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3.
Toxicol Lett ; 332: 56-64, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32621954

RESUMO

The comet assay has been extensively used in biomonitoring studies. To avoid intra-experimental variability, the incorporation of assay controls in each work session for data normalization has been suggested by some authors but has never been thoroughly analyzed. The aim of this study was to address the impact of data normalization in the results of a biomonitoring study using different normalization models. Human peripheral blood mononuclear cells (PBMC) from 140 healthy individuals were analyzed using the alkaline and FPG-modified version of the comet assay across seven different work sessions. In addition to negative standards, methyl methanesulfonate (MMS) and Ro 19-8022 plus light treated PBMC, were also included in the assay as positive standards. To verify the impact of data normalization, some demographic, lifestyle and environmental exposure-related variables were selected. Significant associations with independent study variables were observed using normalized comet endpoints, as opposed to raw data. After normalization, levels of DNA strand breaks were significantly higher among males and older individuals (>71 years), while net FPG-sensitive sites were positively related to smoking habits and environmental exposures (i.e. air pollution and bottled water consumption). This study highlights how the normalization strategies can influence the statistical results of a human biomonitoring study and lead to different data interpretations.


Assuntos
Monitoramento Biológico/estatística & dados numéricos , Ensaio Cometa/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Interpretação Estatística de Dados , Demografia , Determinação de Ponto Final , Exposição Ambiental , Feminino , Humanos , Estilo de Vida , Luz , Masculino , Metanossulfonato de Metila/toxicidade , Pessoa de Meia-Idade , Modelos Estatísticos , Monócitos/metabolismo , Projetos de Pesquisa , Fatores Sexuais
4.
PLoS One ; 15(7): e0235673, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645029

RESUMO

BACKGROUND AND OBJECTIVES: This study sought to compare clinical outcomes between bioresorbable scaffolds (BRS) and durable polymer everolimus-eluting metallic stents (DP-EES) in patients with acute myocardial infarction (AMI) undergoing successful percutaneous coronary intervention (PCI). METHODS: From March 2016 to October 2017, 952 patients with AMI without cardiogenic shock undergoing successful PCI with BRS (n = 136) or DP-EES (n = 816) were enrolled from a multicenter, observational Korea Acute Myocardial Infarction Registry. RESULTS: In the crude population, there was no significant difference in the 1-year rate of device-oriented composite endpoint (DOCE) and device thrombosis between the BRS and DP-EES groups (2.2% vs. 4.8%, hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.13-1.41, p = 0.163; 0.7% vs. 0.5%, HR 1.49, 95% CI 0.16-13.4, p = 0.719, respectively). BRS implantation was opted in younger patients (53.7 vs. 62.6 years, p < 0.001) with low-risk profiles, and intravascular image-guided PCI was more preferred in the BRS group (60.3% vs. 27.2%, p < 0.001). CONCLUSIONS: At 1-year follow-up, no differences in the rate of DOCE and device thrombosis were observed between patients with AMI treated with BRS and those treated with DP-EES. Our data suggest that imaging-guided BRS implantation in young patients with low risk profiles could be a reasonable strategy in the setting of AMI.


Assuntos
Implantes Absorvíveis/efeitos adversos , Stents Farmacológicos/efeitos adversos , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea/efeitos adversos , Doença Aguda/terapia , Adulto , Idoso , Fármacos Cardiovasculares/uso terapêutico , Determinação de Ponto Final , Everolimo/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Modelos de Riscos Proporcionais , República da Coreia , Trombose/etiologia , Tecidos Suporte/efeitos adversos , Resultado do Tratamento
5.
PLoS One ; 15(7): e0236193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692755

RESUMO

BACKGROUND: Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints. METHODS: We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. RESULTS: Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P = 9.3 ×10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P = 0.61). CONCLUSION: Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.


Assuntos
Ivabradina/farmacologia , Modelos Genéticos , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Idoso , Alelos , Doenças Cardiovasculares/fisiopatologia , Determinação de Ponto Final , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/genética , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Proteínas Musculares/genética , Canais de Potássio/genética , Fatores de Risco
7.
Lancet Oncol ; 21(6): e305-e316, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502457

RESUMO

Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/terapia , Determinação de Ponto Final/normas , Glioma/diagnóstico por imagem , Glioma/terapia , Neuroimagem/normas , Idade de Início , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/patologia , Criança , Consenso , Feminino , Glioma/epidemiologia , Glioma/patologia , Humanos , Imagem por Ressonância Magnética/normas , Masculino , Gradação de Tumores , Imagem de Perfusão/normas , Tomografia por Emissão de Pósitrons/normas , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
8.
Toxicol Lett ; 331: 218-226, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32562635

