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1.
Br J Cancer ; 120(6): 612-620, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30792533

RESUMO

BACKGROUND: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. METHODS: We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. RESULTS: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. CONCLUSIONS: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Animais , Células CHO , Ensaios Clínicos Fase II como Assunto , Cricetulus , Resistencia a Medicamentos Antineoplásicos , Feminino , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Camundongos Nus , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridinas/farmacologia , Sunitinibe/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Br J Cancer ; 121(3): 281, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31123346

RESUMO

The additional information of this manuscript originally stated that the authors declare no competing interests. This statement was incorrect, and should instead have stated the following:M.C.H. has the following competing interests to declare: Equity interest at Molecular MD; Consulting at Molecular MD, Blueprint Medicines, Deciphera Pharmaceuticals; Expert Testimony at Novartis; Licensed patent with royalty payments at Novartis. The remaining authors have no competing interests to declare.The authors apologise for any convenience this may have caused.

3.
Angew Chem Int Ed Engl ; 55(36): 10909-12, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27496389

RESUMO

Targeting acquired drug resistance represents the major challenge in the treatment of EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we describe the structure-based design, synthesis, and biological evaluation of a novel class of covalent EGFR inhibitors that exhibit excellent inhibition of EGFR-mutant drug-resistant cells. Protein X-ray crystallography combined with detailed kinetic studies led to a deeper understanding of the mode of inhibition of EGFR-T790M and provided insight into the key principles for effective inhibition of the recently discovered tertiary mutation at EGFR-C797S.


Assuntos
Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Cinética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Fosforilação , Mutação Puntual , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia
4.
Angew Chem Int Ed Engl ; 54(35): 10313-6, 2015 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-26110718

RESUMO

Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homology (PH) domain-dependent covalent-allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chemical biology and medicinal chemistry research.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Regulação Alostérica , Ligação Competitiva , Humanos , Modelos Moleculares
5.
PLoS One ; 19(8): e0308387, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39133752

RESUMO

INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease. STUDY DESIGN: Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE. OBJECTIVES: To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern. METHODS: Settings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression. RESULTS: The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual.


Assuntos
Hemangioendotelioma Epitelioide , Sistema de Registros , Humanos , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/mortalidade , Hemangioendotelioma Epitelioide/terapia , Hemangioendotelioma Epitelioide/diagnóstico , Estudos Prospectivos , Adulto , Prognóstico , Masculino , Feminino
6.
Bioengineering (Basel) ; 10(4)2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-37106651

RESUMO

Resection margin adequacy plays a critical role in the local control of sarcomas. Fluorescence-guided surgery has increased complete resection rates and local recurrence-free survival in several oncological disciplines. The purpose of this study was to determine whether sarcomas exhibit sufficient tumor fluorescence (photodynamic diagnosis (PDD)) after administration of 5-aminolevulinic acid (5-ALA) and whether photodynamic therapy (PDT) has an impact on tumor vitality in vivo. Sixteen primary cell cultures were derived from patient samples of 12 different sarcoma subtypes and transplanted onto the chorio-allantoic membrane (CAM) of chick embryos to generate 3-dimensional cell-derived xenografts (CDXs). After treatment with 5-ALA, the CDXs were incubated for another 4 h. Subsequently accumulated protoporphyrin IX (PPIX) was excited by blue light and the intensity of tumor fluorescence was analyzed. A subset of CDXs was exposed to red light and morphological changes of both CAMs and tumors were documented. Twenty-four hours after PDT, the tumors were excised and examined histologically. High rates of cell-derived engraftments on the CAM were achieved in all sarcoma subtypes and an intense PPIX fluorescence was observed. PDT of CDXs resulted in a disruption of tumor-feeding vessels and 52.4% of CDXs presented as regressive after PDT treatment, whereas control CDXs remained vital in all cases. Therefore, 5-ALA mediated PDD and PDT appear to be promising tools in defining sarcoma resection margins (PDD) and adjuvant treatment of the tumor bed (PDT).

7.
Cancers (Basel) ; 14(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36428589

RESUMO

Circulating tumor DNA (ctDNA) from circulating free DNA (cfDNA) in GIST is of interest for the detection of heterogeneous resistance mutations and treatment monitoring. However, methodologies for use in a local setting are not standardized and are error-prone and difficult to interpret. We established a workflow to evaluate routine tumor tissue NGS (Illumina-based next generation sequencing) panels and pipelines for ctDNA sequencing in an academic setting. Regular blood collection (Sarstedt) EDTA tubes were sufficient for direct processing whereas specialized tubes (STRECK) were better for transportation. Mutation detection rate was higher in automatically extracted (AE) than manually extracted (ME) samples. Sensitivity and specificity for specific mutation detection was higher using digital droplet (dd)PCR compared to NGS. In a retrospective analysis of NGS and clinical data (133 samples from 38 patients), cfDNA concentration correlated with tumor load and mutation detection. A clinical routine pipeline and a novel research pipeline yielded different results, but known and resistance-mediating mutations were detected by both and correlated with the resistance spectrum of TKIs used. In conclusion, NGS routine panel analysis was not sensitive and specific enough to replace solid biopsies in GIST. However, more precise methods (hybridization capture NGS, ddPCR) may comprise important research tools to investigate resistance. Future clinical trials need to compare methodology and protocols.

8.
J Med Chem ; 63(20): 11725-11755, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32931277

RESUMO

Mutated or amplified Her2 serves as a driver of non-small cell lung cancer or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. To date, small-molecule inhibitors targeting Her2 which can be used in clinical routine are lacking, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds, which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion parameters as well as mass spectrometry experiments and western blot analysis substantiated our approach.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Receptor ErbB-2/genética , Receptor ErbB-2/isolamento & purificação , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Mol Cancer Ther ; 18(11): 1985-1996, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31308077

RESUMO

Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of KIT or PDGFRA, favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of KIT secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients-adding further complexity to the scope of resistance. We collected genotyping data for KIT from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary KIT mutations (n = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates (NF1/2, PTEN, RAS, PIK3CA, TSC1/2, AKT, BRAF) potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in KIT, PTEN, KRAS, NF1, and TSC2 We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT-related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Tumores do Estroma Gastrointestinal/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Redes Reguladoras de Genes/efeitos dos fármacos , Heterogeneidade Genética , Humanos , Terapia de Salvação , Análise de Sequência de DNA , Transdução de Sinais
10.
Chem Sci ; 10(46): 10789-10801, 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31857889

RESUMO

Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode.

11.
J Med Chem ; 60(6): 2361-2372, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28225269

RESUMO

The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds. These inhibitors are conformationally less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M, and covalently alkylate Cys797. Western blot analysis, as well as characterization of the binding kinetics and kinase selectivity profiling, substantiates our approach of targeting drug-resistant EGFR-L858R/T790M with inhibitors incorporating the indazole as hinge binder.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Indazóis , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Camundongos , Simulação de Acoplamento Molecular , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia
12.
J Med Chem ; 60(21): 8801-8815, 2017 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-28991465

RESUMO

In modern cancer therapy, the use of small organic molecules against receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy. The association of cancer cells with dysregulated signaling pathways linked to RTKs represents a key element in targeted cancer therapies. The tyrosine kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK. KIT is targeted for cancer therapy in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). However, acquired resistance mutations within the catalytic domain decrease the efficacy of this strategy and are the most common cause of failed therapy. Here, we present the structure-based design and synthesis of novel type II kinase inhibitors to overcome these mutations in KIT. Biochemical and cellular studies revealed promising molecules for the inhibition of mutated KIT.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mutação , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Relação Estrutura-Atividade
13.
Clin Cancer Res ; 20(22): 5745-5755, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25239608

RESUMO

PURPOSE: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST. EXPERIMENTAL DESIGN: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib-KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents. RESULTS: In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST. CONCLUSION: Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/genética , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Piridazinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Benzamidas/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Éxons , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Imidazóis/química , Imidazóis/uso terapêutico , Indóis/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Mutação , Recidiva Local de Neoplasia , Piperazinas/farmacologia , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/química , Piridazinas/química , Piridazinas/uso terapêutico , Pirimidinas/farmacologia , Pirróis/farmacologia , Sunitinibe , Tomografia Computadorizada por Raios X , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Med Chem ; 56(14): 5757-72, 2013 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-23773153

RESUMO

Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug-resistant mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase KIT-T670I and Abl-T315I variants, as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-kit/genética , Relação Estrutura-Atividade
15.
Artigo em Português | LILACS, BBO - odontologia (Brasil) | ID: lil-673938

