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1.
Water Resour Res ; 57(9): e2020WR028876, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34690378

RESUMEN

Spatial estimates of crop evapotranspiration with high accuracy from the field to watershed scale have become increasingly important for water management, particularly over irrigated agriculture in semiarid regions. Here, we provide a comprehensive assessment on patterns of annual agricultural water use over California's Central Valley, using 30-m daily evapotranspiration estimates based on Landsat satellite data. A semiempirical Priestley-Taylor approach was locally optimized and cross-validated with available field measurements for major crops including alfalfa, almond, citrus, corn, pasture, and rice. The evapotranspiration estimates explained >70% variance in daily measurements from independent sites with an RMSE of 0.88 mm day-1. When aggregated over the Valley, we estimated an average evapotranspiration of 820 ± 290 mm yr-1 in 2014. Agricultural water use varied significantly across and within crop types, with a coefficient of variation ranging from 8% for Rice (1,110 ± 85 mm yr-1) to 59% for Pistachio (592 ± 352 mm yr-1). Total water uses in 2016 increased by 9.6%, as compared to 2014, mostly because of land-use conversion from fallow/idle land to cropland. Analysis across 134 Groundwater Sustainability Agencies (GSAs) further showed a large variation of agricultural evapotranspiration among and within GSAs, especially for tree crops, e.g., almond evapotranspiration ranging from 339 ± 80 mm yr-1 in Tracy to 1,240 ± 136 mm yr-1 in Tri-County Water Authority. Continuous monitoring and assessment of the dynamics and spatial heterogeneity of agricultural evapotranspiration provide data-driven guidance for more effective land use and water planning across scales.

2.
Hum Exp Toxicol ; 40(12): 2099-2112, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34085558

RESUMEN

Indole-3-carbinol (I3C) is a phytochemical that exhibits growth-inhibitory activity against various cancer cells. However, there are limited studies on the effects of I3C on colon cancer cells. In this study, the growth-inhibitory activity of I3C against the human colorectal carcinoma cell line (LoVo) was examined. The results of the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, colony formation, and cell counting assays revealed that I3C suppressed the proliferation of LoVo cells. Microscopy and wound-healing analyses revealed that I3C affected the morphology and inhibited the migration of LoVo cells, respectively. I3C induced apoptosis and DNA fragmentation as evidenced by the results of fluorescein isothiocyanate-conjugated annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling assay, respectively. Additionally, I3C arrested the cell cycle at the G0/G1 phase and enhanced the reactive oxygen species levels. Western blotting analysis revealed that treatment with I3C resulted in the activation of apoptotic proteins, such as poly(ADP-ribose) polymerase, caspase-3, caspase-7, caspase-9, Bax, Bim, and p53 in LoVo cells. These results indicate that I3C induces apoptosis in LoVo cells by upregulating p53, leading to the activation of Bax and caspases. Taken together, I3C exerts cytotoxic effects on LoVo cells by activating apoptosis.

3.
J Neurointerv Surg ; 13(2): 102-108, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33115813

RESUMEN

BACKGROUND: Implantable brain-computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation. METHODS: Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks. RESULTS: Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%-100.00%) (trial mean (median, Q1-Q3)) at a rate of 13.81 (13.44, 10.96-16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%-100.00%) at 20.10 (17.73, 12.27-26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants. CONCLUSION: We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis.


Asunto(s)
Actividades Cotidianas , Interfaces Cerebro-Computador , Neuroestimuladores Implantables , Corteza Motora/fisiología , Parálisis/terapia , Índice de Severidad de la Enfermedad , Actividades Cotidianas/psicología , Anciano , Interfaces Cerebro-Computador/psicología , Estudios de Factibilidad , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Corteza Motora/diagnóstico por imagen , Parálisis/diagnóstico por imagen , Parálisis/fisiopatología , Estudios Prospectivos
4.
Hum Exp Toxicol ; 40(2): 231-244, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32787465

