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Nitrification of ammoniacal nitrogen (N-NH4+) to nitrate (N-NO3-) was investigated in a lab-scale sequencing batch reactor (SBR) to evaluate its efficiency. During the nitrification process the removal of N-NH4+ reached 96%, resulting in 73% formation of N-NO3-. A lineal correlation (r2 = 0.9978) was obtained between the concentration of volatile suspended solids (VSS) and the maximal N-NO3- concentration at the end of each batch cycle under stationary state. The bacterial taxons in the initial inoculum were identified, revealing a complex diverse community mainly in the two major bacterial phyla Proteobacteria and Actinobacteria. The FAPROTAX algorithm predicted the presence in the inoculum of taxa involved in relevant processes of the nitrogen metabolism, highlighting the bacterial genera Nitrospira and Nitrosomonas that are both involved in the nitrification process. A kinetic model was formulated for predicting and validating the transformation of N-NH4+, N-NO2- and N-NO3- and the removal of organic and inorganic carbon (TOC and IC, respectively). The results showed how the increase in biomass concentration slowed down the transformation to oxidised forms of nitrogen and increased denitrification in the settling and filling stages under free aeration conditions.
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Desnitrificación , Nitrificación , Reactores Biológicos/microbiología , Genómica , Bacterias/genética , Bacterias/metabolismo , Nitrógeno/análisis , Aguas del Alcantarillado/microbiologíaRESUMEN
In various types of many-particle systems, bidispersity is frequently used to avoid spontaneous ordering in particle configurations. In this study, the relation between bidispersity and disorder degree of particle configurations is investigated. By using magnetic dipole-dipole interaction, magnet particles are dispersed in a two-dimensional cell without any physical contact between them. In this magnetic system, bidispersity is introduced by mixing large and small magnets. Then, the particle system is compressed to produce a uniform particle configuration. The compressed particle configuration is analyzed by using Voronoi tessellation for evaluating the disorder degree, which strongly depends on bidispersity. Specifically, the standard deviation and skewness of the Voronoi cell area distribution are measured. As a result, we find that the peak of standard deviation is observed when the numbers of large and small particles are almost identical. Although the skewness shows a non-monotonic behavior, a zero skewness state (symmetric distribution) can be achieved when the numbers of large and small particles are identical. In this ideally random (disordered) state, the ratio between pentagonal, hexagonal, and heptagonal Voronoi cells becomes roughly identical, while hexagons are dominant under monodisperse (ordered) conditions. The relation between Voronoi cell analysis and the global bond orientational order parameter is also discussed.
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In a previous study, our group detected the cholecystokinin (CCK) protein in the porcine oviduct. This fact, together with the involvement of CCK in the regulation of sperm protein tyrosine phosphorylation by the modulation of HCO3 - uptake (in mice and humans) suggests a role for CCK during sperm capacitation. Therefore, on the one hand, the expression of CCK receptors (CCK1R and CCK2R) on boar testes has been investigated and probed; on the other hand, boar spermatozoa (from seminal doses of 1-day and 5-day storage) were exposed to different concentrations of CCK (0-control, 25 or 50 µM) in a medium supporting capacitation supplemented with 0, 5 or 25 mmol/L of HCO3 - for 1 h at 38.5°C. Sperm motion (total and progressive motility), kinetic parameters, viability, acrosome status, and mitochondrial activity were determined. No differences between groups (0, 25 or 50 µM of CCK) were observed when HCO3 - was absent in the media (p > .05). However, the results showed that when the media was supplemented with 5 mmol/L HCO3 - in 1-day seminal dose storage, the linearity index (LIN, %), straightness index (STR, %) and oscillation index (WOB, %) (sperm kinetics parameters) increased in the presence of CCK regardless the concentration (p < .05). Nevertheless, CCK in sperm from 5-day storage only increased the WOB parameter in comparison to the control (p < .05). Furthermore, the average amplitude of the lateral displacement of the sperm head (ALH, µm) and curvilinear velocity (VCL, µm/s) decreased when CCK was present, depending on its concentration and sperm aging (1-day vs. 5-days) (p < .05). In the case of the media supporting capacitation supplemented with 25 mmol/L HCO3 - , any differences were observed except for sperm viability in the 5-day seminal doses, which increased in the 50 µM-CCK group compared to the control (p < .05). In conclusion, these data suggest an implication of CCK protein during sperm capacitation under low bicarbonate concentration increasing the sperm linear trajectory.
