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1.
Med Sci Monit ; 25: 4665-4674, 2019 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-31230063

RESUMO

BACKGROUND High rates of HBeAg and/or HBsAg seroconversion or clearance have been achieved in chronic hepatitis B (CHB) patients receiving pegylated interferon (pegIFN) in addition to ongoing nucleos(t)ide analogue (NUC) treatment. In the present study, we aimed to evaluate HBsAg kinetics to predict HBeAg seroconversion and HBsAg clearance in these patients. MATERIAL AND METHODS A total of 33 HBeAg-positive and 17 HBeAg-negative patients were enrolled between January 2010 and January 2018. At the end of pegIFN treatment, 9 of 50 patients achieved HBsAg clearance, and 9 of 33 HBeAg-positive patients achieved HBeAg seroconversion. RESULTS The cutoff value of 0.41 log10 IU/mL in HBsAg decline at week 12 had a positive predictive value (PPV) of 58.3% and a negative predictive value (NPV) of 94.6% for HBsAg clearance. The cutoff value of 1.94 log10 IU/mL in HBsAg decline at week 24 had a PPV of 80.0% and an NPV of 97.5% for HBsAg clearance. The cutoff value of 0.47 log10 IU/mL in HBsAg decline at week 12 had a PPV of 83.3% and an NPV of 85.2% for HBeAg seroconversion. The cutoff value of 1.29 log10 IU/mL in in HBsAg decline at week 24 had a PPV of 85.7% and an NPV of 88.5% for HBeAg seroconversion. CONCLUSIONS Early HBsAg drop has a high predictive value for HBsAg clearance and HBeAg seroconversion in patients who were treated with combination therapy of pegIFN and NUCs.


Assuntos
Antígenos de Superfície da Hepatite B/análise , Hepatite B Crônica/tratamento farmacológico , Adulto , Antivirais/uso terapêutico , Biomarcadores Farmacológicos/sangue , DNA Viral/sangue , Feminino , Guanina/análogos & derivados , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/metabolismo , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Hepatite B Crônica/sangue , Humanos , Interferon alfa-2/farmacocinética , Interferon alfa-2/farmacologia , Interferon-alfa/farmacologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/farmacologia , Proteínas Recombinantes/farmacologia , Soroconversão , Resultado do Tratamento
2.
Int Immunopharmacol ; 74: 105708, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254956

RESUMO

BACKGROUND AND AIMS: Soluble E-cadherin (sE-cadherin) has been observed elevated in patients with various diseases, and implicated in the occurrence and development of those diseases. The implications of sE-cadherin in chronic hepatitis C virus (HCV) infection are still unclear. The purpose of this study is to explore the significance of sE-cadherin in chronic hepatitis C infection and the correlation with treatment response. METHODS: 87 chronic HCV infected patients and 60 healthy subjects were enrolled in this study. Blood samples from patients receiving the combined treatment of pegylated interferon-a (Peg-IFN-α) with ribavirin (RBV) were collected before treatment, during 4th, 12th therapy weeks, end of the treatment, and 24 weeks post-therapy. Plasma sE-cadherin level was detected by enzyme-linked immunosorbent assay (ELISA) and the relationship between sE-cadherin and antiviral treatment outcome was analyzed. RESULTS: Plasma sE-cadherin concentrations of Chronic HCV infected patients were significantly higher than that of healthy controls. A strong correlation between sE-cadherin level and the HCV viral load, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and also glutamyl transpeptidase (GGT) level was detected. Chronic HCV infected patients achieving rapid virological response (RVR) and sustained virological response (SVR) had lower baseline sE-cadherin concentrations compared with the non-RVR and non-SVR groups respectively. Univariate and multivariate regression analyses suggested that baseline plasma sE-cadherin level was predictive of therapeutic effect in patients with chronic HCV infection. CONCLUSION: Baseline sE-cadherin level could be considered as an independent predictor of SVR with Peg-IFN-α plus ribavirin therapy in the Chinese Han population chronic HCV infection patients. Effective antiviral therapy might restore sE-cadherin at physiological levels.


Assuntos
Biomarcadores Farmacológicos/sangue , Caderinas/sangue , Hepacivirus/fisiologia , Hepatite C Crônica/diagnóstico , Imunoterapia/métodos , Adulto , Antivirais/uso terapêutico , China , Quimioterapia Combinada , Feminino , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Prognóstico , Ribavirina/uso terapêutico , Carga Viral
3.
Brain Dev ; 41(7): 604-613, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30929765

RESUMO

BACKGROUND: Seizures and/or impaired consciousness accompanied by fever without known etiology (SICF) is common in the pediatric emergency setting. No optimal strategy for the management of SICF in childhood currently exists. We previously demonstrated the effectiveness of targeted temperature management (TTM) against SICF with a high risk of morbidity; however, some patients with SICF develop neurological sequelae despite TTM, which necessitate additional neuroprotective treatment. The clinical characteristics of these severe cases have not been studied. Accordingly, the aim of this study was to identify the clinical characteristics of children with SICF who exhibit poor outcomes after TTM. METHODS: The medical records of children admitted to Kobe Children's Hospital (Kobe, Japan) between October 2002 and September 2016 were retrospectively reviewed. Patients with SICF treated using TTM were included and divided into the satisfactory and poor outcome groups. Univariate and multivariate logistic regression analyses were used to compare clinical characteristics and laboratory findings between the two groups. RESULTS: Of the 73 included children, 10 exhibited poor outcomes. Univariate logistic regression analysis revealed that acute circulatory failure before TTM initiation, the use of four or more types of anticonvulsants, methylprednisolone pulse therapy, and an aspartate aminotransferase (AST) level ≥73 IU/L were associated with poor outcomes. Multivariate logistic regression analysis identified an elevated AST level as a significant independent predictor of a poor outcome. CONCLUSIONS: An elevated AST level within 12 h of onset in children with SICF is an independent predictor of a poor outcome after TTM initiated within 24 h of onset.


Assuntos
Febre de Causa Desconhecida/terapia , Hipotermia Induzida/efeitos adversos , Adolescente , Anticonvulsivantes/uso terapêutico , Aspartato Aminotransferases/análise , Aspartato Aminotransferases/sangue , Biomarcadores Farmacológicos/sangue , Criança , Pré-Escolar , Estado de Consciência , Feminino , Febre/etiologia , Humanos , Hipotermia Induzida/métodos , Lactente , Japão , Masculino , Prognóstico , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Temperatura , Resultado do Tratamento
4.
Genet Test Mol Biomarkers ; 23(5): 316-324, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942616

RESUMO

Objective: Perindopril is an angiotensin-converting enzyme (ACE) inhibitor that is commonly used in the treatment of Chinese Han patients with acute myocardial infarction (AMI). However, there have been few studies on whether polymorphisms of the ACE gene affect the efficacy of perindopril or the prognosis of AMI patients. The purpose of this study was to analyze the relationship among the ACE rs121912703 (C>T), rs767880620 (C>A), and rs397514689 (C>T) gene polymorphisms and the prognosis of AMI patients and the clinical efficacy of perindopril in the treatment of AMI. Methods: The ACE genotypes at the rs121912703, rs767880620, and rs397514689 loci in 225 AMI patients treated with perindopril were determined by polymerase chain reaction/Sanger sequencing. Differences in cardiac structure, functional indicators, hemodynamic parameters, and related laboratory indicators were detected before and after treatment. Results: After administration of perindopril, improved ventricular remodeling in AMI patients with wild-type ACE was better than in patients with the ACE rs121912703, rs767880620, and rs397514689 minor variant alleles. The patients harboring wild-type ACE had lower systolic blood pressure and diastolic blood pressure than the patients harboring the minor variant alleles (p < 0.01). The contents of serum ACE and Ang II (angiotensin II) in AMI patients carrying the wild-type ACE alleles were lower than those of patients harboring any of the minor variant alleles (p < 0.01). The 3-year survival time of AMI patients carrying the wild-type ACE alleles was markedly greater compared with AMI patients carrying the mutant genes (p < 0.01). Conclusion: Mutations at the ACE rs121912703, rs767880620, and rs397514689 loci affect the efficacy of perindopril on ventricular remodeling and hemodynamics in Chinese Han AMI patients. The 3-year survival of AMI patients harboring the variant alleles is less than that of the patients harboring the wild-type gene.


