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1.
J Fungi (Basel) ; 10(2)2024 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-38392798

RESUMEN

In this study, delta-12 desaturase was overexpressed in Yarrowia lipolytica using the single-copy integrative vector pINA1312 and multicopy integrative vector pINA1292, resulting in the engineered yeast strains 1312-12 and 1292-12, respectively. The content of intracellular linoleic acid (LA) in the 1292-12 strain was much higher than in the 1312-12 strain and the control group. One interesting finding was that the 1292-12 strain showed obvious changes in surface morphology. The 1292-12 colonies were much smaller and smoother, whereas their single cells became much larger compared to the control strain. In addition, the dry cell weight (DCW) of the 1292-12 strain was obviously increased from 8.5 to 12.7 g/L, but the viable cell number sharply decreased from 107 to 105/mL. These results indicated that increased LA content in Yarrowia lipolytica could induce morphological changes or even oxidative stress-dependent cell death. The reactive oxygen species (ROS) and malondialdehyde (MDA) were accumulated in the 1292-12 strain, while the antioxidant activities of intracellular catalase (CAT) and superoxide dismutase (SOD) were significantly decreased by 27.6 and 32.0%, respectively. Furthermore, it was also revealed that these issues could be ameliorated by the exogenous supplementation of vitamin C, fish and colza oil.

2.
Appl Opt ; 63(1): 77-84, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38175011

RESUMEN

In this paper, an ANLVENet speckle suppression method in holographic phase fringe patterns with different level noises is proposed based on FFDNet, combined with asymmetric pyramid non-local block with a verge extraction module. The experimental results are compared to three network models and several representative algorithms. It is shown that the ANLVENet method not only has better superiority in the speckle suppression with different noise levels, but also preserves more details of the image edge. In addition, another speckle noise model is applied in the phase fringe patterns to prove the stronger generalization of the ANLVENet algorithm. The proposed method is suitable for suppressing the speckle with different levels in a large noise range under complex environmental conditions.

3.
Eur Radiol ; 34(1): 715-723, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37581653

RESUMEN

OBJECTIVES: Microwave ablation (MWA) has achieved excellent long-term efficacy in treating unifocal papillary thyroid microcarcinoma (UPTMC). The therapeutic effect of this treatment on multifocal papillary thyroid microcarcinoma (MPTMC) is unknown. Therefore, we evaluated the long-term efficacy of MWA for low-risk MPTMC and to provide evidence-based medicine for the revision of clinical guidelines. METHODS: This study included 66 MPTMC patients with a total of 158 lesions, all of whom received MWA. We collected and retrospectively analyzed the patients' follow-up data before MWA, at 1, 3, 6, and 12 months posttreatment and every 6 months thereafter until 5 years posttreatment. We evaluated the MWA complication rate, technical success rate (TSR), lesion volume reduction rate (VRR), and complete disappearance rate (CDR) during follow-up and in those patients with tumor progression and delayed surgery. RESULTS: After 60 months of follow-up, all 158 lesions disappeared in 66 patients, and the volume was reduced from 43.82 mm3 to 0.00 mm3. The TSR and VRR were both 100%. The CDRs at 1 year, 2 years, and 3 years were 57.59%, 93.67%, and 100%, respectively. The complication rate was 3.03% (2/66), and the incidence of tumor progression was 3.03% (2/66), including one new intrathyroidal lesion and one cervical lymph node metastasis (LNM). These lesions were retreated with MWA, and the lesions disappeared during the follow-up period. CONCLUSIONS: Ultrasound-guided MWA for low-risk MPTMC is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance (AS). CLINICAL RELEVANCE STATEMENT: This study concludes that ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective and may serve as an alternative option for patients who refuse surgery or active surveillance. KEY POINTS: • Ultrasound-guided microwave ablation for low-risk multifocal papillary thyroid microcarcinoma is safe and effective. • During 5 years of follow-up, multifocal papillary thyroid microcarcinoma patients treated with microwave ablation had a favorable prognosis. • To provide evidence-based medicine for the revision of clinical guidelines.


Asunto(s)
Carcinoma Papilar , Microondas , Neoplasias de la Tiroides , Humanos , Estudios de Seguimiento , Microondas/uso terapéutico , Estudios Retrospectivos , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , Resultado del Tratamiento , Ultrasonografía Intervencional
4.
Sensors (Basel) ; 23(22)2023 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-38005501

RESUMEN

Coal gangue image recognition is a critical technology for achieving automatic separation in coal processing, characterized by its rapid, environmentally friendly, and energy-saving nature. However, the response characteristics of coal and gangue vary greatly under different illuminance conditions, which poses challenges to the stability of feature extraction and recognition, especially when strict illuminance requirements are necessary. This leads to fluctuating coal gangue recognition accuracy in industrial environments. To address these issues and improve the accuracy and stability of image recognition under variable illuminance conditions, we propose a novel coal gangue recognition method based on laser speckle images. Firstly, we studied the inter-class separability and intra-class compactness of the collected laser speckle images of coal and gangue by extracting gray and texture features from the laser speckle images, and analyzed the performance of laser speckle images in representing the differences between coal and gangue minerals. Subsequently, coal gangue recognition was achieved using an SVM classifier based on the extracted features from the laser speckle images. The fusion feature approach achieved a recognition accuracy of 94.4%, providing further evidence of the feasibility of this method. Lastly, we conducted a comparative experiment between natural images and laser speckle images for coal gangue recognition using the same features. The average accuracy of coal gangue laser speckle image recognition under various lighting conditions is 96.7%, with a standard deviation of the recognition accuracy of 1.7%. This significantly surpasses the recognition accuracy obtained from natural coal and gangue images. The results showed that the proposed laser speckle image features can facilitate more stable coal gangue recognition with illumination factors, providing a new, reliable method for achieving accurate classification of coal and gangue in the industrial environment of mines.

5.
Toxicol Sci ; 196(1): 1-15, 2023 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-37584694

RESUMEN

Estimating human exposure in the safety assessment of chemicals is crucial. Physiologically based kinetic (PBK) models which combine information on exposure, physiology, and chemical properties, describing the absorption, distribution, metabolism, and excretion (ADME) processes of a chemical, can be used to calculate internal exposure metrics such as maximum concentration and area under the concentration-time curve in plasma or tissues of a test chemical in next-generation risk assessment. This article demonstrates the development of PBK models for 3 UV filters, specifically octyl methoxycinnamate, octocrylene, and 4-methylbenzylidene camphor. The models were parameterized entirely based on data obtained from in vitro and/or in silico methods in a bottom-up modeling approach and then validated based on human dermal pharmacokinetic (PK) data. The 3 UV filters are "difficult to test" in in vitro test systems due to high lipophilicity, high binding affinity for proteins, and nonspecific binding, for example, toward plastic. This research work presents critical considerations in ADME data generation, interpretation, and parameterization to assure valid PBK model development to increase confidence in using PBK modeling to help make safety decisions in the absence of human PK data. The developed PBK models of the 3 chemicals successfully simulated the plasma concentration profiles of clinical PK data following dermal application, indicating the reliability of the ADME data generated and the parameters determined. The study also provides insights and lessons learned for characterizing ADME and developing PBK models for highly lipophilic and protein-bound chemicals in the future.


Asunto(s)
Modelos Biológicos , Humanos , Reproducibilidad de los Resultados , Cinética , Medición de Riesgo , Técnicas In Vitro
6.
Arch Toxicol ; 97(6): 1547-1575, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37087486

RESUMEN

In next generation risk assessment (NGRA), the Dietary Comparator Ratio (DCR) can be used to assess the safety of chemical exposures to humans in a 3R compliant approach. The DCR compares the Exposure Activity Ratio (EAR) for exposure to a compound of interest (EARtest) to the EAR for an established safe exposure level to a comparator compound (EARcomparator), acting by the same mode of action. It can be concluded that the exposure to a test compound is safe at a corresponding DCR ≤ 1. In this study, genistein (GEN) was selected as a comparator compound by comparison of reported safe internal exposures to GEN to its BMCL05, as no effect level, the latter determined in the in vitro estrogenic MCF7/Bos proliferation, T47D ER-CALUX, and U2OS ERα-CALUX assay. The EARcomparator was defined using the BMCL05 and EC50 values from the 3 in vitro assays and subsequently used to calculate the DCRs for exposures to 14 test compounds, predicting the (absence of) estrogenicity. The predictions were evaluated by comparison to reported in vivo estrogenicity in humans for these exposures. The results obtained support in the DCR approach as an important animal-free new approach methodology (NAM) in NGRA and show how in vitro assays can be used to define DCR values.


