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BACKGROUND AND AIMS: Around 750,000 patients per year will be cured of HCV infection until 2030. Those with compensated advanced chronic liver disease remain at risk for hepatic decompensation and de novo HCC. Algorithms have been developed to stratify risk early after cure; however, data on long-term outcomes and the prognostic utility of these risk stratification algorithms at later time points are lacking. APPROACH AND RESULTS: We retrospectively analyzed a cohort of 2335 patients with compensated advanced chronic liver disease (liver stiffness measurement≥10 kPa) who achieved HCV-cure by interferon-free therapies from 15 European centers (median age 60.2±11.9 y, 21.1% obesity, 21.2% diabetes).During a median follow-up of 6 years, first hepatic decompensation occurred in 84 patients (3.6%, incidence rate: 0.74%/y, cumulative incidence at 6 y: 3.2%); 183 (7.8%) patients developed de novo HCC (incidence rate: 1.60%/y, cumulative incidence at 6 y: 8.3%), with both risks being strictly linear over time.Baveno VII criteria to exclude (FU-liver stiffness measurement <12 kPa and follow-up platelet count >150 g/L) or rule-in (FU-liver stiffness measurement ≥25 kPa) clinically significant portal hypertension (CSPH) stratified the risk of hepatic decompensation with proportional hazards. Estimated probability of CSPH discriminated patients developing versus not developing hepatic decompensation in the gray zone (ie, patients meeting none of the above criteria).Published HCC risk stratification algorithms identified high-incidence and low-incidence groups; however, the size of the latter group varied substantially (9.9%-69.1%). A granular "HCC-sustained virologic response" model was developed to inform an individual patient's HCC risk after HCV-cure. CONCLUSIONS: In patients with compensated advanced chronic liver disease, the risks of hepatic decompensation and HCC remain constant after HCV-cure, even in the long term (>3 y). One-time post-treatment risk stratification based on noninvasive criteria provides important prognostic information that is maintained during long-term follow-up, as the hazards remain proportional over time.
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BACKGROUND AND AIM: Patients with chronic kidney disease (CKD) and hepatitis C infection can be safely and effectively treated with direct-acting antivirals (DAAs). However, there is scarce data on the long-term impact of hepatitis C cure on CKD. The aim of this study was to assess the long-term mortality, morbidity and hepatic/renal function outcomes in a cohort of HCV-infected individuals with CKD treated with DAAs. METHODS: 135 HCV patients with CKD stage 3b-5 who received ombitasvir/paritaprevir/ritonavir±dasabuvir in a multicenter study were evaluated for long-term hepatic and renal outcomes and their associated mortality. RESULTS: 125 patients achieved SVR and 66 were included. Prior to SVR, 53 were under renal replacement therapy (RRT) and 25 (37.8%) had liver cirrhosis. After a follow-up of 4.5 years, 25 (38%) required kidney transplantation but none combined liver-kidney. No changes in renal function were observed among the 51 patients who did not receive renal transplant although eGFR values improved in those with baseline CKD stage 3b-4. Three (5.6%) subjects were weaned from RRT. Eighteen (27.3%) patients died, mostly from cardiovascular events; 2 developed liver decompensation and 1 hepatocellular carcinoma. No HCV reinfection was observed. CONCLUSIONS: Long-term mortality remained high among end-stage CKD patients despite HCV cure. Overall, no improvement in renal function was observed and a high proportion of patients required kidney transplantation. However, in CKD stage 3b-4 HCV cure may play a positive role in renal function.
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Hepatitis C Crónica , Hepatitis C , Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Antivirales/efectos adversos , Estudios de Seguimiento , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Quimioterapia Combinada , Hepatitis C/tratamiento farmacológico , Hepacivirus , Insuficiencia Renal Crónica/complicaciones , GenotipoRESUMEN
BACKGROUND & AIMS: Patients with chronic hepatitis C and stage 3 fibrosis are thought to remain at risk of hepatocellular carcinoma after sustained virological response. We investigated this risk in a large cohort of patients with well-defined stage 3 fibrosis. METHODS: We performed a multicentre, ambispective, observational study of chronic hepatitis C patients with sustained virological response after treatment with direct-acting antivirals started between January and December 2015. Baseline stage 3 was defined in a two-step procedure: we selected patients with transient elastography values of 9.5-14.5 kPa and subsequently excluded those with nodular liver surface, splenomegaly, ascites or collaterals on imaging, thrombopenia or esophago-gastric varices. Patients were screened twice-yearly using ultrasound. RESULTS: The final sample comprised 506 patients (median age, 57.4 years; males, 59.9%; diabetes, 17.2%; overweight, 44.1%; genotype 3, 8.9%; HIV coinfection, 18.4%; altered liver values, 15.2%). Median follow-up was 33.7 (22.1-39.1) months. Five hepatocellular carcinomas and 1 cholangiocarcinoma were detected after a median of 29.4 months (95% CI: 26.8-39.3), with an incidence of 0.47/100 patients/year (95% CI: 0.17-1.01). In the multivariate analysis, only males older than 55 years had a significant higher risk (hazard ratio 7.2 [95% CI: 1.2-41.7; P = .029]) with an incidence of 1.1/100 patients/year (95% CI: 0.3-2.8). CONCLUSIONS: In a large, well-defined cohort of patients with baseline hepatitis C stage-3 fibrosis, the incidence of primary liver tumours was low after sustained virological response and far from the threshold for cost-effectiveness of screening, except in males older than 55 years.
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Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Humanos , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Respuesta Virológica SostenidaRESUMEN
BACKGROUND AND AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer; most patients die during the first 6 months after diagnosis. With a 5% 5-year survival rate, is the fourth leading cause of cancer death in developed countries. In this regard, several clinical, histopathologic and biological characteristics of the disease favoring long-term survival after pancreaticoduodenectomy have been reported to be significant prognostic factors. Despite the availability of this information, there is no consensus about the different prognostic factors reported in the literature, probably due to variations in patient selection, methods, and sample size studied. The aim of this study was to identify the clinical and pathologic features associated to prognosis of the disease after pancreaticoduodenectomy. MATERIALS AND METHODS: The clinical and pathologic data from 78 patients who underwent a potentially curative resection for PDAC at our institution between 2003 and 2014 were analyzed retrospectively. RESULTS: Overall, high-grade PDAC cases showed larger tumor size (P=0.009) and a higher frequency of deaths in association with a nonsignificantly shortened patient overall survival (median of 12.5 vs. 21.7 mo; P=0.065) as compared with low-grade PDAC patients. High histologic grade (P=0.013), preoperative drainage on the main bile duct (P=0.014) and absence of adjuvant therapy (P=0.035) were associated with a significantly poorer outcome. Overall survival multivariate analysis showed histologic grade (P=0.019) and bile duct preoperative drainage (P=0.016) as the sole independent variables predicting an adverse outcome. CONCLUSIONS: Our results indicate that histologic tumor grade and preoperative biliary drainage are the only significant independent prognostic factors in PDAC patients after pancreatectomy.
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Carcinoma Ductal Pancreático/patología , Drenaje/métodos , Neoplasias Pancreáticas/patología , Pancreaticoduodenectomía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Neoplasias Pancreáticas/cirugía , Cuidados Preoperatorios/métodos , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
A novel electrochemical disposable nucleic acid biosensor for simple, rapid, and specific detection of adulterations with horsemeat is reported in this work. The biosensing platform involves immobilization of a 40-mer RNA probe specific for a characteristic fragment of the mitochondrial DNA D-loop region of horse onto the surface of magnetic microcarriers. In addition, signal amplification was accomplished by using a commercial antibody specific to RNA/DNA duplexes and a bacterial protein conjugated with a horseradish peroxidase homopolymer (ProtA-HRP40). Amperometric detection at -0.20 V vs Ag pseudoreference electrode was carried out at disposable screen-printed carbon electrodes. The methodology achieved a limit of detection (LOD) of 0.12 pM (3.0 attomoles) for the synthetic target and showed ability to discriminate between raw beef and horsemeat using just 50 ng of total extracted mitochondrial DNA (â¼16â¯660 bp in length) without previous fragmentation. The biosensor also allowed discrimination between 100% raw beef and beef meat samples spiked with only 0.5% (w/w) horse meat (levels established by the European Commission) using raw mitochondrial lysates without DNA extraction or polymerase chain reaction (PCR) amplification in just 75 min. These interesting features made the developed methodology an extremely interesting tool for beef meat screening, and it can be easily adapted to the determination of other meat adulterations by selection of the appropriate specific fragments of the mitochondrial DNA region and capture probes.