Assuntos
Infarto do Miocárdio/genética , Peptidil Dipeptidase A/genética , Perindopril/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Enzima Conversora de Angiotensina , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Farmacológicos/sangue , China , Grupos Étnicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Perindopril/metabolismo , Polimorfismo Genético/genética , Resultado do Tratamento
5.
Crit Care ; 23(1): 140, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31018868

RESUMO

Overuse of empiric antibiotic therapy in the ICU is responsible for promoting the dissemination of multidrug-resistant (MDR) bacteria. Shortened antibiotic treatment duration could contribute to palliating the emergence of MDR. Uncertainty about patient evolution is a major concern for deciding to stop antibiotics. Biomarkers could represent a complementary tool to identify those patients for whom antibiotic treatment could be safely discontinued. The biomarker most extensively studied to guide antibiotic withdrawal is procalcitonin (PCT), but its real impact on decreasing the duration of antibiotic treatment is a matter of controversy. Combining biomarkers to rule out complicated outcomes in sepsis patients could represent a better option. Some candidate biomarkers, including mid-regional proadrenomedullin, the percentage of human leukocyte antigen DR (HLA-DR)-positive monocytes, means of fluorescence intensities of HLA-DR on monocytes, interleukin-7 receptor expression levels, immunoglobulin M levels in the serum or the absence of increased proteolysis, have already demonstrated the potential to exclude the risk of progression to septic shock, nosocomial infections, and mortality when tested along the sepsis course. Other promising biomarkers to rule out complicated outcomes are neutrophil protease activity, the adaptive/coagulopathic signatures identified by whole transcriptome analysis by Sweeney et al., and the SRS1 signature identified by Davenport et al. In conclusion, there are a number of promising biomarkers involved in proteolytic, vascular, immunological, and coagulation alterations that could be useful to build composed endotypes to predict uncomplicated outcomes in sepsis. These endotypes could help to identify patients deserving the discontinuation of antibiotics.


Assuntos
Antibacterianos/administração & dosagem , Biomarcadores Farmacológicos/análise , Sepse/tratamento farmacológico , Fatores de Tempo , Adrenomedulina/análise , Adrenomedulina/sangue , Antibacterianos/uso terapêutico , Biomarcadores Farmacológicos/sangue , Humanos , Unidades de Terapia Intensiva/organização & administração , Pró-Calcitonina/análise , Pró-Calcitonina/sangue , Precursores de Proteínas/análise , Precursores de Proteínas/sangue , Resultado do Tratamento
6.
Mol Biol Rep ; 46(3): 2761-2769, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30850966

RESUMO

This study was aimed to investigate the prevalence of the CES1 gene (c.1168-33A > C, rs2244613) polymorphism among 12 different ethnic groups living in Russia to provide a basis for future clinical studies concerning genetic determinants of dabigatran safety. The study involved 1630 apparently healthy, unrelated, and chronic medication-free volunteers of both genders from 12 different ethnic groups in Russia: 136 Russians, 90 Avars, 50 Dargins, 46 Laks, 120 Kabardians, 112 Balkars, 244 Ossetians, 206 Mari, 204 Mordvinians, 238 Chuvashes, 114 Buryats and 70 Nanays. Genotyping was performed by using real-time polymerase chain reaction-based methods. The allelic prevalence of the ethnic groups was compared with Caucasus population participating in the RE-LY study. Statistically significant differences for the following gene polymorphism were found between all ethnic groups and RE-LY participants. Based on obtained results, it can be assumed that patients of all ethnic groups living in Russia taking dabigatran have a lower risk of bleeding.


Assuntos
Hidrolases de Éster Carboxílico/genética , Alelos , Biomarcadores Farmacológicos/sangue , Hidrolases de Éster Carboxílico/metabolismo , Dabigatrana/farmacologia , Dabigatrana/uso terapêutico , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Genética Populacional , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Federação Russa
7.
BMC Infect Dis ; 19(1): 161, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764769

RESUMO

BACKGROUND: A reduction in duration of antibiotic therapy is crucial in minimizing the development of antimicrobial resistance, drug-related side effects and health care costs. The minimal effective duration of antimicrobial therapy for febrile urinary tract infections (fUTI) remains a topic of uncertainty, especially in male patients, those of older age or with comorbidities. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy. METHODS: A secondary analysis of a randomized placebo-controlled trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days. Patients indicated to receive antimicrobial treatment for more than 14 days were excluded from randomization. The biomarkers procalcitonin (PCT), mid-regional proadrenomedullin (MR-proADM), and C-reactive protein (CRP) were compared in their ability to predict clinical cure or failure through the 10-18 day post-treatment visit. RESULTS: Biomarker concentrations were measured in 249 patients, with a clinical cure rate of 94% in the 165 randomized and 88% in the 84 non-randomized patients. PCT, MR-proADM and CRP concentrations did not differ between patients with clinical cure and treatment failure, and did not predict treatment outcome, irrespective of 7 or 14 day treatment duration (ROCAUC 0.521; 0.515; 0.512, respectively). PCT concentrations at presentation were positively correlated with bacteraemia (τ = 0.33, p < 0.001) and presence of shaking chills (τ = 0.25, p < 0.001), and MR-proADM levels with length of hospital stay (τ = 0.40, p < 0.001), bacteraemia (τ = 0.33, p < 0.001), initial intravenous treatment (τ = 0.22, p < 0.001) and time to defervescence (τ = 0.21, p < 0.001). CRP did not display any correlation to relevant clinical parameters. CONCLUSIONS: Although the biomarkers PCT and MR-proADM were correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection who were treated for either 7 or 14 days. CRP had no added value in the management of patients with fUTI. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].


Assuntos
Adrenomedulina/sangue , Biomarcadores Farmacológicos/sangue , Proteína C-Reativa/metabolismo , Infecções Comunitárias Adquiridas/diagnóstico , Febre/diagnóstico , Pró-Calcitonina/sangue , Precursores de Proteínas/sangue , Infecções Urinárias/diagnóstico , Adrenomedulina/análise , Idoso , Antibacterianos/uso terapêutico , Biomarcadores Farmacológicos/análise , Proteína C-Reativa/análise , Infecções Comunitárias Adquiridas/sangue , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/epidemiologia , Feminino , Febre/sangue , Febre/tratamento farmacológico , Febre/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Pró-Calcitonina/análise , Prognóstico , Precursores de Proteínas/análise , Estudos Retrospectivos , Resultado do Tratamento , Infecções Urinárias/sangue , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/epidemiologia
8.
Mol Psychiatry ; 24(4): 501-522, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30755720

RESUMO

We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.


Assuntos
Dor/tratamento farmacológico , Dor/genética , Medicina de Precisão/métodos , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores Farmacológicos/sangue , Biologia Computacional/métodos , Proteínas Contráteis/genética , Proteínas Contráteis/metabolismo , Reposicionamento de Medicamentos/métodos , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Transcriptoma/genética
9.
Genet Test Mol Biomarkers ; 23(3): 223-227, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30758239