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Bicarbonatos , Motilidad Espermática , Humanos , Porcinos , Masculino , Animales , Ratones , Bicarbonatos/farmacología , Motilidad Espermática/fisiología , Colecistoquinina/farmacología , Colecistoquinina/metabolismo , Semen/metabolismo , Espermatozoides/fisiología , Capacitación Espermática/fisiologíaRESUMEN
How lightning initiates inside thunderclouds remains a major puzzle of atmospheric electricity. By monitoring optical emissions from thunderstorms, the Atmosphere-Space Interactions Monitor (ASIM) onboard the International Space Station is providing new clues about lightning initiation by detecting Blue LUminous Events (BLUEs), which are manifestations of electrical corona discharges that sometimes precedes lightning. Here we combine optical and radio observations from a thunderstorm near Malaysia to uncover a new type of event containing multiple optical and radio pulses. We find that the first optical pulse coincides with a strong radio signal in the form of a Narrow Bipolar Event (NBE) but subsequent optical pulses, delayed some milliseconds, have weaker radio signals, possibly because they emanate from a horizontally oriented electrical discharges which does not trigger full-fledged lightning. Our results cast light on the differences between isolated and lightning-initiating electrical discharges.
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The physical mechanism of Narrow bipolar events (NBEs) has been studied for decades but it still holds many mysteries. Recent observations indicate that the fast breakdown discharges that produce NBEs sometimes contain a secondary fast breakdown that propagates back in the opposite direction but this has not been fully addressed so far in electromagnetic models. In this study, we investigate fast breakdown using different approaches that employ a Modified Transmission Line with Exponential decay (MTLE) model and propose a new model, named "rebounding MTLE model," which reproduces the secondary fast breakdown current in NBEs. The model provides new insights into the physics of the fast breakdown mechanism.
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Climate change effects on hostparasite interactions have been poorly studied in arid or semi-arid habitats. Here, we conducted an experiment aimed to increase the temperature inside European roller Coracias garrulus nest boxes located in a semi-arid habitat on different nest-site types to look for effects on different ectoparasite abundances and nestling growth. Average nest temperature was slightly higher in heated nests than in control nests, although differences were not statistically significant. However, relative humidity was significantly lower at night in heated nests as compared to control nests. The abundance of sand flies, mites and carnid flies was significantly higher in heated, less humid, nests while biting midge abundance was significantly lower in heated nests. Other ectoparasites were not significantly affected by treatment. Relative humidity was high even in heated nests, reaching more than 60%. Sand fly abundance was higher in nests located in sandstone walls, while mite abundance was higher in isolated farmhouses. In addition, sand fly prevalence was higher in nests located in isolated farmhouses and sandstone walls. Heat treatment, nest-site type or ectoparasite abundances did not affect the nestling body mass, wing length or their growth at different nestling ages.
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Aves , Ceratopogonidae , Animales , Interacciones Huésped-Parásitos , Humedad , Comportamiento de Nidificación , TemperaturaRESUMEN
We investigate the structural relaxation of a soft-sphere liquid quenched isochorically (Ï = 0.7) and instantaneously to different temperatures Tf above and below the glass transition. For this, we combine extensive Brownian dynamics simulations and theoretical calculations based on the non-equilibrium self-consistent generalized Langevin equation (NE-SCGLE) theory. The response of the liquid to a quench generally consists of a sub-linear increase of the α-relaxation time with system's age. Approaching the ideal glass-transition temperature from above (Tf > Ta), sub-aging appears as a transient process describing a broad equilibration crossover for quenches to nearly arrested states. This allows us to empirically determine an equilibration timescale teq(Tf) that becomes increasingly longer as Tf approaches Ta. For quenches inside the glass (Tf ≤ Ta), the growth rate of the structural relaxation time becomes progressively larger as Tf decreases and, unlike the equilibration scenario, τα remains evolving within the whole observation time-window. These features are consistently found in theory and simulations with remarkable semi-quantitative agreement and coincide with those revealed in a previous and complementary study [P. Mendoza-Méndez et al., Phys. Rev. 96, 022608 (2017)] that considered a sequence of quenches with fixed final temperature Tf = 0 but increasing Ï toward the hard-sphere dynamical arrest volume fraction ÏHS a=0.582. The NE-SCGLE analysis, however, unveils various fundamental aspects of the glass transition, involving the abrupt passage from the ordinary equilibration scenario to the persistent aging effects that are characteristic of glass-forming liquids. The theory also explains that, within the time window of any experimental observation, this can only be observed as a continuous crossover.