Asunto(s)
Estrógenos , Receptores de Estrógenos , Humanos , Estrógenos/toxicidad , Línea Celular Tumoral , Genisteína/toxicidad , Medición de Riesgo
7.
Toxicol Res (Camb) ; 12(1): 1-11, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36866215

RESUMEN

Reliance on animal tests for chemical safety assessment is increasingly being challenged, not only because of ethical reasons, but also because they procrastinate regulatory decisions and because of concerns over the transferability of results to humans. New approach methodologies (NAMs) need to be fit for purpose and new thinking is required to reconsider chemical legislation, validation of NAMs and opportunities to move away from animal tests. This article summarizes the presentations from a symposium at the 2022 Annual Congress of the British Toxicology Society on the topic of the future of chemical risk assessment in the 21st century. The symposium included three case-studies where NAMs have been used in safety assessments. The first case illustrated how read-across augmented with some in vitro tests could be used reliably to perform the risk assessment of analogues lacking data. The second case showed how specific bioactivity assays could identify an NAM point of departure (PoD) and how this could be translated through physiologically based kinetic modelling in an in vivo PoD for the risk assessment. The third case showed how adverse-outcome pathway (AOP) information, including molecular-initiating event and key events with their underlying data, established for certain chemicals could be used to produce an in silico model that is able to associate chemical features of an unstudied substance with specific AOPs or AOP networks. The manuscript presents the discussions that took place regarding the limitations and benefits of these new approaches, and what are the barriers and the opportunities for their increased use in regulatory decision making.

8.
Eur Radiol ; 33(4): 2407-2414, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36472698

RESUMEN

OBJECTIVES: To investigate the value of contrast-enhanced ultrasound (CEUS) combined with feeding artery ablation in the microwave ablation (MWA) of large solid benign thyroid nodules (LSBTNs) with a diameter ≥ 4 cm. METHODS: We retrospectively analyzed 122 patients with LSBTN ≥ 4 cm in diameter treated with MWA. During evaluations before and after MWA, 53 patients who underwent conventional ultrasound examination were classified as the routine group, and 69 patients who underwent CEUS combined with feeding artery ablation were classified as the union group. The differences in ablation energy required per milliliter (AERPM), complication rate, regrowth rate, and volume reduction rate (VRR) were compared between the two groups. RESULTS: The AERPM of the union group was significantly less than that of the routine group (956.3 ± 38.5 J/mL vs. 1025.9 ± 121.5 J/mL, p < 0.001). The complication rate of the routine group was significantly higher than that of the union group (13.2% vs. 2.9%, p = 0.031). The regrowth rate of the routine group (22.6%, 12/53) was significantly higher than that of the union group (7.2%, 5/69) (p = 0.015). At the 1st, 3rd, 6th, 12th, 18th, and 24th month after ablation, the mean VRRs of the routine group were significantly less than those of the union group, with p values of < 0.001, < 0.001, 0.002, 0.007, 0.013, and < 0.001, respectively. CONCLUSIONS: The application of CEUS combined with feeding artery ablation in the MWA of LSBTNs is helpful to reduce the regrowth rate, improve the ablation efficiency, and reduce bleeding. KEY POINTS: • CEUS combined with feeding artery ablation in MWA of LSBTNs is helpful to reduce regrowth rate. • CEUS combined with feeding artery ablation can help improve ablation efficiency than conventional ultrasound in LSBTNs. • CEUS combined with feeding artery ablation helps reduce the incidence of bleeding during MWA.


Asunto(s)
Ablación por Catéter , Nódulo Tiroideo , Humanos , Nódulo Tiroideo/diagnóstico por imagen , Nódulo Tiroideo/cirugía , Microondas/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Arterias
9.
Arch Toxicol ; 96(12): 3407-3419, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36063173

RESUMEN

With an increasing need to incorporate new approach methodologies (NAMs) in chemical risk assessment and the concomitant need to phase out animal testing, the interpretation of in vitro assay readouts for quantitative hazard characterisation becomes more important. Physiologically based kinetic (PBK) models, which simulate the fate of chemicals in tissues of the body, play an essential role in extrapolating in vitro effect concentrations to in vivo bioequivalent exposures. As PBK-based testing approaches evolve, it will become essential to standardise PBK modelling approaches towards a consensus approach that can be used in quantitative in vitro-to-in vivo extrapolation (QIVIVE) studies for regulatory chemical risk assessment based on in vitro assays. Based on results of an ECETOC expert workshop, steps are recommended that can improve regulatory adoption: (1) define context and implementation, taking into consideration model complexity for building fit-for-purpose PBK models, (2) harmonise physiological input parameters and their distribution and define criteria for quality chemical-specific parameters, especially in the absence of in vivo data, (3) apply Good Modelling Practices (GMP) to achieve transparency and design a stepwise approach for PBK model development for risk assessors, (4) evaluate model predictions using alternatives to in vivo PK data including read-across approaches, (5) use case studies to facilitate discussions between modellers and regulators of chemical risk assessment. Proof-of-concepts of generic PBK modelling approaches are published in the scientific literature at an increasing rate. Working on the previously proposed steps is, therefore, needed to gain confidence in PBK modelling approaches for regulatory use.


Asunto(s)
Modelos Biológicos , Animales , Cinética , Medición de Riesgo/métodos
10.
ALTEX ; 39(3): 359­366, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35796331

RESUMEN

New approach methodologies (NAMs) that do not use experimental animals are, in certain settings, entirely appropriate for assuring the safety of chemical ingredients, although regulatory adoption has been slow. In this opinion article we discuss how scientific advances that utilize NAMs to certify systemic safety are available now and merit broader acceptance within the framework of next generation risk assessments (NGRA).


Asunto(s)
Alternativas a las Pruebas en Animales , Seguridad Química , Animales , Medición de Riesgo
11.
Toxicol Sci ; 189(1): 124-147, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-35822611

RESUMEN

An important question in toxicological risk assessment is whether non-animal new approach methodologies (NAMs) can be used to make safety decisions that are protective of human health, without being overly conservative. In this work, we propose a core NAM toolbox and workflow for conducting systemic safety assessments for adult consumers. We also present an approach for evaluating how protective and useful the toolbox and workflow are by benchmarking against historical safety decisions. The toolbox includes physiologically based kinetic (PBK) models to estimate systemic Cmax levels in humans, and 3 bioactivity platforms, comprising high-throughput transcriptomics, a cell stress panel, and in vitro pharmacological profiling, from which points of departure are estimated. A Bayesian model was developed to quantify the uncertainty in the Cmax estimates depending on how the PBK models were parameterized. The feasibility of the evaluation approach was tested using 24 exposure scenarios from 10 chemicals, some of which would be considered high risk from a consumer goods perspective (eg, drugs that are systemically bioactive) and some low risk (eg, existing food or cosmetic ingredients). Using novel protectiveness and utility metrics, it was shown that up to 69% (9/13) of the low risk scenarios could be identified as such using the toolbox, whilst being protective against all (5/5) the high-risk ones. The results demonstrated how robust safety decisions could be made without using animal data. This work will enable a full evaluation to assess how protective and useful the toolbox and workflow are across a broader range of chemical-exposure scenarios.


Asunto(s)
Cosméticos , Adulto , Teorema de Bayes , Benchmarking , Humanos , Medición de Riesgo , Flujo de Trabajo
12.
Front Toxicol ; 4: 881235, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35722059

RESUMEN

In next generation risk assessment (NGRA), non-animal approaches are used to quantify the chemical concentrations required to trigger bioactivity responses, in order to assure safe levels of human exposure. A limitation of many in vitro bioactivity assays, which are used in an NGRA context as new approach methodologies (NAMs), is that toxicokinetics, including biotransformation, are not adequately captured. The present study aimed to include, as a proof of principle, the bioactivity of the metabolite hydroxyflutamide (HF) in an NGRA approach to evaluate the safety of the anti-androgen flutamide (FLU), using the AR-CALUX assay to derive the NAM point of departure (PoD). The NGRA approach applied also included PBK modelling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE). The PBK model describing FLU and HF kinetics in humans was developed using GastroPlus™ and validated against human pharmacokinetic data. PBK model-facilitated QIVIVE was performed to translate the in vitro AR-CALUX derived concentration-response data to a corresponding in vivo dose-response curve for the anti-androgenicity of FLU, excluding and including the activity of HF (-HF and +HF, respectively). The in vivo benchmark dose 5% lower confidence limits (BMDL05) derived from the predicted in vivo dose-response curves for FLU, revealed a 440-fold lower BMDL05 when taking the bioactivity of HF into account. Subsequent comparison of the predicted BMDL05 values to the human therapeutic doses and historical animal derived PoDs, revealed that PBK modelling-facilitated QIVIVE that includes the bioactivity of the active metabolite is protective and provides a more appropriate PoD to assure human safety via NGRA, whereas excluding this would potentially result in an underestimation of the risk of FLU exposure in humans.

13.
Toxicol Appl Pharmacol ; 442: 115992, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35346730

RESUMEN

Combined with in vitro bioactivity data, physiologically based kinetic (PBK) models has increasing applications in next generation risk assessment for animal-free safety decision making. A tiered framework of building PBK models for such application has been developed with increasing complexity and refinements, as model parameters determined in silico, in vitro, and with human pharmacokinetic data become progressively available. PBK modelling has been widely applied for oral/intravenous administration, but less so on topically applied chemicals. Therefore, building PBK models for topical applications and characterizing their uncertainties in the tiered approach is critical to safety decision making. The purpose of this study was to assess the confidence of PBK modelling of topically applied chemicals following the tiered framework, using non-animal methods derived parameters. Prediction of maximum plasma concentration (Cmax) and area under the curve were compared to observed kinetics from published dermal clinical studies for five chemicals (diclofenac, salicylic acid, coumarin, nicotine, caffeine). A bespoke Bayesian statistical model was developed to describe the distributions of Cmax errors between the predicted and observed data. We showed a general trend that confidence in model predictions increases when more quality in vitro data, particularly those on hepatic clearance and dermal absorption, are available as model input. The overall fold error distributions are useful for characterizing model uncertainty. We concluded that by identifying and quantifying the uncertainties in the tiered approach, we can increase the confidence in using PBK modelling to help make safety decisions on topically applied chemicals in the absence of human pharmacokinetic data.


Asunto(s)
Hígado , Modelos Biológicos , Teorema de Bayes , Humanos , Cinética , Medición de Riesgo/métodos , Incertidumbre
14.
Front Toxicol ; 4: 838466, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35295212

RESUMEN

New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals. There are numerous Adverse Outcome Pathways (AOPs) that can lead to DART, which means defining and developing strict testing strategies for every AOP, to predict apical outcomes, is neither a tenable goal nor a necessity to ensure NAM-based safety assessments are fit-for-purpose. Instead, a pragmatic approach is needed that uses the available knowledge and data to ensure NAM-based exposure-led safety assessments are sufficiently protective. To this end, the mechanistic and biological coverage of existing NAMs for DART were assessed and gaps to be addressed were identified, allowing the development of an approach that relies on generating data relevant to the overall mechanisms involved in human reproduction and embryo-foetal development. Using the knowledge of cellular processes and signalling pathways underlying the key stages in reproduction and development, we have developed a broad outline of endpoints informative of DART. When the existing NAMs were compared against this outline to determine whether they provide comprehensive coverage when integrated in a framework, we found them to generally cover the reproductive and developmental processes underlying the traditionally evaluated apical endpoint studies. The application of this safety assessment framework is illustrated using an exposure-led case study.

15.
Chem Commun (Camb) ; 58(4): 581-584, 2022 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-34918016

RESUMEN

Linear polymers containing pillar[5]arenes as the pendant groups were designed and synthesized via a ring-opening metathesis polymerization. Such polymers could form supramolecular brush polymers and exhibited tunable fluorescence properties based on the host-guest interactions.