RESUMO

AIM: The present study looked for variation in the miRNA-24 sequence, and evaluated the associations between the dihydrofolate reductase (DHFR) gene-829 C-T polymorphism and plasma DHFR concentrations with response to methotrexate (MTX) treatment in Mexican patients with rheumatoid arthritis (RA). METHODS: A total of 135 women with RA were classified as responders (disease activity score [DAS28] <3.2) or nonresponders to MTX (DAS28 > 3.2). We determined the genotype of the patients using the polymerase chain reaction-restriction fragment length polymorphism method. Plasma DHFR enzyme levels and mi-RNA24 sequences were assessed by enzyme-linked immunosorbent assay (ELISA) and Sanger sequencing, respectively. Allelic frequencies and the genotypic distribution of the polymorphism were analyzed by the chi-square test. RESULTS: The genotype frequencies of the DHFR -829C-T polymorphism among responders were 37.0% CC, 52.1% CT, and 10.9% TT and for nonresponders were 33.9% CC, 56.4% CT, and 9.7% TT. No significant differences in genotype frequencies were found between the groups (p = 0.88). The DHFR levels relative to genotype for responders were 6.8 ± 2.7, 6.1 ± 2.7, and 6.5 ± 1.5 ng/mL for CC, CT, and TT, respectively, and for nonresponders were 6.5 ± 2.0, 6.1 ± 3.1, and 7.4 ± 1.8 ng/mL for CC, CT, and TT, respectively. No significant differences were found between the two groups. Similarly, both groups showed no sequence variations in miRNA-24 gene. CONCLUSION: The -829C-T polymorphism of DHFR gene was not associated with response to MTX by RA patients, and no variations were found in the miRNA-24 sequence that might modify the response to treatment or DHFR enzyme levels in a Mexican population with RA.


Assuntos
Artrite Reumatoide/genética , MicroRNAs/genética , Tetra-Hidrofolato Desidrogenase/genética , Adulto , Idoso , Alelos , Biomarcadores Farmacológicos/sangue , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Metotrexato/farmacologia , Metotrexato/uso terapêutico , México , MicroRNAs/fisiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Tetra-Hidrofolato Desidrogenase/fisiologia
10.
Int J Rheum Dis ; 22(4): 646-653, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30358109

RESUMO

AIM: The aim of our study was to identify pharmacodynamic biomarkers and assess differential effects of tumor necrosis factor (TNF)- and non-TNF-targeting agents on rheumatoid arthritis (RA) patients with an inadequate response to anti-TNF agents (anti-TNF-IR) in comparison with biologic-naïve patients. METHODS: EARTH EXPLORER 2, a phase IIb trial, evaluated golimumab, an anti-TNF antibody, and mavrilimumab, an granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor antibody, in disease-modifying antirheumatic drug (DMARD)-IR and anti-TNF-IR patients. Our current study assessed peripheral protein markers and gene expression levels in association with clinical response post-treatment in two disease strata. RESULTS: Serum proteomics results indicated the existence of specific pharmacodynamic markers for golimumab and mavrilimumab, regardless of prior anti-TNF treatment. In contrast, both antibodies induced early and sustained suppression of RA disease markers, including interleukin (IL)-6, C-reactive protein, IL2RA, and matrix metalloproteinase 1, in DMARD-IR patients. Golimumab-induced early changes rapidly returned toward baseline concentrations in anti-TNF-IR patients, whereas mavrilimumab-induced changes were maintained through to day 169. RNA sequencing demonstrated gene expression changes at day 169 after administration of mavrilimumab but not golimumab in anti-TNF-IR patients. Additionally, receiver operating characteristic curve and regression analysis showed the association of early IL-6 change and subsequent clinical responses to golimumab in anti-TNF-IR patients. CONCLUSION: Our results revealed golimumab- and mavrilimumab-specific pharmacodynamic biomarkers, and demonstrated differential biomarker-treatment relationships in anti-TNF-IR and DMARD-IR patients, respectively. Early IL-6 change after anti-TNF antibody treatment may be a potential predictive biomarker for selection of different treatment regimens in anti-TNF-IR patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores Farmacológicos/sangue , Monitoramento de Medicamentos/métodos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Mediadores da Inflamação/sangue , Proteômica , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Método Duplo-Cego , Feminino , Perfilação da Expressão Gênica , Marcadores Genéticos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
11.
Per Med ; 16(2): 115-122, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30569826