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Vidrio , Simulación de Dinámica Molecular , Temperatura , Temperatura de Transición , Vidrio/químicaRESUMEN
Fermentation of grape must to wine is carried out by a complex microbial mixture, which also involves spoilage yeasts of wine. The latter yeasts produce organoleptic changes that cause significant economic losses to the wine industry. SO2 is traditionally used to control this spoilage populations, but because of its harmful effects on human health, biocontrol has emerged as an alternative treatment. Although studies have been carried out to select biocontroller yeasts and examine their underlying mechanisms of action, reports on their application have not been published yet. To better understand the interaction and the successful application of biocontrol, the use of mathematical models, among other methods, is important, as they facilitate the prediction of success or failure of the antagonist. The objective of the present study was to use an existing mathematical model to obtain information about the yeast's interaction assayed and to validate its predictive use under different physicochemical conditions during the wine fermentation, and eventually predict biocontrol kinetics. The mathematical model was applied to the fermentation conditions and provided information on the kinetic parameters of the biocontrol interaction and allowed interpretations about other parameters. The model was applied in the different physicochemical conditions for the biocontrol and did not fit correctly to experimental data, and therefore an improvement was proposed which was successful and presented new hypotheses.
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Vino , Fermentación , Humanos , Cinética , Modelos Teóricos , LevadurasRESUMEN
Superficial fungal infections are common in dermatology and are often caused by opportunistic species in the Candida and Malassezia genera. The aim of this study was to analyze changes in the expression of genes coding for enzymes involved in the biosynthesis of glycosaminoglycans (GAGs) chains following the adherence of Candida and Malassezia yeasts to skin cell lines. Gene expression was analyzed using reverse transcriptase-quantitative polymerase chain reaction assays. Interactions between the yeasts and the skin cells induced the following changes in genes involved in the biosynthesis of heparan sulfate and chondroitin sulfate: downregulation of CHPF in keratinocytes and downregulation of EXT1, EXT2, CHSY3, and CHPF in fibroblasts. Adherence to fibroblasts had an even greater effect on GAG biosynthetic enzymes, inducing the downregulation of 13 genes and the upregulation of two (CHST15 and CHST7). Interactions between yeasts and skin cells might affect the binding affinity of GAG chains, possibly changing their ability to function as receptors for pathogens and interfering with a key stage at the start of infection.
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Sulfatos de Condroitina , Malassezia , Candida albicans/genética , Candida albicans/metabolismo , Sulfatos de Condroitina/análisis , Glicosaminoglicanos/análisis , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/análisis , Heparitina Sulfato/metabolismo , Humanos , Malassezia/genética , Malassezia/metabolismo , Glicoproteínas de Membrana , SulfotransferasasRESUMEN
We report on the collision-coalescence dynamics of drops in Leidenfrost state using liquids with different physicochemical properties. Drops of the same liquid deposited on a hot concave surface coalesce practically at contact, but when drops of different liquids collide, they can bounce several times before finally coalescing when the one that evaporates faster reaches a size similar to its capillary length. The bouncing dynamics is produced because the drops are not only in Leidenfrost state with the substrate, they also experience Leidenfrost effect between them at the moment of collision. This happens due to their different boiling temperatures, and therefore, the hotter drop works as a hot surface for the drop with lower boiling point, producing three contact zones of Leidenfrost state simultaneously. We called this scenario the triple Leidenfrost effect.
