Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Thorac Oncol ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31843683

RESUMO

INTRODUCTION: Blood-based tumor mutational burden (bTMB) has been studied to differentiate non-small cell lung cancer (NSCLC) patients who would benefit from anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. METHODS: Three independent cohorts of NSCLC patients treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N=211 and OAK, N=462) and further validated in the third National Cancer Center cohort (NCC, N=64). RESULTS: bTMB-H (bTMB≥cut-off point) was not associated with favorable OS following immunotherapy regardless of the cut-off points in either the POPLAR and OAK or the NCC cohorts (P>0.05) due to its correlation with the circulating tumor DNA (ctDNA) amount, which was associated with poor OS. In the POPLAR and OAK cohorts, upon allele frequency (AF) adjustment, a high allele frequency bTMB (HAF-bTMB, mutation counts with an AF>5%) was strongly correlated with the ctDNA amount (Pearson's r=0.65), while a low allele frequency bTMB (LAF-bTMB, mutation counts with an AF≤5%) was not (Pearson's r=0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [[HR], 0.70; 95% confidence interval [CI], 0.52-0.95; P=0.02), progression-free survival (PFS) (HR, 0.62; 95% CI, 0.47-0.80; P<0.001), and the objective response rate (ORR) (P<0.001) following immunotherapy but not chemotherapy, with a cut-off point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR, 0.20; 95% CI, 0.05-0.84; P=0.02), PFS (HR, 0.30; 95% CI, 0.13-0.70; P=0.003), and the ORR (P=0.001). CONCLUSIONS: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and the ORR following anti-PD-1/PD-L1 therapies in NSCLC patients, which needs to be prospectively validated.

2.
J Cancer Res Clin Oncol ; 145(12): 3055-3065, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31522278

RESUMO

PURPOSE: Combined immunotherapy with anti-programmed cell death-ligand 1 (PD-L1) and an inhibitor of cluster of differentiation 47 (CD47) have exhibited preliminary anti-tumor effect. Our study attempted to describe the PD-L1/CD47 expression status in pulmonary sarcomatoid carcinoma (PSC), and explore its survival impact and relevance with cytotoxic T lymphocytes and macrophages infiltration. METHODS: 148 patients with PSC who underwent surgeries were retrospectively reviewed. Tissue microarrays were conducted for immunohistochemistry (IHC) of PD-L1, CD47, CD8 and CD68. RESULTS: 54 (36.5%) and 78 (52.7%) cases were positive for PD-L1 and CD47, respectively, and 36 (24.3%) of them demonstrated PD-L1/CD47 co-expression. There was a significant correlation between PD-L1 and CD47 expression (P = 0.011). The median overall survival (OS) was 22.5 months (range 0.9-102.4 months). The univariate analysis demonstrated a significantly worse OS in cases with CD47 expression (hazard ratio [HR], 1.66; 95% CI, 1.14-2.42, P = 0.008) and PD-L1/CD47 co-expression (HR, 1.75; 95% CI, 1.15-2.67, P = 0.009). The multivariate analysis demonstrated PD-L1/CD47 co-expression (HR, 1.83; 95% CI, 1.17-2.87, P = 0.008), T stage, M stage, completeness of resection and adjuvant therapy were independent prognostic factors for OS. There was a significant relevance between PD-L1 expression and PD-L1/CD47 co-expression with higher densities of CD8-positive T lymphocytes (P = 0.004, 0.012, respectively) and CD68-positive macrophages (P = 0.026, 0.034, respectively). CONCLUSION: We demonstrated the PD-L1/CD47 co-expression status in PSC. PD-L1 expression correlated with CD47 expression, and PD-L1/CD47 co-expression correlated with poorer prognosis and may serve as a predictive biomarker for combined dual-targeting immunotherapy in PSC patients.


