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1.
Med Sci Monit ; 25: 5191-5200, 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31300636

RESUMO

BACKGROUND Aspirin hyporesponsiveness increases the risk of ischemic events. Therefore, it is important to investigate the factors influencing aspirin hyporesponsiveness. MATERIAL AND METHODS Patients aged 60 years or older who did not take aspirin before enrollment were included, with aspirin 100 mg/day administered after enrollment. The arachidonic acid-induced platelet aggregation rate (Ara) was measured by light transmission assay to evaluate aspirin responsiveness. Patients with Ara in the upper quartile after taking aspirin were assigned to the aspirin hyporesponsive group (Ara-Q4). RESULTS A total of 292 elderly patients were included. The median value of Ara after taking aspirin was 5.87% (interquartile range 3.86-10.04%). Compared with the aspirin non-hyporesponsive group (Ara-Q1-3, Ara ≤10.04%, n=220), the level of uric acid (UA) (341.30 µmol/L vs. 299.10 µmol/L, p=0.027) and the ratios of ß-blockers (9.72% vs. 2.27%, p=0.015) and diuretics (6.94% vs. 1.36%, p=0.036) were higher in the aspirin hyporesponsive group (Ara-Q4, Ara >10.04%, n=72). After multivariate adjustment, the results demonstrated baseline Ara (odds ratio [OR]: 1.030, 95% confidence interval [CI]: 1.004-1.056, p=0.021), UA level (OR: 1.003, 95% CI: 1.000-1.006, p=0.038), and ß-blockers use (OR: 5.487, 95% CI: 1.515-19.870, p=0.010) were independently and positively associated with aspirin hyporesponsiveness. CONCLUSIONS This study found that baseline Ara, UA level, and ß-blockers use were independently and positively associated with aspirin hyporesponsiveness in elderly Chinese patients, which needs to be validated in large-scale studies.


Assuntos
Aspirina/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Antagonistas Adrenérgicos beta/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Biomarcadores Farmacológicos/metabolismo , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Inibidores da Agregação de Plaquetas/farmacologia , Testes de Função Plaquetária , Ácido Úrico/análise
2.
Crit Rev Oncol Hematol ; 141: 82-94, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255992

RESUMO

INTRODUCTION: Chemotherapy is the mainstay of systemic treatment of biliary tract cancer (BTC). However, the treatment response to chemotherapy varies between patients. Currently, no prognostic biomarkers for chemotherapy efficacy have been considered for use in clinical practice. A systematic review was conducted to evaluate the prognostic value of immunohistochemical biomarkers for chemotherapy in patients with resected as well as with advanced BTC. METHOD: Medline and EMBASE databases were searched up to March 2017 for studies that evaluated biomarker expression by immunohistochemistry in resected or advanced BTC patients treated with chemotherapy. The primary endpoints were overall survival (OS) and disease or progression free survival (DFS or PFS). RESULT: Twenty-six studies, including a total of 1348 patients and 26 different biomarkers, met the inclusion criteria and were included in this review. The most frequently studied prognostic biomarkers in BTC were the human Equilibrative Nucleoside Transporter 1 (hENT1), Ribonucleotide Reductase M1 (RRM1), and excision repair cross-complementation 1 (ERCC1). In the meta-analysis of patients treated with gemcitabine-based chemotherapy, high hENT1 expression was associated with longer OS (HR 0.43, 95% CI: 0.28 to 0.64) and DFS/PFS (HR 0.45, 95% CI: 0.33 to 0.61). CONCLUSION: hENT1 is a promising prognostic biomarker for gemcitabine-based chemotherapy in resected as well as in advanced BTC and should be further validated for the selection of patients for chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/tratamento farmacológico , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias dos Ductos Biliares/epidemiologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias do Sistema Biliar/epidemiologia , Neoplasias do Sistema Biliar/metabolismo , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/classificação , Intervalo Livre de Doença , Humanos , Imuno-Histoquímica , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
3.
PLoS One ; 14(6): e0218269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188873

RESUMO

Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Farmacológicos/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Isotretinoína/farmacologia , Neuroblastoma/genética , Tretinoína/análogos & derivados , Tretinoína/farmacologia , Adolescente , Bexaroteno/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fenretinida/farmacologia , Proteína HMGA1a/genética , Proteína HMGA1a/metabolismo , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias do Sistema Nervoso/genética , Neoplasias do Sistema Nervoso/metabolismo , Neoplasias do Sistema Nervoso/patologia , Neoplasias do Sistema Nervoso/cirurgia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Inclusão em Parafina , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Fixação de Tecidos , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-31122183

RESUMO

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a worldwide disorder as the most important challenges of health-care systems. Controlling the normal glycaemia greatly profit long-term prognosis and gives explanation for early, effective, constant, and safe intervention. MATERIAL AND METHODS: Finding the main genetic and epigenetic profile of T2DM and the exact molecular targets of T2DM medications can shed light on its personalized management. The comprehensive information of T2DM was earned through the genome-wide association study (GWAS) studies. In the current review, we represent the most important candidate genes of T2DM like CAPN10, TCF7L2, PPAR-γ, IRSs, KCNJ11, WFS1, and HNF homeoboxes. Different genetic variations of a candidate gene can predict the efficacy of T2DM personalized strategy medication. RESULTS: SLCs and AMPK variations are considered for metformin, CYP2C9, KATP channel, CDKAL1, CDKN2A/2B and KCNQ1 for sulphonylureas, OATP1B, and KCNQ1 for repaglinide and the last but not the least ADIPOQ, PPAR-γ, SLC, CYP2C8, and SLCO1B1 for thiazolidinediones response prediction. CONCLUSION: Taken everything into consideration, there is an extreme need to determine the genetic status of T2DM patients in some known genetic region before planning the medication strategies.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Epigênese Genética/fisiologia , Farmacogenética/métodos , Medicina de Precisão , Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Farmacogenética/tendências , Medicina de Precisão/métodos , Medicina de Precisão/tendências
5.
Br J Cancer ; 120(9): 941-951, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30944457

RESUMO

BACKGROUND: Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients. METHODS: We investigated a biomarker of response for MEK inhibition in KRAS mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in PIK3CA wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo. RESULTS: We identified ß-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in ß-catenin in PIK3CA wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing PIK3CA wt. CONCLUSIONS: We propose that inhibition of the WNT pathway, particularly ß-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that ß-catenin is a potential predictive marker of MEK inhibitor resistance.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , beta Catenina/metabolismo , Acetamidas/farmacologia , Animais , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias do Colo/metabolismo , Farmacorresistência Viral , Humanos , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 3/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Pirimidinonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/antagonistas & inibidores
6.
Anticancer Res ; 39(1): 41-56, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591439

RESUMO

Recent translational studies in cancer have produced a wealth of evidence to support an association between sphingolipid metabolism and clinical outcomes, which underscores the clinical importance of sphingolipid-related biomarkers in cancer diagnosis and prognosis. Importantly, circulating levels of bioactive sphingolipids were demonstrated to correlate with patient survival and treatment response in different tumour types, which could provide novel non-invasive cancer biomarkers. Here, we give a comprehensive overview of recent findings on bioactive sphingolipid species and protein regulators of their metabolism and signalling as novel potential biomarkers for risk assessment, prevention and prediction of treatment response in several types of solid cancers, including prostate, liver, pancreatic, breast and colon cancer, head and neck squamous cell carcinoma and gliomas. Finally, we critically discuss current issues in clinical translation of sphingolipid biomarkers and give our perspective on how these problems could be handled to facilitate implementation of sphingolipid-based diagnostics into clinical practice.


Assuntos
Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias/genética , Esfingolipídeos/genética , Ceramidas/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Medição de Risco , Esfingolipídeos/metabolismo , Taxa de Sobrevida
7.
Acta Pharmacol Sin ; 40(2): 151-159, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29950613

RESUMO

Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.


Assuntos
Biomarcadores Farmacológicos/metabolismo , Inibidores de Calcineurina/efeitos adversos , Rejeição de Enxerto/fisiopatologia , Imunossupressores/efeitos adversos , Transplante de Órgãos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Inibidores de Calcineurina/farmacocinética , Inibidores de Calcineurina/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Monitoramento de Medicamentos , Rejeição de Enxerto/prevenção & controle , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Lipocalina-2/metabolismo , Polimorfismo de Nucleotídeo Único
8.
J Immunol Res ; 2018: 5615109, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30584542

RESUMO

Chronic spontaneous urticaria (CSU) is defined by the appearance of wheals and a variable presence of angioedema which persists for at least 6 weeks. It represents the most common subtype of chronic urticaria and is gaining importance in civil society because of its association with impaired quality of life. Moreover, CSU has a growing impact on national health systems representing a great burden due to its variable rate of response to the approved therapies. In this scenario, the identification of clinical and molecular biomarkers is of pivotal importance. Some groups are trying to detect molecules which would be able to help clinicians in reaching a proper diagnosis; additionally, the opportunity to describe disease severity which leads to cluster patients in different groups could fill the gap in the numerous unmet clinical needs. Several biomarkers are currently being studied with the purpose to predict the response to a defined therapy; unfortunately, none of them are ready to be translated from bench to bedside.