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Our objective was to perform two studies: a cross-sectional study in order to identify the main psychological variables associated to treatment adherence in rheumatoid arthritis and an intervention based on psychoeducation to assess its impact on the variables identified in the first study. We measured treatment adherence, self-efficacy, beliefs about medication, emotional intelligence and disability along with personal and disease variables in the cross-sectional study and the same variables were measured in the intervention before and after the program and 3 months later in 2 groups (an experimental group and an active control group). In the cross-sectional study (N=33) we found that the variables most associated with treatment adherence were emotional clarity (r=0.352, p<0.05) and emotional repair (r=0.363, p<0.05). In the intervention, we divided the patients into 2 groups: the control group (N=7) and the intervention group (N=10). At the end of the study and at follow-up, we found a significant increase in adherence and self-efficacy in the intervention group, when compared with the control group. Emotional clarity was increased only in the post-test, and at follow up a decrease in beliefs of concern about medication was found. Psychoeducational programs based on information about the disease and its treatment together with emotional management are effective in increasing treatment adherence in the long term.
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Artritis Reumatoide , Artritis Reumatoide/tratamiento farmacológico , Estudios Transversales , Inteligencia Emocional , Humanos , Proyectos Piloto , Cumplimiento y Adherencia al TratamientoRESUMEN
Submicrosecond (0.476 µs per frame with an exposure time of 160 ns) high-resolution (0.38 nm) time-resolved spectra of laboratory-produced lightning-like electrical discharges have been recorded for the first time within the visible spectral range (645-665 nm). The spectra were recorded with the GrAnada LIghtning Ultrafast Spectrograph (GALIUS), a high-speed imaging spectrograph recently developed for lightning research in the IAA-CSIC. Unprecedented spectral time dynamics are explored for meter long laboratory electrical discharges produced with a 2.0 MV Marx generator. The maximum electron density and gas temperature measured in a timescale of ≤0.50 µs (160 ns) were, respectively, ≃1018 cm-3 and ≃32,000 K. Overpressure in the lightning-like plasma channel, black-body dynamics, and self-absorption in spectral lines were investigated.
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OBJECTIVE: Perampanel (PER) has been shown to be effective as an adjunctive therapy for controlling refractory focal-onset seizures (FOS). However, the information as early add-on for the treatment of FOS in the clinical practice is still scarce and must be further assessed. METHODS: An observational prospective study was conducted to evaluate the effectiveness of early add-on PER, assessed as 50% responders (seizure frequency reduced by at least 50% during the last 3â¯months as compared with baseline) rate at 6 and 12â¯months, in patients with FOS in the routine clinical practice of Spain. RESULTS: One hundred and thirteen patients (mean age: 40.3â¯years, 51.3% male) with FOS received PER as early add-on (1st add-on: 37.2% and 2nd: 62.8%) for a mean exposure of 11â¯months (mean PER dose: 6.3â¯mg/day at month 12). At 6â¯months, 50.4% and 20.4% of the patients were responders and seizure-free (respectively) relative to baseline (3â¯months prior to PER initiation), and at 12â¯months, 68.1% and 26.5% of the patients were responders and seizure-free (respectively), relative to baseline (3â¯months prior to PER initiation). The retention rate at 6 and 12â¯months was 83.2% and 80.5%, respectively. The percentage of seizure-free patients at 12â¯months was significantly (pâ¯=â¯0.033) higher when PER was added as first vs. second add-on. The number of concomitant antiepileptic drugs (AEDs) was significantly reduced from baseline to 6 and 12â¯months (pâ¯=â¯0.001). Treatment was simplified in 23.9% of patients at the end of the observation period. Drug-related adverse events (AEs), most mild or moderate, were reported in 30.1% of patients, with irritability (8%) and dizziness (7.1%) as the most frequent ones. CONCLUSIONS: This is the first observational, prospective study to evaluate efficacy and safety of early adjunctive treatment with PER in patients with focal epilepsy at 12â¯months. Perampanel demonstrated a good efficacy and safety profile when used at a median dose of 6â¯mg/day, regardless of the combination with other AEDs. Adverse events were mild or moderate, with dizziness being the most frequent one.