Assuntos
Antígeno B7-H1/metabolismo , Antígeno CD47/metabolismo , Carcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma/patologia , Diferenciação Celular/fisiologia , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologia
3.
Cancer Res ; 79(1): 7-20, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30389703

RESUMO

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis. SIGNIFICANCE: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Evolução Molecular , Neoplasias Pulmonares/genética , Mutação , Osteossarcoma/genética , Sequenciamento Completo do Exoma/métodos , Neoplasias Ósseas/patologia , Estudos de Coortes , Exoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia
4.
J Med Chem ; 61(21): 9513-9533, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30351001

RESUMO

As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Descoberta de Drogas , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP70/metabolismo , Concentração Inibidora 50 , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Camundongos , Relação Estrutura-Atividade
5.
PLoS One ; 13(8): e0202674, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30161148

RESUMO

The theoretical foundations of Big Data Science are not fully developed, yet. This study proposes a new scalable framework for Big Data representation, high-throughput analytics (variable selection and noise reduction), and model-free inference. Specifically, we explore the core principles of distribution-free and model-agnostic methods for scientific inference based on Big Data sets. Compressive Big Data analytics (CBDA) iteratively generates random (sub)samples from a big and complex dataset. This subsampling with replacement is conducted on the feature and case levels and results in samples that are not necessarily consistent or congruent across iterations. The approach relies on an ensemble predictor where established model-based or model-free inference techniques are iteratively applied to preprocessed and harmonized samples. Repeating the subsampling and prediction steps many times, yields derived likelihoods, probabilities, or parameter estimates, which can be used to assess the algorithm reliability and accuracy of findings via bootstrapping methods, or to extract important features via controlled variable selection. CBDA provides a scalable algorithm for addressing some of the challenges associated with handling complex, incongruent, incomplete and multi-source data and analytics challenges. Albeit not fully developed yet, a CBDA mathematical framework will enable the study of the ergodic properties and the asymptotics of the specific statistical inference approaches via CBDA. We implemented the high-throughput CBDA method using pure R as well as via the graphical pipeline environment. To validate the technique, we used several simulated datasets as well as a real neuroimaging-genetics of Alzheimer's disease case-study. The CBDA approach may be customized to provide generic representation of complex multimodal datasets and to provide stable scientific inference for large, incomplete, and multisource datasets.


Assuntos
Algoritmos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Mineração de Dados , Bases de Dados Factuais , Humanos , Neuroimagem
6.
Bioresour Technol ; 250: 821-827, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30001589

RESUMO

The microwave-assisted fast co-pyrolysis of chlorella and tire with additive under N2 and CO2 atmospheres were investigated. The pyrolysis profiles, yields of three-phase, the chemical composition of liquid and the ultimate analyses of solid residues were gained. With the tire ratio increasing, all the characters had the changes. The finial temperature had a wave change. The yield of liquid decreased and the chemical composition obtained in liquid of oxygenates compounds decreased, while hydrocarbon compounds increased, among which aromatic hydrocarbons had the highest content. The yield of solid increased, the HHV had a wave change and the values of H/C decreased. Under CO2 atmosphere, the final temperatures were lower with 70% and 100% chlorella ratios, the yield difference of liquid reached the minimal with 70% and 30% chlorella ratios. According to the quantity and quality of liquid and solid, and the former results, 50% percentage of tire was the suitable ratio.


Assuntos
Dióxido de Carbono , Chlorella , Micro-Ondas , Biocombustíveis , Temperatura Alta , Temperatura Ambiente
7.
Br J Cancer ; 119(5): 538-545, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29755117

RESUMO

BACKGROUND: To assess the safety profile, pharmacokinetics, pharmacodynamics and preliminary antitumour activity of fixed-dose SHR-1210, a novel anti-PD-1 antibody, in advanced solid tumours. METHODS: A total of 36 patients with advanced solid tumours received intravenous SHR-1210 at 60 mg, 200 mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The concentration of SHR-1210 was detected for pharmacokinetics, and receptor occupancy on circulating T lymphocytes was assessed for pharmacodynamics. RESULTS: No dose-limiting toxicities were observed. Maximum administered dose was not reached. Most adverse events were grade 1 or 2. Treatment-related severe adverse events were found in two patients. No treatment-related death was reported. Two complete responses (gastric cancer, bladder carcinoma) and seven partial responses were seen. In responders, the median follow-up time was 16.0 months (range 8.3-19.5), and the median duration of response was not reached (range 2.7-17.5+ months). The half-life of SHR-1210 was 2.94 d, 5.61 d and 11.0 d for 3 dose levels, respectively. CONCLUSIONS: Our results demonstrated a promising antitumour activity and a manageable safety profile of SHR-1210, displayed an explicit PK evidence of the feasibility of fixed dose, and established the foundation for further exploration.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Neoplasias/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento
10.
J Lipid Res ; 56(3): 537-45, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25605874

RESUMO

Sphingomyelin synthase-related protein (SMSr) synthesizes the sphingomyelin analog ceramide phosphoethanolamine (CPE) in cells. Previous cell studies indicated that SMSr is involved in ceramide homeostasis and is crucial for cell function. To further examine SMSr function in vivo, we generated Smsr KO mice that were fertile and had no obvious phenotypic alterations. Quantitative MS analyses of plasma, liver, and macrophages from the KO mice revealed only marginal changes in CPE and ceramide as well as other sphingolipid levels. Because SMS2 also has CPE synthase activity, we prepared Smsr/Sms2 double KO mice. We found that CPE levels were not significantly changed in macrophages, suggesting that CPE levels are not exclusively dependent on SMSr and SMS2 activities. We then measured CPE levels in Sms1 KO mice and found that Sms1 deficiency also reduced plasma CPE levels. Importantly, we found that expression of Sms1 or Sms2 in SF9 insect cells significantly increased not only SM but also CPE formation, indicating that SMS1 also has CPE synthase activity. Moreover, we measured CPE synthase Km and Vmax for SMS1, SMS2, and SMSr using different NBD ceramides. Our study reveals that all mouse SMS family members (SMSr, SMS1, and SMS2) have CPE synthase activity. However, neither CPE nor SMSr appears to be a critical regulator of ceramide levels in vivo.


Assuntos
Esfingomielinas/biossíntese , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Animais , Camundongos , Camundongos Knockout , Esfingomielinas/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética
11.
Expert Opin Ther Pat ; 24(7): 791-800, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24798577

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is a serious illness with dramatically increasing incidence. Tremendous worldwide efforts have been exerted to find better ways to treat the disease, delay its onset and prevent it from progressing. In order to discover future anti-AD medicines more rationally, it is crucial to understand the evolving process of existing related technologies from the perspective of technology flow. AREAS COVERED: Patent citation has been used broadly as a powerful tool to capture technology flows. This study collects patent data from IMS Health databases on anti-AD drugs, both marketed and in the research and development (R&D) pipeline. In all, 329 US patents from 1978 through 2013 and citations between them are analyzed, in addition to patents related to marketed drugs. EXPERT OPINION: To discover effective agents for AD treatment, one promising strategy is to integrate various technology clusters related to anti-AD drugs in terms of the extremely dispersed patent citation network in this area. In this context, governments should pay more attention to encourage basic research, especially to focus on cross-mechanism anti-AD agents. New theories and targets for AD, such as the tau protein hypothesis, are worthy of researcher note. Drugs targeting ß-amyloid peptide theory show promise for investors.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Animais , Bases de Dados Factuais , Humanos , Patentes como Assunto
12.
Ther Innov Regul Sci ; 48(2): 226-235, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30227501

RESUMO

The Chinese pharmaceutical market is undergoing dramatic growth, with a huge population, urbanization, a growing number of elderly patients, and increases in the standard of living. As a research-based and high-tech sector, the pharmaceutical industry depends highly upon technological innovation, especially the spatial diffusion of technologies from the perspective of economic geography. In this context, an analysis of technology flowing between regions is of great significance for the investment in a regional market. This article differs from previous studies by focusing on geographic patterns of pharmaceutical technology transfer captured by patent licensing in China, which are further used to analyze investment strategies. The research sample is composed of all pharmaceutical patent licenses filed with the State Intellectual Property Office of China from January 1, 2009, through December 31, 2012. As a result, a geographic network of pharmaceutical technology diffusion in China could be visualized, and province-level regions were ranked and classified into 3 types-input, output, and balance-by various network indicators. Finally, potential investment strategies on different types of regions are recommended for firms abroad, technology holders, contract research organizations, and technology agencies.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA