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The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1ß, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1ß with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated.
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The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3-AID with recurrent episodes of sore throat and extensive oropharyngeal ulceration. Unlike previously reported patients, who responded well to anakinra, her oral ulcers did not significantly improve until the PDE4 inhibitor, apremilast, was added to her treatment regimen. Here, we show that this mutation enhances interactions between NLRP3 and its endogenous inhibitor, NIMA-related kinase 7 (NEK7), by affecting charge complementarity between the two proteins. We also demonstrate that additional inflammatory mediators, including the NF-кB and IL-17 signalling pathways and IL-8 chemokine, are upregulated in the patient's macrophages and may be directly involved in disease pathogenesis. These results highlight the role of the NLRP3 LRR domain in NLRP3-AIDs and demonstrate that the p.R920Q mutation can cause diverse phenotypes between families.
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Enfermedades Autoinflamatorias Hereditarias , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Femenino , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Enfermedades Autoinflamatorias Hereditarias/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Mutación/genética , FN-kappa B/genética , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-ß-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding ß-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720∗] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs∗18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that ß-catenin signaling plays in the development of the retinal vasculature.
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Enfermedades de la Retina/genética , Transducción de Señal , beta Catenina/metabolismo , Secuencia de Bases , Enfermedades Hereditarias del Ojo , Vitreorretinopatías Exudativas Familiares , Femenino , Heterocigoto , Humanos , Luciferasas/metabolismo , Masculino , Modelos Biológicos , Proteínas Mutantes/metabolismo , Mutación/genética , Linaje , Fenotipo , Transcripción GenéticaRESUMEN
BACKGROUND: Neurofilament (NF) proteins detection in biological fluids as a by-product of axonal loss is technically challenging and to date relies mostly on cerebrospinal fluid (CSF) measurements. Plasma antibodies against NF proteins and particularly to their soluble light chain (NF-L) could be a more practical surrogate marker for disease staging in amyotrophic lateral sclerosis (ALS), an invariably fatal and clinically heterogeneous neuromuscular disorder. METHODOLOGY: We have used a recombinant neurofilament light chain (NF-L) protein for the ELISA detection of antibodies against NF proteins in plasma samples from a well-characterised cohort of ALS individuals (n:73). The use of an established functional rating scale and of a recently proposed staging of disease progression allowed stratification of the ALS cohort based on disease stage, site of onset, survival and speed of disease progression. RESULTS: Antibody levels to NF proteins in plasma were significantly higher in ALS individuals compared to healthy controls (p<0.001). Higher NF plasma immunoreactivity was seen in advanced ALS cases (stage IVA-B) compared to earlier phases of the disease (p<0.05). There was no difference in anti-NF plasma antibodies between ALS individuals treated with riluzole and untreated patients; although riluzole-treated ALS cases with an earlier age of onset and with a shorter diagnostic delay displayed higher anti-NFL antibody levels compared to untreated ALS patients with similar features. CONCLUSIONS: Immunoreactivity to plasma NF-L and homologous NF proteins is informative of the stage of disease progression in ALS. The determination of NF antibody levels in plasma could be added to the growing panel of disease-monitoring biomarkers in ALS targeting cytoskeletal antigens.
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Esclerosis Amiotrófica Lateral/diagnóstico , Proteínas de Neurofilamentos/inmunología , Anciano , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/inmunología , Anticuerpos/sangre , Anticuerpos/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Fármacos Neuroprotectores/uso terapéutico , Proteínas Recombinantes , Riluzol/uso terapéuticoRESUMEN
High IgG titers against the Epstein-Barr virus nuclear antigen, EBNA-1, have been strongly correlated with the risk of developing multiple sclerosis. ELISAs are used frequently to measure EBNA-1 titers, however concerns remain regarding the accuracy of results. Ordering absolute results into rank quintiles for analysis may be preferable. Using 120 serum samples, two commercially available ELISAs (produced by DiaSorin and VirionSerion) were compared, both in terms of absolute results and rank quintiles. The positive predictive value of the VirionSerion ELISA was 99.1% when compared to the DiaSorin ELISA, however, the negative predictive value was 64.3%. Sensitivity and specificity were acceptable at 95.5% and 90.0%, respectively. There was poor correlation between absolute results, R(2) = 0.49; and the kappa coefficient for rank quintiles was low at 0.23. Although sensitivity and specificity appear adequate, the poor negative predictive value and kappa coefficient are of major concern. Care must be taken when selecting assays for experimental use.