RESUMO

AIM: Major depressive disorder (MDD) is a common psychiatric disorder with a complicated pathogenesis and genetic predisposition. The objective of this article is to explore the relationship between the four SNPs of circadian locomotor output cycles kaput (CLOCK) gene (rs11932595, rs12504300, rs3805148, rs534654) and the efficacy of antidepressants. Materials & methods: This study enrolled a total of 600 patients, who met the DSM-V diagnostic criteria for MDD. All subjects were treated with single selective serotonin reuptake inhibitors. The HAMD17 and adverse reaction scale (TESS/UKU) were used to assess the efficacy of antidepressants and adverse effects. The PCR and DNA sequencing analysis were used to genotype loci of CLOCK gene. RESULTS: The antidepressants efficacy of subjects with rs11932595 AA genotype was significantly higher than those with GG+GA genotypes (p = 0.035). But this p-value was not significant after false discovery rate (FDR) adjustment. CONCLUSION: The variant of CLOCK gene may be associated with the efficacy of selective serotonin reuptake inhibitors in Chinese Han MDD patients.


Assuntos
Proteínas CLOCK/genética , Transtorno Depressivo Maior/genética , Adulto , Idoso , Alelos , Antidepressivos/farmacologia , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Farmacológicos/sangue , China , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
12.
Br J Cancer ; 120(3): 346-355, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30587849

RESUMO

BACKGROUND: Anti-PD-1 immunotherapies have shown clinical benefit in multiple cancers, but response was only observed in a subset of patients. Predicting which patients will respond is an urgent clinical need, but current companion diagnosis based on PD-L1 IHC staining shows limited predictability. METHODS: A dynamic, metrics-based biomarker was developed to discriminate responders from non-responders for anti-PD-1 immunotherapy in B16F10 melanoma-bearing mice. RESULTS: Similar to patients, there was considerable heterogeneity in response to anti-PD-1 immunotherapy in mice. Compared with the control group, 45% of anti-PD-1 antibody-treated mice displayed improved survival (defined as responders) and the remainder only gained little, if any, survival benefit from PD-1 blockade (non-responders). Interestingly, the dynamics of IFN-γ secretion by peripheral lymphocytes was associated with faster secretion onset (shorter lag time), stronger exponential phase, shorter time to half magnitude, and higher magnitude of secretion in responders at day 10 after tumour inoculation. To sufficiently predict responders from non-responders, IFN-γ secretion descriptors as well as phenotypic markers were subjected to multivariate analysis using orthogonal partial least-squares discriminant analysis (OPLS-DA). CONCLUSIONS: By integrating phenotypic markers, IFN-γ secretion descriptors sufficiently predict response to anti-PD-1 immunotherapy. Such a dynamic, metrics-based biomarker holds high diagnostic potential for anti-PD-1 checkpoint immunotherapy.


Assuntos
Imunoterapia/efeitos adversos , Interferon gama/sangue , Melanoma Experimental/terapia , Receptor de Morte Celular Programada 1/sangue , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Farmacológicos/sangue , Humanos , Interferon gama/genética , Linfócitos/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
13.
Anticancer Res ; 39(1): 519-526, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591504

RESUMO

BACKGROUND/AIM: Neoadjuvant chemoradiotherapy has side-effects that adversely affect patients' quality of life. The aim of this study was to identify serum metabolite biomarkers that might be used to predict the side-effects of neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Metabolomic analysis of serum samples from 26 patients with ESCC that were collected before neoadjuvant chemoradiotherapy was performed. The metabolites associated with hematological toxicity or nephrotoxicity were evaluated. RESULTS: Serum levels of glutaric acid, glucuronic acid, and cystine were significantly higher in hematological toxicity, and phosphatidylcholines and phosphatidylethanolamines exhibited a tendency to be higher in those with hematological toxicity. The serum level of pyruvic acid was significantly lower in nephrotoxicity, and lysophosphatidylcholines and lysophosphatidylethanolamines tended to be lower in those with nephrotoxicity. CONCLUSION: Our study found that serum levels of some metabolites differed significantly between patients with and without hematological or renal side-effects. These metabolites may be useful biomarkers for predicting hematological toxicity or nephrotoxicity after neoadjuvant chemoradiotherapy for ESCC.


