Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic ...progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined.
In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival.
A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval CI, 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group.
In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).
The iron(II) oxidation kinetic process was studied at 25 stations in coastal seawater of the Macaronesia region (9 around Cape Verde, 11 around the Canary Islands, and 5 around Madeira). In a ...physicochemical context, experiments were carried out to study the pseudo-first-order oxidation rate constant (k′, min–1) over a range of pH (7.8, 7.9, 8.0, and 8.1) and temperature (10, 15, 20, and 25 °C). Deviations from the calculated k cal ′ at the same T, pH, and S were observed for most of the stations. The measured t 1/2 (ln 2/k′, min) values at the 25 stations ranged from 1.82 to 3.47 min (mean 1.93 ± 0.76 min) and for all but two stations were lower than the calculated t 1/2 of 3.21 ± 0.2 min. In a biogeochemical context, nutrients and variables associated with the organic matter spectral properties (CDOM and FDOM) were analyzed to explain the observed deviations. The application of a multilinear regression model indicated that k′ can be described (R = 0.921 and SEE = 0.064 for pH = 8 and T = 25 °C) from a linear combination of three organic variables, k′OM = k cal ′ −0.11* TDN + 29.9*b DOM + 33.4*C1humic, where TDN is the total dissolved nitrogen, b DOM is the spectral peak obtained from colored dissolved organic matter (DOM) analysis when protein-like or tyrosine-like components are present, and C1humic is the component associated with humic-like compounds obtained from the parallel factor analysis of the fluorescent DOM. Results show that compounds with N in their structures mainly explain the observed k′ increase for most of the samples, although other components could also play a relevant role. Experimentally, k′ provides the net result between the compounds that accelerate the process and those that slow it down.
The presence and fate of pharmaceutical residues in environmental samples are of great interest. There is a vast number of studies published regarding their input, presence, effects and risks in ...ecosystems. Moreover, it has been demonstrated that the primary source of input of these contaminants in the environment is from Wastewater Treatment Plants (WWTPs). It is therefore essential to evaluate the efficiency of commonly used treatments and the necessity of applying novel purification processes in order to eliminate or reduce the concentration of pharmaceuticals from wastewater or from the effluent of WWTPs.
The aim of this work was to quantify twenty-three pharmaceutical compounds in the aqueous phase at different stages of a conventional and a natural WWTP situated in Gran Canaria (Spain). The results indicate concentration levels in the range of 0.004±0.001 to 59.2±11.7μgL−1 and 0.018±0.001 to 148±14.7μgL−1 from conventional and natural WWTPs, respectively. Better efficiency was, however, offered by the conventional WWTP with a removal median of 99.7%. In addition, the impact on different aquatic organisms (algae, daphnids and fish) was assessed in terms of risk quotients. The results reveal a possible highly harmful effect towards organisms by gemfibrozil, ibuprofen and ofloxacin.
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•Twenty-three pharmaceuticals were monitoring in sewage from WWTPs.•Simplified SPE-LC-MS/MS was employed to analyse pharmaceuticals from sewage samples.•Removal efficiencies of pharmaceuticals from two different WWTPs were evaluated.•Environmental risk assessment of pharmaceuticals was determined.
Candida auris is an emerging healthcare-associated pathogen of global concern. Recent reports have identified C. auris isolates that grow in cellular aggregates or filaments, often without a clear ...genetic explanation. To investigate the regulation of C. auris morphogenesis, we applied an Agrobacterium-mediated transformation system to all four C. auris clades. We identified aggregating mutants associated with disruption of chitin regulation, while disruption of ELM1 produced a polarized, filamentous growth morphology. We developed a transiently expressed Cas9 and sgRNA system for C. auris that significantly increased targeted transformation efficiency across the four C. auris clades. Using this system, we confirmed the roles of C. auris morphogenesis regulators. Morphogenic mutants showed dysregulated chitinase expression, attenuated virulence, and altered antifungal susceptibility. Our findings provide insights into the genetic regulation of aggregating and filamentous morphogenesis in C. auris. Furthermore, the genetic tools described here will allow for efficient manipulation of the C. auris genome.
Summary
Current therapies for inflammatory bowel diseases (IBD) are aimed at controlling the exacerbated response in the gut, but no treatment is fully effective for many refractory patients. ...Mesenchymal stromal cells (MSC) are multi‐potent cells with regulatory immunosuppressive activity that may control inflammatory diseases. In this study, we investigated the short‐ and especially the long‐term protective effects of MSC on experimental colitis. We show that MSC elicited protection to acute intestinal inflammation with gain of weight, improvement in the clinical disease score and expressive reduction in the mortality rate of treated mice. MSC changed the population of neutrophils, eosinophils and augmented the frequency of CD4 T lymphocytes in the gut‐draining lymph nodes, together with reduced accumulation of these cells in the colon intraepithelial compartment. Interestingly, there were increased levels of programmed death 1 (PD‐1) and glucocorticoid‐induced tumour necrosis factor receptor family‐related receptor (GITR) in the spleen regulatory T cells of mice that received MSC treatment, which also presented a reversal in the pattern of immune response in the gut, with diminished inflammatory, T helper type 1 (Th1) and Th17 profile, in contrast to augmented Th2 responses. Most strikingly, this balanced response elicited by a single administration of MSC during the acute colitis persisted long‐term, with restored goblet cells, eosinophils and maintenance of elevated gut interleukin (IL)‐4, besides increased CD4+CD25+PD‐1+ cells in the spleen and reduced Th17 response in mesenteric lymph nodes (MLN) of treated mice on day 60. Taken together, our findings provided a significant contribution to translational immunology by pointing human adipose tissue‐derived MSC as a novel therapeutic approach with long‐term beneficial regulatory effects in experimental colitis.
An early and unique administration of adipose tissue‐derived mesenchymal stromal cells produced persistent protective effects on experimental colitis
To encourage the reutilization of treated wastewaters as an adaptation strategy to climate change it is necessary to demonstrate their quality. If this is ensured, reclaimed waters could be a ...valuable resource that produces very little environmental impact and risks to human health. However, wastewaters are one of the main sources of emerging pollutants that are discharged in the environment. For this, it is essential to assess the presence of these pollutants, especially pharmaceutical compounds, in treated wastewaters. Moreover, the different treatment processes must be evaluated in order to know if conventional and natural treatment technologies are efficient in the removal of these types of compounds. This is an important consideration if the treated wastewaters are used in agricultural activities. Owing to the complexity of wastewater matrixes and the low concentrations of pharmaceutical residues in these types of samples, it is necessary to use sensitive analytical methodologies. In this study, the presence of 11 pharmaceutical compounds were assessed in three different wastewater treatment plants (WWTPs) in Gran Canaria (Spain). Two of these WWTPs use conventional purification technologies and they are located in densely populated areas, while the other studied WWTP is based in constructed wetlands which purify the wastewaters of a rural area. The sampling was performed monthly for two years. A solid phase extraction (SPE) coupled to ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was applied for the analysis of the samples, and the 11 pharmaceuticals were detected in all the studied WWTPs. The concentrations were variable and ranged from ng·L
in some compounds like diclofenac or carbamazepine to µg·L
in common pharmaceutical compounds such as caffeine, naproxen or ibuprofen. In addition, removal efficiencies in both conventional and natural purification systems were evaluated. Similar removal efficiencies were obtained using different purifying treatments, especially for some pharmaceutical families as stimulants or anti-inflammatories. Other compounds like carbamazepine showed a recalcitrant behavior. Secondary treatments presented similar removal efficiencies in both conventional and natural wastewater treatment plants, but conventional treatments showed slightly higher elimination ratios. Regarding tertiary system, the treatment with highest removal efficiencies was reverse osmosis in comparison with microfiltration and electrodialysis reversal.
Aims. During the last ~50 years, the population of black hole candidates in X-ray binaries has increased considerably, with 59 Galactic objects being detected in transient low-mass X-ray binaries, as ...well as a few in persistent systems (including ~5 extragalactic binaries). Methods. We collect near-infrared, optical, and X-ray information spread over hundreds of references to study the population of black holes in X-ray transients as a whole. Results. We present the most updated catalogue of black hole transients. This contains X-ray, optical, and near-infrared observations, together with their astrometric and dynamical properties. The catalogue provides new and useful information in both statistical and observational parameters and provides a thorough and complete overview of the black hole population in the Milky Way. Analysing the distances and spatial distribution of the observed systems, we estimate a total population of ~1300 Galactic black hole transients. This means that we have only discovered less than ~5% of the total Galactic distribution.