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Anticonvulsivantes/administración & dosificación , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Piridonas/administración & dosificación , Convulsiones/tratamiento farmacológico , Convulsiones/epidemiología , Adulto , Anticonvulsivantes/efectos adversos , Mareo/inducido químicamente , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Estudios Prospectivos , Piridonas/efectos adversos , España/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Nivolumab is a fully human programmed death control immune point 1 immune checkpoint inhibitor antibody which promotes antitumor immunity. Cutaneous toxicity associated with nivolumab, immune system related, could be linked to a more durable response in patients with squamous cell lung cancer. CASE REPORT: We present the case of a 62-year-old male diagnosed with metastatic squamous cell lung cancer, who was treated with nivolumab after cytotoxic chemotherapy. After treatment discontinuation, due to grade 2 cutaneous toxicity, the patient is maintaining with durable partial response for more than one year with close follow-up. MANAGEMENT AND OUTCOME: Cumulative doses of nivolumab could cause immunological toxicities that may prolong survival of these patients even after discontinuation of treatment. DISCUSSION: Nivolumab was approved by European Medicines Agency (EMA), as second-line therapeutic, for the treatment of squamous cell lung cancer, showing a median of 9.23 months of overall survival. The development of immune-related skin toxicities has been associated with greater clinical benefit in patients with lung cancer. When cutaneous toxicity forces to nivolumab suspension, in certain cases, the option of not starting again and closely following up the patient may appear reasonable, even though there are no survival data in this context. Suspension of treatment with close monitoring of these patients until progression may be an alternative, since immune-related skin toxicities could be related to a greater clinical benefit and a durable response to nivolumab.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Nivolumab/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversosRESUMEN
BACKGROUND: Cancer is a high-impact disease throughout the world. A negative correlation has been established between the development of cancer and the Th2 immune response. Infection by helminth parasites is characterized by the induction of a strong and long-lasting Th2 response. The aim of this work was to evaluate the effect of the immune response induced by the infection with the helminth Hymenolepis nana, on the tumorigenesis induced by dimethylbenz-anthracene (DMBA) in mice. METHODOLOGY: Four different groups of 14 female BALB/c mice were formed; Group A, dimethyl sulfoxide (DMSO) (vehicle) was administered cutaneously, Group B infected with H. nana, group C, cutaneously DMBA and finally Group D infected with H. nana and cutaneous DMBA. The tumor load was determined in those animals that developed cancerous lesions. In all groups were determined: serum concentration of IgE, IFNγ, IL-10, IL-5 and malondialdehyde (MDA). The inflammatory infiltrate was analyzed from skin samples and the expression of the main eosinophilic protein and myeloperoxidase was determined. RESULTS: The group previously infected with H. nana had a reduced amount of tumors with smaller size, in comparison to the group that received only DMBA; this reduction was associated with lower levels of IFNγ and IL-10, while levels of IgE, IL-5 and MDA were higher. Further, the number of eosinophils and neutrophils was statistically higher in the animals that were previously infected with the helminth and developed less tumors. CONCLUSION: The immune response induced by H. nana infection is associated with the reduction of tumors probably due to the activity of eosinophils and neutrophils.
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9,10-Dimetil-1,2-benzantraceno/toxicidad , Carcinogénesis/inmunología , Citocinas/inmunología , Himenolepiasis/inmunología , Hymenolepis nana/inmunología , Células Th2/inmunología , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/patología , Femenino , Himenolepiasis/patología , Ratones , Ratones Endogámicos BALB C , Células Th2/patologíaRESUMEN
The impact of a spherical projectile on an evened-out granular bed generates a uniform ejecta of material and a crater with a raised circular rim. Recently, Sabuwala et al. [Phys. Rev. Lett. 120, 264501 (2018)PRLTAO0031-900710.1103/PhysRevLett.120.264501] found that the uniform blanket of ejecta changes to a set of radial streaks when a spherical body impacts on an undulated granular surface, being a plausible explanation to the enigmatic ray systems on planetary bodies. Here, we show that ray systems can also be generated by the impact of nonspherical projectiles on a flat granular surface. This is a reasonable explanation considering that meteorites are rarely spherical. Moreover, by impacting bodies of different geometries, we show that the crater size follows the same power-law scaling with the impact energy found for spherical projectiles, and the crater rim becomes circular as the impact energy is increased regardless of the projectile shape, which helps to understand why most impact craters in nature are rounded.