Assuntos
Basófilos/imunologia , Biomarcadores/metabolismo , Urticária/diagnóstico , Animais , Antialérgicos/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Doença Crônica , Citocinas/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Omalizumab/uso terapêutico , Fenótipo , Urticária/terapia
9.
Front Immunol ; 9: 2602, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30505303

RESUMO

Phase I/II clinical trials of autologous hematopoietic stem cell transplantation (AHSCT) have led to increased safety and efficacy of this therapy for severe and refractory autoimmune diseases (AD). Recent phase III randomized studies have demonstrated that AHSCT induces long-term disease remission in most patients without any further immunosuppression, with superior efficacy when compared to conventional treatments. Immune monitoring studies have revealed the regeneration of a self-tolerant T and B cell repertoire, enhancement of immune regulatory mechanisms, and changes toward an anti-inflammatory milieu in patients that are responsive to AHSCT. However, some patients reactivate the disease after transplantation due to reasons not yet completely understood. This scenario emphasizes that additional specific immunological interventions are still required to improve or sustain therapeutic efficacy of AHSCT in patients with AD. Here, we critically review the current knowledge about the operating immune mechanisms or established mechanistic biomarkers of AHSCT for AD. In addition, we suggest recommendations for future immune monitoring studies and biobanking to allow discovery and development of biomarkers. In our view, AHSCT for AD has entered a new era and researchers of this field should work to identify robust predictive, prognostic, treatment-response biomarkers and to establish new guidelines for immune monitoring studies and combined therapeutic interventions to further improve the AHSCT protocols and their therapeutic efficacy.


Assuntos
Doenças Autoimunes/terapia , Biomarcadores Farmacológicos/metabolismo , Biomarcadores/metabolismo , Transplante de Células-Tronco Hematopoéticas , Animais , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Monitorização Imunológica , Guias de Prática Clínica como Assunto , Tolerância a Antígenos Próprios , Transplante Autólogo
10.
Artigo em Inglês | MEDLINE | ID: mdl-30520339

RESUMO

In this study changes in thymidine kinase 1 (TK1) levels after 24 hours of Doxorubicin (Dox) exposure of CEM and MDA MB-231 cells were determined using the commercially available AroCell TK 210 ELISA test. In cell extracts, TK1 levels increased twofold with 1 µM Dox in both cell lines, while the TK1 levels in the culture media increased with 5 and 10 µM of Dox only in case of CEM cells. In conclusion, this study reveals that the TK 210 ELISA can measure changes in intra- and extracellular TK1 levels apparently related to the mechanism of cytotoxicity of anti-cancer agents.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Leucemia/tratamento farmacológico , Timidina Quinase/metabolismo , Biomarcadores Farmacológicos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenvolvimento de Medicamentos , Feminino , Humanos , Transdução de Sinais
11.
Lipids ; 53(10): 947-960, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30592062

RESUMO

Proteins involved in lipid homeostasis are often regulated through the nuclear peroxisome proliferator-activated receptors (PPAR). PPARα is the target for the fibrate-class of drugs. Fenofibrate has been approved for its lipid-lowering effects in patients with hypercholesterolemia and hypertriglyceridemia. We were interested in understanding the expression of the energy transporters in energy-utilizing tissues like liver, heart, muscle, and adipose tissues in rat with the hypothesis that the change in transporter expression would align with the known lipid-lowering effects of PPARα agonists like fenofibrate. We found that several fatty-acid transporter proteins had significantly altered levels following 8 days of fenofibrate dosing. The mRNA levels of the highly abundant Fatp2 and Fatp5 in rat liver increased approximately twofold and decreased fourfold, respectively. Several fatty-acid-binding proteins and acyl-CoA-binding proteins had a significant increase in mRNA abundance but not the major liver fatty-acid-binding protein, Fabp1. Of particular interest was the increased liver expression of Fabp3 also known as heart-fatty acid binding protein (H-FABP or FABP3). FABP3 has been proposed as a circulating clinical biomarker for cardiomyopathy and muscle toxicity, as well as a preclinical marker for PPARα-induced muscle toxicity. Here, we show that fenofibrate induces liver mRNA levels of Fabp3 ~5000-fold resulting in an approximately 50-fold increase in FABP3 protein levels in the whole liver. This increased liver expression complicates the interpretation and potential use of FABP3 as a specific biomarker for PPARα-induced muscle toxicities.


