDVI mayor a 0.4, textura franco arcillosa, potasio intercambiable 0.6-1 meq 100gS°-1, la materia orgánica es de 0.55-1.5%, el porcentaje de nitrógeno total esta entre los 0.2-0.3%, el fósforo disponible supera las 50 ppm, finalmente la capacidad de intercambio catiónico (CIC) entre 17.50-20.64 meq 100gS°-1. Según los parámetros utilizados en el análisis multicriterio, un suelo apto para la agroecología no necesita tener el máximo nivel de clasificación en sus propiedades. Solo el 1.1 % de toda el área total es apta, lo cual corresponde a aproximadamente 1 800 m2, mas el resto son forestales y para conservación.
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Martins Junior, Valter, Simone Mendonça Dos Santos, Beatriz Cruz Gonzalez, Lia Lorena Pimentel, and Regina Márcia Longo. "FILTRAÇÃO LENTA DOMICILIAR COM MEIOS FILTRANTES RECICLADOS PROVENIENTES DE RESÍDUOS DA CONSTRUÇÃO CIVIL." Científic@ - Multidisciplinary Journal 6, no. 1 (May 29, 2019): 87–103. http://dx.doi.org/10.29247/2358-260x.2019v6i1.p87-103.
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Um sistema de tratamento de água apto para utilização em comunidades isoladas é o filtro lento domiciliar. Este trabalho comparou a eficiência de um filtro lento domiciliar com meios filtrantes oriundos de resíduos da (FLD reciclado), com um filtro lento domiciliar convencional, avaliando características físico-químicas e microbiológicas da água filtrada, segundo critérios estabelecidos pela Portaria do Ministério da Saúde nº 5/2017 que consolidou a Portaria nº 2914/2011 sobre procedimentos de controle e vigilância da qualidade da água para consumo humano e seu padrão de potabilidade. Os resultados sinalizam que o FLD reciclado pode atender todos os parâmetros analisados, destacando-se a turbidez e os coliformes totais. Sugere-se, portanto, a realização de estudos para determinação do tempo de maturação e da redução do tempo de repouso necessário para que a água filtrada esteja apta para o consumo, tendo em vista a promoção do FLD reciclado como alternativa atrativa em localidades com baixo adensamento populacional.
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Do Nascimento Silva, G. E. "As qualidades diplomáticas e as condições de ingresso na carreira." Revista do Serviço Público 79, no. 01 (January 17, 2020): 20–43. http://dx.doi.org/10.21874/rsp.v79i01.4215.
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Não há com o negar a importân cia da diplomacia no sentido do fortalecimento do p tencial nacional, não só no campo externo, senão também no interno .Graças a uma diplomacia alerta e bem estruturada, pode um govêrnoser mantido a par do desenvolvimento das demais nações, desta parte aproveitando-se da experiência dos mesmos. Mas para tal é indispensável que o resto do país esteja apto a utilizar as informações enviadas.E ’ ainda a diplomacia que negocia os tratados de comércio que irão proporcionar às fo n tes produtoras d o resp ectiv o p aís n o v o s m ercados, mercadosêstes aptos a fornecer em troca as m aqu inarias e matérias-primas indispensáveis ao progresso nacio n a l.O forn ecim en to d e assistên cia técn ica — por p aís am igo ou a través d eorgan ism o in tern a cio n a l — se con cretiza, outrossim , graças à ação d i plomática.
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Silva, Elsie Frances, Vitor Miranda Batista Pereira, Raul De Barros Neto, and Kátia Tomagnini Passaglio. "Formação do Psicólogo no SUS: revisando a base de sua formação." Percurso Acadêmico 7, no. 13 (August 30, 2017): 230. http://dx.doi.org/10.5752/p.2236-0603.2017v7n13p230.
