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Rivaroxaban is a direct factor Xa inhibitor. Its interindividual variability is large and may be connected to the occurrence of adverse drug reactions or drug inefficacy. Pharmacogenetics studies concentrating on the reasons underlying rivaroxaban's inadequate response could help explain the differences in treatment results and medication safety profiles. Against this background, this study evaluated whether polymorphisms in the gene encoding the ABCG2 transporter modify the pharmacokinetic characteristics of rivaroxaban. A total of 117 healthy volunteers participated in two bioequivalence experiments with a single oral dose of 20 mg rivaroxaban, with one group fasting and the other being fed. Ultra-high-performance liquid chromatography coupled with mass spectrometry was employed to determine the plasma concentrations of rivaroxaban, and the WinNonlin program was used to calculate the pharmacokinetics parameters. In the fasting group, the rivaroxaban pharmacokinetic parameters of Vd (508.27 vs 334.45 vs 275.59 L) and t1/2 (41.04 vs 16.43 vs 15.47 h) were significantly higher in ABCG2 421 A/A genotype carriers than in ABCG2 421 C/C and 421 C/A genotype carriers (P<0.05). The mean values of Cmax (145.81 vs 176.27 vs 190.19 ng/mL), AUC0-t (1193.81 vs 1374.69 vs 1570.77 ng/mL·h), and Cl (11.82 vs 14.50 vs 13.01 mL/h) for these groups were lower, but this difference was not statistically significant (P>0.05). These findings suggested that the ABCG2 421 A/A genotype may impact rivaroxaban parameters after a single dose in healthy subjects. This finding must be validated before it is applied in clinical practice.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Inibidores do Fator Xa , Genótipo , Proteínas de Neoplasias , Rivaroxabana , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Área Sob a Curva , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Cromatografia Líquida de Alta Pressão , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/sangue , Voluntários Saudáveis , Proteínas de Neoplasias/genética , Polimorfismo Genético , Rivaroxabana/farmacocinética , Rivaroxabana/administração & dosagem , Equivalência TerapêuticaRESUMO
The photo-induced dynamics of o-nitrophenol, particularly its photolysis, has garnered significant scientific interest as a potential source of nitrous acid in the atmosphere. Although the photolysis products and preceding photo-induced electronic structure dynamics have been investigated extensively, the nuclear dynamics accompanying the non-radiative relaxation of o-nitrophenol on the ultrafast timescale, which include an intramolecular proton transfer step, have not been experimentally resolved. Herein, we present a direct observation of the ultrafast nuclear motions mediating photo-relaxation using ultrafast electron diffraction. This work spatiotemporally resolves the loss of planarity which enables access to a conical intersection between the first excited state and the ground state after the proton transfer step, on the femtosecond timescale and with sub-Angstrom resolution. Our observations, supported by ab initio multiple spawning simulations, provide new insights into the proton transfer mediated relaxation mechanism in o-nitrophenol.
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Sharks of the genus Sphyrna are under intense exploitation globally. In Brazil's northern coast, this genus represents a high proportion of fisheries landings and comprises four species. However, due to difficulty of specific identification when specimens are landed, most of the records are limited to the genus level. Here we analyzed the effectiveness of ITS2 (Internal Transcribed Spacer 2 of rDNA) fragment length protocol (Abercrombie et al., 2005) for identifying hammerhead shark species, comparing with the analysis of COI (Cytochrome oxidase subunit I) and ITS2 sequences. We evaluated samples of muscle tissue acquired in the main fishing ports of Maranhão: Carutapera, Raposa e Tutóia. Sampling was conducted between March 2017 to March 2018 and complemented with material deposited in collection (2015). COI results indicated the occurrence of endangered species which are prohibited to be landed. These include Sphyrna mokarran (67%), S. lewini (15%), S. tudes (3%), and S. tiburo (15%). For the ITS2 marker, we investigated the optimization of the protocol developed by Abercrombie (2005) for to improve the use in this geographical area througout design of a new primers.
Assuntos
Tubarões , Animais , Tubarões/genética , Brasil , Espécies em Perigo de Extinção , Pesqueiros , Alimentos MarinhosRESUMO
Rivaroxaban is a direct factor Xa inhibitor. Its interindividual variability is large and may be connected to the occurrence of adverse drug reactions or drug inefficacy. Pharmacogenetics studies concentrating on the reasons underlying rivaroxaban's inadequate response could help explain the differences in treatment results and medication safety profiles. Against this background, this study evaluated whether polymorphisms in the gene encoding the ABCG2 transporter modify the pharmacokinetic characteristics of rivaroxaban. A total of 117 healthy volunteers participated in two bioequivalence experiments with a single oral dose of 20 mg rivaroxaban, with one group fasting and the other being fed. Ultra-high-performance liquid chromatography coupled with mass spectrometry was employed to determine the plasma concentrations of rivaroxaban, and the WinNonlin program was used to calculate the pharmacokinetics parameters. In the fasting group, the rivaroxaban pharmacokinetic parameters of Vd (508.27 vs 334.45 vs 275.59 L) and t1/2 (41.04 vs 16.43 vs 15.47 h) were significantly higher in ABCG2 421 A/A genotype carriers than in ABCG2 421 C/C and 421 C/A genotype carriers (P<0.05). The mean values of Cmax (145.81 vs 176.27 vs 190.19 ng/mL), AUC0-t (1193.81 vs 1374.69 vs 1570.77 ng/mL·h), and Cl (11.82 vs 14.50 vs 13.01 mL/h) for these groups were lower, but this difference was not statistically significant (P>0.05). These findings suggested that the ABCG2 421 A/A genotype may impact rivaroxaban parameters after a single dose in healthy subjects. This finding must be validated before it is applied in clinical practice.
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Molecular ions are ubiquitous and play pivotal roles1-3 in many reactions, particularly in the context of atmospheric and interstellar chemistry4-6. However, their structures and conformational transitions7,8, particularly in the gas phase, are less explored than those of neutral molecules owing to experimental difficulties. A case in point is the halonium ions9-11, whose highly reactive nature and ring strain make them short-lived intermediates that are readily attacked even by weak nucleophiles and thus challenging to isolate or capture before they undergo further reaction. Here we show that mega-electronvolt ultrafast electron diffraction (MeV-UED)12-14, used in conjunction with resonance-enhanced multiphoton ionization, can monitor the formation of 1,3-dibromopropane (DBP) cations and their subsequent structural dynamics forming a halonium ion. We find that the DBP+ cation remains for a substantial duration of 3.6 ps in aptly named 'dark states' that are structurally indistinguishable from the DBP electronic ground state. The structural data, supported by surface-hopping simulations15 and ab initio calculations16, reveal that the cation subsequently decays to iso-DBP+, an unusual intermediate with a four-membered ring containing a loosely bound17,18 bromine atom, and eventually loses the bromine atom and forms a bromonium ion with a three-membered-ring structure19. We anticipate that the approach used here can also be applied to examine the structural dynamics of other molecular ions and thereby deepen our understanding of ion chemistry.
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Directly imaging structural dynamics involving hydrogen atoms by ultrafast diffraction methods is complicated by their low scattering cross sections. Here we demonstrate that megaelectronvolt ultrafast electron diffraction is sufficiently sensitive to follow hydrogen dynamics in isolated molecules. In a study of the photodissociation of gas phase ammonia, we simultaneously observe signatures of the nuclear and corresponding electronic structure changes resulting from the dissociation dynamics in the time-dependent diffraction. Both assignments are confirmed by ab initio simulations of the photochemical dynamics and the resulting diffraction observable. While the temporal resolution of the experiment is insufficient to resolve the dissociation in time, our results represent an important step towards the observation of proton dynamics in real space and time.
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Electrocyclic reactions are characterized by the concerted formation and cleavage of both σ and π bonds through a cyclic structure. This structure is known as a pericyclic transition state for thermal reactions and a pericyclic minimum in the excited state for photochemical reactions. However, the structure of the pericyclic geometry has yet to be observed experimentally. We use a combination of ultrafast electron diffraction and excited state wavepacket simulations to image structural dynamics through the pericyclic minimum of a photochemical electrocyclic ring-opening reaction in the molecule α-terpinene. The structural motion into the pericyclic minimum is dominated by rehybridization of two carbon atoms, which is required for the transformation from two to three conjugated π bonds. The σ bond dissociation largely happens after internal conversion from the pericyclic minimum to the electronic ground state. These findings may be transferrable to electrocyclic reactions in general.