Candida auris is an emerging fungal pathogen with unusual evolutionary history-there are multiple distinct phylogeographic clades showing a near simultaneous transition from a currently unknown ...reservoir to nosocomial pathogen. Each of these clades has experienced different selective pressures over time, likely resulting in selection for genotypes with differential fitness or phenotypic consequences when introduced to new environments. We also observe diversification within clades, providing additional opportunities for phenotypic differences. These differences can have large impacts on pathogenic potential, drug resistance profile, evolutionary trajectory, and transmissibility. In recent years, there have been significant advances in our understanding of strain-specific behavior in other microbes, including bacterial and fungal pathogens, and we have an opportunity to take this strain variation into account when describing aspects of C. auris biology. Here, we critically review the literature to gain insight into differences at both the strain and clade levels in C. auris, focusing on phenotypes associated with clinical disease or transmission. Our goal is to integrate clinical and epidemiological perspectives with molecular perspectives in a way that would be valuable for both audiences. Identifying differences between strains and understanding which phenotypes are strain specific will be crucial for understanding this emerging pathogen, and an important caveat when describing the analysis of a singular isolate.
Introduction. Osteoarthritis is a disease characterized by progressive wear and tear of the joint, with the knee being the most affected region. These patients have reduced mobility and mobility, ...among other symptoms. Thus, it is necessary to know the variables that influence the ability to walk. Objective. To analyze how much the gait capacity, in the performance of the six-minute walk test, can be influenced by the maximum isometric strength of the quadriceps or by kinesiophobia in women with knee osteoarthritis. Materials and Methods. This is a cross-sectional study with a sample of 49 women diagnosed with osteoarthritis. The evaluation was carried out in a single moment. Variables studied isometric quadriceps strength, level of fear of movement (kinesiophobia), and ability to walk. Simple linear regression analyzes were performed, with gait ability as the dependent variable and maximum isometric strength and kinesiophobia as independent. Data were presented with mean and standard deviation and were analyzed by the SPSS Statistic 22.0 software, considering p<0.05 as significant. Results. The maximum isometric strength presents a significant difference, directly interfering with the gait ability; as kinesiophobia does not show a statistically significant difference, it does not directly interfere with the ability to walk. Conclusion. Maximal quadriceps isometric strength directly interferes with gait ability in women with knee osteoarthritis, thus suggesting the inclusion of this strategy in treatment programs for this population.
Given concerns about potential toxicological hazards of the thousands of data-poor per- and polyfluorinated alkyl substances (PFAS) currently in commerce and detected in the environment, tiered ...testing strategies that employ high-throughput in vitro screening as an initial testing tier have been implemented. The present study evaluated the effectiveness of previous in vitro screening for identifying PFAS capable, or incapable, of inducing estrogenic responses in fish exposed in vivo. Fathead minnows (Pimephales promelas) were exposed for 96 h to five PFAS (perfluorooctanoic acid PFOA; 1H,1H,8H,8H-perfluorooctane-1,8-diol FC8-diol; 1H,1H,10H,10H-perfluorodecane-1,10-diol FC10-diol; 1H,1H,8H,8H-perfluoro-3,6-dioxaoctane-1,8-diol FC8-DOD; and perfluoro-2-methyl-3-oxahexanoic acid HFPO-DA) that showed varying levels of in vitro estrogenic potency. In agreement with in vitro screening results, exposure to FC8-diol, FC10-diol, and FC8-DOD caused concentration-dependent increases in the expression of transcript coding for vitellogenin and estrogen receptor alpha and reduced expression of insulin-like growth factor and apolipoprotein eb. Once differences in bioconcentration were accounted for, the rank order of potency in vivo matched that determined in vitro. These results provide a screening level benchmark for worst-case estimates of potential estrogenic hazards of PFAS and a basis for identifying structurally similar PFAS to scrutinize for putative estrogenic activity.
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