RESUMEN

Tomentosin, a sesquiterpene lactone, is known to possess various biological activities. However, its anticarcinogenic activity against human hepatocellular carcinoma (HCC) cells has not been investigated in detail. Thus, this study aimed to elucidate the cytotoxic mechanism of tomentosin in human HCC cell lines HepG2 and Huh7. WST-1, cell counting, and colony formation assay results showed that treatment with tomentosin decreased the viability and suppressed the proliferation rate of HepG2 and Huh7 cells in a dose- and time-dependent manner. Cell cycle analysis revealed increased population of cells at the SubG1 and G2/M stage, and decreased population of cells at the G0/1 stage in HepG2 and Huh7 cells treated with tomentosin. Annexin V/propidium iodide double staining and TUNEL assay results showed increased apoptotic cell population and DNA fragmentation in HepG2 and Huh7 cells treated with tomentosin. Western blotting analysis results showed that tomentosin treatment significantly increased the expression level of Bax, Bim (short form), cleaved PARP1, FOXO3, p53, pSer15p53, pSer20p53, pSer46p53, p21, and p27, but decreased the expression of Bcl2, caspase3, caspase7, caspase9, cyclin-dependent kinase 2 (CDK2), CDK4, CDK6, cyclinB1, cyclinD1, cyclinD2, cyclinD3, and cyclinE in a dose-dependent manner. Taken together, this study revealed that tomentosin, which acted through cell cycle arrest and apoptosis, may be a useful therapeutic option against HCC.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Lactonas/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Sesquiterpenos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Caspasas/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismo , Proteína Forkhead Box O3/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
5.
Sci Adv ; 6(19): eaaz0571, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32494707

RESUMEN

The prototypical genetic autoimmune disease is immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a severe pediatric disease with limited treatment options. IPEX syndrome is caused by mutations in the forkhead box protein 3 (FOXP3) gene, which plays a critical role in immune regulation. As a monogenic disease, IPEX is an ideal candidate for a therapeutic approach in which autologous hematopoietic stem and progenitor (HSPC) cells or T cells are gene edited ex vivo and reinfused. Here, we describe a CRISPR-based gene correction permitting regulated expression of FOXP3 protein. We demonstrate that gene editing preserves HSPC differentiation potential, and that edited regulatory and effector T cells maintain their in vitro phenotype and function. Additionally, we show that this strategy is suitable for IPEX patient cells with diverse mutations. These results demonstrate the feasibility of gene correction, which will be instrumental for the development of therapeutic approaches for other genetic autoimmune diseases.

6.
Phys Rev Lett ; 124(6): 067701, 2020 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-32109120

RESUMEN

Spins in silicon quantum devices are promising candidates for large-scale quantum computing. Gate-based sensing of spin qubits offers a compact and scalable readout with high fidelity, however, further improvements in sensitivity are required to meet the fidelity thresholds and measurement timescales needed for the implementation of fast feedback in error correction protocols. Here, we combine radio-frequency gate-based sensing at 622 MHz with a Josephson parametric amplifier, that operates in the 500-800 MHz band, to reduce the integration time required to read the state of a silicon double quantum dot formed in a nanowire transistor. Based on our achieved signal-to-noise ratio, we estimate that singlet-triplet single-shot readout with an average fidelity of 99.7% could be performed in 1 µs, well below the requirements for fault-tolerant readout and 30 times faster than without the Josephson parametric amplifier. Additionally, the Josephson parametric amplifier allows operation at a lower radio-frequency power while maintaining identical signal-to-noise ratio. We determine a noise temperature of 200 mK with a contribution from the Josephson parametric amplifier (25%), cryogenic amplifier (25%) and the resonator (50%), showing routes to further increase the readout speed.

7.
Sci Rep ; 10(1): 1350, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992801

RESUMEN

Stacking fault energies (SFE) were determined in additively manufactured (AM) stainless steel (SS 316 L) and equiatomic CrCoNi medium-entropy alloys. AM specimens were fabricated via directed energy deposition and tensile loaded at room temperature. In situ neutron diffraction was performed to obtain a number of faulting-embedded diffraction peaks simultaneously from a set of (hkl) grains during deformation. The peak profiles diffracted from imperfect crystal structures were analyzed to correlate stacking fault probabilities and mean-square lattice strains to the SFE. The result shows that averaged SFEs are 32.8 mJ/m2 for the AM SS 316 L and 15.1 mJ/m2 for the AM CrCoNi alloys. Meanwhile, during deformation, the SFE varies from 46 to 21 mJ/m2 (AM SS 316 L) and 24 to 11 mJ/m2 (AM CrCoNi) from initial to stabilized stages, respectively. The transient SFEs are attributed to the deformation activity changes from dislocation slip to twinning as straining. The twinning deformation substructure and atomic stacking faults were confirmed by electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM). The significant variance of the SFE suggests the critical twinning stress as 830 ± 25 MPa for the AM SS 316 L and 790 ± 40 MPa for AM CrCoNi, respectively.