Assuntos
Biomarcadores Farmacológicos/sangue , Biomarcadores Tumorais/sangue , Quimiorradioterapia/efeitos adversos , Carcinoma de Células Escamosas do Esôfago/sangue , Adulto , Idoso , Cisplatino/efeitos adversos , Terapia Combinada/efeitos adversos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Qualidade de Vida
14.
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
16.
AAPS J ; 21(1): 9, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30547287

RESUMO

The interleukin (IL)-17 pathway has been implicated in the pathophysiology of many autoimmune diseases. MCAF5352A is a humanized monoclonal antibody which targets both IL-17A and IL-17F, thereby inhibiting the activity of IL-17 dimers (IL-17AA, IL-17AF, and IL-17FF). The pharmacokinetic profile of MCAF5352A has been characterized in both a Phase Ia single ascending dose study and a Phase Ib multiple ascending dose study. Two qualified enzyme-linked immunosorbent assays were used to measure total IL-17AA and IL-17FF levels in serum as pharmacodynamic biomarkers in the Phase I studies. The two assays demonstrated specificity for IL-17AA or IL-17FF with sensitivity at low picogram/milliliter levels. The assay precision and accuracy also met acceptance criteria. Although total serum IL-17AA and IL-17FF levels were below the assay detection limits prior to administration of MCAF5352A, post-treatment levels in both the single and multiple dose cohorts became detectable and increased in a dose-dependent manner. These data are consistent with target engagement by MCAF5352A. Our work highlights bioanalytical challenges encountered while developing biomarker assays requiring high sensitivity and specificity. Data generated using these assays enabled the confirmation of target engagement during early clinical drug development.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Biomarcadores Farmacológicos/sangue , Interleucina-17/sangue , Adulto , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Desenvolvimento de Medicamentos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Voluntários Saudáveis , Humanos , Interleucina-17/antagonistas & inibidores , Limite de Detecção , Masculino , Camundongos , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto Jovem
17.
J Immunol Res ; 2018: 5349837, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30426025

RESUMO

Background: Defining new prognostic biomarkers has become one of the most promising perspectives for the long-term care of patients with juvenile idiopathic arthritis (JIA). The new efficient indicators of disease activity and potential response to treatment are crucial in establishing new therapeutic plans in accordance with the "treat to target" strategy. One of the most studied proteins is called S100A12, which is an alarmin specific for granulocytes, considered as a marker of their activity. Materials and Methods: Study involved 80 patients diagnosed with JIA. Children with systemic subtype were not included in the study. In 53 cases, blood samples were obtained in two time points. Results from the study group were compared to 29 age- and sex-matched healthy individuals. Results: Serum S100A12 levels were higher in JIA than in healthy controls at the study baseline (11.67 ± 6.59 vs. 6.01 ± 2.33 ng/ml). There were no significant differences in S100A12 values between assessed subtypes of JIA. The highest concentrations were observed in patients within a disease flare. S100A12 levels were not dependent from using glucocorticosteroids. The studied protein appeared to be an efficient biomarker for JIA patients: 100% specificity as a diagnostic marker (cut-off level: 10.73 ng/ml) and 100% sensitivity as an indicator of exacerbations within a 3-month observation (cut-off level: 5.48 ng/ml). Conclusions: S100A12 may become an important factor influencing decisions on aggressiveness of JIA therapy. Further elaboration on the clinical algorithm is necessary for that protein to be included in everyday practice.


Assuntos
Artrite Juvenil/diagnóstico , Biomarcadores Farmacológicos/sangue , Biomarcadores/sangue , Granulócitos/fisiologia , Proteína S100A12/sangue , Adolescente , Artrite Juvenil/terapia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Bull Exp Biol Med ; 166(2): 213-216, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30488214

RESUMO

We studied the effect of Fe2+ ions in polymerized hemoglobin (Krunidon blood substitute) and in molecular hemoglobin (Sigma) on OH• radical initiation in the Fenton system. It was found that polymerized hemoglobin, as a component of Krunidon preparation, in contrast to hemoglobin tetramer, did not intensify OH• radical generation. The oxidant potential of Krunidon was evaluated in vivo by measuring malondialdehyde level in dog blood plasma after repeated intravenous administration (5 days in a dose of 114 mg/kg) as a biomarker. Administration of the preparation did not significantly increased malondialdehyde content on days 1 and 4 after exposure and did not affect total protein content in blood plasma. Our findings suggest that polymerized hemoglobin in the Krunidon preparation exhibits no pro-oxidant activity and can be used as the basis for the development of non-oxygenic forms of blood substitutes.