RESUMO

INTRODUCTION: The benchmark dose (BMD) is a dose that produces a predetermined change in the response rate of an adverse effect. This approach is increasingly utilized to analyze quantitative dose-response relationships. To proof this concept, statistical analysis was compared with the BMD approach in order to rank the sensitivity as well as the toxicity and to describe the mode of action. METHODS: Bronchial (BEAS-2B) and alveolar epithelial cells (A549) were exposed to a wide concentration range (0.4-100 µg/mL) of five metal oxide nanoparticles (CeO2, CuO, TiO2, ZnO, ZrO2). Eight toxicity endpoints were determined representing integrity of lysosomal and cell membrane, oxidative stress level, glutathione based detoxification (glutathione S-transferase), oxidative metabolism (cytochrome P450), alteration of the mitochondrial membrane potential, alteration of phase II antioxidative enzyme (NAD(P)H:quinone oxidoreductase), and de novo DNA synthesis. RESULTS: Based on the BMD calculated for the most sensitive test, the toxicity decreased in the following order: ZnO > CuO > TiO2>ZrO2>CeO2 in BEAS-2B. Both statistical evaluation methods revealed a higher sensitivity of BEAS-2B cells. The BMD-derived mode of action for CuO confirmed the existing hypotheses and provided insights into less known mechanisms. CONCLUSION: The findings proofed that BMD analysis is an effective tool to evaluate different aspects of risk assessment.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Células A549 , Benchmarking , Brônquios/citologia , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Humanos , Pulmão/citologia , Óxidos , Medição de Risco
9.
Lancet Oncol ; 21(6): e317-e329, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502458

RESUMO

Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/terapia , Imagem de Difusão por Ressonância Magnética/normas , Determinação de Ponto Final/normas , Glioma/diagnóstico por imagem , Glioma/terapia , Neuroimagem/normas , Adolescente , Idade de Início , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/patologia , Criança , Consenso , Feminino , Glioma/epidemiologia , Glioma/patologia , Humanos , Masculino , Gradação de Tumores , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
10.
Bratisl Lek Listy ; 121(6): 411-414, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484704

RESUMO

INTRODUCTION: Recent breakthrough recognition of metastasis-free survival as a clinically relevant endpoint has opened a new era in the management of advanced prostate cancer. The need for new, intermediate endpoints is the logical consequence of scientific advances in prostate carcinoma. The treatment algorithms for non-metastatic castration-resistant prostate cancer (M0 CRPC) have recently been updated by adding novel anti-androgen apalutamide, and also enzalutamide for high-risk patients. OBJECTIVE: To review clinical evidence of metastasis-free survival as an efficacy endpoint used in prostate cancer studies, especially those in an advanced stage of the disease and identify its clinical benefit and correlation with overall survival. METHODS: Literature search up to October 2019  was conducted, including clinical trials and clinical practice guidelines. EVIDENCE SYNTHESIS: Metastasis-free survival (MFS) was used as the primary endpoint in the registration of clinical trials of second-generation anti-androgens. The study results have demonstrated the beneficial effect of these anti-androgens on delaying the development of metastases or death (MFS), with median MFSextended by 22‒24 months. The correlation tests have shown a positive correlation of MFS and overall survival. CONCLUSION: The metastasis-free survival can be considered a clinically significant and reliable efficacy endpoint in both localized prostate cancer patients and M0 CRPC patients being at high-risk of disease progression (Ref. 15).


Assuntos
Antagonistas de Androgênios , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração , Castração , Progressão da Doença , Determinação de Ponto Final , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/terapia
13.
Lancet Oncol ; 21(6): e330-e336, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502459

RESUMO

Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/terapia , Determinação de Ponto Final/normas , Imagem por Ressonância Magnética/normas , Neuroimagem/normas , Idade de Início , Neoplasias do Tronco Encefálico/epidemiologia , Neoplasias do Tronco Encefálico/patologia , Glioma Pontino Intrínseco Difuso/epidemiologia , Glioma Pontino Intrínseco Difuso/patologia , Humanos , Gradação de Tumores , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
15.
Ecotoxicol Environ Saf ; 199: 110751, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446104