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<p>A atuação do Psicólogo no Sistema Único de Saúde (SUS) se torna cada vez mais importante, por sua capacidade de trabalhar o sujeito em diversos contextos. Dentro daquilo que se aprende enquanto graduando de Psicologia, o aluno deve estar apto a desenvolver a criticidade frente aos modos como a Psicologia se constrói e dentro da atual demanda dos profissionais dessa área. Uma revisão bibliográfica foi realizada, junto à análise dos ementários dos cursos de psicologia de cinco universidades brasileiras, para averiguação do andamento do ensino voltado para a atuação do Psicólogo no SUS. Esse assunto é pertinente pela necessidade de se formarem profissionais aptos para a atuação nesse sistema, de acordo com as proposições dos Ministérios da Saúde e da Educação e Diretrizes Curriculares Nacionais. O que foi evidenciado em nosso estudo é que há pouco direcionamento da formação do psicólogo para o SUS nos cursos investigados, mas há grandes potencialidades para tal, exigindo adequações curriculares.</p>
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Iocohama, Celso Hiroshi, Camila Kienen Bruno, and Joice Duarte Gonçalves Bergamaschi. "O ESCOPO EDUCATIVO DO PROCESSO E A EDUCAÇÃO DA SOCIEDADE POR MEIO DA TUTELA JURISDICIONAL." Revista Jurídica Cesumar - Mestrado 17, no. 1 (May 5, 2017): 11. http://dx.doi.org/10.17765/2176-9184.2017v17n1p11-41.
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O processo judicial mostra-se apto a realizar ações educativas. Contudo, é importante trazer informações do plano educativo para que se viabilize uma reflexão mais ampla sobre a contribuição que a Educação pode fazer para o funcionamento do processo. Nesse contexto, faz-se um corte para focar a atuação do juiz e suas interações com os sujeitos processuais (e nele participantes). Neste sentido, o estudo procura demonstrar a importância dessa concepção nas ações do juiz, considerando esta responsabilidade como uma ferramenta apta a (re)construir as relações processuais e as ações de cada sujeito em um contexto formativo e de compreensão das responsabilidades (individuais e sociais). Desse modo, colocando-se sob análise a função da tutela jurisdicional e a atuação de um dos principais sujeitos do processo - o juiz -, demonstra-se que a educação é possível no processo judicial e pode ser trabalhada como um instrumento para aprimorar as relações pessoais bem além do conflito individual.
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Perieira, Adriana Gomes, and Regina de Barros Cianconi. "Potencial de atuação do bibliotecário em atividades de inteligência organizacional: estudo de caso na Universidade Federal Fluminense." Transinformação 20, no. 1 (April 2008): 83–98. http://dx.doi.org/10.1590/s0103-37862008000100007.
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Visando comprovar que o bibliotecário está apto a atuar em atividades de inteligência organizacional, foram identificadas as competências e habilidades essenciais para atuar em Sistemas de Inteligência Organizacional e as competências e habilidades do bibliotecário, com o intuito de identificar se o bibliotecário está potencialmente capacitado para atuar nesse mercado. Foi pesquisada literatura sobre os temas envolvidos, analisado um programa de curso e aplicado questionário aos professores do curso de Biblioteconomia e Documentação da Universidade Federal Fluminense, de modo a identificar que competências e habilidades procuram formar em seus alunos. De acordo com as respostas, cerca de 70% das disciplinas de Biblioteconomia atendem às competências e habilidades demandadas pelos sistemas de inteligência organizacional. Verificou-se que o bibliotecário formado pela UFF está apto a atuar em algumas das atividades relacionadas à inteligência organizacional. Foi sugerido, porém, que o bibliotecário, por meio de cursos de pós-graduação em Inteligência Organizacional, amplie sua formação profissional, fazendo desse mercado especializado uma nova área de atuação.
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Van Oort, Johannes. "Notes on Augustine’s De pulchro et apto and its Manichaean Context." Revue d'Etudes Augustiniennes et Patristiques 66, no. 2 (May 2020): 293–324. http://dx.doi.org/10.1484/j.rea.5.125875.
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Alzate, Gastón. "Un Espectáculo No Apto Para Mochos: Astrid Hadad y Sus Tarzanes." Chasqui 29, no. 1 (2000): 3. http://dx.doi.org/10.2307/29741564.
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Teixeira Herig, Margarida. "O Problema da Educação Nacional." Revista do Serviço Público 66, no. 03 (December 25, 2020): 512–14. http://dx.doi.org/10.21874/rsp.v66i03.5324.
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Educação é, no entendimento completo do têrmo, desenvolvimento harmônico do homem, capaz de torná-lo fisica, intelectual, espiritual e moralmente apto a integrar-se na vida como fôrça positiva do progresso. Educação é, pois, cultura e treinamento, conhecimento da vida, compreensão da natureza humana, conceituação verdadeira de si mesmo.
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Mariños Roncal, Alfonso. "El ingeniero industrial y el diseño de productos." Ingeniería Industrial, no. 002 (July 1, 1992): 73–75. http://dx.doi.org/10.26439/ing.ind1992.n002.3228.
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El diseño de productos es un arte. El ingeniero indusrial está virtualmente apto para desarrollar un diseño industrial. La ingeniería industrial y el diseño del producto tienen mucho en común y es más son complementarios, ya que un ingeniero puede por inspiración ser artista, pero no éste último por inspiración ingeniero.
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Filho, Itamar da Silva Santos, and Paulo Rangel Araújo Ferreira. "PRINCIPIOS FUNDAMENTALES DE LA TRIBUTACIÓN AMBIENTAL." Veredas do Direito: Direito Ambiental e Desenvolvimento Sustentável 14, no. 29 (October 10, 2017): 125–51. http://dx.doi.org/10.18623/rvd.v14i29.1011.
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El trabajo aborda el estudio de los principales principios jurídicos que fundamentan fiscalidad ambiental, poniendo el énfasis en las importantes dificultades técnico-jurídicas que la implantación de estos instrumentos fiscales implican; así como, en las estrategias jurídicas para superarlas con la intención de establecer medios tributarios aptos para alcanzar sus objetivos, que son producir efectos positivos para el medio ambiente, además de recaudar ingresos para el Tesoro Público. Desde luego, la preocupación actual de la protección del medio ambiente es inherente al todo ordenamiento legal, así la orden jurídica-fiscal no puede quedarse insensible. Además, se estudió la viabilidad legal de tales impuestos y su eficacia en la preservación del medio ambiente. Tales imposiciones se presentan como un medio para internalizar las externalidades negativas. A través de investigación bibliográfica, se demuestra que la complejidad de los problemas fiscales ambientales enfrentados, con el objetivo de averiguar cómo se puede llegar a una solución a la problemática subrayada. Se concluye que el deber de contribuir, cuyo fundamento es el principio de solidaridad, se presenta como un instrumento apto de preservación del medio.
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JORGE, ANNA. "A LEITURA E SEU PAPEL NA SOCIEDADE LETRADA E TECNOLÓGICA." Revista Territórios 03, no. 08 (August 31, 2021): 62–73. http://dx.doi.org/10.53782/270.
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O tema desse estudo pauta-se nas implicações no processo de letramento a partir do uso das TDIC. A tecnologia vem possibilitando profundas transformações nas formas de comunicação e informação da sociedade, e isso afetou o processo de ensinar e aprender. Na era das TDIC, os textos são multimodais, unem a língua escrita, imagens, sons e necessitam de um leitor apto a compreendê-los. No conceito de multiletramento, o processo de inserção da criança e do jovem no mundo da leitura e da escrita revela a necessidade de reflexão sobre o processo de ensino aprendizagem diante das novas tecnologias. O objetivo do estudo é compreender a leitura e a escrita a em seus usos sociais mediados pela tecnologia . É um estudo qualitativo, com uso de metodologia de revisão bibliográfica. Os resultados apontam que as novas tecnologias são recursos importantes para o aprendizado, sendo necessário que o seu uso tenha um objetivo claro que contribua para formar leitores e escritores aptos a lidar com as novas formas de leitura e de escrita presentes na era digital tão necessário na sociedade letrada contemporânea.
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Bruno, Martín, Eduardo Cittadini, and Sebastián Grenoville. "Dinámica de la generación de residuos sólidos y desperdicio de alimentos en los mercados concentradores de frutas y verduras del Área Metropolitana de Buenos Aires (AMBA)." Siembra 10, no. 1 (February 9, 2023): e4201. http://dx.doi.org/10.29166/siembra.v10i1.4201.
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Los mercados frutihortícolas constituyen un eslabón relevante en la trama comercial de alimentos del amba, proporcionando un soporte logístico que permite absorber grandes volúmenes de productos y ubicarlos rápidamente. El objetivo de este trabajo es comprender la dinámica de la generación de residuos sólidos, usando como caso de estudio el Mercado de Pilar. La investigación incluyó la caracterización de dicho mercado, el análisis de su dinámica en la generación de pérdidas y desperdicios de alimentos y la cuantificación de la generación de residuos. En el ámbito del mercado, se retiraron 675 toneladas de residuos anuales, de los cuales el 92 % se trata de residuos vegetales. La mayor parte de los residuos provienen de los puestos de verduras y el 68 % de los descartes es mercadería recuperable como alimento apto para consumo humano. La información cualitativa y cuantitativa obtenida en este estudio permitió identificar puntos críticos de la dinámica de la generación de residuos y es fundamental para el diseño de estrategias de minimización de pérdidas, de recuperación de alimentos aptos para consumo humano y de reaprovechamiento de los residuos orgánicos.
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Román Álvarez, Alejandro. "Manual de Derecho Administrativo del Sector Turístico." Revista Andaluza de Administración Pública, no. 87 (December 31, 2013): 432–34. http://dx.doi.org/10.46735/raap.n87.1048.
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Obra que realiza una notable labor de síntesis de las cuestiones más importantes en Derecho Administrativo del sector turístico, apto para profesionales y estudiantes con una escasa o nula vinculación con el mundo del Derecho, pero que no renuncia en ningún momento a la exposición completa de las instituciones fundamentales del ámbito turístico.
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Ramos dos Reis, Róbson. "Heidegger: a vida como possibilidade e mistério." Revista de Filosofia Aurora 24, no. 35 (May 10, 2012): 481. http://dx.doi.org/10.7213/revistadefilosofiaaurora.7515.
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O objetivo deste artigo é identificar uma estrutura fundamental, resultante da ontologia da vida orgânica esboçada por Heidegger nos Conceitos Fundamentais da Metafísica,que pode ser designada como “o mistério na vida”. Na primeira parte do texto destacoalguns elementos gerais da hermenêutica da vida. Na segunda, reconstruo a interpretação ontológica dos organismos animais que conduz ao conceito de aptidão, cuja determinação ontológica é que faz necessária a introdução de uma classe especial depossibilidade: o ser-possível como ser-apto. Na terceira parte, apresento a caracterização heideggeriana das aptidões como envolvimentos em comportamentos estruturados pela perturbação cativada (Benommenheit), ressaltando como a perturbação impedeque aos comportamentos possa ser atribuída a estrutura do algo enquanto algo, implicando que os organismos estão abertos a algo que não se lhes apresenta como aberto. Considerando a relacionalidade intrínseca aos organismos, essa limitação implica aimpossibilidade de determinar completamente a essência da vida. Portanto, argumento na última parte, a ontologia da vida elaborada por Heidegger não apenas exige um tipo especial de possibilidade para conceitualizar o ser apto orgânico, mas também resulta no reconhecimento de um mistério na vida.
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Ferreira, Keila Pacheco. "DESAFIOS DA COMPLEXIDADE E DIMENSÃO SISTÊMICA DA RESPONSABILIDADE CIVIL." Conpedi Law Review 3, no. 2 (December 1, 2017): 394. http://dx.doi.org/10.26668/2448-3931_conpedilawreview/2017.v3i2.492.