RESUMO

Objetivo: Conhecer a percepção de crianças sobre o atendimento odontológico.Método: Estudo exploratório, com abordagem qualitativa. A população-alvo foi formada por crianças matriculadas em escolas públicas e particulares do perímetro urbano de Itajaí (SC), mediante consentimento livre e esclarecido de seus pais. Para a coleta dos dados, foi utilizada a técnica do desenho-estória com tema. O número de crianças que integraram a pesquisa foi delimitado pela técnica de saturação dos dados. Para a estruturação dos dados, foram consideradas quatro categorias, desdobradas em subcategorias As manifestações foram tabuladas, segundo categorias e subcategorias e tipo de escola. Os dados foram apresentados por meio de estatística descritiva.Resultados: Integraram a pesquisa 40 crianças de escolas públicas e 36 de escolas particulares. As idades variaram de quatro a nove anos. Na escola pública, as meninas corresponderam a 47,5% e os meninos a 52,5%. Na escola particular, as meninas totalizaram 55,5% e os meninos 44,5%. Identificou-se no grupo pesquisado, tanto da rede pública como particular, que a categoria ambiente odontológico obteve a maior frequência (47,5% e 40,6%, respectivamente). Nesta categoria, as subcategorias cirurgião-dentista, paciente e instrumental/equipamentos/EPIs foram suscitadas em frequências muito próximas. Na escola pública, a segunda categoria mais frequente foi tratamento odontológico, com 21,7%, sendo o tratamento preventivo o mais destacado. Na escola particular, a segunda categoria mais lembrada foi a imagem do dentista (37,7%), sendo que a imagem humanizada foi a mais prevalente. E, finalmente, a categoria manifestação comportamental foi a menos destacada para ambos os tipos de escola. Conclusão: Para os dois grupos investigados, o contexto da consulta odontológica estrutura-se, principalmente, pelas situações agradáveis que são balizadas por uma prática educativo-preventiva, permeada por uma visão humanizada do cirurgião-dentista.


Objective: To know the perception of children about the dental treatment.Method: This was an exploratory study with a qualitative approach. The target population was formed by children attending public and private schools of the urban perimeter of Itajaí (SC), Brazil, who participated after written informed consent from their parents. The drawing-story with theme procedure was used for data collection. The number of children in the study was determined by the data saturation technique. For structuring the data, four categories were considered and further separated into subcategories. The manifestations were tabulated, according to the categories and subcategories and type of school. Data were presented by descriptive statistics.Results: Forty children from public and 36 from private schools were enrolled in the study. Ages varied from 4 to 9 years. In the public schools, the girls were 47.5% and boys were 52.5%. In the private schools, girls were 55.5% and boys were 44.5%. In both public and private schools, the category ?dental setting? had the highest frequency (47.5% and 40.6%, respectively). In this category, the subcategories ?dentist?, ?patient? and ?instruments/equipments/IPEs? had too close frequencies. In the public schools, the second most frequent category was ?dental treatment? (21.7%), with ?preventive treatment? standing out from the others subcategories. In the private schools, the second most mentioned category was ?dentist image? (37.7%), having ?humanized image? as the most prevalent subcategory. Finally, the category ?behavioral manifestation? was the least frequent in both types of school. Conclusion: For both groups of children investigated in this study, the context of dental consultation is primordially structured on pleasant situations that are governed by an educative-preventive practice permeated by a humanized vision of the dentist.


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Criança , Saúde Bucal , Assistência Odontológica , Odontólogos , Brasil , /métodos , Ensino Fundamental e Médio , Educação em Odontologia
16.
Rev. Salusvita (Online) ; 29(1): 7-16, 2010. graf, tab
Artigo em Português | LILACS | ID: lil-598263

RESUMO

Introdução: A escola tem sido considerada um local adequado para a efetivação de programas de saúde por reunir crianças em estágio propício ao desenvolvimento de hábitos e atitudes saudáveis. A possibilidade de implantação destes programas foi o fator motivador desta pesquisa. Objetivo: Avaliar atitudes e conhecimentos de professores do ensino fundamental do município de Itajaí (Santa Catarina) sobre saúde e higiene oral. Método: A investigação constou de um estudo descritivo, do tipo transversal. A população-alvo foram os 145 professores de 1ª a 4ª série, da qual foi constituída uma amostra não probabilística, que representou 53,8 por cento desta população. O instrumento de coleta de dados foi um questionário auto-aplicável, com perguntas fechadas e abertas, distribuídas em quatro campos (caracterização profissional; procedimentos para abordagem de conteúdos; atitudes quanto a um projeto de educação em saúde; e domínio cognitivo)...


Introduction: The school has been considered a suitable location for programs to meet oral health for children in placement to the development of healthy habits and attitudes. The possibility of implementing these programs was the motivating factor of this research. Objective: To assess attitudes and knowledge of teachers of elementary schools in the municipality of Itajaí (Santa Catarina) on the process of teaching about health and oral hygiene. Method: The consisted of a descriptive study type of cross. The target population was 145 teachers from elementary school, which was formed a non probability sample, representing 53.8 per cent of this population. The data collection instrument was a self-administered questionnaire, with questions of open and closed types, distributed in four fields (professional characteristics, procedures to address the content, attitudes on a project of health education and the cognitive domain)...


Assuntos
Humanos , Masculino , Feminino , Educação em Saúde Bucal , Promoção da Saúde , Planejamento em Saúde , Mão de Obra em Saúde
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