RESUMO
End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test-retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen's d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log10NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen's d 0.81), whereas the effect size for the 6 min walk test (Cohen's d 0.22) and log10NT-proBNP (Cohen's d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials.Trial registration number NCT03841344.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Volume Sistólico , Função Ventricular Direita , Teste de CaminhadaRESUMO
BACKGROUND: Social risk factors (SRFs) such as minority race-and-ethnicity or low income are associated with quality-of-care, health, and healthcare outcomes. Organizations might prioritize improving care for easier-to-treat groups over those with SRFs, but measuring, reporting, and further incentivizing quality-of-care for SRF groups may improve their care. OBJECTIVE: To develop, as a proof-of-concept, a Health Equity Summary Score (HESS): a succinct, easy-to-understand score that could be used to promote high-quality care to those with SRFs in Medicare Advantage (MA) health plans, which provide care for almost twenty million older and disabled Americans and collect extensive quality measure and SRF data. DESIGN: We estimated, standardized, and combined performance scores for two sets of quality measures for enrollees in 2013-2016 MA health plans, considering both current levels of care, within-plan improvement, and nationally benchmarked improvement for those with SRFs (specifically, racial-and-ethnic minority status and dual-eligibility for Medicare and Medicaid). PARTICIPANTS: All MA plans with publicly reported quality scores and 500 or more 2016 enrollees. MAIN MEASURES: Publicly reported clinical quality and patient experience measures. KEY RESULTS: Almost 90% of plans measured for MA Star Ratings received a HESS; plans serving few patients with SRFs were excluded. The summary score was moderately positively correlated with publicly reported overall Star Ratings (r = 0.66-0.67). High-scoring plans typically had sizable enrollment of both racial-and-ethnic minorities (38-42%) and dually eligible beneficiaries (29-38%). CONCLUSIONS: We demonstrated the feasibility of developing and estimating a HESS that is intended to promote and incentivize excellent care for racial-and-ethnic minorities and dually eligible MA enrollees. The HESS measures SRF-specific performance and does not simply duplicate overall plan Star Ratings. It also identifies plans that provide excellent care to large numbers of those with SRFs. Our methodology could be extended to other SRFs, quality measures, and settings.
Assuntos
Equidade em Saúde , Medicare Part C , Idoso , Etnicidade , Humanos , Grupos Minoritários , Motivação , Estados UnidosRESUMO
BACKGROUND: We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. METHODS: This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070. FINDINGS: Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths. INTERPRETATION: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted. FUNDING: Merck and the Yale Cancer Center.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/genética , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
BACKGROUND: Little is known about the health care experiences of American Indians and Alaska Natives (AIANs) due to limited data. OBJECTIVE: The objective of this study was to investigate the health care experiences of AIAN Medicare beneficiaries relative to non-Hispanic Whites using national survey data pooled over 5 years. SUBJECTS: A total of 1,193,248 beneficiaries who responded to the nationally representative 2012-2016 Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys. METHODS: Linear regression models predicted CAHPS measures from race and ethnicity. Scores on the CAHPS measures were linearly transformed to a 0-100 range and case-mix adjusted. Three AIAN groups were compared with non-Hispanic Whites: single-race AIANs (n=2491; 0.4% of the total sample), multiple-race AIANs (n=15,502; 1.3%), and Hispanic AIANs (n=2264; 0.2%). RESULTS: Among AIAN groups, single-race AIANs were most likely to live in rural areas and areas served by the Indian Health Service; Hispanic AIANs were most likely to be Spanish-language-preferring (P's<0.05). Compared with non-Hispanic Whites, single-race AIANs reported worse experiences with getting needed care (adjusted disparity of -5 points; a "large" difference), getting care quickly (-4 points; a "medium" difference), doctor communication (-2 points; a "small" difference), care coordination (-2 points), and customer service (-7 points; P<0.001 for all comparisons). Disparities were similar for Hispanic AIANs but more limited for multiple-race AIANs. CONCLUSIONS: Quality improvement efforts are needed to reduce disparities faced by older AIANs. These findings may assist in developing targeted efforts to address cultural, communication, and health system factors presumed to underlie disparities in health care access and customer service.