Assuntos
Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/sangue , Proteína 3 Ligante de Ácido Graxo/análise , Proteína 3 Ligante de Ácido Graxo/sangue , Fenofibrato/efeitos adversos , Hipolipemiantes/efeitos adversos , Fígado/efeitos dos fármacos , Animais , Biomarcadores Farmacológicos/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Fenofibrato/toxicidade , Coração/efeitos dos fármacos , Hipolipemiantes/toxicidade , Fígado/metabolismo , Fígado/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
12.
Med Sci Monit ; 24: 8264-8271, 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30446633

RESUMO

BACKGROUND Although several complicated models have been built to evaluate the prognosis of NSCLC patients receiving chemotherapy, simple economic models are still needed to give a preliminary survival assessment of these patients. MATERIAL AND METHODS This study retrospectively assessed the clinical and biological parameters of 223 patients with advanced NSCLC. Univariate and multivariate analyses of overall survival (OS) and progression-free survival (PFS) for the parameters and the prognostic score were assessed. RESULTS Performance status (PS) score=1, smoking history, fibrinogenemia, thrombocytosis, increased lactate dehydrogenase (LDH) level, and anemia were independent predictors of poor prognosis in the univariate analysis of OS and were assessed in multivariate analysis. There was a significant difference in PS=1 (HR=2.134, p<0.0001), increased LDH level (HR=1.508, p=0.014), thrombocytosis (HR=1.547, p=0.012), and smoking history (HR=1.491, p=0.008), based on which the patients were classified into 3 risk groups: low risk (0-1 points), moderate risk (2 points), and high risk (3-5 points). At p values of <0.0001, the median OS was 565, 340, and 273 days and the median progression-free survival was 250, 209, and 135 days, respectively in these 3 risk groups. CONCLUSIONS We established a new prognostic score model using PS, LDH level, PLT count, and smoking history to predict the survival of patients receiving first-line chemotherapy for advanced NSCLC, which might be useful in clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos
13.
DNA Cell Biol ; 37(11): 903-908, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30277797

RESUMO

Gefitinib is currently one of the mostly used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for treating nonsmall cell lung cancer. However, drug resistance is observed among the majority of patients after initial treatment. Factors that predict treatment prognosis and drug resistance to EGFR-TKIs remain elusive. The objective of this study is to investigate whether leukocyte relative telomere length (RTL) can be used as a prognostic biomarker of EGFR-TKIs therapy. In this study, 369 patients with stage IIIB or IV lung adenocarcinoma were recruited and treated with gefitinib as first-line monotherapy. Leukocyte RTL of each patient was measured using quantitative polymerase chain reaction protocol and calculated according to Cawthon's formula. Finally, we examined the association between leukocyte RTL and prognosis or drug resistance of advanced lung adenocarcinoma to gefitinib treatment. Our results indicated that compared with long RTL, short leukocyte RTL was significantly associated with poor prognosis in all patients after gefitinib treatment (overall survival [OS]: 12.9 months vs. 17.8 months, p = 1.2 × 10-4; progression-free survival: 7.8 months vs. 13.0 months, p = 0.043). In addition, statistically significant association between short leukocyte RTL and short OS still existed among the EGFR mutant patients (hazards ratio [HR] = 1.65, 95% confidence interval [CI] = 1.28-2.12; p = 0.006). Besides EGFR mutation status, short RTL also contributed to remarkably elevated risk of gefitinib primary resistance (HR = 1.50, 95% CI = 1.05-2.15, p = 0.027). Our results highlight the clinical potential of leukocyte RTL as a novel biomarker in advanced lung adenocarcinoma treated with EGFR-TKIs.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Telômero/química , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Idoso , Biomarcadores Farmacológicos/metabolismo , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Gefitinibe , Expressão Gênica , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/enzimologia , Leucócitos/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
14.
Brain Behav Immun ; 73: 717-724, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30102967