8.
J Eur Acad Dermatol Venereol ; 34(1): 54-58, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31407395

RESUMEN

Skin ageing can be divided according to phenotypical features into intrinsic (by the passage of time) and extrinsic (with the addition of the effects of environmental factors). Photoageing is by far the most researched factor of extrinsic ageing but the additional impact of other factors such as cigarette smoking and exposure to air pollution ought to be taken into account. One of the least researched topics in relation to extrinsic skin ageing is the impact of psychological stress. A contemporary review of response of human skin to stress describes the molecular mechanisms of extrinsic skin ageing, but has fallen short of explaining resilience to stress exhibited by people. Mechanisms to regulate gene expression, define cellular identity and promote functionality are responsible for the adaptive response to stressful events. Conversely, maladaptive response of human tissues to chronic stress appears to have an impact on gene regulation. Epigenetics is the study of heritable changes in organisms due to modifications in gene activity and expression, as opposed to the genetic code (DNA genome). Chronic stress appears to be an important factor in determining an individual's vulnerability to ageing and age-related comorbidities via epigenetic modifications. Forerunners in epigenetic research recognized the necessity of a reliable biomarker in order to develop a better understanding of the role of epigenomics in ageing. Genomic DNA methylation patterns (DNAm) appear to be valuable in age prediction but variability in specificity exists across species of mammals, human races and tissues. Neuroscience research appears to be leading the way in epigenomics whilst the lack of a valid and reliable DNAm-associated age predictor compatible with human skin tissue hinders research endeavours for the epigenetics of skin ageing.


Asunto(s)
Envejecimiento de la Piel/fisiología , Estrés Psicológico/complicaciones , Epigénesis Genética , Humanos
9.
J Geophys Res Oceans ; 124(5): 3333-3360, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31341755

RESUMEN

The cumulative Greenland freshwater flux anomaly has exceeded 5,000 km3 since the 1990s. The volume of this surplus freshwater is expected to cause substantial freshening in the North Atlantic. Analysis of hydrographic observations in the subpolar seas reveals freshening signals in the 2010s. The sources of this freshening are yet to be determined. In this study, the relationship between the surplus Greenland freshwater flux and this freshening is tested by analyzing the propagation of the Greenland freshwater anomaly and its impact on salinity in the subpolar North Atlantic based on observational data and numerical experiments with and without the Greenland runoff. A passive tracer is continuously released during the simulations at freshwater sources along the coast of Greenland to track the Greenland freshwater anomaly. Tracer budget analysis shows that 44% of the volume of the Greenland freshwater anomaly is retained in the subpolar North Atlantic by the end of the simulation. This volume is sufficient to cause strong freshening in the subpolar seas if it stays in the upper 50-100 m. However, in the model the anomaly is mixed down to several hundred meters of the water column resulting in smaller magnitudes of freshening compared to the observations. Therefore, the simulations suggest that the accelerated Greenland melting would not be sufficient to cause the observed freshening in the subpolar seas and other sources of freshwater have contributed to the freshening. Impacts on salinity in the subpolar seas of the freshwater transport through Fram Strait and precipitation are discussed.

10.
Hum Exp Toxicol ; 38(8): 992-1003, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31079487

RESUMEN

Cadmium (Cd) is a heavy metal widely used in industry, and the skin is an important target of this metal. Taxifolin (Tax), a natural source of bioflavonoids found in various conifers, exerts multiple biologic effects on skin cells. However, the mechanisms by which Tax protects keratinocytes against Cd are currently unclear. We investigated the cytoprotective effects of Tax against Cd-induced apoptosis in the human HaCaT keratinocyte. The water-soluble tetrazolium salt (WST-1) assay and Annexin V/propidium iodide double-staining assay results showed that Cd-induced cell death was lower in cells treated with Tax (0-100 µM) than in cells treated with Cd alone. Additionally, a reduction of Cd-induced DNA fragmentation by Tax was shown by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling assay. The levels of reactive oxygen species were also lower in Cd/Tax-treated cells than in Cd-treated cells. We employed a two-dimensional electrophoresis-based proteomic analysis to identify treatment-related alterations in protein expression. Tax downregulated cathepsin B and D and upregulated hsp27, cyclophilin A, and peroxiredowin-1. Western blotting confirmed the downregulation of cathepsin B and D and the upregulation of hsp27. The cytoprotective effects of Tax against Cd-induced apoptosis were also characterized by the changes in the activity of caspase 3, -7, poly ADP-ribose polymerase, the cellular proliferation-related ERK1/2, and AKT. Furthermore, the levels of cell cycle-related proteins, such as SP1 and p21, decreased, whereas p53 level increased. We concluded that Tax reduced Cd cytotoxicity and Cd-induced apoptosis by inhibiting the apoptotic pathway.


Asunto(s)
Cadmio/toxicidad , Citoprotección/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Quercetina/análogos & derivados , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Quercetina/farmacología , Especies Reactivas de Oxígeno/metabolismo
11.
Hum Exp Toxicol ; 38(1): 136-147, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29992829

RESUMEN

Many cruciferous vegetables, including cabbage, contain indole-3-carbinol (I3C), which is a known anticarcinogen. However, the anticarcinogenic effects of I3C on liver cancer have not been investigated. Therefore, this study was conducted to evaluate the anticarcinogenic effects of I3C in human hepatocellular carcinoma (HCC) SNU449 cells. The results of MTT and WST-1 assays indicated that treatment of SNU449 cells with I3C decreased viability in dose- and time-dependent manners, while colony formation assays indicated that I3C also inhibited proliferation of SNU449 cells. Moreover, fluorescence-activated cell sorter analysis showed that I3C induced apoptosis in SNU449 cells in dose- and time-dependent manners. Furthermore, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling revealed that I3C induced DNA fragmentation in SNU449 cells in a time-dependent manner, while Western blotting showed that apoptotic proteins such as p53, cleaved PARP, caspase-3, and caspase-7 were activated in SNU449 cells following treatment with I3C. Finally, reactive oxygen species-related protein peroxiredoxin-1 and thioredoxin-1 expression decreased in I3C-treated SNU449 cells. The aim of our study is to investigate the unknown mechanisms responsible for the apoptotic effects of I3C on human HCC SNU449 cells, and the results suggest that I3C may be useful for the prevention and treatment of liver cancer.


Asunto(s)
Anticarcinógenos/farmacología , Antineoplásicos/farmacología , Indoles/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Fragmentación del ADN , Humanos , Neoplasias Hepáticas/tratamiento farmacológico
12.
Allergy ; 73(8): 1686-1699, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29420850

RESUMEN

BACKGROUND: Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma. METHODS: Wild-type and Chit1-deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control. RESULTS: The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF-ß1 were significantly decreased with a diminished number of Foxp3+ regulatory T cells (Treg) in the lungs of Chit1-/- mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF-ß-stimulated conversion of CD4+ CD25- naïve T cells to CD4+ Foxp3+ Treg cells, suggesting Chit1 is required for optimal effect of TGF-ß1 in Treg cell differentiation. CONCLUSION: Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF-ß expression and Foxp3+ Treg cells.


Asunto(s)
Asma/metabolismo , Factores de Transcripción Forkhead/biosíntesis , Hexosaminidasas/análisis , Hexosaminidasas/metabolismo , Hipersensibilidad/metabolismo , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Análisis de Varianza , Animales , Distribución de Chi-Cuadrado , Niño , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-10/metabolismo , Mutación con Pérdida de Función , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Transgénicos , Esputo/enzimología , Células Th2/metabolismo
13.
Clin Microbiol Infect ; 24(9): 997-1003, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29288020