16.
Toxicol In Vitro ; 74: 105171, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33848589

RESUMEN

Using the chemical doxorubicin (DOX), the objective of the present study was to evaluate the impact of dose metrics selection in the new approach method of integrating physiologically-based kinetic (PBK) modelling and relevant human cell-based assays to inform a priori the point of departure for human health risk. We reviewed the literature on the clinical consequences of DOX treatment to identify dosing scenarios with no or mild cardiotoxicity observed. Key concentrations of DOX that induced cardiomyocyte toxicity in vitro were derived from studies of our own and others. A human population-based PBK model of DOX was developed and verified against pharmacokinetic data. The model was then used to predict plasma and extracellular and intracellular heart concentrations of DOX under selected clinical settings and compared with in vitro outcomes, based on several dose metrics: Cmax (maximum concentration) or AUC (area under concentration-time curve) in free or total form of DOX. We found when using in vitro assays to predict cardiotoxicity for DOX, AUC is a better indicator. Our study illustrates that when appropriate dose metrics are used, it is possible to combine PBK modelling with in vitro-derived toxicity information to define margins of safety and predict low-risk human exposure levels.


Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Modelos Biológicos , Medición de Riesgo/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/sangre , Línea Celular , Doxorrubicina/administración & dosificación , Doxorrubicina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Adulto Joven
17.
Toxicol In Vitro ; 73: 105132, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33662517

RESUMEN

Next Generation Risk Assessment (NGRA) can use the so-called Dietary Comparator Ratio (DCR) to evaluate the safety of a defined exposure to a compound of interest. The DCR compares the Exposure Activity Ratio (EAR) for the compound of interest, to the EAR of an established safe level of human exposure to a comparator compound with the same putative mode of action. A DCR ≤ 1 indicates the exposure evaluated is safe. The present study aimed at defining adequate and safe comparator compound exposures for evaluation of anti-androgenic effects, using 3,3-diindolylmethane (DIM), from cruciferous vegetables, and the anti-androgenic drug bicalutamide (BIC). EAR values for these comparator compounds were defined using the AR-CALUX assay. The adequacy of the new comparator EAR values was evaluated using PBK modelling and by comparing the generated DCRs of a series of test compound exposures to actual knowledge on their safety regarding in vivo anti-androgenicity. Results obtained supported the use of AR-CALUX-based comparator EARs for DCR-based NGRA for putative anti-androgenic compounds. This further validates the DCR approach as an animal free in silico/in vitro 3R compliant method in NGRA.


Asunto(s)
Antagonistas de Andrógenos/toxicidad , Anilidas/toxicidad , Indoles/toxicidad , Modelos Biológicos , Nitrilos/toxicidad , Receptores Androgénicos/metabolismo , Medición de Riesgo/métodos , Compuestos de Tosilo/toxicidad , Adulto , Antagonistas de Andrógenos/farmacocinética , Anilidas/farmacocinética , Alternativas a las Pruebas en Animales , Bioensayo , Línea Celular Tumoral , Exposición a Riesgos Ambientales , Humanos , Indoles/farmacocinética , Masculino , Nitrilos/farmacocinética , Compuestos de Tosilo/farmacocinética
18.
Front Pharmacol ; 12: 802514, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35058784