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O manancial jurídico utilizado no ultrapassado paradigma da modernidade, especialmente no tocante à responsabilidade civil, não está totalmente apto a regular os desafios do terceiro milênio. Contingências e riscos nunca antes visitados acabam por compelir à busca por novas soluções, o que indica a inevitabilidade de uma transição paradigmática e gestão reconstrutiva da hermenêutica jurídica.
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Mathias, Maria Isabel da Cunha. "OCDE E GOVERNANÇA PÚBLICA: O BRASIL ESTÁ APTO A INTEGRAR A ORGANIZAÇÃO?" Setembro 2020/Dezembro 2020, no. 28 (February 24, 2021): 115–26. http://dx.doi.org/10.38116/bepi28art6.
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Ide, Cilene Aparecida Costardi. "Delineando as propriedades que conferem ao cuidar em enfermagem seu estatuto singular: o quadro e o fato." Revista da Escola de Enfermagem da USP 33, no. 4 (December 1999): 411–20. http://dx.doi.org/10.1590/s0080-62341999000400013.
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O ensaio reconsidera o processo de institucionalização do cuidar evidenciando a ordem própria desse fato mobilizado por essa interdição. Evidencia os efeitos desse processo na conformação do pacto identificatório profissional instituição, o arcabouço estrutural que lhe dá sustentação, identificando suas propriedades, assim como as possibilidades de criar um dispositivo de trabalho apto a promover o reencontro com a tarefa primária resignificada.
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Meyers Skredsvig, Kari. "The Kilimanjaro kaleidoscope: A sociocritical approach to Retorno al Kilimanjaro." Revista de Filología y Lingüística de la Universidad de Costa Rica 17, no. 1-2 (August 31, 2015): 29. http://dx.doi.org/10.15517/rfl.v17i1-2.20993.
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Sociocrítica es un instrumento particularmente apto para el análisis de la novela corta de Duran. Este enfoque examina toda la complejidad de la intertextualidad a través del cual se desarrolla la novela. El análisis de los discursos literarios y religiosos revela que una encantadora fantasía de la novela sólo es superficial, una fachada divertida para el humor negro de su núcleo.
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RAMOS, Liane Slaviero. "7. SENTENÇAS ILÍQUIDAS: CAUSAS (?)." REVISTA JURÍDICA DO CESUCA - ISSN 2317-9554 1, no. 2 (December 19, 2013): 123. http://dx.doi.org/10.17793/rjc.v1i2.437.
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<p>O presente trabalho tem por finalidade perquirir dentro do sistema jurídico brasileiro quais as causas que geram um provimento jurisdicional ilíquido, ou seja, que não está apto a embasar uma demanda executiva eis que carente de um requisito, bem como investigar se a iliquidez é prejudicial à tutela jurisdicional constitucional.</p><p> </p>
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Mata, Bruna Emmanuelle Linhares Fonseca, Juliana Santos Bayerl de Oliveira, and Damião Ranulfo Fernandes Soares. "Miofibromatose infantil: relato de uma rara doença." Radiologia Brasileira 45, no. 2 (April 2012): 118–20. http://dx.doi.org/10.1590/s0100-39842012000200011.
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A miofibromatose infantil é uma rara doença que tem várias formas de apresentação. Habitualmente, manifesta-se com nódulos subcutâneos, que podem ou não estar associados à presença de nódulos viscerais. Deve-se estar apto a fazer o diagnóstico por meio do exame físico e de imagem, que evidenciarão o padrão das lesões para estadiar/classificar a doença. O tratamento ainda é controverso.
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Souza, Cristiane Naiara Araújo de. "Jornalismo de coalizão: uma proposta de fortalecimento do ecossistema midiático baseada na coordenação de interesses compartilhados." Lumina 16, no. 2 (August 30, 2022): 150–65. http://dx.doi.org/10.34019/1981-4070.2022.v16.34313.
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A proposta do ensaio, mais do que contribuir com ideias conclusivas sobre a práxis jornalística e a eventual desconexão da realidade política, social e econômica do século XXI, é propor uma autorreflexão acerca de pressupostos norteadores desse ethos. Sustentamos sim a responsabilidade do jornalismo, como instituição qualificadora das democracias e ator social apto a acrescentar efetivas contribuições em prol da perspectiva dialógica, transformadora e crítica da sociedade atual, dos poderes instituídos e do seu próprio ethos. A accountability, a perspectiva construtivista em oposição aos velhos ideais de objetivismo e de neutralidade, o reconhecimento da democracia digital como força e o avanço da ultradireita no cenário global e regional como a grande ameaça às conquistas democráticas das últimas décadas são os eixos mais evidentes da discussão. Dessa perspectiva — tanto teórica quanto empírica — enxergamos os contornos de uma alternativa factível ao ecossistema jornalístico concorrencial em declínio: o jornalismo de coalizão, apto a se organizar coordenadamente em torno de objetivos comuns, ainda que o faça sob a vigilância de determinados limites capazes de resguardar, de algum modo, as idiossincrasias de cada organização, seja ela independente ou de mídia tradicional.
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Jehmlich, Ulrike, Adnan Alahmad, Doreen Biedenweg, and Matthias Hundt. "The role of palmitoyl-protein thioesterases in T cell activation (P1398)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 204.2. http://dx.doi.org/10.4049/jimmunol.190.supp.204.2.
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Abstract Reversible protein palmitoylation is a posttranslational modification important for transport, localization and function of proteins. The acyl-protein thioesterase 1 (APT1) also known as lysophospholipase 1 (LYPLA1) is a cytosolic depalmitoylating enzyme. Another thioesterase APT2 (LYPLA2) is highly homologous to APT1. Jurkat T cells were chosen to analyze the role of APT1 and APT2 in T cell activation. APT1/2 mRNA expression was measured by qPCR and knockdown of APT1/2 gene expression was accomplished by RNA interference, which consisted of transient siRNA expression by electroporation or by stable expression of shRNA by lentiviral infection. Palmostatin B was used to inhibit the APT thioesterase activity pharmacologically. The functional effects of APT1/2 knockdown or inhibition were measured by IL-2 secretion (ELISA) and CD69 upregulation (flow cytometry) after CD3/CD28 stimulation. Jurkat cells expressed APT2 mRNA 3.5-fold higher than APT1 mRNA. Even greater differences were found in primary human and murine T cells. Both, transient and stable knockdown of each of the APTs alone reduced IL-2 secretion and CD69 upregulation following CD3/CD28 stimulation. The effect of APT2 knockdown was always stronger than that of APT1. Inhibition with palmostatin B blocked cell activation in Jurkat cells and in human peripheral T cells. Thus, both palmitoyl-protein thioesterases APT1 and APT2 are involved in T cell activation, but APT2 seems to be the predominant enzyme in T cells.
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Gil Báez, C., R. Ordinola Agüero, R. D. Ernst, and M. A. Ruiz. "Caracterización morfológica, biomasa aérea y calidad en distintas poblaciones de Trichloris crinita." Archivos de Zootecnia 64, no. 245 (March 16, 2015): 49–56. http://dx.doi.org/10.21071/az.v64i245.374.