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Anticuerpos Antivirales/sangre , Técnicas de Laboratorio Clínico/métodos , Infecciones por Virus de Epstein-Barr/diagnóstico , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Inmunoglobulina G/sangre , Virología/métodos , Adolescente , Adulto , Anciano , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Adulto JovenRESUMEN
UNLABELLED: Information on the long-term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either naïve or non-responders to treatment. Both cohorts were Child-Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6-297), there were 48 (19.4%) liver-related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6-238), there were 47 (16.7%) liver-related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver-related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotransferase (ALT) levels were associated with liver-related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver-related mortality. CONCLUSIONS: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver-related complications and other outcomes in patients with NAFLD.
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Hígado Graso/mortalidad , Hígado Graso/patología , Hepatitis C Crónica/mortalidad , Hepatitis C Crónica/patología , Cirrosis Hepática/mortalidad , Cirrosis Hepática/patología , Adulto , Australia , Biopsia con Aguja , Causas de Muerte , Estudios de Cohortes , Intervalos de Confianza , Progresión de la Enfermedad , Hígado Graso/cirugía , Femenino , Hepatitis C Crónica/fisiopatología , Humanos , Inmunohistoquímica , Cooperación Internacional , Italia , Cirrosis Hepática/cirugía , Pruebas de Función Hepática , Trasplante de Hígado/métodos , Trasplante de Hígado/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Enfermedad del Hígado Graso no Alcohólico , Oportunidad Relativa , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Estados UnidosRESUMEN
Inflammasomes are assembled by innate immune sensors that cells employ to detect a range of danger signals and respond with pro-inflammatory signalling. Inflammasomes activate inflammatory caspases, which trigger a cascade of molecular events with the potential to compromise cellular integrity and release the IL-1ß and IL-18 pro-inflammatory cytokines. Several molecular mechanisms, working in concert, ensure that inflammasome activation is tightly regulated; these include NLRP3 post-translational modifications, ubiquitination and phosphorylation, as well as single-domain proteins that competitively bind to key inflammasome components, such as the CARD-only proteins (COPs) and PYD-only proteins (POPs). These diverse regulatory systems ensure that a suitable level of inflammation is initiated to counteract any cellular insult, while simultaneously preserving tissue architecture. When inflammasomes are aberrantly activated can drive excessive production of pro-inflammatory cytokines and cell death, leading to tissue damage. In several autoinflammatory conditions, inflammasomes are aberrantly activated with subsequent development of clinical features that reflect the degree of underlying tissue and organ damage. Several of the resulting disease complications may be successfully controlled by anti-inflammatory drugs and/or specific cytokine inhibitors, in addition to more recently developed small-molecule inhibitors. In this review, we will explore the molecular processes underlying the activation of several inflammasomes and highlight their role during health and disease. We also describe the detrimental effects of these inflammasome complexes, in some pathological conditions, and review current therapeutic approaches as well as future prospective treatments.
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OBJECTIVE: To determine the association of maternal CYP17 gene polymorphisms and prenatal alcohol consumption with intrauterine growth restriction (IUGR). STUDY DESIGN: A case-control study in singleton livebirths was conducted at the Liverpool Women's Hospital between 2004 and 2005. Cases (n=90) were mothers with an IUGR baby and controls (n=180) those with a normal birthweight infant. Maternal genomic DNA was extracted from buccal smears and PCR (RFLP) was used for genotyping. RESULTS: Amongst cases, the prevalence of the maternal CYP17 homozygous wild type "A1A1", heterozygous "A1A2" and homozygous "A2A2" variants was 36.7%, 47.7% and 15.6%, which did not differ significantly from their prevalence amongst controls (p=0.6). The proportion with prenatal alcohol exposure was significantly higher in cases than controls (45.6% versus 30.6%, p=0.01). Mean birthweight was significantly lower in mothers with the CYP17 A1A1 genotype compared to those with variant genotypes (A1A2/A2A2) in both the alcohol-exposed (p=0.03) and non-exposed groups (p=0.01). In all women regardless of genotype, IUGR risk increased in mothers exposed to alcohol during pregnancy (OR, 2.9, 95% CI; 1.8-4.2, p=0.01). There was a significant interaction between the CYP17 A1A1 genotype and prenatal alcohol consumption for fetal growth restriction (adjusted OR, 1.4, 95% CI; 1.1-1.9, p=0.04). CONCLUSION: The association between prenatal alcohol exposure and intrauterine fetal growth restriction was modulated by the maternal CYP17 A1A1 genotype.
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Bebidas Alcohólicas/efectos adversos , Retardo del Crecimiento Fetal/inducido químicamente , Retardo del Crecimiento Fetal/genética , Efectos Tardíos de la Exposición Prenatal , Esteroide 17-alfa-Hidroxilasa/genética , Adolescente , Adulto , Peso al Nacer , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genéticaRESUMEN
PURPOSE: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases. EXPERIMENTAL DESIGN: Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation. RESULTS: B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis. CONCLUSIONS: Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response. Clin Cancer Res; 23(1); 250-62. ©2016 AACR.
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Linfocitos B/inmunología , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/inmunología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/inmunología , Formación de Anticuerpos/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos B/metabolismo , Biomarcadores , Línea Celular Tumoral , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Humanos , Inmunohistoquímica , Memoria Inmunológica , Inmunofenotipificación , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Proteoma , Proteómica/métodosRESUMEN
OBJECTIVE: Multiple sclerosis (MS) develops as a result of environmental influences on the genetically susceptible. Siblings of people with MS have an increased risk of both MS and demonstrating asymptomatic changes in keeping with MS. We set out to develop an MS risk score integrating both genetic and environmental risk factors. We used this score to identify siblings at extremes of MS risk and attempted to validate the score using brain MRI. METHODS: 78 probands with MS, 121 of their unaffected siblings and 103 healthy controls were studied. Personal history was taken, and serological and genetic analysis using the illumina immunochip was performed. Odds ratios for MS associated with each risk factor were derived from existing literature, and the log values of the odds ratios from each of the risk factors were combined in an additive model to provide an overall score. Scores were initially calculated using log odds ratio from the HLA-DRB1*1501 allele only, secondly using data from all MS-associated SNPs identified in the 2011 GWAS. Subjects with extreme risk scores underwent validation studies. MRI was performed on selected individuals. RESULTS: There was a significant difference in the both risk scores between people with MS, their unaffected siblings and healthy controls (p<0.0005). Unaffected siblings had a risk score intermediate to people with MS and controls (p<0.0005). The best performing risk score generated an AUC of 0.82 (95%CI 0.75-0.88). INTERPRETATIONS: The risk score demonstrates an AUC on the threshold for clinical utility. Our score enables the identification of a high-risk sibling group to inform pre-symptomatic longitudinal studies.
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Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Adolescente , Adulto , Anciano , Alelos , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas/métodos , Genotipo , Cadenas HLA-DRB1/genética , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVES: Clinical trials of IV-rituximab have proved successful. It is unclear whether intrathecal (IT)-rituximab is more efficacious at lower doses. We examine its effects on B-cell biomarkers. METHODS: MS patients received IT-rituximab at 3 time-points. CSF and serum samples were obtained at up to 5 time-points (days 0, 7, 14, 56 and 112). Serum and CSF BAFF and CXCL13, and CSF kappa and lambda free light chains (FLC) were measured. Flow cytometry was performed, examining effects on lymphocytes, CD3-19+ and CD3-20+ cells. RESULTS: CSF BAFF fell following rituximab (p=0.0091 absolute values, p=0.0284 change from baseline) whilst serum BAFF increased across time-points 1-4 (p=0.0005 absolute values, p=0.0017 change from baseline). There were significant reductions in CD20+ and CD19+ cells in blood from baseline (p<0.0001) but not in CSF. CSF kappa FLC levels significantly increased (p=0.0480). CONCLUSIONS: BAFF levels fall in CSF but increase in serum following IT-rituximab. Rituximab appears to act peripherally with dramatic decreases in peripheral CD20+ and CD19+ cells. It is likely that CSF B-cell counts were too low to enable differences to be seen. The rapid reduction in B-cells suggests rituximab has immediate effects. The profound depletion of B-cells, despite low doses of rituximab, underlines rituximab's efficacy.