Assuntos
/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Indígenas Norte-Americanos/estatística & dados numéricos , Medicare/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Comunicação , Continuidade da Assistência ao Paciente/organização & administração , Feminino , Pesquisas sobre Atenção à Saúde , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Nível de Saúde , Humanos , Masculino , Qualidade da Assistência à Saúde/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Fatores Socioeconômicos , Fatores de Tempo , Estados Unidos , United States Indian Health Service/estatística & dados numéricos , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.
Assuntos
Butiratos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Volume de Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Idoso , Antígenos de Neoplasias , Teorema de Bayes , Butiratos/administração & dosagem , Butiratos/farmacocinética , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Nebulizadores e Vaporizadores , Tomografia por Emissão de Pósitrons , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Resultado do TratamentoRESUMO
PURPOSE: Integrin αvß6 belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvß6 in rodent lung to support human translational studies. METHODS: The synthesis of [18F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αvß6 antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software. RESULTS: [18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/µmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30-60 min post-administration of [18F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 µSv/MBq. CONCLUSION: [18F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvß6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies.
Assuntos
Integrinas , Roedores , Animais , Antígenos de Neoplasias , Cadeias beta de Integrinas , Integrinas/metabolismo , Pulmão/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Roedores/metabolismo , Distribuição TecidualRESUMO
PURPOSE: The RGD-integrin, αvß6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFß). This study sought to quantify expression of αvß6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvß6-selective [18F]FB-A20FMDV2 PET ligand. METHODS: [18F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (VT) were used to quantify αvß6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvß6 expression and the distribution of fibrosis on high resolution computed tomography was conducted. RESULTS: A total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled. VT and SUV of [18F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric mean VT (95% CI) was 0.88 (0.60, 1.29) mL/cm3 for healthy subjects, and 1.40 (1.22, 1.61) mL/cm3 for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthy VT ratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [18F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [18F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [18F]FB-A20FMDV2 was safe and well tolerated. CONCLUSIONS: Lung uptake of [18F]FB-A20FMDV2, a measure of expression of the integrin αvß6, was markedly increased in subjects with PF compared with healthy subjects.
Assuntos
Integrinas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígenos de Neoplasias , Humanos , Pulmão/diagnóstico por imagem , Tomografia por Emissão de PósitronsRESUMO
Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25â mg, 1â mg and 2â mg twice daily for 8â days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2â mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.
Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Quinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fluordesoxiglucose F18 , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Piridazinas , Serina-Treonina Quinases TOR/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Researchers are increasingly interested in measuring race/ethnicity, but some survey respondents skip race/ethnicity items. OBJECTIVES: The main objectives of this study were to investigate the extent to which racial/ethnic groups differ in skipping race/ethnicity survey items, the degree to which this reflects reluctance to disclose race/ethnicity, and the utility of imputing missing race/ethnicity. RESEARCH DESIGN: We applied a previously developed method for imputing race/ethnicity from administrative data (Medicare Bayesian Improved Surname and Geocoding 2.0) to data from a national survey where race/ethnicity was usually self-reported, but was sometimes missing. A linear mixed-effects regression model predicted the probability of self-reporting race/ethnicity from imputed racial/ethnic probabilities. SUBJECTS: In total, 508,497 Medicare beneficiaries responding to the 2013-2014 Medicare Consumer Assessment of Healthcare Providers and Systems surveys were included in this study. MEASURES: Self-reported race/ethnicity and estimated racial/ethnic probabilities. RESULTS: Black beneficiaries were most likely to not self-report their race/ethnicity (6.6%), followed by Hispanic (4.7%) and Asian/Pacific Islander (4.7%) beneficiaries. Non-Hispanic whites were the least likely to skip these items (3.2%). The 3.7% overall rate of missingness is similar to adjacent demographic items. General patterns of item missingness rather than a specific reluctance to disclose race/ethnicity appears to explain the elevated rate of missing race/ethnicity among Asian/Pacific Islander and Hispanic beneficiaries and most but not all among Black beneficiaries. Adding imputed cases to the data set did not substantially alter the estimated overall racial/ethnic distribution, but it did modestly increase sample size and statistical power. CONCLUSIONS: It may be worthwhile to impute race/ethnicity when this information is unavailable in survey data sets due to item nonresponse, especially when missingness is high.
