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INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes. DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. HIGHLIGHTS: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Amiloide , Peptídeos beta-Amiloides , Proteínas Amiloidogênicas , Biomarcadores , Método Duplo-Cego , Análise de Classes Latentes , Tomografia por Emissão de Pósitrons/métodosRESUMO
Very low birth weight (VLBW) neonates present a high risk of metabolic bone disease (MBD). Our main objective was to determine the easiest way to make an early diagnosis of this disease by identifying surrogate biomarkers before any radiological signs occurred. We conducted in our NICU a 6-month observational prospective study, with inclusion of all singleton VLBW neonates. We collected clinical and biological data, and nutritional intakes during hospitalization. We defined biological MBD (bMBD) as alkaline phosphatase (ALP) levels superior to 600 UI/L at day of life 30 (DOL30) and performed a case-control analysis. Nine out of 30 patients (30%) exhibited bMBD. All have extremely low birth weight and were significantly younger in gestational age (GA) and smaller at birth. There was no statistically significant difference in nutritional intake between bMBD and control groups. In the bMBD group, phosphatemia was lower since DOL3. ALP was already significantly higher at DOL15, and way beyond normal range. CONCLUSIONS: Our results showed that even the strict respect of nutritional guidelines cannot completely prevent bMBD in high-risk patients and suggest that an early screening from DOL15, with ALP levels greater than 500 UI/L, could be sufficient for detection of upcoming MBD. WHAT IS KNOWN: ⢠Metabolic bone disease of prematurity (MBD) definition is not consensual, but biological changes appear earlier than radiological signs of rickets. ⢠MBD management relies on biological evidence. Treatment is based on phosphate and/or calcium and calcitriol supplementation. WHAT IS NEW: ⢠Studying phosphocalcic biological assessment in very low birth weight neonates, we showed respect of nutritional guidelines could not protect from biological MBD. ⢠Increase in alkaline phosphatase (ALP), about 500 UI/l at day of life 15, could be a biomarker of MBD with no need of X-ray evaluation and sufficient to begin a treatment to prevent osteopenia.
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Fosfatase Alcalina , Doenças Ósseas Metabólicas , Recém-Nascido , Humanos , Estudos Prospectivos , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/terapia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , BiomarcadoresRESUMO
In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal post-remission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Biomarcadores , Neoplasia Residual/diagnóstico , RecidivaRESUMO
BACKGROUND: Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under therapy with Abiraterone. METHODS: Men with bone mCRPC (bmCRPC) on Abiraterone 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis. RESULTS: Thirty-nine pre- and 45 post-chemotherapy patients with a median follow up of 14.0 months were analyzed. ALP-Bouncing can be observed very early during therapy with Abiraterone. ALP-Bouncing is defined as rapidly rising ALP-levels independent of baseline ALP during the first 2-4 weeks of Abiraterone-therapy with subsequent equally marked decline to pretreatment levels or better within 8 weeks of therapy, preceding potentially delayed PSA-decline. In univariate analysis failure of PSA-reduction ≥ 50% and failure of ALP-Bouncing were the strongest predictors of progressive disease (p = 0.003 and 0.021). Rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing were strongest predictors of poor OS, (all p < 0.001). Kaplan-Meier-analysis showed worse OS for rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing (p < 0.001). In subgroup-analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, with no PSA-reduction ≥ 50% and rising ALP at 12 weeks being the strongest (p < 0.001). In multivariate analysis PSA-reduction ≥ 50% remained an independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (both p = 0.014). No patient with ALP-Bouncing had PD for best clinical benefit. Patients with rising ALP at 12 weeks had no further benefit of Abiraterone. CONCLUSIONS: Dynamic changes of ALP, LDH and PSA during Abiraterone-therapy are associated with best clinical benefit and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes as well as prior to equivocal imaging results and rising ALP at 12 weeks under Abiraterone may help to decide whether to discontinue Abiraterone. An external validation of these findings on a prospective cohort is planned.