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PURPOSE: In Brazil, access to breast cancer screening outside of urban centers is limited. This study aims to describe the coverage and performance of a breast cancer screening program implemented with Mobile Screening Units (MSU) in northern São Paulo state. METHODS: This is a retrospective cohort study of a population-based mammography program targeting women ages 40-69 in 108 municipalities from 12/2010 to 07/2015. Screening coverage rates were estimated using the Brazil 2010 census data. We calculated performance measures for the number of exams, recalls, and detected cases of cancer. Screen-detected cases were compared to clinically detected cases using hospital cancer registry data and a propensity-score matching method. The down-staging of screen-detected cases relative to clinically detected cases was assessed using logistic regression to calculate risk ratios (RRs) with 95% confidence intervals. RESULTS: 122,634 women were screened through the MSU program, representing a cumulative coverage rate of 54.8% in the target population. For initial and subsequent rounds, recall rates were 12.25 and 6.10% and cancer detection rates were 3.63 (95% CI 3.23-4.10) and 1.94 (95% CI 1.59-2.41), respectively. 92.51% of referrals were successful. Screen-detected cases had more favorable prognoses than clinically detected cases, including smaller tumor size and a decreased risk of late-stage detection (RR 0.14 95% CI 0.074-0.25). CONCLUSIONS: MSUs are a feasible method for the delivery of mammography services in this setting. Patients who had breast cancer detected on an MSU had favorable prognostic factors when compared with clinically detected cases arising from the same target population.
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Neoplasias de la Mama/diagnóstico , Mamografía/métodos , Tamizaje Masivo/métodos , Adulto , Anciano , Brasil , Detección Precoz del Cáncer , Femenino , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Sistema de Registros , Estudios RetrospectivosRESUMEN
Previous researches have showed that Lachancea thermotolerans strains RCKT4 and RCKT5 inhibited the growth of Aspergillus. However, currently, there are no data on their nutritional preferences, as a possible substrate competitor against Saccharomyces cerevisiae, and their effects on fermentation. In this work, we observed that the biocontrol yeasts and S. cerevisiae BSc203, based on the utilization of 16 carbonate sources, revealed significant differences in the nutritional profile (biocontrol yeasts NS:0·25, BSc203 NS:0·56). Lachancea thermotolerans strains did not occupy the same niche as that of BSc203 (NOI:0·44). The biocontrol agents and BSc203 presented similar competitive attitude in terms of the sugar, ethanol and sulphite tolerances. During fermentation, the biocontrol yeasts were found to tolerate up to 12% v/v ethanol, 250 mg ml-1 of total SO2 and 30° Brix sugar. In mixed cultures, L. thermotolerans strains did not negatively affect the growth of BSc203 and the wine quality, except when RCKT4 was initially inoculated at a high proportion in the mixed culture 1MSK4 (1%BSc203/99%RCKT4), resulting in a lower production of CO2 and ethanol, in comparison with pure BSc203. RCKT5, at a high proportion, in 1MSK5 (1%BSc203/99%RCKT5) presented promising oenological properties. This fermentation showed lower acetic acid contents and higher total acidity than pure BSc203. SIGNIFICANCE AND IMPACT OF THE STUDY: Generally it is not evaluated if the biofungicide yeasts sprayed on vegetables alter the quality of the fermented products. This work focused on the importance of assessing the possible effects of yeast-based fungicides used in vineyards on grape fermentation, especially on Saccharomyces cerevisiae growth. In this context, the competition between biofungicide yeasts and S. cerevisiae under winemaking conditions is investigated.
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Antibiosis/fisiología , Agentes de Control Biológico/farmacología , Fermentación/efectos de los fármacos , Fungicidas Industriales/farmacología , Saccharomyces cerevisiae/crecimiento & desarrollo , Vitis/microbiología , Ácido Acético/metabolismo , Etanol/farmacología , Vino/análisisRESUMEN
BACKGROUND: RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice. PATIENTS AND METHODS: RAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated. RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients. RESULTS: Analysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment. CONCLUSION: The high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.
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Neoplasias Colorrectales/diagnóstico , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/sangre , Genes ras , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Receptores ErbB/antagonistas & inhibidores , Humanos , Monitoreo Fisiológico/métodos , Metástasis de la Neoplasia , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine. PATIENTS AND METHODS: This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. RESULTS: Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms. CONCLUSION: This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously. TRIAL NUMBER: NCT01830231.