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ADN Mitocondrial/química , Técnicas Electroquímicas/instrumentación , Carne/análisis , Reacción en Cadena de la Polimerasa/métodos , Reacción en Cadena de la Polimerasa/veterinaria , Animales , Bovinos , ADN Mitocondrial/genética , Equipos Desechables , Análisis de los Alimentos , Caballos , Reacción en Cadena de la Polimerasa/instrumentaciónRESUMEN
BACKGROUND: Long-term antiviral therapy has resulted in viral suppression and biochemical response in chronic hepatitis B, although the risk of hepatocellular carcinoma has not been abolished. The Page-B score could be useful to estimate the probability of HCC. AIMS: To analyze the effectiveness and safety of entecavir or tenofovir for more than 4 years and the usefulness of Page-B score in the real-world setting. METHODS: Analysis of Caucasian chronic hepatitis B subjects treated with entecavir or tenofovir from the prospective, multicenter database CIBERHEP. RESULTS: A total of 611 patients were enrolled: 187 received entecavir and 424 tenofovir. Most were men, mean age 50 years, 32% cirrhotic and 16.5% HBeAg-positive. Mean follow-up was 55 (entecavir) and 49 (tenofovir) months. >90% achieved HBV DNA <69 IU/mL and biochemical normalization by months 12 and 36, respectively. Cumulative HBeAg loss and anti-HBe seroconversion were achieved by 33.7 and 23.8%. Four patients lost HBsAg; three HBeAg-positive. Renal function remained stable on long-term follow-up. Fourteen (2.29%) developed HCC during follow-up all of them with baseline Page-B ≥10. Nine were diagnosed within the first 5 years of therapy. This contrasts with the 27 estimated by Page-B, a difference that highlights the importance of regular HCC surveillance even in patients with virological suppression. CONCLUSIONS: Entecavir and tenofovir achieved high biochemical and virological response. Renal function remained stable with both drugs. A Page-B cut-off ≥10 selected all patients at risk of HCC development.
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Carcinoma Hepatocelular , Guanina/análogos & derivados , Virus de la Hepatitis B , Hepatitis B Crónica , Neoplasias Hepáticas , Medición de Riesgo/métodos , Tenofovir , Adulto , Antivirales/administración & dosificación , Antivirales/efectos adversos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , ADN Viral/análisis , Femenino , Estudios de Seguimiento , Guanina/administración & dosificación , Guanina/efectos adversos , Antígenos e de la Hepatitis B/análisis , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/epidemiología , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Proyectos de Investigación/normas , España/epidemiología , Tenofovir/administración & dosificación , Tenofovir/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Metastatic dissemination is the most frequent cause of death in patients with sporadic colorectal cancer (sCRC). It is believed that the metastatic process is related at least in part to a specific background of genetic alterations accumulated in cells from primary tumors, and the ability to detect such alterations is critical for the identification of patients with sCRC who are at risk of developing metastases. METHODS: The authors used high-resolution, 500-K single nucleotide polymorphism arrays to identify copy number alteration profiles present at diagnosis in primary tumors from patients with metastatic (n = 23) versus nonmetastatic (n = 26) sCRC. RESULTS: The results revealed a characteristic pattern of copy number alterations in metastatic sCRC tumors that involved losses of 23 regions at chromosomes 1p, 17p, and 18q, together with gains of 35 regions at chromosomes 7 and 13q. CONCLUSIONS: In line with expectations, the copy number profile investigated involved multiple genes that were associated previously with sCRC (ie, SMAD2) and/or the metastatic process (ie, podocalyxin-like [PODXL]), and it also was associated with a poorer outcome.