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Fosfatase Alcalina/sangue , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/sangue , L-Lactato Desidrogenase/sangue , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Androstenos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.
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Acetato de Abiraterona/administração & dosagem , Antineoplásicos/administração & dosagem , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/uso terapêutico , Idoso , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and three IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology (p < 0.001) and demonstrated the worst overall survival among our cohort (p = 0.004). IHC expression subtype (Transitional, Basal vs Classical) was an independent poor prognosticator in multivariate analysis [HR 1.58 (95% CI 1.01-2.38), p = 0.047]. Furthermore, CK5/6 expression was an independent poor prognostic factor in histological glandular type PDAC [HR 2.82 (95% CI 1.31-6.08), p = 0.008]. Our results suggest that IHC expression patterns successfully predict molecular features indicative of the Basal-like subgroup in advanced PDAC. These results provide the basis for appropriate stratification for therapeutic selection and prognostic estimation of advanced PDAC in a simplified manner.
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Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Fator de Transcrição GATA6 , Fator 4 Nuclear de Hepatócito , Imuno-Histoquímica , Neoplasias Pancreáticas , Humanos , Fator de Transcrição GATA6/metabolismo , Fator de Transcrição GATA6/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Masculino , Feminino , Fator 4 Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Idoso , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/genética , Prognóstico , Queratina-5/metabolismo , Queratina-6/metabolismo , Idoso de 80 Anos ou mais , Adulto , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Fatores de Transcrição , Proteínas Supressoras de TumorRESUMO
Given the widespread occurrence of insulin resistance, a key factor in metabolic syndrome and a distinct condition altogether, there is a clear need for effective, surrogate markers. The triglyceride-to-high-density lipoprotein (TG/HDL) ratio stands out as a viable option, indicative of changes in lipid metabolism associated with insulin resistance, offering a cost-effective and straightforward alternative to traditional, more complex biomarkers. This review, in line with PRISMA guidelines, assesses the TG/HDL ratio's potential as an indirect indicator of insulin resistance. Analysing 32 studies over 20 years, involving 49,782 participants of diverse ethnic backgrounds, including adults and children, this review primarily uses a cross-sectional analysis with the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) to gauge insulin resistance. It reveals the TG/HDL ratio's varied predictive power across ethnicities and sexes, with specific thresholds providing greater accuracy for Caucasians, Asians, and Hispanics over African Americans and for men over women. Valid across different weights and ages, for adults and children, it suggests average cutoffs of 2.53 for women and 2.8 for men. The analysis supports the TG/HDL ratio as a simple, accessible marker for insulin resistance, though it advises further research on tailored cutoffs reflecting ethnic and gender differences.
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We investigated possible associations between the internal concentrations of POPs and correlations between blood and tumor tissue concentrations in patients who underwent surgery for breast cancer and breast reduction as controls. Genetic variations in CYP1A1, GSTP1, GSTM1, and GSTT1 and hOGG1 were evaluated to determine whether they represent risk factors for breast cancer. Certain POPs have been found to be associated with breast cancer development. GST-P1 polymorphism represented a significant risk for breast cancer with unadjusted OR. However, the GSTT1 null polymorphism represented a significant risk for breast cancer when OR adjusted for age and smoking status. CYP1A1 polymorphism was a significant risk factor for breast cancer, regardless of whether the OR was adjusted. These results suggest that exposure to certain POPs, GSTT1 and CYP1A1 polymorphisms, age, and smoking status are risk factors for breast cancer. In addition, the blood concentrations of some POPs represent surrogates for breast tissue concentrations.
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Neoplasias da Mama , Citocromo P-450 CYP1A1 , Predisposição Genética para Doença , Glutationa Transferase , Poluentes Orgânicos Persistentes , Humanos , Neoplasias da Mama/genética , Feminino , Glutationa Transferase/genética , Citocromo P-450 CYP1A1/genética , Pessoa de Meia-Idade , Adulto , Poluentes Orgânicos Persistentes/sangue , Polimorfismo Genético , Idoso , Glutationa S-Transferase pi/genética , Fatores de Risco , DNA GlicosilasesRESUMO
According to the 2021 World Health Organization classification of brain tumors, astrocytomas containing a CDKN2A/B homozygous deletion (HD) are designated as grade 4 even when no microvascular proliferation and/or necrosis is present. In this study, we aimed to investigate the relationship between CDKN2A HD and loss of methylthioadenosine phosphorylase (MTAP) expression in adult-type IDH-mutant gliomas and to assess the sensitivity and specificity of MTAP immunohistochemistry (IHC) along with interobserver agreement as a surrogate biomarker for CDKN2A HD. Eighty-eight astrocytomas and 71 oligodendrogliomas cases that were diagnosed between 2014 and 2021 at Hacettepe University were selected and tissue microarrays were conducted to perform CDKN2A fluorescence in situ hybridization and MTAP IHC. Twenty-five (15.7%) cases harbored CDKN2A HD. MTAP loss was detected in 28 (15.7%) cases by the first observer and 27 (17%) cases by the second observer. The sensitivity and specificity of MTAP were calculated as 88% and 95.52%-96.27% for 2 observers. A very good/perfect agreement was noted between the observers (Cohen kappa coefficient = 0.938). Intratumoral heterogeneity was observed in 4 cases. MTAP IHC was found to be a reliable surrogate biomarker as a possible alternative to CDKN2A HD identification with a high sensitivity and specificity along with high interobserver agreement.
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Astrocitoma , Glioma , Purina-Núcleosídeo Fosforilase , Adulto , Humanos , Imuno-Histoquímica , Homozigoto , Hibridização in Situ Fluorescente , Reprodutibilidade dos Testes , Deleção de Sequência , Glioma/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Astrocitoma/genéticaRESUMO
The therapeutic potential of directly reprogrammed neural stem cells (iNSCs) for neurodegenerative diseases relies on reducing the innate tumorigenicity of pluripotent stem cells. However, the heterogeneity within iNSCs is a major hurdle in quality control prior to clinical applications. Herein, we generated iNSCs from human fibroblasts, by transfecting transcription factors using Sendai virus particles, and characterized the expression of iNSC markers. Using immunostaining and quantitative real time -polymerase chain reaction (RT -qPCR), no differences were observed between colonies of iNSCs and iNSC-derived neurons. Unexpectedly, patch-clamp analysis of iNSC-derived neurons revealed distinctive action potential firing even within the same batch product. We performed single-cell RNA sequencing in fibroblasts, iNSCs, and iNSC-derived neurons to dissect their functional heterogeneity and identify cell fate regulators during direct reprogramming followed by neuronal differentiation. Pseudotime trajectory analysis revealed distinct cell types depending on their gene expression profiles. Differential gene expression analysis showed distinct NEUROG1, PEG3, and STMN2 expression patterns in iNSCs and iNSC-derived neurons. Taken together, we recommend performing a predictable functional assessment with appropriate surrogate markers to ensure the quality control of iNSCs and their differentiated neurons, particularly before cell banking for regenerative cell therapy.
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Células-Tronco Neurais , Células-Tronco Pluripotentes , Humanos , Neurônios , Células-Tronco Neurais/metabolismo , Diferenciação Celular/genética , Análise de Sequência de RNARESUMO
Despite technological advances in diagnostic abilities and improved treatment methods, the burden of cancers remains high, leading to significant morbidity and mortality. One primary reason is that cancer cell secretory factors modulate the tumor microenvironment, supporting tumor growth and circumvents anticancer activities of conventional therapies. Macrophage inhibitory cytokine-1 (MIC-1) is a pleiotropic cytokine elevated in various cancers. MIC-1 regulates various cancer hallmarks, including sustained proliferation, tumor-promoting inflammation, avoiding immune destruction, inducing invasion, metastasis, angiogenesis, and resisting cell death. Despite these facts, the molecular regulation and downstream signaling of MIC-1 in cancer remain elusive, partly because its receptor (GFRAL) was unknown until recently. Binding of MIC-1 to GFRAL recruits the coreceptor tyrosine kinase RET to execute its downstream signaling. So far, studies have shown that GFRAL expression is restricted to the brain stem and is responsible for MIC-1/GFRAL/RET-mediated metabolic disorders. Nevertheless, abundant levels of MIC-1 expression have been reported in all cancer types and have been proposed as a surrogate biomarker. Given the ubiquitous expression of MIC-1 in cancers, it is crucial to understand both upstream regulation and downstream MIC-1/GFRAL/RET signaling in cancer hallmark traits.
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Fator 15 de Diferenciação de Crescimento/metabolismo , Neoplasias , Citocinas/genética , Fator 15 de Diferenciação de Crescimento/genética , Fator 15 de Diferenciação de Crescimento/farmacologia , Humanos , Macrófagos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Fenótipo , Transdução de Sinais , Microambiente TumoralRESUMO
Vascular dysfunction is a key hallmark of hypertension and related cardiovascular outcomes. As a well-known hemodynamic disease, hypertension is characterized by abnormal ventricular-vascular interactions. Complementing non-invasive systemic hemodynamics in hypertensive vascular risk assessment is of promising significance. We aimed to investigate the effects of abnormal hemodynamic states other than elevated blood pressure on vascular damage and establish a united index of systemic hemodynamics for generalized vascular risk evaluation. Non-invasive systemic hemodynamics, assessed by impedance cardiography, was compared among blood pressure stages. Vascular function was evaluated by flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV). Systemic hemodynamics was obtained from a total of 88 enrollees with a mean (±SD) systolic blood pressure 140 (±17) mm Hg, and aged 17 to 91 years. Both stroke systemic vascular resistance index and left stroke work index exhibited a significant alteration among blood pressure stages (p < 0.001; p = 0.01, respectively), whereas heterogeneous hemodynamic and vascular function subsets existed within similar blood pressure. In addition, blood pressure categories failed to recognize between-group differences in endothelial dysfunction (p = 0.88) and arterial stiffness (p = 0.26). An increase in myocardial contractility and a parallel decrease in afterload was associated with the decline of vascular dysfunction. Systemic Hemodynamic Index (SHI), as a surrogate marker, demonstrated a significantly negative correlation with vascular damage index (VDI, r = -0.49, p < 0.001). These findings illustrate that systemic hemodynamics underlying hypertensives provides more vascular information. The SHI/VDI score may be a feasible tool for cardiovascular function assessment.
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Targeting the unique glioma immune microenvironment is a promising approach in developing breakthrough immunotherapy treatments. However, recent advances in immunotherapy, including the development of immune checkpoint inhibitors, have not improved the outcomes of patients with glioma. A way of monitoring biological activity of immune cells in neural tissues affected by glioma should be developed to address this lack of sensitivity to immunotherapy. Thus, in this study, we sought to examine the feasibility of non-invasive monitoring of glioma-associated microglia/macrophages (GAM) by utilizing our previously developed induced microglia-like (iMG) cells. Primary microglia (pMG) were isolated from surgically obtained brain tissues of 22 patients with neurological diseases. iMG cells were produced from monocytes extracted from the patients' peripheral blood. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed a significant correlation of the expression levels of representative markers for M1 and M2 microglia phenotypes between pMG and the corresponding iMG cells in each patient (Spearman's correlation coefficient = 0.5225, P <0.0001). Synchronous upregulation of CD206 expression levels was observed in most patients with glioma (6/9, 66.7%) and almost all patients with glioblastoma (4/5, 80%). Therefore, iMG cells can be used as a minimally invasive tool for monitoring the disease-related immunological state of GAM in various brain diseases, including glioma. CD206 upregulation detected in iMG cells can be used as a surrogate biomarker of glioma.
