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BACKGROUND: The short-read whole-genome sequencing (WGS) approach has been widely applied to investigate the genomic variation in the natural populations of many plant species. With the rapid advancements in long-read sequencing and genome assembly technologies, high-quality genome sequences are available for a group of varieties for many plant species. These genome sequences are expected to help researchers comprehensively investigate any type of genomic variants that are missed by the WGS technology. However, multiple genome alignment (MGA) tools designed by the human genome research community might be unsuitable for plant genomes. RESULTS: To fill this gap, we developed the AnchorWave-Cactus Multiple Genome Alignment (ACMGA) pipeline, which improved the alignment of repeat elements and could identify long (> 50 bp) deletions or insertions (INDELs). We conducted MGA using ACMGA and Cactus for 8 Arabidopsis (Arabidopsis thaliana) and 26 Maize (Zea mays) de novo assembled genome sequences and compared them with the previously published short-read variant calling results. MGA identified more single nucleotide variants (SNVs) and long INDELs than did previously published WGS variant callings. Additionally, ACMGA detected significantly more SNVs and long INDELs in repetitive regions and the whole genome than did Cactus. Compared with the results of Cactus, the results of ACMGA were more similar to the previously published variants called using short-read. These two MGA pipelines identified numerous multi-allelic variants that were missed by the WGS variant calling pipeline. CONCLUSIONS: Aligning de novo assembled genome sequences could identify more SNVs and INDELs than mapping short-read. ACMGA combines the advantages of AnchorWave and Cactus and offers a practical solution for plant MGA by integrating global alignment, a 2-piece-affine-gap cost strategy, and the progressive MGA algorithm.
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Arabidopsis , Genoma de Planta , Zea mays , Arabidopsis/genética , Zea mays/genética , Alineación de Secuencia , Mutación INDEL , Genómica/métodos , Polimorfismo de Nucleótido Simple , Secuenciación Completa del Genoma/métodos , Programas InformáticosRESUMEN
Shotcrete is widely used in tunnels, bridges, culverts, and other large-scale projects. The accelerator is an additive employed to expedite the setting time of shotcrete. Previous research primarily concentrated on enhancing the early strength of accelerators, whereas their long-term stability has been inadequately investigated. In this study, pseudoboehmite (PB) and amorphous aluminum hydroxide (AAH) were incorporated into the accelerator to enhance its stability over a period of 90 days without any signs of crystallization or delamination. Furthermore, the accelerator exhibited an initial setting time of 170 s, a final setting time of 550 s, and a compressive strength of 11.58 MPa after 1 day. The mechanism of effects was studied by isothermal calorimetry, FTIR, XRD, TG-DTG, and SEM analysis. The enhancement in stability is attributed to the distinctive adsorption and thixotropic properties of PB, which facilitate the formation of an electrical double-layer structure in acidic solutions. The expedited setting and hardening are primarily due to the equilibrium between Al3+, SO42-, and Ca2+ ions, which accelerates the hydration process of cement. This research offers a methodology for developing a high-performance, alkali-free liquid accelerator.
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WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan. WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).
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It is crucial that a highly effective adsorbent can be used to simultaneously remove the composite pollution including both inorganic and organic arsenic from wastewater. In this work, the iron modified corncob biochar (MCCB), prepared via the co-precipitation of ferric chloride hexahydrate (FeCl3â 6H2O) with sodium hydroxide (NaOH) on corncob biochar, was studied for the high efficiency removal of arsenilic acid (ASA) and arsenate [As(V)] in wastewater. X-ray diffraction, scanning electron microscopy, and fourier transform infrared spectroscopy were carried out to characterize the MCCB. At pH of 4.0-5.0, initial concentration of 10 mg/L ASA and 1 mg/L As(V), adsorbent dose of 0.4 g/L, the maximum adsorption capacities of ASA and As(V) were 49.20 and 4.89 mg/g, respectively. The adsorption performance of MCCB for ASA and As(V) was fitted well to the pseudo-second-order kinetic model. Results from this study indicate the promise of MCCB as an efficient, low-cost and environmentally friendly adsorbent for composite arsenic pollution.
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Arsénico , Contaminantes Químicos del Agua , Adsorción , Arseniatos , Arsénico/química , Carbón Orgánico , Concentración de Iones de Hidrógeno , Hierro/química , Cinética , Espectroscopía Infrarroja por Transformada de Fourier , Aguas Residuales , Contaminantes Químicos del Agua/química , Zea maysRESUMEN
The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo-controlled study of ambrisentan in IPF with mild-moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48â weeks. The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left-sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12â months. Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1â year in the majority of the cohort.
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Hipertensión Pulmonar/fisiopatología , Fibrosis Pulmonar Idiopática/complicaciones , Pulmón/fisiopatología , Fenilpropionatos/administración & dosificación , Presión Esfenoidal Pulmonar/efectos de los fármacos , Piridazinas/administración & dosificación , Anciano , Presión Arterial , Cateterismo Cardíaco , Método Doble Ciego , Femenino , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Disfunción Ventricular Izquierda , Organización Mundial de la SaludRESUMEN
PURPOSE: Pembrolizumab is standard therapy for patients with metastatic urothelial cancer (mUC) who progress after first-line platinum-based chemotherapy; however, only approximately 21% of patients respond. Sacituzumab govitecan (SG) is a trophoblast cell surface antigen-2-directed antibody-drug conjugate with US Food and Drug Administration-accelerated approval to treat patients with locally advanced or mUC who previously received platinum-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report the primary analysis of TROPHY-U-01 cohort 3. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Patients were CPI-naïve and had mUC progression after platinum-based chemotherapy in the metastatic setting or ≤12 months in the (neo)adjuvant setting. Patients received 10 mg/kg of SG once on days 1 and 8 and 200 mg of pembrolizumab once on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per central review. Secondary end points included clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS) per central review, and safety. RESULTS: Cohort 3 included 41 patients (median age 67 years; 83% male; 78% visceral metastases [29% liver]). With a median follow-up of 14.8 months, the ORR was 41% (95% CI, 26.3 to 57.9; 20% complete response rate), CBR was 46% (95% CI, 30.7 to 62.6), median DOR was 11.1 months (95% CI, 4.8 to not estimable [NE]), and median PFS was 5.3 months (95% CI, 3.4 to 10.2). The median overall survival was 12.7 months (range, 10.7-NE). Grade ≥3 treatment-related adverse events occurred in 61% of patients; most common were neutropenia (37%), leukopenia (20%), and diarrhea (20%). CONCLUSION: SG plus pembrolizumab demonstrated a high response rate with an overall manageable toxicity profile in patients with mUC who progressed after platinum-based chemotherapy. No new safety signals were detected. These data support further evaluation of SG plus CPI in mUC.
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Anticuerpos Monoclonales Humanizados , Camptotecina/análogos & derivados , Carcinoma de Células Transicionales , Inmunoconjugados , Humanos , Masculino , Anciano , Femenino , Platino (Metal)/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Coenzyme Q10-loaded lecithin nanocapsules (CoQ10-LNCs), composed of a CoQ10/lecithin/ GTCC/glycerol aqueous solution, were prepared by high-pressure homogenization. The zeta potential of the CoQ10-LNCs above -60 mV was determined on a Malvern Zetasize 2000 (Malvern Instruments, UK). The spherical shape of the CoQ10-LNCs was observed by using freeze-fracture transmission electron microscopy (FF-TEM), and the particle size was found to be below 100 nm. The supercooled state of the CoQ10-LNCs was observed by differential scanning calorimetry (DSC). In an oral bioavailability study, the CoQ10 plasma level after administering CoQ10-LNCs was higher than that after administering a CoQ10 tablet over 24 hours, and the relative bioavailability of CoQ10 was improved to 176.6% in mice. Based on the above results, the LNC delivery system might be a potential vehicle for improving the oral bioavailability of CoQ10.
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Lecitinas/química , Boca/metabolismo , Nanocápsulas/administración & dosificación , Nanocápsulas/química , Ubiquinona/análogos & derivados , Animales , Disponibilidad Biológica , Ensayo de Materiales , Ratones , Ubiquinona/administración & dosificación , Ubiquinona/química , Ubiquinona/farmacocinéticaRESUMEN
A Bayesian approach to handling below limit of quantification (BLOQ) pharmacodynamic (PD) data in pharmacokinetic/pharmacodynamic (PK/PD) modeling is described. The inhibitory sigmoid Emax model is used to illustrate the implementation of the Bayesian approach for modeling BLOQ PD data. Details on how to implement this Bayesian approach via the Markov-chain Monte Carlo (MCMC) technique using WinBUGS software are presented. A simulation study was conducted to evaluate the performance of the proposed Bayesian approach and to compare the Bayesian approach with two other ad hoc approaches: replacing BLOQ data with ½LOQ, and ignoring the BLOQ data. The simulation study indicates that the proposed Bayesian approach performs better than the other two ad hoc approaches and should be considered in practice as a complementary tool for BLOQ data analysis. A case study with real PK/PD data is provided to illustrate the application of the Bayesian approach of handling BLOQ PD data in PK/PD modeling.
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Teorema de Bayes , Límite de Detección , Modelos Biológicos , Preparaciones Farmacéuticas/sangre , Farmacocinética , Farmacología , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase I como Asunto/estadística & datos numéricos , Simulación por Computador , Humanos , Funciones de Verosimilitud , Masculino , Cadenas de Markov , Método de Montecarlo , Preparaciones Farmacéuticas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Método Simple CiegoRESUMEN
BACKGROUND: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. METHODS: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. FINDINGS: Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. INTERPRETATION: Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. FUNDING: CTI BioPharma Corp.
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Hidrocarburos Aromáticos con Puentes/farmacología , Pancitopenia/complicaciones , Mielofibrosis Primaria/tratamiento farmacológico , Pirimidinas/farmacología , Bazo/efectos de los fármacos , Anciano , Anemia/complicaciones , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Janus Quinasa 2/efectos de los fármacos , Imagen por Resonancia Magnética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/epidemiología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Bazo/diagnóstico por imagen , Trombocitopenia/complicaciones , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/efectos de los fármacosRESUMEN
Participation in a health promotion program for 192 overweight and obese adults with mental retardation was associated with behavior change resulting in reduction of body mass index-BMI (weight in kg, divided by height in meters, squared) by the end of the program. We analyzed the mediating and intermediate factors contributing to weight reduction and found knowledge and exercise to be the primary contributing factors. The curriculum emphasized exercise, nutritional choices, and stress reduction. Participation in the program was associated with a reduction of 0.8 BMI or approximately 2.3 kg for 26% of the participants. Increased knowledge about healthy diet and exercise was the most significant mediator of program impact on BMI.
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Conductas Relacionadas con la Salud , Servicios de Salud/provisión & distribución , Discapacidad Intelectual , Obesidad/terapia , Desarrollo de Programa , Adulto , Índice de Masa Corporal , Femenino , Humanos , Discapacidad Intelectual/epidemiología , Masculino , Obesidad/epidemiología , Obesidad/prevención & control , Factores de Riesgo , Prevención SecundariaRESUMEN
PURPOSE: Idelalisib is a potent PI3Kδ inhibitor that was recently approved for treating hematologic malignancies. The objective of this analysis was to develop a population pharmacokinetic model for idelalisib and its inactive metabolite GS-563117 and to evaluate the impact of covariates on idelalisib/GS-563117 PK. METHODS: Data from 10 phase I or II studies in healthy volunteers or patients with hematologic malignancies (n = 736) were analyzed using NONMEM. Stepwise forward addition followed by backward elimination was implemented in the covariate (age, gender, race, body weight, baseline CLcr, AST, ALT, disease status, and type of cancer) model building process. Various model assessment methods were used to evaluate the models. RESULTS: Idelalisib plasma PK was best described by a two-compartment model with first-order absorption, first-order elimination from the central compartment, and a lag time. A nonlinear relationship between dose and relative bioavailability was included in the final model. Two statistically significant covariates were identified and incorporated into the final model: health status (healthy vs. patient) on CL/F and Q/F and body weight on CL/F. Despite being a statistically significant covariate, the effect of body weight on idelalisib exposures was weak, as evidenced by minor changes of steady-state exposure (C trough: 16%; AUC and C max: 10%) for a patient with extreme body weight (5th and 95th percentile) relative to the typical patient, and not considered to be clinically relevant. CONCLUSIONS: PopPK models were developed to adequately describe the plasma concentrations of idelalisib and GS-563117. There were no covariate that had a clinically meaningful impact on idelalisib or GS-563117 exposure.
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Antineoplásicos/farmacocinética , Neoplasias Hematológicas/tratamiento farmacológico , Modelos Biológicos , Purinas/farmacocinética , Quinazolinonas/farmacocinética , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Estudios de Casos y Controles , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Femenino , Humanos , Masculino , Dinámicas no Lineales , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/uso terapéutico , Quinazolinonas/uso terapéuticoRESUMEN
Idelalisib, a phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117, an inactive metabolite, and is metabolized to a lesser extent by cytochrome P450 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In a mass balance study, the orally administered idelalisib dose was recovered mainly in feces (â¼78%). This study evaluated the pharmacokinetics and safety of a single 150-mg dose of idelalisib in subjects with moderate or severe hepatic impairment and in age-, sex-, and weight-matched, healthy controls. The idelalisib maximum observed plasma concentration was generally comparable in subjects with moderate or severe hepatic impairment versus healthy controls, whereas the mean area under the curve was higher (58% to 59%). GS-563117 exposures were lower in impaired versus healthy control subjects, likely because of lower formation in the setting of liver impairment. Exploratory analyses indicated no relevant relationships between idelalisib or GS-563117 plasma exposures and Child-Pugh-Turcotte scores. Single oral doses of idelalisib 150 mg were well tolerated, with most treatment-emergent adverse events (AEs) and laboratory abnormalities being grades 1 or 2 in severity. As such, no dose adjustment was required when initiating idelalisib treatment in patients with mild or moderate hepatic impairment, although close monitoring for potential AEs is recommended.
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Antineoplásicos/farmacocinética , Hepatopatías/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Purinas/farmacocinética , Quinazolinonas/farmacocinética , Adulto , Anciano , Antineoplásicos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Unión Proteica , Inhibidores de Proteínas Quinasas/efectos adversos , Purinas/efectos adversos , Quinazolinonas/efectos adversosRESUMEN
Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ], respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.
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Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Purinas/farmacología , Purinas/farmacocinética , Quinazolinonas/farmacología , Quinazolinonas/farmacocinética , Adulto , Antineoplásicos/sangre , Digoxina/sangre , Digoxina/farmacocinética , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Masculino , Midazolam/sangre , Midazolam/farmacocinética , Persona de Mediana Edad , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/sangre , Quinazolinonas/sangre , Rifampin/farmacología , Rosuvastatina Cálcica/sangre , Rosuvastatina Cálcica/farmacocinética , Adulto JovenRESUMEN
To improve the bioavailability of orally administered lipophilic coenzyme Q10 (CoQ10), we formulated a novel lipid-free nano-CoQ10 system stabilized by various surfactants. Nano-CoQ10s, composed of 2.5% (w/w) CoQ10, 1.67% (w/w) surfactant, and 41.67% (w/w) glycerol, were prepared by hot high-pressure homogenization. The resulting formulations were characterized by particle size, zeta potential, differential scanning calorimetry, and cryogenic transmission electron microscopy. We found that the mean particle size of all nano-CoQ10s ranged from 66.3 ± 1.5 nm to 92.7 ± 1.5 nm and the zeta potential ranged from -12.8 ± 1.4 mV to -41.6 ± 1.4 mV. The CoQ10 in nano-CoQ10s likely existed in a supercooled state, and nano-CoQ10s stored in a brown sealed bottle were stable for 180 days at 25 °C. The bioavailability of CoQ10 was evaluated following oral administration of CoQ10 formulations in Sprague-Dawley rats. Compared to the values observed following administration of CoQ10-Suspension, nano-CoQ10 modified with various surfactants significantly increased the maximum plasma concentration and the area under the plasma concentration-time curve. Thus, the lipid-free system of a nano-CoQ10 stabilized with a surfactant may be an effective vehicle for improving oral bioavailability of CoQ10.
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Disponibilidad Biológica , Sistemas de Liberación de Medicamentos , Ubiquinona/análogos & derivados , Administración Oral , Animales , Humanos , Nanopartículas/administración & dosificación , Nanopartículas/química , Ratas , Ratas Sprague-Dawley , Solubilidad , Ubiquinona/administración & dosificación , Ubiquinona/químicaRESUMEN
BACKGROUND: Present guidelines for the diagnosis of idiopathic pulmonary fibrosis require histological confirmation of surgical lung biopsy samples when high-resolution CT images are not definitive for usual interstitial pneumonia. We aimed to assess the predictive value of high-resolution CT in a cohort of patients with suspected idiopathic pulmonary fibrosis from a previous randomised trial. METHODS: ARTEMIS-IPF was a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial of ambrisentan for adults aged 40-80 years with well-defined idiopathic pulmonary fibrosis and 5% or less honeycombing on high-resolution CT. In December, 2010, an interim analysis showed lack of efficacy and the trial was stopped. In the present follow-on analysis, we assessed patients who were screened for ARTEMIS-IPF who underwent high-resolution CT as part of screening and surgical lung biopsy as part of standard clinical care. A radiologist and a pathologist from a central panel independently assessed anonymised CT scans and biopsy samples. We calculated the positive and negative predictive value of high-resolution CT (classified as usual interstitial pneumonia, possible usual interstitial pneumonia, and inconsistent with usual interstitial pneumonia) for confirmation of histological patterns of usual interstitial pneumonia. This study is registered with ClinicalTrials.gov, number NCT00768300. FINDINGS: 315 (29%) of 1087 consecutively screened patients in ARTEMIS-IPF had both high-resolution CT and surgical lung biopsy samples. 108 of 111 patients who met high-resolution CT criteria for usual interstitial pneumonia had histologically confirmed usual interstitial pneumonia (positive predictive value 97·3%, 95% CI 92·3-99·4), as did 79 of 84 patients who met high-resolution CT criteria for possible usual interstitial pneumonia (94·0%, 86·7-98·0). 22 of 120 patients had an inconsistent high-resolution CT pattern for usual interstitial pneumonia that was histologically confirmed as not or possible usual interstitial pneumonia (negative predictive value 18·3%, 95% CI 11·9-26·4). INTERPRETATION: In the appropriate clinical setting, for patients with possible usual interstitial pneumonia pattern on high resolution CT, surgical lung biopsy sampling might not be necessary to reach a diagnosis of idiopathic pulmonary fibrosis if high-resolution CT scans are assessed by experts at regional sites familiar with patterns of usual interstitial pneumonia and management of idiopathic interstitial pneumonia. FUNDING: Gilead Sciences.
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Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Ensayos Clínicos Fase III como Asunto , Diagnóstico Diferencial , Método Doble Ciego , Femenino , Humanos , Fibrosis Pulmonar Idiopática/patología , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Skin photo-ageing induced by ultraviolet (UV) radiation is mainly ascribed to oxidative stress and reactive oxygen species (ROS). Coenzyme Q10 (CoQ10) has been reported as a powerful antioxidant in plasma. However, CoQ10 was barely satisfactory in topical drug delivery because of its lipid solubility. To improve the anti-oxidative efficiency of CoQ10 in skin photo-ageing, the present research prepared a novel CoQ10 nano-structured lipid carrier (CoQ10-NLC) and characterised it by size and freeze-fracture transmission electron microscopy (FF-TEM). In UVA-irradiated fibroblasts, the protection of CoQ10-NLC was more effective than the CoQ10-emulsion as demonstrated by cell viability and morphological changes of the cell body and nucleus. In addition, malondialdehyde (MDA, the product of lipid peroxidation) concentration decreased by 61.5% in the group treated with CoQ10-NLC compared to the group subjected to general CoQ10-emulsion. In the presence of CoQ10-NLC, the activities of the anti-oxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) were reinstated to 81% and 75%, respectively, of the control group. In vivo, the CoQ10-NLC displayed a stronger capability to penetrate the stratum corneum and permeate the dermis after a topical skin application. These results reveal that CoQ10-NLC has greater antioxidant properties and topical skin penetration than the CoQ10-emulsion.
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Portadores de Fármacos/química , Lípidos/química , Nanoestructuras/química , Envejecimiento de la Piel , Protectores Solares/administración & dosificación , Ubiquinona/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Células Cultivadas , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/efectos de la radiación , Glutatión Peroxidasa/metabolismo , Humanos , Peróxidos Lipídicos/metabolismo , Microscopía Electrónica de Transmisión , Modelos Biológicos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Piel/efectos de los fármacos , Piel/enzimología , Piel/metabolismo , Piel/efectos de la radiación , Absorción Cutánea/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiación , Solubilidad , Protectores Solares/química , Protectores Solares/farmacocinética , Superóxido Dismutasa/metabolismo , Propiedades de Superficie , Ubiquinona/administración & dosificación , Ubiquinona/química , Ubiquinona/farmacocinética , Rayos Ultravioleta/efectos adversosRESUMEN
The purpose of this study was to investigate the influence of the inner lipid ratio on the physicochemical properties and skin targeting of surfactant-free lecithin-based coenzyme Q10-loaded lipid nanocapsules (CoQ10-LNCs). The smaller particle size of CoQ10-LNCs was achieved by high pressure and a lower ratio of CoQ10/GTCC (Caprylic/capric triglyceride); however, the zeta potential of CoQ10-LNCs was above /- 60 mV/ with no distinct difference among them at different ratios of CoQ10/GTCC. Both the crystallisation point and the index decreased with the decreasing ratio of CoQ10/GTCC and smaller particle size; interestingly, the supercooled state of CoQ10-LNCs was observed at particle size below about 200 nm, as verified by differential scanning calorimetry (DSC) in one heating-cooling cycle. The lecithin monolayer sphere structure of CoQ10-LNCs was investigated by cryogenic transmission electron microscopy (Cryo-TEM). The skin penetration results revealed that the distribution of Nile red-loaded CoQ10-LNCs depended on the ratio of inner CoQ10/GTCC; moreover, epidermal targeting and superficial dermal targeting were achieved by the CoQ10-LNCs application. The highest fluorescence response was observed at a ratio of inner CoQ10/GTCC of 1:1. These observations suggest that lecithin-based LNCs could be used as a promising topical delivery vehicle for lipophilic compounds.
RESUMEN
Purpose of this study was to establish a lecithin nanoemulsion (LNE) without any synthetic surfactant as a topical delivery vehicle and to evaluate its topical delivery potential by the following factors: particle size, morphology, viscosity, stability, skin hydration and skin penetration. Experimental results demonstrated that an increasing concentration of soybean lecithin and glycerol resulted in a smaller size LNE droplet and increasing viscosity, respectively. The droplet size of optimized LNE, with the glycerol concentration above 75% (w/w), changed from 92 (F10) to 58 nm (F14). Additionally, LNE, incorporated into o/w cream, improved the skin hydration capacity of the cream significantly with about 2.5-fold increase when the concentration of LNE reached 10%. LNE was also demonstrated to improve the penetrability of Nile red (NR) dye into the dermis layer, when an o/w cream, incorporated with NR-loaded LNE, applied on the abdominal skin of rat in vivo. Specifically, the arbitrary unit (ABU) of fluorescence in the dermis layer that had received the cream with a NR-loaded LNE was about 9.9-fold higher than the cream with a NR-loaded general emulsion (GE). These observations suggest that LNE could be used as a promising topical delivery vehicle for lipophilic compounds.
RESUMEN
In this paper a novel method for the monitoring of disease maps over time in a surveillance setting is described. The approach relies upon the use of a spatial model that is fitted to current spatial data and is smoothed with historical spatial estimates. The method of smoothing is a vector exponentially weighted moving average procedure. A simulation study with a range of scenarios is presented and finally a case study of monitoring infectious disease spread is presented.
Asunto(s)
Teorema de Bayes , Vigilancia de la Población/métodos , Enfermedades Transmisibles , Brotes de Enfermedades , Humanos , Método de Montecarlo , Infecciones por Salmonella/epidemiología , South Carolina/epidemiologíaRESUMEN
Prostate cancer (PrCA) is the most common malignancy in men and a leading cause of cancer mortality among males in the United States. Large geographical variation and racial disparities exist in both the incidence of PrCA and the survival rate after diagnosis. In this population-based study, a joint spatial survival model is constructed to investigate factors that affect the age at diagnosis of PrCA and the subsequent survival. The joint model for these two time-to-event outcomes is specified through parametric models for age at diagnosis and survival time conditional on diagnosis age. To account for possible correlation in these outcomes among men from the same geographical region, frailty terms are included in the survival model. Both spatially correlated and uncorrelated frailties are incorporated in each model considered. The deviance information criterion is used to select a best-fitting model within the Bayesian framework. The results from our final best-fitting model indicate that race, marital status at diagnosis, and cancer stage are significantly associated with both of the two time-to-event outcomes. No pattern emerged in the geographical distribution of age at PrCA diagnosis. In contrast, a spatially clustered pattern was observed in the geographic distribution of survival experience post diagnosis.