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Gran parte de la superficie del territorio de Argentina se encuentra cubierta por pastizales naturales, siendo éstos aptos para el uso ganadero. Sin embargo, dichos ecosistemas han perdido biodiversidad y productividad a causa del uso antrópico, fundamentalmente debido al desplazamiento de las actividades ganaderas hacia áreas marginales presentando importantes restricciones productivas, lo cual acentúa la fragilidad de estos ambientes. Trichloris crinita (Lag.) Parodi, es una especie clave de manejo en los pastizales naturales de las regiones del Caldenal y del Monte; por lo tanto, es considerada apta para ser utilizada en procesos de rehabilitación, debido a que ha evolucionado en este tipo de ambientes. El objetivo de este trabajo fue caracterizar y evaluar en campo el comportamiento agronómico de 13 poblaciones de Trichloris crinita. En invernáculo se evaluó la germinación de las semillas, altura y número de hojas de las plantas. El transplante a campo se realizó cuando las plantas alcanzaron el estado de 4-5 hojas. Las determinaciones comenzaron a realizarse a los 8 meses del transplante; se hicieron recuentos de número de panojas, altura de planta y de dosel, diámetro de mata, biomasa aérea y calidad del forraje (proteína, fibra y digestibilidad). Se encontraron poblaciones de mayor biomasa, lo cual también coincidió con macollamiento y diámetro de mata. Si bien en este trabajo no se midió la producción de semilla, se pudo observar una mayor cantidad de inflorescencias en algunas poblaciones, entre ellas las del Caldenal y Ecotono Caldenal-Monte. Una de las poblaciones mostró muy baja persistencia luego de ser cortada, este fenotipo no es apto para pastoreos. En general las poblaciones presentaron calidad de forraje similar a otras especies estivales. Una de las poblaciones (Catamarca) además de su alta biomasa aérea, también mostró buena calidad de forraje. De acuerdo a los resultados obtenidos, se puede concluir que existe variabilidad entre las poblaciones de Trichloris crinita estudiadas, lo que permitirá seleccionar de acuerdo a su importancia agronómica, teniendo en cuenta fundamentalmente la biomasa total, la calidad del forraje, la producción de semillas y su persistencia bajo corte.
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Chinini Mojica, Rodrigo. "Efetividade vs. Segurança: quando se inicia o dever de cumprir a sentença com base no art. 475-J do código de processo civil?" Direito e Desenvolvimento 3, no. 5 (May 24, 2017): 211–60. http://dx.doi.org/10.26843/direitoedesenvolvimento.v3i5.203.
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O ensaio discute acerca da adequada exegese do 475-J do Código de Processo Civil, com especial enfoque no marco a partir do qual se considera o réu intimado e apto a cumprir a obrigação de pagar quantia, haja vista o patente antagonismo entre dois bens juridicamente relevantes e tutelados pela Constituição Federal.
Palavras-chave: Cumprimento de sentença. Obrigação de pagar quantia. Segurança jurídica. Efetividade do processo.
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Rigotti, Thais Toledo. "Coisa julgada tributária inconstitucional: análise acerca da existência de instrumento processual apto à flexibilização da coisa julgada / Unconstitutional res judicata: analysis about the existence of a procedural instrument able to flexible the res judicata effects." Brazilian Journal of Development 8, no. 7 (July 5, 2022): 49416–34. http://dx.doi.org/10.34117/bjdv8n7-049.
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O presente artigo visa a expor o problema da chamada coisa julgada inconstitucional, que ocorre quando uma decisão judicial com eficácia interpartes transita em julgado estabelecendo tratamento tributário diverso do que posteriormente vem a ser firmado pelo Supremo Tribunal Federal em julgamento com efeitos erga omnes. Partindo do problema, busca-se a verificação da existência de algum mecanismo processual apto à resolução do problema, mediante a flexibilização da coisa julgada.
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Lemos, Vinícius Silva. "O procedimento e a decisão de afetação no IRDR." Revista de Direito da Faculdade Guanambi 6, no. 01 (July 20, 2019): e254. http://dx.doi.org/10.29293/rdfg.v6i01.254.
Full textAbstract:
Este artigo tem o propósito de analisar o incidente de resolução de demandas repetitivas a partir do seu procedimento, com o delinear dos pontos necessários, desde o pedido de suscitação, admissibilidade, decisão de afetação e organização, as manifestações de todos os atores possíveis, com o intuito de instruir cognitivamente o incidente, para deixá-lo apto para a prolação da decisão que será transformada em precedente judicial naquele Tribunal de segundo grau.