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Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/sangue , Glioma/sangue , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Estudos de Viabilidade , Feminino , Glioma/imunologia , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Glicoproteínas de Membrana/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/imunologia , Microglia/patologia , Monitorização Imunológica , Fenótipo , Prognóstico , Receptores Imunológicos/genética , Microambiente TumoralRESUMO
MicroRNAs have emerged as important regulators of the metastatic process. In addition, circulating miRNAs appear to be surprisingly stable in peripheral blood making them ideal noninvasive biomarkers for disease diagnosis. Here, we performed a proof-of-principle study to investigate the expression profile of circulating miRNAs and their association with the metastatic lymph node status in early breast cancer patients. Sentinel lymph node status was detected by one-step nucleic acid (OSNA) analysis. We performed RNA-sequencing in 16 plasma samples and validated the results by qPCR. Gene Ontology term enrichment and KEGG pathway analyses were carried out using DAVID tools. We found16 differentially expressed miRNAs (q < 0.01) in patients with positive SLNs. Fourteen miRNAs were down-regulated (miR-339-5p, miR-133a-3p, miR-326, miR-331-3p, miR-369-3p, miR-328-3p, miR-26a-3p, miR-139-3p, miR-493-3p, miR-664a-5p, miR-146a-5p, miR-323b-3p, miR-1307-3p and miR-423-3p) and 2 were up-regulated (miR-101-3pand miR-144-3p). Hierarchical clustering using differentially expressed miRNAs clearly distinguished patients according to their lymph node status. Gene ontology analysis showed a significant enrichment of biological processes associated with the regulation of the epithelial mesenchymal transition, cell proliferation and transcriptional regulation. Our results suggest the potential role of several circulating miRNAs as surrogate markers of lymph node metastases in early breast cancer patients. Further validation in a larger cohort of patients will be necessary to confirm our results.
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Aim: We aimed to investigate biomarkers of inflammation, oxidative stress as surrogate markers of subclinical atherosclerosis in patients with Type 2 diabetes mellitus (T2DM). Materials & methods: Subjects were grouped based on carotid intima media thickness (CIMT). Group 1: healthy controls (CIMT <0.57 mm); Group 2: T2DM without subclinical atherosclerosis (CIMT <0.57 mm); Group 3: T2DM with subclinical atherosclerosis (CIMT ≥0.57 mm). Results: Significantly higher MDA, Hs-CRP, Ox-LDL, PTX-3, IL-6, ICAM-1 and lower FRAP, IL-10 levels in T2DM groups compared with controls (p = 0.001). Changes were more significant in Group 3 compared with Group 2. ICAM-1 had the highest sensitivity and specificity at a cut-off value of >40.34 ng/ml compared with Ox-LDL and PTX-3 (p < 0.001). Conclusion: ICAM can be considered as an alternate surrogate biomarker of CIMT.
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Molécula 1 de Adesão Intercelular , Adulto , Aterosclerose , Biomarcadores , Diabetes Mellitus Tipo 2 , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We previously reported that CIMAvax-EGF vaccine is safe, immunogenic and efficacious to treat advanced non-small-cell lung cancer (NSCLC) patients. A phase III trial was designed using an optimized immunization schedule. It included higher antigen dose and injections at multiple sites. Immune response and circulating biomarkers were studied in a subset of patients. EGF-specific antibody titers, IgG subclasses, peptide immunodominance and circulating biomarkers were assessed by ELISA. In vitro EGF-neutralization capacity of immune sera and EGF-IgG binding kinetics was evaluated by Western Blot and Surface Plasmon Resonance (SPR) technology, respectively. We show that CIMAvax-EGF elicited mainly IgG3/IgG4 antibodies at titers exceeding 1:4000 in 80% of vaccinated patients after 3 months of treatment. The EGF-specific humoral response was directed against the central region of the EGF molecule. For the first time, the kinetic constants of EGF-specific antibodies were measured evidencing affinity maturation of antibody repertoire up to month 12 of vaccination. Notably, the capacity of post-immune sera to inhibit EGFR phosphorylation significantly increased during the course of the immunization scheme and was related to clinical outcome (P = .013, log-rank test). Basal concentrations of EGF and TGFα in the serum were affected by EGF-based immunization. In conclusion, the CIMAvax-EGF vaccine induces an EGF-specific protective humoral response in a high percent of NSCLC vaccinated patients, the quantity and quality of which were associated with clinical benefit (clinical trial registration number: RPCEC00000161, http://registroclinico.sld.cu/). Abbreviations: EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; Ab: antibody; AR: amphiregulin; NSCLC: non-small-cell lung cancer; rhEGF: recombinant human epidermal growth factor; BSC: best supportive care; TGFα: tumor growth factor alpha; IL-8: interleukin 8; MAb: monoclonal antibody; SPR: surface plasmon resonance.