Assuntos
Etnicidade/estatística & dados numéricos , Controle de Formulários e Registros/métodos , Medicare/estatística & dados numéricos , Autorrelato , Idoso , Teorema de Bayes , Feminino , Humanos , Masculino , Inquéritos e Questionários , Estados UnidosRESUMO
PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care. METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences. RESULTS: At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach. CONCLUSION: The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.
Assuntos
Sequenciamento do Exoma/métodos , Exoma/genética , Medicina de Precisão/métodos , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Neoplasias Colorretais/genética , Bases de Dados Genéticas , Genômica/métodos , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/genética , Mutação/genética , Estudos Prospectivos , Análise de Sequência de DNA/métodosRESUMO
Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Receptores ErbB/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/enzimologia , Sistema de Sinalização das MAP Quinases , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Proteínas Tirosina Quinases/biossíntese , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-mos/biossíntese , Proteínas Proto-Oncogênicas c-mos/genética , Proteínas Proto-Oncogênicas c-raf/biossíntese , Proteínas Proto-Oncogênicas c-raf/genética , Receptores Proteína Tirosina Quinases/biossíntese , Receptores Proteína Tirosina Quinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor trkA/biossíntese , Receptor trkA/genética , Receptor trkBRESUMO
The pharmaceutical industry has been suffering from low clinical success rates of new drugs for some time with particularly high attrition in early clinical development, especially for drugs aimed at central targets. Both pharmaco-electroencephalography (EEG) and pharmaco-sleep, along with other biomarker techniques, have significant potential to assist with this problem by enabling early decisions to be made about the likelihood of a compound proving successful in the clinic. This paper discusses the role and points of application of biomarker techniques in early drug development. It proposes a framework for the use of pharmaco-EEG and pharmaco-sleep in drug development that (i) relies on the combination of preclinical data and an understanding of translatability to generate robust hypotheses for testing in early clinical studies and (ii) is backed up by a clear decision-making process. The areas that need further development before this framework can be put fully into practice are discussed, along with some possible routes by which this could be achieved through precompetitive co-operation within the industry.
Assuntos
Tomada de Decisões , Desenho de Fármacos , Sono/fisiologia , Pesquisa Translacional Biomédica , Animais , Biomarcadores/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Eletroencefalografia/métodos , Humanos , Polissonografia , Sono/efeitos dos fármacos , Sono/éticaRESUMO
Pharmaco-electroencephalography (EEG) is a non-invasive method used to assess the effects of pharmacological compounds on the central nervous system by processing the EEG signals which directly reveal the spontaneous synchronised postsynaptic neuronal activity of the cortex with high temporal resolution. The International Pharmaco-Encephalography Society (IPEG) has recently published guidelines, which were produced by a global panel of EEG experts, with the goal to increase the standardisation of pharmaco-EEG studies in human subjects and facilitate the comparability of data across laboratories, thus enabling data-pooling and meta-analyses. The recommended standard experimental procedure is to measure EEG activity under vigilance-controlled and resting conditions. The IPEG guidelines thoroughly present the technical details and therefore constitute a robust reference. The complementary aim of the present paper is to focus on practical aspects, pitfalls and precautions to be considered when processing pharmaco-EEG data by covering the following topics: (1) investigate the stability and reliability of 5-min EEG recordings under both vigilance-controlled and resting conditions; (2) assess the spontaneous time-dependent changes in spectral activity over time, and (3) apply the data-processing strategies suggested in the pharmaco-EEG guidelines and designed to optimally capture drug effects. For this purpose, the EEG data from a randomised, double-blind, crossover trial aimed at comparing the effect of diazepam (10 mg) and placebo in 16 healthy male volunteers is used to illustrate the discussion of the processing techniques and difficulties commonly faced when analysing pharmaco-EEG data.