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Aberraciones Cromosómicas , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Variaciones en el Número de Copia de ADN , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
The use-dependent regulation of the GABAA receptor occurs under physiological, pathological, and pharmacological conditions. Tolerance induced by prolonged administration of benzodiazepines is associated with changes in GABAA receptor function. Chronic exposure of neurons to GABA for 48 hr induces a downregulation of the GABAA receptor number and an uncoupling of the GABA/benzodiazepine site interactions. A single brief exposure ((t1/2) = 3 min) of rat neocortical neurons to the neurotransmitter initiates a process that results in uncoupling hours later (t(1/2) = 12 hr) without alterations in the number of GABAA receptors and provides a paradigm to study the uncoupling mechanism selectively. Here we report that uncoupling induced by a brief GABAA receptor activation is blocked by the coincubation with inhibitors of protein kinases A and C, indicating that the uncoupling is mediated by the activation of a phosphorylation cascade. GABA-induced uncoupling is accompanied by subunit-selective changes in the GABAA receptor mRNA levels. However, the GABA-induced downregulation of the α3 subunit mRNA level is not altered by the kinase inhibitors, suggesting that the uncoupling is the result of a posttranscriptional regulatory process. GABA exposure also produces an increase in the serine phosphorylation on the GABAA receptor γ2 subunit. Taken together, our results suggest that the GABA-induced uncoupling is mediated by a posttranscriptional mechanism involving an increase in the phosphorylation of GABAA receptors. The uncoupling of the GABAA receptor may represent a compensatory mechanism to control GABAergic neurotransmission under conditions in which receptors are persistently activated.
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Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Subunidades de Proteína/metabolismo , Receptores de GABA-A/metabolismo , Ácido gamma-Aminobutírico/farmacología , Animales , Células Cultivadas , Hipocampo/citología , Hipocampo/metabolismo , Neuronas/citología , Neuronas/metabolismo , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
Glycosaminoglycans (GAGs) are accumulated in various organs in both mucopolysaccharidoses (MPS) and mucolipidoses II and III (ML II and III). MPS and ML II and III patients can not properly degrade dermatan sulfate (DS) and/or heparan sulfate (HS). HS storage occurs in the brain leading to neurological signs while DS storage involves mainly visceral and skeletal manifestations. Excessive DS and HS released into circulation and thus blood levels of both are elevated, therefore, DS and HS in blood could be critical biomarkers for MPS and ML. Such measurement can provide a potential early screening, assessment of the clinical course and efficacy of therapies. We here assay DS and HS levels in MPS and ML patients using liquid chromatography tandem mass spectrometry (LC/MS/MS). Plasma samples were digested by heparitinase and chondroitinase B to obtain disaccharides of DS and HS, followed by LC/MS/MS analysis. One hundred-twenty samples from patients and 112 control samples were analyzed. We found that all MPS I, II, III and VI patients had a significant elevation of all DS+HS compositions analyzed in plasma, compared with the controls (P<0.0001). Specificity and sensitivity was 100% if the cut off value is 800 ng/ml between control and these types of MPS group. All MPS I, II and III patients also had a significant elevation of plasma HS, compared with the controls (P<0.0001). All MPS VI patients had a significant elevation of plasma DS, compared with the controls (P<0.0001). These findings suggest measurement of DS and/or HS levels by LC/MS/MS is applicable to the screening for MPS I, II, III and VI patients.
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Dermatán Sulfato/sangre , Disacáridos/sangre , Heparitina Sulfato/sangre , Mucolipidosis/sangre , Mucopolisacaridosis/sangre , Espectrometría de Masas en Tándem/métodos , Adolescente , Adulto , Niño , Preescolar , Dermatán Sulfato/orina , Glicosaminoglicanos/orina , Heparitina Sulfato/orina , Humanos , Lactante , Persona de Mediana Edad , Mucolipidosis/orina , Mucopolisacaridosis/orina , Adulto JovenRESUMEN
Mucopolysaccharidosis type IVA (MPS IVA, Morquio A disease), a progressive lysosomal storage disease, causes skeletal chondrodysplasia through excessive storage of keratan sulfate (KS). KS is synthesized mainly in cartilage and released to the circulation. The excess storage of KS disrupts cartilage, consequently releasing more KS into circulation, which is a critical biomarker for MPS IVA. Thus, assessment of KS level provides a potential screening strategy and determines clinical course and efficacy of therapies. We have recently developed a tandem mass spectrometry liquid chromatography [LC/MS/MS] method to assay KS levels in blood. Forty-nine blood specimens from patients with MPS IVA [severe (n = 33), attenuated (n = 11) and undefined (n = 5)] were analyzed for comparison of blood KS concentration with that of healthy subjects and for correlation with clinical severity. Plasma samples were digested by keratanase II to obtain disaccharides of KS. Digested samples were assayed by LC/MS/MS. We found that blood KS levels (0.4-26 µg/ml) in MPS IVA patients were significantly higher than those in age-matched controls (0.67-4.6 µg/ml; P < 0.0001). It was found that blood KS level varied with age and clinical severity in the patients. Blood KS levels in MPS IVA peaked between 2 years and 5 years of age (mean 11.4 µg/ml). Blood KS levels in severe MPS IVA (mean 7.3 µg/ml) were higher than in the attenuated form (mean 2.1 µg/ml) (P = 0.012). We also found elevated blood KS levels in other types of MPS. These findings indicate that the new KS assay for blood is suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.
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Cromatografía Liquida , Sulfato de Queratano/sangre , Mucopolisacaridosis IV/sangre , Mucopolisacaridosis IV/diagnóstico , Espectrometría de Masas en Tándem , Adolescente , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Diagnóstico Precoz , Humanos , Lactante , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Regulación hacia Arriba , Adulto JovenRESUMEN
Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by deficiency of alpha-L-iduronidase leading to accumulation of its catabolic substrates, dermatan sulfate (DS) and heparan sulfate (HS), in lysosomes. This results in progressive multiorgan dysfunction and death in early childhood. The recent success of enzyme replacement therapy (ERT) for MPS I highlights the need for biomarkers that reflect response to such therapy. To determine which biochemical markers are better, we determined serum and urine DS and HS levels by liquid chromatography tandem mass spectrometry in ERT-treated MPS I patients. The group included one Hurler, 11 Hurler/Scheie, and two Scheie patients. Seven patients were treated from week 1, whereas the other seven were treated from week 26. Serum and urine DS (DeltaDi-4S/6S) and HS (DeltaDiHS-0S, DeltaDiHS-NS) were measured at baseline, week 26, and week 72. Serum DeltaDi-4S/6S, DeltaDiHS-0S, and DeltaDiHS-NS levels decreased by 72%, 56%, and 56%, respectively, from baseline at week 72. Urinary glycosaminoglycan level decreased by 61.2%, whereas urine DeltaDi-4S/6S, DeltaDiHS-0S, and DeltaDiHS-NS decreased by 66.8%, 71.8%, and 71%, respectively. Regardless of age and clinical severity, all patients showed marked decrease of DS and HS in blood and urine samples. We also evaluated serum DS and HS from dried blood-spot samples of three MPS I newborn patients, showing marked elevation of DS and HS levels compared with those in control newborns. In conclusion, blood and urine levels of DS and HS provide an intrinsic monitoring and screening tool for MPS I patients.
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Dermatán Sulfato/sangre , Dermatán Sulfato/orina , Heparitina Sulfato/sangre , Heparitina Sulfato/orina , Mucopolisacaridosis I , Adolescente , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Niño , Preescolar , Cromatografía Liquida , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Recién Nacido , Masculino , Tamizaje Masivo/métodos , Mucopolisacaridosis I/sangre , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/orina , Tamizaje Neonatal/métodos , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015. MATERIAL AND METHODS: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records. RESULTS: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision. CONCLUSIONS: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.
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Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , 2-Naftilamina , Anciano , Anilidas/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Carbamatos/uso terapéutico , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Lactamas Macrocíclicas , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Diálisis Renal , Estudios Retrospectivos , Ribavirina/uso terapéutico , Ritonavir/uso terapéutico , España , Sulfonamidas/uso terapéutico , Respuesta Virológica Sostenida , Resultado del Tratamiento , Uracilo/análogos & derivados , Uracilo/uso terapéutico , ValinaRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0184550.].
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BACKGROUND: Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy. METHODS: PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc-positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I to investigate TDF safety. RESULTS: Sixty-one patients were enrolled in the study, 33 in the TDF treatment group and 28 in the observation group. By ITT analysis, HBV reactivation was 0% (0/33) in the study group and 10.7% (3/28) in the observation group (p = 0.091). None of the patients in either group showed significant differences in liver function parameters between baseline and the last follow-up sample. TDF was generally well tolerated and there were no severe treatment-related adverse events. CONCLUSION: In patients with hematological malignancy and resolved hepatitis B infection receiving RTX-based regimens, HBV reactivation did not occur in patients given TDF prophylaxis.
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Antivirales/efectos adversos , Hepatitis B/tratamiento farmacológico , Leucemia/virología , Tenofovir/efectos adversos , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Femenino , Hepatitis B/sangre , Hepatitis B/complicaciones , Hepatitis B/prevención & control , Virus de la Hepatitis B/inmunología , Humanos , Leucemia/complicaciones , Leucemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Profilaxis Posexposición/métodos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Pruebas Serológicas , Tenofovir/administración & dosificación , Tenofovir/uso terapéuticoRESUMEN
Mitochondria are highly dynamic organelles that in response to the cell's bio-energetic state continuously undergo structural remodeling fission and fusion processes. This mitochondrial dynamic activity has been implicated in cell cycle, autophagy, and age-related diseases. Adult tissue-derived mesenchymal stromal/stem cells present a therapeutic potential. However, to obtain an adequate mesenchymal stromal/stem cell number for clinical use, extensive in vitro expansion is required. Unfortunately, these cells undergo replicative senescence rapidly by mechanisms that are not well understood. Senescence has been associated with metabolic changes in the oxidative state of the cell, a process that has been also linked to mitochondrial fission and fusion events, suggesting an association between mitochondrial dynamics and senescence. In the present work, we studied the mitochondrial structural remodeling process of mesenchymal stromal/stem cells isolated from adipose tissue in vitro to determine if mitochondrial phenotypic changes were associated with mesenchymal stromal/stem cell senescence. For this purpose, mitochondrial dynamics and oxidative state of stromal/stem cell were compared between young and old cells. With increased cell passage, we observed a significant change in cell morphology that was associated with an increase in ß-galactosidase activity. In addition, old cells (population doubling seven) also showed increased mitochondrial mass, augmented superoxide production, and decreased mitochondrial membrane potential. These changes in morphology were related to slightly levels increases in mitochondrial fusion proteins, Mitofusion 1 (MFN1), and Dynamin-related GTPase (OPA1). Collectively, our results showed that adipose tissue-derived MSCs at population doubling seven developed a senescent phenotype that was characterized by metabolic cell changes that can lead to mitochondrial fusion.
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OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of entecavir monotherapy in nucleos(t)ide-naive chronic hepatitis B patients and to analyse the influence of the comorbidity burden on therapy outcome. METHODS: We retrospectively analysed data from 237 nucleos(t)ide-naive chronic hepatitis B white patients treated with entecavir (0.5 mg/day) at 23 Spanish centres. For the efficacy and safety analyses, patients were grouped according to their baseline comorbidities. RESULTS: The mean age of the cohort was 43 years (range: 19-82 years); 73% were male, 83% were white, and 33% were hepatitis B e antigen (HBeAg) positive. At baseline, the median hepatitis B virus DNA level was 6.20 log10 IU/ml. Of the patients, 18% had cirrhosis, 9.7% had diabetes, 16.3% had hypertension, and 15.7% had obesity; 13.4% of patients had more than one comorbid condition. Virological and biochemical responses at month 36 were obtained independently of the patients' baseline comorbid condition. Of 10 HBeAg-positive patients who discontinued treatment after HBeAg seroconversion, those who had not also cleared HBsAg (six) experienced virological recurrence in a median 5.6 months. There were no treatment discontinuations due to adverse events. Three patients were diagnosed with hepatocellular carcinoma at months 12, 30 and 54, and six experienced hepatic decompensation during follow-up. The median serum creatinine levels did not increase after 36 months of treatment, even in patients with comorbidities. CONCLUSION: Entecavir is safe, well tolerated, and highly effective, even in patients with comorbid condition(s). Discontinuation of treatment in patients who have not been cleared of HBsAg may lead to virological recurrence.
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Antivirales/uso terapéutico , Guanina/análogos & derivados , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/sangre , Antivirales/efectos adversos , Creatinina/sangre , ADN Viral/sangre , Diabetes Mellitus , Femenino , Estudios de Seguimiento , Guanina/efectos adversos , Guanina/uso terapéutico , Anticuerpos contra la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/inmunología , Antígenos e de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Hepatitis B Crónica/sangre , Humanos , Hipertensión/complicaciones , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Recurrencia , Estudios Retrospectivos , Población Blanca , Adulto JovenRESUMEN
Neoadjuvant radiochemotherapy to locally advanced rectal carcinoma patients has proven efficient in a high percentage of cases. Despite this, some patients show nonresponse or even disease progression. Recent studies suggest that different genetic alterations may be associated with sensitivity versus resistance of rectal cancer tumor cells to neoadjuvant therapy. We investigated the relationship between intratumoral pathways of clonal evolution as assessed by interphase fluorescence in situ hybridization (51 different probes) and response to neoadjuvant radiochemotherapy, evaluated by Dworak criteria in 45 rectal cancer tumors before (nâ=â45) and after (nâ=â31) treatment. Losses of chromosomes 1p (44%), 8p (53%), 17p (47%), and 18q (38%) and gains of 1q (49%) and 13q (75%) as well as amplification of 8q (38%) and 20q (47%) chromosomal regions were those specific alterations found at higher frequencies. Significant association (Pâ<â0.05) was found between alteration of 1p, 1q, 11p, 12p, and 17p chromosomal regions and degree of response to neoadjuvant therapy. A clear association was observed between cytogenetic profile of the ancestral tumor cell clone and response to radiochemotherapy; cases presenting with del(17p) showed a poor response to neoadjuvant treatment (Pâ=â0.03), whereas presence of del(1p) was more frequently observed in responder patients (Pâ=â0.0002). Moreover, a significantly higher number of copies of chromosomes 8q (Pâ=â0.004), 13q (Pâ=â0.003), and 20q (Pâ=â0.002) were found after therapy versus paired pretreatment rectal cancer samples. Our results point out the existence of an association between tumor cytogenetics and response to neoadjuvant therapy in locally advanced rectal cancer. Further studies in larger series of patients are necessary to confirm our results.
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Quimioradioterapia Adyuvante , Aberraciones Cromosómicas , Terapia Neoadyuvante , Neoplasias del Recto/genética , Neoplasias del Recto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina , Evolución Clonal , Estudios de Cohortes , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Fraccionamiento de la Dosis de Radiación , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Neoplasias del Recto/patología , Resultado del TratamientoRESUMEN
Most patients with pancreatic ductal adenocarcinoma (PDAC) die within 6 months of diagnosis. However, 20% to 25% patients undergoing total tumor resection remain alive and disease-free 5 years after diagnostic surgery. Few studies on tumor markers have predicted patient prognosis and/or survival. We evaluated the effect of tumor cytogenetic copy number changes detected by interphase fluorescence in situ hybridization on overall survival (OS) of 55 PDAC patients. The prognostic value of copy number changes showing an effect on OS was validated in an external cohort of 44 surgically resected PDAC patients by comparative genomic hybridization arrays, and the genes coded in altered chromosomes with prognostic value were identified by high-density single-nucleotide polymorphism arrays in 20 cases. Copy number changes of chromosomes 4 and 9q34 with gains of 8q24 were independently associated with shorter OS. On the basis of these three chromosomal alterations, a score is proposed that identifies patients with significantly different (P < 0.001) 5-year OS rates: 60% ± 20%, 16% ± 8%, and 0% ± 0%, respectively. Our results show an association between tumor cytogenetics and OS of PDAC patients and provide the basis for further prognostic stratification of patients undergoing complete tumor resection. Further studies to identify specific genes coded in these chromosomes and their functional consequences are necessary to understand the clinical effect of these changes.
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Carcinoma Ductal Pancreático/genética , Cromosomas Humanos , Hibridación Fluorescente in Situ , Interfase , Neoplasias Pancreáticas/genética , Resultado del Tratamiento , Anciano , Carcinoma Ductal Pancreático/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/fisiopatologíaRESUMEN
INTRODUCTION: Dentinogenesis, odontoblast dentin formation, includes dentinal growth, mineralization and dentinal tubule formation. Odontoblasts synthesize collagen resulting in collagen apposition contributing to dentinogenesis. Furthermore, within the tubule, they express non-collagenous proteins, such as dentin phosphoprotein (DPP), associated with hydroxyapatite crystal formation and growth. The aim of this work was to determine patterns of growth and dentin formation and quantification of its mineralization. Findings from our work are relevant to endodontics for future regenerative treatment. METHODS: We formulated a 3D domain mathematical model, which recreates the events that lead to dentinal tubule mineralization. As reference we used collagen apposition and DPP activity. RESULTS: We obtained a model depicting predentin's mineralization distribution during dentin development. Furthermore, we verified different DPP diffusion coefficients to test the model's sensitivity. CONCLUSIONS: We present a model to shed light on the process of dentin and dentinal tubule formation, and its relation to diffusion and mineralization processes.
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Dentinogénesis/fisiología , Modelos Dentales , Diferenciación Celular , Colágeno/metabolismo , Simulación por Computador , Dentina/crecimiento & desarrollo , Dentina/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Análisis de Elementos Finitos , Humanos , Imagenología Tridimensional , Odontoblastos/citología , Odontoblastos/fisiología , Fosfoproteínas/metabolismo , Sialoglicoproteínas/metabolismo , Calcificación de Dientes/fisiologíaRESUMEN
Occult hepatitis B infection (OBI) is characterized by hepatitis B virus (HBV) DNA in serum in the absence of hepatitis B surface antigen (HBsAg) presenting HBsAg-negative and anti-HBc positive serological patterns. Occult HBV status is associated in some cases with mutant viruses undetectable by HBsAg assays; but more frequently it is due to a strong suppression of viral replication and gene expression. OBI is an entity with world-wide diffusion. The failure to detect HBsAg, despite the persistence of the viral DNA, is due in most cases to the strong suppression of viral replication and gene expression that characterizes this "occult" HBV infection; although the mechanisms responsible for suppression of HBV are not well understood. The majority of OBI cases are secondary to overt HBV infection and represent a residual low viremia level suppressed by a strong immune response together with histological derangements which occurred during acute or chronic HBV infection. Much evidence suggests that it can favour the progression of liver fibrosis and the development of hepatocellular carcinoma.