Biomarker profiling in plants to distinguish between exposure to chlorine gas and bleach using LC-HRMS/MS and chemometrics

Since its first employment in World War I, chlorine gas has often been used as chemical warfare agent. Unfortunately, after suspected release, it is difficult to prove the use of chlorine as a chemical weapon and unambiguous verification is still challenging. Furthermore, similar evidence can be found for exposure to chlorine gas and other, less harmful chlorinating agents. Therefore, the current study aims to use untargeted high resolution mass spectrometric analysis of chlorinated biomarkers together with machine learning techniques to be able to differentiate between exposure of plants to various chlorinating agents. Green spire (Euonymus japonicus), stinging nettle (Urtica dioica), and feathergrass (Stipa tenuifolia) were exposed to 1000 and 7500 ppm chlorine gas and household bleach, pool bleach, and concentrated sodium hypochlorite. After sample preparation and digestion, the samples were analyzed by liquid chromatography high resolution tandem mass spectrometry (LC-HRMS/MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS). More than 150 chlorinated compounds including plant fatty acids, proteins, and DNA adducts were tentatively identified. Principal component analysis (PCA) and linear discriminant analysis (LDA) showed clear discrimination between chlorine gas and bleach exposure and grouping of the samples according to chlorine concentration and type of bleach. The identity of a set of novel biomarkers was confirmed using commercially available or synthetic reference standards. Chlorodopamine, dichlorodopamine, and trichlorodopamine were identified as specific markers for chlorine gas exposure. Fenclonine (Cl-Phe), 3-chlorotyrosine (Cl-Tyr), 3,5-dichlorotyrosine (di-Cl-Tyr), and 5-chlorocytosine (Cl-Cyt) were more abundantly present in plants after chlorine contact. In contrast, the DNA adduct 2-amino-6-chloropurine (Cl-Ade) was identified in both types of samples at a similar level. None of these chlorinated biomarkers were observed in untreated samples. The DNA adducts Cl-Cyt and Cl-Ade could clearly be identified even three months after the actual exposure. This study demonstrates the feasibility of forensic biomarker profiling in plants to distinguish between exposure to chlorine gas and bleach

Vochtvoorziening in keten nog te vaak nattevingerwerk

Om goed de keten door te komen, hebben pot- en containerplanten voldoende vocht nodig. In de parktijk blijkt lang niet altijd aan deze voorwaarde te worden voldaan. Het PPO en HAS Kennis Transfer brachten de praktijk in kaart en stelden een protocol op voor de optimale vochtvoorziening in de afzetketen

Epinephrine auto-injector prescriptions to food-allergic patients in primary care in The Netherlands

BACKGROUND: The knowledge of general practitioner(s) (GPs) regarding food allergy and anaphylaxis and practices in the prescription of epinephrine auto-injector(s) (EAIs) among GPs has previously only been studied using questionnaires and hypothetical cases. Therefore, there are currently no data as to whether or not GPs prescribe EAIs to high risk food-allergic patients presenting to primary care practices. The aim of this study was therefore to describe and evaluate practice in EAI prescription by GPs to food-allergic patients in The Netherlands. METHODS: Patients aged 12–23 years who consulted their GP for allergic symptoms were identified in a primary care database. Patients were classified as probably or unlikely to be food-allergic. A risk factor assessment was done to identify probably food-allergic patients at high risk for anaphylaxis to assess the need for an EAI. RESULTS: One hundred forty-eight out of 1015 patients consulted their GP for allergic symptoms due to food. Eighty patients were excluded from analysis because of incomplete records. Thirty-four patients were classified as probably food-allergic. Twenty-seven of them were considered high risk patients and candidates for an EAI. Importantly, only 10 of them had actually been prescribed an EAI by their GP. CONCLUSIONS: This study shows that high risk food-allergic patients that visit their GPs are often not prescribed an EAI. Thus, previously identified low rates of EAI ownership may be partly due to GPs not prescribing this medication to patients for whom it would be appropriate to do so. These data suggest that there is a need for improvement of the quality of care for high risk food-allergic patients in primary care

