Methods standardisation in microplastics research is needed. Apart from reagent-dependent effects on microplastics, varying target particle sizes can hinder result comparison between studies. Human ...health concerns warrant recovery of small microplastics. We compared existing techniques using hydrogen peroxide, Proteinase-K, Trypsin and potassium hydroxide to digest bivalve tissue. Filterability, digestion efficacy, recoverability of microplastics and subsequent polymer identification using Raman spectroscopy and a matching software were assessed. Only KOH allowed filtration at ≤25 μm. When adding a neutralisation step prior to filtration, KOH digestates were filterable using 1.2-μm filters. Digestion efficacies were >95.0% for oysters, but lower for clams. KOH destroyed rayon at 60 °C but not at 40 °C. Acrylic fibre identification was affected due to changes in Raman spectra peaks. Despite those effects, we recommend KOH as the most viable extraction method for exposure risk studies, due to microplastics recovery from bivalve tissues of single-digit micrometre size.
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•Neutralising KOH prior to filtration allows for recovery of particles to 1.2 μm.•Polymer damage can be prevented by incubating samples at 40 °C instead of 60 °C.•Validation with an extended range of microplastics, including fibres and film.•Ultrapure water can effect Raman spectra.•Evaluation of Raman spectra of KOH-exposed microplastics with a matching software.
High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 ...mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer.
In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment.
Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6–81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2–69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9–72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7–36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33–0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 39% of 36 patients in the gemcitabine alone group vs 16 47% of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two 6% vs eight 24%). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis.
To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting.
US National Cancer Institute.
Dynamic population mapping using mobile phone data Deville, Pierre; Linard, Catherine; Martin, Samuel ...
Proceedings of the National Academy of Sciences - PNAS,
11/2014, Letnik:
111, Številka:
45
Journal Article
Recenzirano
Odprti dostop
During the past few decades, technologies such as remote sensing, geographical information systems, and global positioning systems have transformed the way the distribution of human population is ...studied and modeled in space and time. However, the mapping of populations remains constrained by the logistics of censuses and surveys. Consequently, spatially detailed changes across scales of days, weeks, or months, or even year to year, are difficult to assess and limit the application of human population maps in situations in which timely information is required, such as disasters, conflicts, or epidemics. Mobile phones (MPs) now have an extremely high penetration rate across the globe, and analyzing the spatiotemporal distribution of MP calls geolocated to the tower level may overcome many limitations of census-based approaches, provided that the use of MP data is properly assessed and calibrated. Using datasets of more than 1 billion MP call records from Portugal and France, we show how spatially and temporarily explicit estimations of population densities can be produced at national scales, and how these estimates compare with outputs produced using alternative human population mapping methods. We also demonstrate how maps of human population changes can be produced over multiple timescales while preserving the anonymity of MP users. With similar data being collected every day by MP network providers across the world, the prospect of being able to map contemporary and changing human population distributions over relatively short intervals exists, paving the way for new applications and a near real-time understanding of patterns and processes in human geography.
Microplastics are contaminants of emerging concern; they are ingested by marine biota. About a quarter of global marine fish landings is used to produce fishmeal for animal and aquaculture feed. To ...provide a knowledge foundation for this matrix we reviewed the existing literature for studies of microplastics in fishmeal-relevant species. 55% of studies were deemed unsuitable due to focus on large microplastics (> 1 mm), lack of, or limited contamination control and polymer testing techniques. Overall, fishmeal-relevant species exhibit 0.72 microplastics/individual, with studies generally only assessing digestive organs. We validated a density separation method for effectiveness of microplastic extraction from this medium and assessed two commercial products for microplastics. Recovery rates of a range of dosed microplastics from whitefish fishmeal samples were 71.3 ± 1.2%. Commercial samples contained 123.9 ± 16.5 microplastics per kg of fishmeal-mainly polyethylene-including 52.0 ± 14.0 microfibres-mainly rayon. Concentrations in processed fishmeal seem higher than in captured fish, suggesting potential augmentation during the production process. Based on conservative estimates, over 300 million microplastic particles (mostly < 1 mm) could be released annually to the oceans through marine aquaculture alone. Fishmeal is both a source of microplastics to the environment, and directly exposes organisms for human consumption to these particles.
Small-molecule synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of ...compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block–based synthesis platform to include even Csp3-rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-molecule synthesis.
Summary
Background
Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC).
Aim
To evaluate effectiveness, safety and use of tofacitinib in daily practice.
...Methods
UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid‐free clinical remission (short clinical colitis activity index SCCAI ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid‐free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation.
Results
In total, 123 UC patients (95% anti‐TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12‐26). The proportion of patients in corticosteroid‐free clinical, biochemical, and combined corticosteroid‐free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval CI 0.11‐0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib‐related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9‐26), 18% (95% CI 8‐28) and 21% (95% CI 14‐39) respectively.
Conclusion
Tofacitinib is an effective treatment for UC after anti‐TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.
Semi-arid areas, defined as those areas of the world where water is an important limitation for plant growth, have become the subject of increased interest due to the impacts of current global ...changes and sustainability of human lifestyles. While many ground-based reports of declining vegetation productivity have been published over the last decades, a number of recent publications have shown a nuanced and, for some regions, positive picture. With this background, the paper provides an analysis of trends in vegetation greenness of semi-arid areas using AVHRR GIMMS from 1981 to 2007. The vegetation index dataset is used as a proxy for vegetation productivity and trends are analyzed for characterization of changes in semi-arid vegetation greenness. Calculated vegetation trends are analyzed with gridded data on potential climatic constraints to plant growth to explore possible causes of the observed changes. An analysis of changes in the seasonal variation of vegetation greenness and climatic drivers is conducted for selected regions to further understand the causes of observed inter-annual vegetation changes in semi-arid areas across the globe. It is concluded that semi-arid areas, across the globe, on average experience an increase in greenness (0.015 NDVI units over the period of analysis). Further it is observed that increases in greenness are found both in semi-arid areas where precipitation is the dominating limiting factor for plant production (0.019 NDVI units) and in semi-arid areas where air temperature is the primarily growth constraint (0.013 NDVI units). Finally, in the analysis of changes in the intra-annual variation of greenness it is found that seemingly similar increases in greenness over the study period may have widely different explanations. This implies that current generalizations, claiming that land degradation is ongoing in semi-arid areas worldwide, are not supported by the satellite based analysis of vegetation greenness.
► Trends in dryland vegetation greenness (NDVI) based on AVHRR data are analyzed. ► Climatic constraints to plant growth are anlysed to study causes of NDVI changes. ► Global drylands on average experience an increase in NDVI from 1981 to 2007. ► Trends have regional specific explanations and generalizations are not supported.
Summary
Background
Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 ...months of treatment.
Aim
The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands.
Methods
Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid‐free clinical remission (CSFR, Simple Clinical Colitis Activity Index SCCAI ≤2) at week 104. Secondary outcomes included biochemical remission (C‐reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 μg/g), safety, and discontinuation rate.
Results
We included 110 patients of whom 104 (94.5%) were anti‐TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty‐one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7–34). The main reasons for discontinuation were non‐response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib‐related adverse events per 100 patient‐years during follow‐up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient‐years.
Conclusion
Tofacitinib was effective in 31.8% of patients after 24 months of treatment.
Effectiveness and safety of tofacitinib for ulcerative colitis: Two‐year results of the ICC Registry
The pyrochlore solid solution (Na0.33Ce0.67)2(Ir1−xRux)2O7 (0≤x≤1), containing B‐site RuIV and IrIV is prepared by hydrothermal synthesis and used as a catalyst layer for electrochemical oxygen ...evolution from water at pH<7. The materials have atomically mixed Ru and Ir and their nanocrystalline form allows effective fabrication of electrode coatings with improved charge densities over a typical (Ru,Ir)O2 catalyst. An in situ study of the catalyst layers using XANES spectroscopy at the Ir LIII and Ru K edges shows that both Ru and Ir participate in redox chemistry at oxygen evolution conditions and that Ru is more active than Ir, being oxidized by almost one oxidation state at maximum applied potential, with no evidence for ruthenate or iridate in +6 or higher oxidation states.
Ru/Ir cooperativity: A pyrochlore solid solution (Na0.33Ce0.67)2(Ir1−xRux)2O7 formed as nanocrystalline powder under hydrothermal conditions shows high activity for electrochemical oxygen evolution in aqueous acid. In situ XAFS experiments show a cooperative effect of Ru and Ir that depends on the composition of the material. OER=oxygen evolution reaction.
Physiological homeostasis is essential for organism survival. Highly responsive neuronal networks are involved, but their constituent neurons are just beginning to be resolved. To query brain ...serotonergic neurons in homeostasis, we used a neuronal silencing tool, mouse RC::FPDi (based on the synthetic G protein—coupled receptor Di), designed for cell type—specific, ligand-inducible, and reversible suppression of action potential firing. In mice harboring Di-expressing serotonergic neurons, administration of the ligand clozapine-N-oxide (CNO) by systemic injection attenuated the chemoreflex that normally increases respiration in response to tissue carbon dioxide (CO 2 ) elevation and acidosis. At the cellular level, CNO suppressed firing rate increases evoked by CO 2 acidosis. Body thermoregulation at room temperature was also disrupted after CNO triggering of Di; core temperatures plummeted, then recovered. This work establishes that serotonergic neurons regulate life-sustaining respiratory and thermoregulatory networks, and demonstrates a noninvasive tool for mapping neuron function.
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