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PURPOSE: The first aim was to generate and compare synthetic-CT (sCT) images using a conditional generative adversarial network (cGAN) method (Pix2Pix) for MRI-only prostate radiotherapy planning by testing several generators, loss functions, and hyper-parameters. The second aim was to compare the optimized Pix2Pix model with five other architectures (bulk-density, atlas-based, patch-based, U-Net, and GAN). METHODS: For 39 patients treated by VMAT for prostate cancer, T2-weighted MRI images were acquired in addition to CT images for treatment planning. sCT images were generated using the Pix2Pix model. The generator, loss function, and hyper-parameters were tuned to improve sCT image generation (in terms of imaging endpoints). The final evaluation was performed by 3-fold cross-validation. This method was compared to five other methods using the following imaging endpoints: the mean absolute error (MAE) and mean error (ME) between sCT and reference CT images (rCT) of the whole pelvis, bones, prostate, bladder, and rectum. For dose planning analysis, the dose-volume histogram metric differences and 3D gamma analysis (local, 1 %/1 mm) were calculated using the sCT and reference CT images. RESULTS: Compared with the other architectures, Pix2Pix with Perceptual loss function and generator ResNet 9 blocks showed the lowest MAE (29.5, 107.7, 16.0, 13.4, and 49.1 HU for the whole pelvis, bones, prostate, bladder, and rectum, respectively) and the highest gamma passing rates (99.4 %, using the 1 %/1mm and 10 % dose threshold criterion). Concerning the DVH points, the mean errors were -0.2% for the planning target volume V95%, 0.1 % for the rectum V70Gy, and -0.1 % for the bladder V50Gy. CONCLUSION: The sCT images generated from MRI data with the Pix2Pix architecture had the lowest image errors and similar dose uncertainties (in term of gamma pass-rate and dose-volume histogram metric differences) than other deep learning methods.
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Aprendizado Profundo , Próstata , Masculino , Humanos , Tomografia Computadorizada por Raios X/métodos , Imageamento por Ressonância Magnética/métodos , Pelve , Planejamento da Radioterapia Assistida por Computador/métodos , Dosagem RadioterapêuticaRESUMO
This study aimed to evaluate yield, quality, nematode incidence, chlorophyll content, and primary foliar macronutrients of yam in response to nitrogen and potassium fertilization. A complete randomized block design was used in a factorial scheme (5 x 5), with five nitrogen (0; 60; 120; 180 and 240 kg ha-1 of N) and five potassium doses (0; 60; 120; 180 and 240 kg ha-1 of K2O), with four replicates. The mass, total and commercial productivity of tubers, starch content, ash, leaf N, P, and K content, chlorophyll, and nematode incidence were evaluated. The average mass of tubers obtained was 1.935 kg with doses of 133 kg ha-1 of N and 105 kg ha-1 of K2O. The dose of 178 kg ha-1 of N promoted maximum total tuber productivity (22.56 t ha-1). The doses of 132 kg ha-1 of N and 118 kg ha-1 of K2O resulted in maximum productivity of commercial tubers with 20.35 t ha-1. Leaf N and K, starch, and ash contents were within the standards for yam. The incidence of Meloidogyne, Scutellonema, and Pratylenchus reduced with the increasing simple effect doses of N and K2O. The maximum chlorophyll content was obtained at the dose of 240 kg ha-1 of N. The nitrogen and potassium interaction, despite the antagonistic effects on the accumulation of foliar P and starch, increased the productivity and average mass of commercial tubers, consequently ensuring the profitability of yam cultivation.
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Dioscorea , Nitrogênio , Clorofila , Fertilizantes , Potássio , AmidoRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming. We previously demonstrated the potency of allogeneic lysate-dendritic cell (DC) vaccination in a preclinical model. Here we translate this concept to patients. METHODS: In this phase I study, patients with resected PDAC were included when they demonstrated no radiologic signs of recurrence after standard-of-care treatment. Allogeneic tumour lysate-loaded autologous monocyte-derived DCs were injected at weeks 0, 2, 4 and at months 3 and 6. Objectives are feasibility, safety and immunogenicity of allogeneic tumour-DCs. The presence of tumour antigens shared between the vaccine and patient tumours was investigated. Immunological analyses were performed on peripheral blood, skin and tumour. RESULTS: Ten patients were included. DC production and administration were successful. All patients experienced a grade 1 injection-site and infusion-related reaction. Two patients experienced a grade 2 fever and 1 patient experienced a grade 3 dyspnoea. No vaccine-related serious adverse events were observed. Shared tumour antigens were found between the vaccine and patient tumours. All evaluated patients displayed a vaccine-induced response indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T-cells. In addition, treatment-induced T-cell reactivity to autologous tumour of study patients was detected. Seven out of ten patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15-32 months). CONCLUSION: Allogeneic tumour lysate-DC treatment is feasible, safe and induces immune reactivity to PDAC expressed antigens.
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Vacinas Anticâncer , Transplante de Células-Tronco Hematopoéticas , Neoplasias Pancreáticas , Antígenos de Neoplasias , Vacinas Anticâncer/efeitos adversos , Células Dendríticas , Humanos , Imunoterapia/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Linfócitos T , Neoplasias PancreáticasRESUMO
We report on the design and testing of glass nozzles used to produce liquid sheets. The sheet nozzles use a single converging channel chemically etched into glass wafers by standard lithographic methods. Operation in ambient air and vacuum was demonstrated. The measured sheet thickness ranges over one order of magnitude with the smallest thickness of 250 nm and the largest of 2.5 µm. Sheet thickness was shown to be independent of liquid flow rate, and dependent on the nozzle outlet area. Sheet surface roughness was dependent on nozzle surface finish and was on the order of 10 nm for polished nozzles. Electron transmission data is presented for various sheet thicknesses near the MeV mean free path and the charge pair distribution function for D2O is determined from electron scattering data.
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Vidro , VácuoRESUMO
This study presents a list of parasitic fish nematodes from the Brazilian Amazon based on the previous Brazilian list including scientific assessments carried out between 2010 and 2021. A total of 16 families, 48 species and 28 undetermined species of nematodes associated with fish are included in the checklist, in addition to 93 host species and 15 geographical records.
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Doenças dos Peixes , Nematoides , Animais , Brasil , Lista de Checagem , Doenças dos Peixes/epidemiologia , Peixes , Especificidade de Hospedeiro , HumanosRESUMO
Conformational isomers (conformers) of molecules play a decisive role in biology and organic chemistry. However, experimental methods for investigating chemical reaction dynamics are typically not conformer-sensitive. We report on a gas-phase megaelectronvolt ultrafast electron diffraction investigation of α-phellandrene undergoing an electrocyclic ring-opening reaction. We directly imaged the evolution of a specific set of α-phellandrene conformers into the product isomer predicted by the Woodward-Hoffmann rules in real space and time. Our experimental results are in quantitative agreement with nonadiabatic quantum molecular dynamics simulations, which provide considerable detail of how conformation influences the time scale and quantum efficiency of photoinduced ring-opening reactions.
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The radiolysis of water is ubiquitous in nature and plays a critical role in numerous biochemical and technological applications. Although the elementary reaction pathways for ionized water have been studied, the short-lived intermediate complex and structural dynamic response after the proton transfer reaction remain poorly understood. Using a liquid-phase ultrafast electron diffraction technique to measure the intermolecular oxygen···oxygen and oxygen···hydrogen bonds, we captured the short-lived radical-cation complex OH(H3O+) that was formed within 140 femtoseconds through a direct oxygen···oxygen bond contraction and proton transfer, followed by the radical-cation pair dissociation and the subsequent structural relaxation of water within 250 femtoseconds. These measurements provide direct evidence of capturing this metastable radical-cation complex before separation, thereby improving our fundamental understanding of elementary reaction dynamics in ionized liquid water.
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Water is one of the most important, yet least understood, liquids in nature. Many anomalous properties of liquid water originate from its well-connected hydrogen bond network1, including unusually efficient vibrational energy redistribution and relaxation2. An accurate description of the ultrafast vibrational motion of water molecules is essential for understanding the nature of hydrogen bonds and many solution-phase chemical reactions. Most existing knowledge of vibrational relaxation in water is built upon ultrafast spectroscopy experiments2-7. However, these experiments cannot directly resolve the motion of the atomic positions and require difficult translation of spectral dynamics into hydrogen bond dynamics. Here, we measure the ultrafast structural response to the excitation of the OH stretching vibration in liquid water with femtosecond temporal and atomic spatial resolution using liquid ultrafast electron scattering. We observed a transient hydrogen bond contraction of roughly 0.04 Å on a timescale of 80 femtoseconds, followed by a thermalization on a timescale of approximately 1 picosecond. Molecular dynamics simulations reveal the need to treat the distribution of the shared proton in the hydrogen bond quantum mechanically to capture the structural dynamics on femtosecond timescales. Our experiment and simulations unveil the intermolecular character of the water vibration preceding the relaxation of the OH stretch.