RESUMEN

Ethical and legal considerations have led to increased use of non-animal methods to evaluate the safety of chemicals for human use. We describe the development and qualification of a physiologically-based kinetics (PBK) model for the cosmetic UV filter ingredient, homosalate, to support its safety without the need of generating further animal data. The intravenous (IV) rat PBK model, using PK-Sim®, was developed and validated using legacy in vivo data generated prior to the 2013 EU animal-testing ban. Input data included literature or predicted physicochemical and pharmacokinetic properties. The refined IV rat PBK model was subject to sensitivity analysis to identify homosalate-specific sensitive parameters impacting the prediction of Cmax (more sensitive than AUC(0-∞)). These were then considered, together with population modeling, to calculate the confidence interval (CI) 95% Cmax and AUC(0-∞). Final model parameters were established by visual inspection of the simulations and biological plausibility. The IV rat model was extrapolated to oral administration, and used to estimate internal exposures to doses tested in an oral repeated dose toxicity study. Next, a human PBK dermal model was developed using measured human in vitro ADME data and a module to represent the dermal route. Model performance was confirmed by comparing predicted and measured values from a US-FDA clinical trial (Identifier: NCT03582215, https://clinicaltrials.gov/). Final exposure estimations were obtained in a virtual population and considering the in vitro and input parameter uncertainty. This model was then used to estimate the Cmax and AUC(0-24 h) of homosalate according to consumer use in a sunscreen. The developed rat and human PBK models had a good biological basis and reproduced in vivo legacy rat and human clinical kinetics data. They also complied with the most recent WHO and OECD recommendations for assessing the confidence level. In conclusion, we have developed a PBK model which predicted reasonably well the internal exposure of homosalate according to different exposure scenarios with a medium to high level of confidence. In the absence of in vivo data, such human PBK models will be the heart of future completely non-animal risk assessments; therefore, valid approaches will be key in gaining their regulatory acceptance. Clinical Trial Registration: https://clinicaltrials.gov/, identifier, NCT03582215.

19.
Ultrasound Med Biol ; 47(2): 272-278, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33153804

RESUMEN

The aim of the study described here was to explore the value of hepatic transit time (HTT) and shear wave velocity (SWV) in diagnosing cirrhotic portal hypertension. Fifty-seven patients had undergone esophagogastric varicose vein embolization (group OBS) and 50 healthy controls (group CON) were retrospectively compared with respect to HTT (arterial-hepatic vein [HA-HVTT], portal vein-hepatic vein [PV-HVTT], liver parenchyma-hepatic vein [PA-HVTT]) and SWV to analyze their efficacy in diagnosing cirrhotic portal hypertension. The correlations between SWV/HTT and free portal pressure (FPP) in group OBS were also analyzed. Compared with group CON, group OBS had a shorter HTT and faster SWV. The area under the curve (AUC) of PV-HVTT (0.93) was higher than those of HA-HVTT (0.75) and PA-HVTT (0.64), the AUCs of PV-HVTT (0.93, threshold 7.9 s) and SWV (0.91, threshold 2.0 cm/s) did not statistically differ (z = 0.35, p = 0.73). HTT and FPP in group OBS had a negative correlation. In conclusion, HTT and SWV can be used to diagnose cirrhotic portal hypertension without difference in diagnostic efficacy, and HTT is more meaningful for assessing the changes in portal pressure.


Asunto(s)
Hipertensión Portal/diagnóstico por imagen , Hipertensión Portal/fisiopatología , Cirrosis Hepática/complicaciones , Presión Portal , Ultrasonografía , Anciano , Estudios de Casos y Controles , Medios de Contraste , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/cirugía , Femenino , Arteria Hepática/fisiopatología , Venas Hepáticas/fisiopatología , Humanos , Hipertensión Portal/etiología , Circulación Hepática , Masculino , Persona de Mediana Edad , Fosfolípidos , Vena Porta/fisiopatología , Estudios Retrospectivos , Hexafluoruro de Azufre , Ultrasonografía/métodos
20.
J Contemp Brachytherapy ; 12(4): 375-382, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33293977

RESUMEN

PURPOSE: To investigate the role of transrectal ultrasound guidance in interstitial brachytherapy for cervical cancer. MATERIAL AND METHODS: Forty-eight patients who underwent interstitial brachytherapy treatment for cervical cancer between January 2017 and January 2018 were enrolled in the study. The distances between each inserted needle and the lesion were measured at seven sites by ultrasound (D1-D7) and compared to the corresponding distances (M1-M7) when visualised with nuclear magnetic resonance imaging (MRI). Measurements were paired on the basis of the observation sites, e.g. D1 and M1, D2 and M2. The statistical differences, intraclass correlation coefficients (ICCs), and linear relationships for the paired measurements were calculated. RESULTS: No significant differences were found between the paired M and D measurements, with all ICCs showing high levels of concordance (0.81-0.93). CONCLUSIONS: Transrectal ultrasound showed strong agreement with MRI results in determining the position of the inserted needles. Transrectal ultrasound is a useful tool for guided interstitial brachytherapy and is appropriate for widespread use in the treatment of locally advanced cervical cancer.

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