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fator de Crescimento Epidérmico , Feminino , Humanos , Esquemas de Imunização , Imunoterapia Ativa , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Resultado do Tratamento , VacinaçãoRESUMO
Aim: Detection of drug-induced dystrophin in patient muscle biopsy is a surrogate outcome measure for Duchenne muscular dystrophy. We sought to establish and validate an orthogonal approach to measurement of dystrophin protein and RNA in muscle biopsies. Materials & methods: Validated methods were developed for dystrophin western blotting, mass spectrometry, immunostaining and reverse transcriptase PCR of biopsy mRNA using muscle biopsy standards. Results: Both western blotting and mass spectrometry validated methods demonstrated good linearity, and acceptable precision and accuracy with a lower limit of quantitation at 1%. Immunostaining and reverse transcriptase PCR methods were shown to be reliable. Conclusion: The described orthogonal approach is sufficient to support measures of dystrophin as a surrogate outcome in a clinical trial.
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Descoberta de Drogas , Distrofina/análise , Biópsia , Western Blotting , Éxons/genética , Humanos , Espectrometria de Massas , RNA Mensageiro/análiseRESUMO
Myeloproliferative neoplasms (MPNs), including polycythemia vera and essential thrombocythemia, are frequently associated with thrombotic complications. Prevention of thrombotic events is thus a primary aim of the current treatment for these disorders. Although it is known that microparticles (MPs), which are small vesicles released from cell membranes and circulate in the blood, directly contribute to thrombosis via their procoagulant activity, potential associations between plasma levels of MPs and the risk of thrombotic events in MPNs have not been reported. In the present study, we characterized plasma levels of MPs and assessed their potential association with the occurrence of thrombotic events in 59 patients with MPNs. Plasma levels of procoagulant MPs expressing tissue factor (TF+ MPs) were significantly higher in patients suffering thrombotic events than in patients without such events (median/µl plasma: 33.8 vs 47.2, p = 0.02). Among patients who developed thrombotic events, irrespective of patients' blood counts, TF+ MP were significantly higher in patients without cytoreductive therapy than in those receiving cytoreductive therapy (101.2 vs. 42.5, p < 0.001). These results suggest that elevated levels of TF+ MP may be considered as a novel surrogate marker for thrombotic events in MPN patients. Further studies are needed to clarify the mechanism involved.
Assuntos
Biomarcadores Tumorais/sangue , Micropartículas Derivadas de Células/metabolismo , Neoplasias Hematológicas/sangue , Transtornos Mieloproliferativos/sangue , Trombose/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/tratamento farmacológico , Trombose/tratamento farmacológico , Trombose/etiologiaRESUMO
Lignans and their in vivo metabolites, especially enterolactone (ENL), have attracted substantial interest as potential chemopreventive agents for prostate cancer. Preclinical and clinical interventions performed with lignan-rich flaxseed that use surrogate biomarkers as endpoints suggest that lignans may attenuate prostate carcinogenesis in individuals with increased risk or with diagnosed cancer. No unequivocal prostate cancer risk reduction has been found for lignans in epidemiological studies, suggesting that lignan concentrations found in populations consuming a regular non-supplemented diet are not chemopreventive in prostate cancer. Presumably, the main obstacles in assessing the efficacy of food lignans is limited knowledge of the serum and tissue lignan concentrations required for the putative prevention. Further clinical studies performed with the purified compounds are required to substantiate a health claim.