Assuntos
Substitutos Sanguíneos/química , Hemoglobinas/química , Malondialdeído/sangue , Animais , Biomarcadores Farmacológicos/sangue , Substitutos Sanguíneos/farmacocinética , Bovinos , Cães , Hemoglobinas/farmacocinética , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Ferro/química , Masculino , Oxirredução
19.
Per Med ; 15(6): 503-510, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30383478

RESUMO

AIM: The correlation of IL28-B genetic variants (rs12979860) with combinational therapy (peg-interferon, sofosbuvir plus ribavirin) of hepatitis C virus infection were studied in 154 chronic hepatitis C patients. METHODS & RESULTS: The sustained virological response for efficient antiviral regimen was achieved in 75.32% treated individuals. Three genotypes of rs12979860 (CC, CT and TT) were compared both in sustained virological response and nonresponders groups (p = 0.25, p ≤ 0.001, p = 0.10, respectively). CT genotype demonstrated a significant correlation (p ≤ 0.001) in both groups with higher positive predictive value (81.55%). CONCLUSION: IL28 polymorphism and positive predictive value may be considered as the markers for the evaluation of the effectiveness of the treatment regimen. Further clinical trials are recommended to verify the role of IL28-B in hepatitis C virus treatment.


Assuntos
Hepatite C Crônica/genética , Interferon-alfa/uso terapêutico , Interleucinas/genética , Adulto , Antivirais , Biomarcadores Farmacológicos/sangue , Estudos Transversais , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/patogenicidade , Hepatite C/genética , Hepatite C/metabolismo , Hepatite C Crônica/metabolismo , Humanos , Interferons , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Polietilenoglicóis , Polimorfismo de Nucleotídeo Único/genética , Ribavirina/farmacologia , Sofosbuvir/farmacologia , Resposta Viral Sustentada , Resultado do Tratamento
20.
Genet Test Mol Biomarkers ; 22(11): 652-655, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30351207

RESUMO

AIMS: To validate a laboratory-developed test for the nucleoside transporter, SLC28A3, which has been associated with an increased risk of anthracycline-induced cardiomyopathy. METHODS: We used Taqman® allele discrimination to test for two variants of the SLC28A3 gene: rs7853758 (c.1381C>T) and rs885004 (c.862-360C>T). RESULTS: During the validation process, we noted that several DNA samples obtained from the Coriell Cell Repository (Camden, NJ) were positive for both the c.1381 C > T and c.862-360C>T variants and another variant allele for either c.1381 C > T or c.862-360C>T (e.g., c.1381C>T homozygous/c.862-360C>T heterozygous, c.1381C>T homozygous/c.862-360C>T homozygous). We used de-identified DNA samples from trios of family members (mother, father, and child) to establish that the c.1381 C > T and c.862-360C>T variant alleles could be inherited in cis on the same chromosome. CONCLUSIONS: Samples containing three variant alleles suggest that the c.1381 C > T and c.862-360C>T are in cis on the chromosome in some individuals and may have implications when calculating anthracycline-induced cardiomyopathy risk. In this study, we confirm a novel haplotype of SLC28A3 using familial studies.


Assuntos
Técnicas de Genotipagem/métodos , Proteínas de Membrana Transportadoras/genética , Alelos , Antraciclinas , Biomarcadores Farmacológicos/sangue , Cardiomiopatias/genética , DNA/genética , Feminino , Frequência do Gene/genética , Haplótipos/genética , Humanos , Masculino , Proteínas de Membrana Transportadoras/análise , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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