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Factores Inmunológicos/administración & dosificación , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Rituximab/administración & dosificación , Adulto , Antígenos CD19/metabolismo , Antígenos CD20/metabolismo , Factor Activador de Células B/sangre , Factor Activador de Células B/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Quimiocina CXCL13/sangre , Quimiocina CXCL13/líquido cefalorraquídeo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Cadenas kappa de Inmunoglobulina/líquido cefalorraquídeo , Cadenas lambda de Inmunoglobulina/líquido cefalorraquídeo , Factores Inmunológicos/sangre , Factores Inmunológicos/líquido cefalorraquídeo , Inyecciones Espinales , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Rituximab/sangre , Rituximab/líquido cefalorraquídeo , Resultado del TratamientoRESUMEN
PURPOSE: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response. EXPERIMENTAL DESIGN: We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response. RESULTS: There was evidence of T-cell activation in omental biopsies after NACT: CD4(+) T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8(+) T-cell and CD45RO(+) memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3(+) T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. CONCLUSIONS: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025-36. ©2016 AACR.
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Linfocitos T CD8-positivos/inmunología , Terapia Neoadyuvante/métodos , Neoplasias Ováricas/patología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Adulto , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Antígeno CTLA-4/metabolismo , Citocinas/sangre , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Inmunoterapia/métodos , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Persona de Mediana Edad , Neoplasias Ováricas/terapia , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
OBJECTIVE: Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies. METHODS: We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF. RESULTS: Patients with Alzheimer's disease (AD) (30.8 pg/ml, n=20), Guillain-Barré-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002 for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001). Similar differences were seen in corresponding CSF samples. CSF and serum levels correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70, p<0.0001), but not in CP (r=0.11, p=0.3739). The sensitivity and specificity of serum NfL for separating ALS from healthy controls was 91.3% and 91.0%. CONCLUSIONS: We developed and validated a novel ECL based sandwich immunoassay for the NfL protein in serum (NfL(Umea47:3)); levels in ALS were more than 20-fold higher than in controls. Our data supports further longitudinal studies of serum NfL in neurodegenerative diseases as a potential biomarker of on-going disease progression, and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.
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Enfermedad de Alzheimer/diagnóstico , Esclerosis Amiotrófica Lateral/diagnóstico , Biomarcadores/sangre , Síndrome de Guillain-Barré/diagnóstico , Proteínas de Neurofilamentos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Estudios de Casos y Controles , Técnicas Electroquímicas , Femenino , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/líquido cefalorraquídeo , Humanos , Inmunoensayo , Mediciones Luminiscentes , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To determine the role of maternal CYP1A1, GSTT1, and GSTM1 metabolic gene polymorphisms in modulating the association between pregnancy smoking exposure and fetal growth restriction. STUDY DESIGN: A case-control study was conducted to investigate if the association of pregnancy smoking and birth outcome was modulated by maternal gene polymorphisms. A total of 90 mothers with an IUGR baby (cases) and 180 mothers without IUGR (controls) were enrolled. RESULTS: Almost half of smokers who carried a CYP1A1 variant (51.3%), GSTT1 null (43.6%), or GSTM1 null genotypes (64.1%) delivered a baby with IUGR. Smokers with the variant CYP1A1 "aa" genotype had babies with lower mean birthweight than non-smokers with the same genotype (p=0.004). An interaction test showed increased prevalence of IUGR in smokers with the CYP1A1 (Aa/aa) variant (adjusted OR, 1.9; 95% CI, 1.4-5.5, p=0.01), or with the GSTT1 null (AOR, 1.5; 1.1-3.1, p=0.001), or GSTM1 null genotypes (AOR, 1.5; 1.2-3.7, p=0.001). CONCLUSIONS: Risk of fetal growth restriction in mothers who smoked during pregnancy was modulated by maternal metabolic gene polymorphisms. The genetic control of the conversion of toxic metabolites of tobacco smoke to less damaging substances is important for maternal and fetal health.
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Peso al Nacer , Citocromo P-450 CYP1A1/genética , Retardo del Crecimiento Fetal/genética , Glutatión Transferasa/genética , Fumar/efectos adversos , Estudios de Casos y Controles , Femenino , Humanos , Polimorfismo Genético , Embarazo , Factores de RiesgoRESUMEN
Transabdominal cerclage is a recognised treatment for cervical weakness with a history of recurrent mid-trimester loss and a failed elective vaginal suture. The emergence of dual pathology, such as antiphospholipid syndrome and bacterial vaginosis, is associated with an increased risk of preterm delivery (RR 2.34, 95% CI 1.15-5.8). The first 40 cases are described where strict adherence to an investigation protocol and consistent treatment plan has been implemented.