Assuntos
Ondas Encefálicas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Diazepam/farmacologia , Eletroencefalografia , Hipnóticos e Sedativos/farmacologia , Mapeamento Encefálico , Estudos Cross-Over , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Tempo de Reação/efeitos dos fármacos , Reprodutibilidade dos Testes , Análise Espectral , Fatores de TempoRESUMO
Place (geographic location), birthplace, the number of years in the United States, and gender are important social determinants of health essential to our understanding of health disparities. In this study, we examined the association between place and diabetes in white and Hispanic/Latino men and found that place and the number of years in the United States are important social determinants of health. Our findings provide implications for a nuanced perspective by highlighting the importance of examining social determinants of health to identify tailored interventions to address disparities in diabetes for diverse groups of Hispanic/Latino men.
Assuntos
Diabetes Mellitus Tipo 2/etnologia , Comportamentos Relacionados com a Saúde/etnologia , Disparidades nos Níveis de Saúde , Hispânico ou Latino/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Determinantes Sociais da Saúde , População Branca/estatística & dados numéricos , Diabetes Mellitus Tipo 2/prevenção & controle , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Masculino , Obesidade/etnologia , Estados UnidosAssuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Humanos , Mutação , Neoplasias/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Receptor trkC/antagonistas & inibidoresRESUMO
OBJECTIVE: The objective of the study was to determine whether race disparities in physical inactivity are present among urban low-income Blacks and Whites living in similar social context. DESIGN: This analysis included Black and White respondents ( > or = 18 years) from the Exploring Health Disparities in Integrated Communities-Southwest Baltimore (EHDIC-SWB; N=1350) Study and the National Health Interview Survey (NHIS; N = 67790). Respondents who reported no levels of moderate or vigorous physical activity, during leisure time, over a usual week were considered physically inactive. RESULTS: After controlling for confounders, Blacks had higher adjusted odds of physical inactivity compared to Whites in the national sample (odds ratio [OR] = 1.40; 95% confidence interval [CI] =1.30-1.51). In EHDIC-SWB, Blacks and Whites had a similar odds of physical inactivity (OR = 1.09; 95% CI .86-1.40). CONCLUSION: Social context contributes to our understanding of racial disparities in physical inactivity.
Assuntos
Negro ou Afro-Americano , Exercício Físico , Disparidades nos Níveis de Saúde , Meio Social , Saúde da População Urbana/etnologia , População Branca , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pobreza/etnologia , Comportamento Sedentário/etnologia , Condições SociaisRESUMO
EGFR tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutated non-small cell lung carcinoma (NSCLC); however, therapeutic resistance remains a clinical challenge. Acquired secondary EGFR mutations that increase ATP affinity and/or impair inhibitor binding are well-described mediators of resistance. Here we identify a de novo EGFR Y891D secondary alteration in a NSCLC with EGFR L858R. Acquired EGFR Y891D alterations were previously reported in association with resistance to first generation EGFR TKIs. Functional studies in Ba/F3 cells demonstrate reduced TKI sensitivity of EGFR L858R + Y891D, with the greatest reduction observed for first and second generation TKIs. Unlike other EGFR mutations associated with TKI resistance, Y891D does not significantly alter ATP affinity or promote steric hindrance to inhibitor binding. Our data suggest that the Y891D mutation destabilizes EGFR L858R, potentially generating a population of misfolded receptor with preserved signaling capacity but reduced sensitivity to EGFR inhibitors. These findings raise the possibility of protein misfolding as a mechanism of resistance to EGFR inhibition in EGFR-mutated NSCLC.