RESUMEN

OBJECTIVE: To investigate the long-term incidence and predictors for hepatitis B surface antigen (HBsAg) loss after nucleoside analogue therapy. METHODS: The study included 411 noncirrhotic chronic hepatitis B patients (148 hepatitis B e antigen (HBeAg)-positive and 263 HBeAg-negative patients) who were treated with lamivudine (n = 110) or entecavir (n = 301) with posttreatment follow-up of at least 12 months. RESULTS: In HBeAg-positive patients, the 8-year cumulative rates of virologic relapse, clinical relapse and HBsAg loss were 55.6%, 47.7% and 19.6%, respectively. In HBeAg-negative patients, the rates were 69.3%, 58.9% and 33.1%, respectively. Cox regression analysis showed that hepatitis B virus genotype C and lower end-of-treatment HBsAg levels were independent predictors of HBsAg loss in HBeAg-positive and -negative patients. The 5-year HBsAg loss rate was 47.3% in HBeAg-positive patients with end-of-treatment HBsAg levels <300 IU/mL, while the 8-year HBsAg loss rate was 69.3% in HBeAg-negative patients with end-of-treatment HBsAg levels <200 IU/mL. Five patients experienced hepatitis flares with decompensation after stopping nucleoside analogue therapy, and one died after retreatment. Of the 48 patients who developed off-therapy HBsAg loss, two developed hepatocellular carcinoma. CONCLUSIONS: The rate of HBsAg loss was relatively high and the rate of hepatic events was low in noncirrhotic patients who discontinued nucleoside analogue therapy.


Asunto(s)
Antivirales/administración & dosificación , Antígenos de Superficie de la Hepatitis B/metabolismo , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Adulto , Antivirales/farmacología , Femenino , Genotipo , Guanina/administración & dosificación , Guanina/análogos & derivados , Guanina/farmacología , Antígenos de Superficie de la Hepatitis B/genética , Antígenos e de la Hepatitis B/genética , Antígenos e de la Hepatitis B/metabolismo , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Humanos , Incidencia , Lamivudine/administración & dosificación , Lamivudine/farmacología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
14.
J Viral Hepat ; 25(5): 590-597, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29274189

RESUMEN

This study investigates the incidences and predictors of hepatitis B virus (HBV) relapse after tenofovir disoproxil fumarate (TDF) therapy in hepatitis B e antigen (HBeAg)-positive and -negative patients. We retrospectively recruited 143 chronic hepatitis B (CHB) patients without cirrhosis (39 HBeAg-positive and 104 HBeAg-negative patients) who were previously treated with TDF and had post-treatment follow-up for at least 6 months (median: 55, IQR 36-85 weeks). All the patients fulfilled the stopping criteria of APASL 2012. The virological and clinical relapse rates at 104 weeks in HBeAg-positive patients were 66.6% and 59.1%, while they were 72.3% and 55.9%, respectively, in HBeAg-negative patients. Cox regression analysis revealed that the higher end-of-treatment HBsAg levels were an independent factor of virological relapse in HBeAg-positive and HBeAg-negative patients. The end-of-treatment HBsAg levels of 200 (area under the receiver operating characteristic (AUROC): 0.624) and 80 IU/mL (AUROC: 0.959) were the optimal values for predicting HBV relapse in HBeAg-positive and HBeAg-negative patients, respectively. The virological relapse rate at 78 weeks was 14.3% and 19.6% in HBeAg-positive and HBeAg-negative patients who achieved HBsAg ≤200 IU/mL and HBsAg ≤80 IU/mL, respectively. Two patients experienced hepatic decompensation upon hepatitis flares, and no patient died after timely retreatment. Seven patients experienced off-therapy HBsAg loss. The cumulative rates of HBsAg loss at 104 weeks were 45.5% and 59.3% in patients with end-of-treatment HBsAg ≤80 IU/mL and ≤50 IU/mL, respectively. In conclusions, the end-of-treatment HBsAg levels were a useful marker for predicting HBV relapse in HBeAg-positive and HBeAg-negative CHB patients.