RESUMO

Prior studies suggest that the inflammatory biomarker c-reactive protein (CRP) holds promise for predicting antidepressant response in patients with major depressive disorder. The objective of this study was to evaluate whether CRP might similarly predict antidepressant responses to lurasidone in patients with bipolar I depression. Serum CRP concentration was measured prior to, and following, 6 weeks of treatment in 485 outpatients with bipolar I depression. Patients were randomized to receive monotherapy with lurasidone 20-60 mg/day (N = 161), lurasidone 80-120 mg/day (N = 162) or placebo (N = 162). CRP was assessed using the wide-range CRP assay (wr-CRP). The primary efficacy endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Mixed models and statistical interaction tests were applied to investigate the moderating effects of pre-treatment wr-CRP on clinical endpoints. CRP was evaluated as a log-transformed continuous variable and by clinically-relevant cut-points. Increasing pre-treatment wr-CRP level predicted a larger overall antidepressant response to lurasidone, as well as an increased response for a number of individual depressive symptoms. These moderating effects of pre-treatment wr-CRP remained significant after adjustment for potential confounds (e.g. baseline BMI and weight change). Treatment with lurasidone did not affect serum concentrations of CRP compared to placebo during the study. Elevated CRP level prior to treatment was associated with an enhanced clinical response to lurasidone in patients with bipolar I depression. If confirmed in future studies, CRP may represent a clinically useful diagnostic and predictive biomarker supporting a precision medicine approach to the treatment of bipolar depression.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Proteína C-Reativa/metabolismo , Cloridrato de Lurasidona/farmacologia , Adulto , Antidepressivos/uso terapêutico , Antimaníacos/uso terapêutico , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/metabolismo , Transtorno Bipolar/fisiopatologia , Proteína C-Reativa/análise , Proteína C-Reativa/fisiologia , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Cloridrato de Lurasidona/metabolismo , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
16.
Exp Mol Pathol ; 105(2): 175-180, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30028960

RESUMO

We have previously shown that SIRT1 mRNA expression was significantly lower in relapsing MS patients compared to those in remission. Our goal was to longitudinally investigate the role of active, phosphorylated SIRT1 (p-SIRT1) as a potential biomarker of relapse and predictor for response to glatiramer acetate (GA) treatment in patients with relapsing remitting multiple sclerosis (MS). We also want to investigate the downstream effects of SIRT1 activation by measuring the trimethylation of histone 3 at lysine 9 (H3K9me3). A cohort of 15 GA-treated patients was clinically monitored using the Expanded Disability Status Scale (EDSS) and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12 months after initiation of the therapy. P-SIRT1 and H3K9me3 levels were assayed by Western blotting using specific antibodies. Statistically significant lower levels of p-SIRT1 protein (p < 0.0001) and H3K9me3 (p = 0.001) were found during relapses when compared to stable MS patients. Non-responders to GA treatment were defined as patients who exhibited at least two relapses following initiation of GA treatment. Statistically significant lower levels of p-SIRT1 protein (p = 0.02) and H3K9me3 (p = 0.004) were found in GA non-responders compared to responders. Using receiver operating characteristic analysis, area under the curve (AUC) for p-SIRT1 was 77% (p = 0.007) and for H3K9me3 was 81% (p = 0.002) for prediction of relapse. For predicting responsiveness to GA treatment, AUC was 75% (P = 0.01) for H3K9me3. Our data suggest that p-SIRT1 and H3K9me3 could serve as potential biomarkers for MS relapse. In addition, H3K9me3 could serve as possible biomarker to predict response to GA treatment.


Assuntos
Acetato de Glatiramer/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Sirtuína 1/metabolismo , Adulto , Biomarcadores Farmacológicos/metabolismo , Estudos de Coortes , Metilação de DNA , Feminino , Histonas/genética , Histonas/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/enzimologia , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fosforilação , Recidiva , Sirtuína 1/genética
17.
J Biochem Mol Toxicol ; 32(9): e22189, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29992668

RESUMO

Acute renal failure is one of the most frequent effects observed after taking medicine. Such situations have been tardily discovered, given that existing methods for assessing toxicity are not predictive. In this light, the present work evaluated the effects of gentamicin, a form of nephrotoxic drug, on HK-2 and HEK-293 cells. By using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and flow cytometry, both cells demonstrated that cytotoxicity occurs in a dose-dependent manner through the processes of apoptosis and cell necrosis. Gene expression analysis showed a relative increase of expression for genes related to cell processes and classic biomarkers, such as TP53, CASP3, CASP8, CASP9, ICAM-1, EXOC3, KIM-1, and CST3. A decrease in expression for genes BCL2L1 and EGF was observed. This study, therefore, indicates that, when the methods are used together, gene expression analysis is able to evaluate the nephrotoxic potential of a substance.


Assuntos
Antibacterianos/efeitos adversos , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Gentamicinas/efeitos adversos , Rim/efeitos dos fármacos , Inibidores da Síntese de Proteínas/efeitos adversos , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Alternativas ao Uso de Animais , Biomarcadores Farmacológicos/metabolismo , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Cistatina C/agonistas , Cistatina C/genética , Cistatina C/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Receptor Celular 1 do Vírus da Hepatite A/agonistas , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Concentração Inibidora 50 , Interleucina-18/antagonistas & inibidores , Interleucina-18/genética , Interleucina-18/metabolismo , Rim/metabolismo , Rim/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Necrose
18.
Curr Protein Pept Sci ; 19(11): 1049-1057, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29984651

RESUMO

Connexins are a family of gap junction proteins widely distributed in human organs and tissues. Gap junctions are organized systems of intercellular protein channels that allow the exchange of ions, chemical signals, and energy substrates between two adjacent cells. Connexin43 (Cx43) is the most abundant isoform of connexins in the heart which play an important role in myocardium disease. Numerous studies have shown that Cx43 was involved in tumor migration and invasion by mediating gap junctions between tumor cells and normal cells. Changes in the expression and distribution of Cx43 contribute to heart disease and cancer. This review discusses current knowledge on the functional and structural abnormalities in Cx43 associated with heart disease and cancer, aiming to highlight the importance of this connexin as an emerging therapeutic target. Here, the current knowledge on the pharmacology of Gap Junction Channels and Hemichannels were also summarized. Finally, we propose that these knowledges can be exploited to identify new diagnostic and effective therapeutic approaches for ischemic heart disease and cancer.


Assuntos
Conexina 43/metabolismo , Cardiopatias/metabolismo , Neoplasias/metabolismo , Animais , Biomarcadores Farmacológicos/metabolismo , Conexina 43/química , Junções Comunicantes/metabolismo , Humanos , Conformação Proteica
19.
J Biochem Mol Toxicol ; 32(9): e22190, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29984871

RESUMO

The intermediate metabolites and redox status imbalance were supported as the two major points for N,N-dimethylformamide (DMF)-induced hepatotoxicity. However, the potential mechanism has not yet been concerned. By applying two inhibitors, this study tried to seek the major role in DMF-induced toxicity on HL7702 cell. We observed that DMF induced cell apoptosis through mitochondrial-dependent and p53 pathway. Inhibition reactive oxygen species by catalase remarkably attenuated the mitochondrial transmembrane potential (MMP), apoptotic proteins, and apoptosis. On the contrary, it reduced the biodegradation rate of DMF by coincubation with CYP2E1 antagonist (DDC) partially reduced late apoptosis. However, the change in MMP, the ratio of Bax to Bcl-xl, and cleaved-caspase 9 was not attenuated by DDC. The pathway in DDC coincubation groups was related to the p53 rather than the mitochondrial pathway. Restoring the redox balance during biodegradation is much more effective than attenuating the metabolite rate of DMF. This study may provide a suitable prevention method to occupational workers.


Assuntos
Apoptose/efeitos dos fármacos , Dimetilformamida/toxicidade , Hepatócitos/efeitos dos fármacos , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Solventes/toxicidade , Biomarcadores Farmacológicos/metabolismo , Catalase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Dimetilformamida/análogos & derivados , Dimetilformamida/metabolismo , Formamidas/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Inativação Metabólica/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Oxidantes/metabolismo , Proteólise/efeitos dos fármacos , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Solventes/metabolismo , Tiocarbamatos/farmacologia , Proteína Supressora de Tumor p53/metabolismo
20.
PLoS One ; 13(6): e0198116, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29870556

RESUMO

There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Biomarcadores Farmacológicos/metabolismo , Colestenonas/uso terapêutico , Metabolômica/métodos , Adulto , Idoso , Esclerose Amiotrófica Lateral/patologia , Biomarcadores Farmacológicos/análise , Progressão da Doença , Método Duplo-Cego , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Humanos , Masculino , Metaboloma/efeitos dos fármacos , Pessoa de Meia-Idade , Placebos , Prognóstico
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