RESUMO

Tonalide or acetyl hexamethyl tetralin (AHTN) is used as a fragrance additive in various household products. Recently, AHTN has drawn attention owing to its negative health effects on aquatic organisms. Data on AHTN toxicity toward aquatic species are limited. Therefore, this study tested the oxidative stress induced by AHTN exposure on the Rhodeinae sinensis Gunther and Macrobrachium nipponense. In this study, malonaldehyde (MDA) content and the activities of acetyl cholinesterase (AchE), superoxide dismutase (SOD), glutathione S-transferase (GST), and catalase (CAT) in R. sinensis Gunther were tested after 30 days of exposure to 30.093, 34.005, 38.426, 43.421, 49.067, 55.444, 62.652, 70.800, and 80.000 µg/L AHTN, respectively. The MDA, AchE, SOD, GST and CAT in M. nipponense were tested after 40 days of exposure to 60.000, 72.000, 86.400, 103.680, 124.416, 149.299, 179.159, 214.991, and 257.989 µg/L AHTN, respectively. In addition, an integrated biomarker response (IBR) index was utilised to evaluate the integrated toxic effects of AHTN on R. sinensis Gunther and M. nipponense. Finally, the predicted no-effect concentrations (PNECs) of AHTN, based on reproduction, biochemistry, survival, chronic toxicity, and acute toxicity endpoints were derived. The results indicated that low concentrations of AHTN can induce significant changes of oxidative stress biomarkers. The no observed effect concentrations (NOECs) of SOD, GST, AchE, CAT, and MDA were 103.680, 72.000, <60.000, 72.000, and <60.000 µg/L for R. sinensis Gunther and 38.426, 43.421, 30.093, 30.093, and 38.426 µg/L for M. nipponense, respectively. The IBR calculation results showed that 149.299 µg/L AHTN caused the highest toxic effect on R. sinensis Gunther after 30 days of exposure, whereas 70.797 µg/L AHTN caused the greatest damage to M. nipponense after 40 days of exposure. The PNECs of AHTN based on the non-traditional endpoints of biochemistry and reproduction were 0.00145 µg/L and 0.000395 µg/L, respectively, which were significantly lower than the PNEC of 2.636 µg/L for traditional endpoint survival. Therefore, the protection of aquatic organisms based on non-traditional toxicity endpoints should be considered in ecological risk assessment.


Assuntos
Antioxidantes/metabolismo , Organismos Aquáticos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Palaemonidae/efeitos dos fármacos , Perfumes/toxicidade , Tetra-Hidronaftalenos/toxicidade , Poluentes Químicos da Água/toxicidade , Acetilcolinesterase/metabolismo , Animais , Organismos Aquáticos/enzimologia , Catalase/metabolismo , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Glutationa Transferase/metabolismo , Malondialdeído/metabolismo , Nível de Efeito Adverso não Observado , Palaemonidae/enzimologia , Valor Preditivo dos Testes , Superóxido Dismutase/metabolismo
16.
Lancet Oncol ; 21(5): e252-e264, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32359501

RESUMO

There is a large variability regarding the definition and choice of primary endpoints in phase 2 and phase 3 multimodal rectal cancer trials, resulting in inconsistency and difficulty of data interpretation. Also, surrogate properties of early and intermediate endpoints have not been systematically assessed. We provide a comprehensive review of clinical and surrogate endpoints used in trials for non-metastatic rectal cancer. The applicability, advantages, and disadvantages of these endpoints are summarised, with recommendations on clinical endpoints for the different phase trials, including limited surgery or non-operative management for organ preservation. We discuss how early and intermediate endpoints, including patient-reported outcomes and involvement of patients in decision making, can be used to guide trial design and facilitate consistency in reporting trial results in rectal cancer.


Assuntos
Ensaios Clínicos como Assunto/métodos , Determinação de Ponto Final , Medidas de Resultados Relatados pelo Paciente , Neoplasias Retais/terapia , Projetos de Pesquisa , Terapia Combinada , Humanos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Fatores de Tempo , Resultado do Tratamento
20.
Am J Cardiol ; 125(12): 1770-1773, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32307092

RESUMO

With the routine use of primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), the rate of short-term complications is low and the optimal length-of-stay in the coronary care unit (CCU) following reperfusion is unknown. We hypothesized that the rate of complications would not differ between two groups of stable patients admitted to the CCU following primary-PCI for STEMI: (1) those for whom a minimum 24-hour stay was enforced (≥24 hour Standard Stay) and (2) those with no minimum length-of-stay (Physician-guided Stay). Data were collected retrospectively. We performed a regression analysis to determine predictors of the primary endpoint (a composite of in-hospital death, re-infarction and/or re-intervention, heart failure requiring intravenous diuretics, cardiac arrest, central nervous system and/or peripheral embolization, bleeding requiring transfusion, arrhythmia resulting in initiation of a class I or III antiarrhythmic drug, initiation of assisted ventilation, requirement for vasopressors or inotropes, or transfer to intensive care). A total of 242 patients were included in the analysis. The rate of the primary endpoint was 8% in the physician-guided stay group and 16% in the standard ≥24 hour stay group (p = 0.06). The most common complication in both groups was heart failure requiring diuretics (42%), which was predicted by the left ventricular end diastolic pressure on catheterization (area under the Receiver-Operator Curve of 0.75). In conclusion, Patients who are stable following primary PCI for STEMI have a low rate of complications. Stable STEMI patients do not appear to benefit from a mandatory ≥24 hours stay in the CCU.


Assuntos
Unidades de Cuidados Coronarianos/organização & administração , Tempo de Internação/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Comorbidade , Determinação de Ponto Final , Feminino , Humanos , Masculino , Manitoba , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos
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