Asunto(s)
Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/epidemiología , Tenofovir/uso terapéutico , Adulto , Anciano , Femenino , Estudios de Seguimiento , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Medición de Riesgo
15.
Obes Sci Pract ; 3(2): 171-184, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28702212

RESUMEN

OBJECTIVE: Obesity is an established risk factor for cardiovascular disease. The mechanisms by which obesity affects cardiovascular risk have not been fully elucidated. This paper reports a comprehensive systematic review and meta-analysis on obesity and two key aspects of vascular health using gold-standard non-invasive measures - arterial endothelial function (brachial flow-mediated dilatation) and subclinical atherosclerosis (carotid intima-media thickness). METHODS: Electronic searches for 'Obesity and flow-mediated dilatation' and 'Obesity and intima-media thickness' were performed using Ovid Medline and Embase databases. A meta-analysis was undertaken for brachial flow-mediated dilatation and carotid intima-media thickness to obtain pooled estimates for adults with obesity and those with healthy weight. RESULTS: Of the 5,810 articles retrieved, 19 studies on flow-mediated dilatation and 19 studies on intima-media thickness were included. Meta-analysis demonstrated that obesity was associated with lower flow-mediated dilatation (-1.92 % [95% CI -2.92, -0.92], P = 0.0002) and greater carotid intima-media thickness (0.07 mm [95% CI 0.05, 0.08], P < 0.0001). CONCLUSIONS: Obesity is associated with poorer arterial endothelial function and increased subclinical atherosclerosis, consistent with these aspects of vascular health at least partially contributing to the increased risk of cardiovascular events in adults with obesity. These estimated effect sizes will enable vascular health benefits in response to weight loss treatment to be put in greater perspective, both in the research setting and potentially also clinical practice.

16.
Cancer Gene Ther ; 24(7): 277-281, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28497777

RESUMEN

Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, single-arm, phase I/II clinical trial in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E. Patients with CRPC who were docetaxel-resistant or could not receive docetaxel treatment were eligible. HVJ-E was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a 3+3 dose-escalation design. The primary end points were to evaluate safety and tolerability of HVJ-E. The secondary end points were to analyze tumor immunity and antitumor effect. The study is registered at UMIN Clinical Trials Registry, number UMIN000006142. Seven patients were enrolled, and six patients received HVJ-E. Grade 2 or 3 adverse events (Common Terminology Criteria for Adverse Events Ver. 4.0) were urinary retention and lymphopenia from which the patients recovered spontaneously. No Grade 4 adverse events were observed. Radiographically, three patients had stable disease in the low-dose group, and one patient had stable disease and two had progressive disease in the high-dose group. The prostate-specific antigen (PSA) declined from 14 to 1.9 ng ml-1 in one patient in the low-dose group after two cycles of HVJ-E treatment, and the PSA response rate was 16.6%. NK cell activity was elevated from day 12 to day 28 after HVJ-E administration, whereas serum interleukin-6, interferon (IFN)-α, IFN-ß and IFN-γ levels were not affected by HVJ-E treatment. Intratumoral and subcutaneous injections of HVJ-E are feasible and PSA response was observed in a subgroup of CRPC patients.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Virus Sendai/inmunología , Vacunas de Partículas Similares a Virus/inmunología , Proteínas del Envoltorio Viral/inmunología , Anciano , Anciano de 80 o más Años , Citocinas/metabolismo , Esquema de Medicación , Humanos , Inyecciones Subcutáneas , Interleucinas , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/inmunología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Terapéutica , Vacunas de Partículas Similares a Virus/administración & dosificación , Vacunas de Partículas Similares a Virus/efectos adversos
17.
Clin Microbiol Infect ; 23(7): 464-469, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28189857

RESUMEN

OBJECTIVES: The aims of this study are to compare the long-term efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue (NA)-naive patients with chronic hepatitis B (CHB) with high hepatitis B virus (HBV) DNA (> 6 log10 IU/mL). METHODS: We recruited 419 NA-naive patients for analysis (313 entecavir, 106 tenofovir). We used propensity-score matching to match 106 patients in the tenofovir group with 212 patients in the entecavir group by age, baseline HBV DNA levels and cirrhosis after subgrouping by hepatitis B e antigen (HBeAg) status. RESULTS: There was no significant difference in 3-year cumulative rates of virological response (VR) (96.4% versus 92.1%, p 0.26 in HBeAg-positive or 98.2% versus 98.6%, p 0.64 in HBeAg-negative patients), HBeAg loss (53.8% versus 47.4%, p 0.89) or seroconversion (40.2% versus 41.3%, p 0.77), and hepatocellular carcinoma (HCC) development (4% versus 2.7%, p 0.55) between the tenofovir and entecavir groups in either cohort or propensity-score matching patients. In subgroup analysis of patients with HBV DNA >108 IU/mL, entecavir and tenofovir showed similar effectiveness in achieving VR (90.9% versus 87.7% at 3 years; p 0.13). Tenofovir and diabetes mellitus were independent factors for acute kidney injury during treatment. Multivariate analysis showed that HBeAg-negative status, and lower baseline HBV DNA and HBV surface antigen levels were independent factors for achieving VR. Older age, lower baseline HBV DNA levels, cirrhosis and α-fetoprotein ≥8 ng/mL at 12 months of treatment were independently associated with HCC development. CONCLUSIONS: Tenofovir and entecavir have similar effectiveness in NA-naive CHB patients with high viraemia. Tenofovir might have a higher incidence of acute kidney injury compared with entecavir during treatment.


Asunto(s)
Antivirales/efectos adversos , Antivirales/uso terapéutico , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Tenofovir/efectos adversos , Tenofovir/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Adulto , Anciano , ADN Viral/sangre , Femenino , Guanina/efectos adversos , Guanina/uso terapéutico , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Carga Viral
18.
J Viral Hepat ; 24(7): 599-607, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28130815

RESUMEN

We investigated the incidence and predictors of post-treatment hepatitis B virus (HBV) relapse and hepatitis B surface antigen (HBsAg) loss. After cessation of nucleoside analogue (NA) treatment in hepatitis B e antigen (HBeAg)-negative patients with cirrhosis. The rates of HBsAg loss and hepatocellular carcinoma (HCC) development in HBeAg-negative patients with cirrhosis who continued NA treatment were compared with those who discontinued treatment. Patients with compensated cirrhosis who had discontinued NA treatment for at least 12 months (discontinuing group; n=73) and patients who continued entecavir treatment for at least 4 years (continuing group; n=158) were recruited. Serum HBsAg levels were analysed at the end of treatment (discontinuing group) or at 2.5-3 years of treatment (continuing group). In the discontinuing group, the 6-year cumulative incidence of post-treatment virological relapse and HBsAg loss were 56.3% and 46.7%, respectively. The end-of-treatment HBsAg level of 300 IU/mL was a cut-off value for subsequent post-treatment HBsAg loss and sustained response. In the continuing group, HBsAg loss occurred in five of 158 patients. Cox regression analysis showed that HBsAg levels in the discontinuing group were independent predictors for HBsAg loss in all patients and 104 propensity score (PS)-matched patients. There was no significant difference in HCC development between the groups in all patients and 104 PS-matched patients. Two patients experienced post-treatment alanine aminotransferase flare with hepatic decompensation, and neither of them died after retreatment. In conclusion, HBeAg-negative patients with cirrhosis who discontinued NA treatment might have a higher rate of HBsAg loss and their risk of developing HCC did not increase compared with those who continued entecavir treatment.


Asunto(s)
Antivirales/uso terapéutico , Carcinoma Hepatocelular/epidemiología , Guanina/análogos & derivados , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/epidemiología , Adulto , Anciano , Femenino , Guanina/uso terapéutico , Hepatitis B Crónica/complicaciones , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento
19.
Aliment Pharmacol Ther ; 44(9): 957-966, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27629859

RESUMEN

BACKGROUND: In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG-IFN) for 48-weeks results in higher rates of hepatitis B surface antigen (HBsAg) loss than either monotherapy. AIM: To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. METHODS: A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG-IFN (PI, 180 µg/week, subcutaneous) for 48 weeks (TDF/PI-48w); TDF plus PEG-IFN for 16 weeks, TDF for 32 weeks (TDF/PI-16w+TDF-32w); TDF for 120 weeks (TDF-120w) or PEG-IFN for 48 weeks (PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. RESULTS: Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. CONCLUSIONS: HBsAg decline at Week 24 of TDF plus PEG-IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.


Asunto(s)
Antivirales/administración & dosificación , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Polietilenglicoles/administración & dosificación , Tenofovir/administración & dosificación , Administración Oral , Adulto , ADN Viral/sangre , Quimioterapia Combinada , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Proteínas Recombinantes/administración & dosificación , Resultado del Tratamiento
20.
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