Effects of Nightshift Work on Blood Metabolites in Female Nurses and Paramedic Staff: A Cross-sectional Study

Nightshift work disturbs the circadian rhythm, which might contribute to the development of cardio-metabolic disorders. In this cross-sectional study, we aimed to gain insight into perturbations of disease relevant metabolic pathways due to nightshift work. We characterized the metabolic profiles of 237 female nurses and paramedic staff participating in the Klokwerk study using the Nightingale Health platform. We performed analyses on plasma levels of 225 metabolites, including cholesterol, triglycerides, fatty acids, and amino acids. Using both principal component- and univariate-regression, we compared metabolic profiles of nightshift workers to metabolic profiles from workers that did not work night shifts (defined as day workers). We also assessed whether differential effects were observed between recently started versus more experienced workers. Within the group of nightshift workers, we compared metabolic profiles measured right after a nightshift with metabolic profiles measured on a day when no nightshift work was conducted. We observed evidence for an impact of nightshift work on the presence of unfavorable fatty acid profiles in blood. Amongst the fatty acids, effects were most prominent for PUFA/FA ratios (consistently decreased) and SFA/FA ratios (consistently elevated). This pattern of less favorable fatty acid profiles was also observed in samples collected directly after a night shift. Amino acid levels (histidine, glutamine, isoleucine, and leucine) and lipoproteins (especially HDL-cholesterol, VLDL-cholesterol, and triglycerides) were elevated when comparing nightshift workers with day workers. Amino acid levels were decreased in the samples that were collected directly after working a nightshift (compared to levels in samples that were collected during a non-nightshift period). The observed effects were generally more pronounced in samples collected directly after the nightshift and among recently started compared to more experienced nightshift workers. Our finding of a suggested impact of shift work on impaired lipid metabolism is in line with evidence that links disruption of circadian rhythmicity to obesity and metabolic disorders

Comparative assessment of the vulnerability and resilience of deltas, extended version with 14 deltas : work document

Worldwide, deltas host dense populations and are important centres of agricultural and industrial production, and economic activity. Many deltas are areas of great ecological importance as well, featuring wetlands of high and unique biodiversity. Deltas are vulnerable to changes by natural forces and human activities. Major drivers of change are population growth, economic development, climate change and subsidence

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study

Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation. Results: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test). Conclusion: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies

A missing high-spin molecule in the family of cyano-bridged heptanuclear heterometal complexes, [(LCuII)6FeIII(CN)6]3+, and its CoIII and CrIII analogues, accompanied in the crystal by a novel octameric water cluster

Three isostructural cyano-bridged heptanuclear complexes, [{CuII(saldmen)(H2O)}6{MIII(CN)6}](ClO4)3$\cdotp$8H2O (M = FeIII 2; CoIII, 3; CrIII 4), have been obtained by reacting the binuclear copper(II) complex, [Cu2(saldmen)2(mu-H2O)(H2O)2](ClO4)2$\cdotp$2H2O 1, with K3[Co(CN)6], K4[Fe(CN)6], and, respectively, K3[Cr(CN)6] (Hsaldmen is the Schiff base resulted from the condensation of salicylaldehyde with N,N-dimethylethylenediamine). A unique octameric water cluster, with bicyclo[2,2,2]octane-like structure, is sandwiched between the heptanuclear cations in 2, 3 and 4. The cryomagnetic investigations of compounds 2 and 4 reveal ferromagnetic couplings of the central FeIII or CrIII ions with the CuII ions (JCuFe = +0.87 cm-1, JCuCr = +30.4 cm-1). The intramolecular Cu-Cu exchange interaction in 3, across the diamagnetic cobalt(III) ion, is -0.3 cm-1. The solid-state1H-NMR spectra of compounds 2 and 3 have been investigated

Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies

<p>Background: Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.</p> <p>Methods and Findings: We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.</p> <p>Conclusions: Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.</p&gt

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions