The occurrence of pharmaceuticals in source waters is increasing. Although UV advanced oxidation is known to be an effective barrier against micropollutants, degradation rates are only available for ...limited amounts of pharmaceuticals. Therefore, the degradation of a large group of pharmaceuticals has been studied in this research for the UV/H2O2 process under different conditions, including pharmaceuticals of which the degradation by UV/H2O2 was never reported before (e.g., metformin, paroxetine, pindolol, sotalol, venlafaxine, etc.). Monochromatic low pressure (LP) and polychromatic medium pressure (MP) lamps were used for three different water matrices. In order to have well defined hydraulic conditions, all experiments were conducted in a collimated beam apparatus. Degradation rates for the pharmaceuticals were determined. For those compounds used in this research that are also reported in literature, measured degradation results are in good agreement with literature data. Pharmaceutical degradation for only photolysis with LP lamps is small, which is increased by using a MP lamp. Most of the pharmaceuticals are well removed when applying both UV (either LP or MP) and H2O2. However, differences in degradation rates between pharmaceuticals can be large. For example, ketoprofen, prednisolone, pindolol are very well removed by UV/H2O2, whereas metformin, cyclophosphamide, ifosfamide are very little removed by UV/H2O2.
Display omitted
•Degradation of 40 pharmaceuticals by UV/H2O2.•Some were not yet reported (metformin, paroxetine, pindolol, sotalol, venlafaxine).•Comparison of pharmaceutical degradation by low-pressure (LP) and medium-pressure (MP) UV lamps.•Comparison of pharmaceutical degradation by UV/H2O2 for different water matrices.
Abstract
Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to ...poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (Le
Y
)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, Le
Y
CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although Le
Y
CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.
UV/H2O2 treatment is a well-established technique to degrade organic micropollutants. A CFD model in combination with an advanced kinetic model is presented to predict the degradation of organic ...micropollutants in UV (LP)/H2O2 reactors, accounting for the hydraulics, fluence rate, complex (photo)chemical reactions in the water matrix and the interactions between these processes. The model incorporates compound degradation by means of direct UV photolysis, OH radical and carbonate radical reactions. Measurements of pharmaceutical degradations in pilot-scale UV/H2O2 reactors are presented under different operating conditions. A comparison between measured and modeled degradation for a group of 35 pharmaceuticals resulted in good model predictions for most of the compounds. The research also shows that the degradation of organic micropollutants can be dependent on temperature, which is relevant for full-scale installations that are operated at different temperatures over the year.
Display omitted
•Prediction of degradation of organic micropollutants by UV/H2O2 reactors.•Combination of CFD model and (photo) kinetic model.•Validation of model with UV/H2O2 pilot reactors with large group of pharmaceuticals.•Validation of model under different operating conditions.•Influence of water temperature on pharmaceutical degradation is studied.
To develop and validate a prognostic model for incident knee osteoarthritis (KOA) in a general population and determine the value of different risk factor groups to prediction.
The prognostic model ...was developed in 2628 individuals from the Rotterdam Study-I (RS-I). Univariate and multivariate analyses were performed for questionnaire/easily obtainable variables, imaging variables, genetic and biochemical markers. The extended multivariate model was tested on discrimination (receiver operating characteristic curve and area under the curve (AUC)) in two other population-based cohorts: Rotterdam Study-II and Chingford Study.
In RS-I, there was moderate predictive value for incident KOA based on the genetic score alone in subjects aged <65 years (AUC 0.65), while it was only 0.55 for subjects aged ≥65 years. The AUC for gender, age and body mass index (BMI) in prediction for KOA was 0.66. Addition of the questionnaire variables, genetic score or biochemical marker urinary C-terminal cross-linked telopeptide of type II collagen to the model did not change the AUC. However, when adding the knee baseline KL score to the model the AUC increased to 0.79. Applying external validation, similar results were observed in the Rotterdam Study-II and the Chingford Study.
Easy obtainable 'Questionnaire' variables, genetic markers, OA at other joint sites and biochemical markers add only modestly to the prediction of KOA incidence using age, gender and BMI in an elderly population. Doubtful minor radiographic degenerative features in the knee, however, are a very strong predictor of future KOA. This is an important finding, as many radiologists do not report minor degenerative changes in the knee.
Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the ...potential to improve prediction.
To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.
Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.
Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.
Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.
Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval CI, 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio HR, 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 95% CI, 2.3-3.7 for men vs 3.0 95% CI, 2.0-4.4 for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.
Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.
How Ribosomes Translate Cancer Sulima, Sergey O; Hofman, Isabel J F; De Keersmaecker, Kim ...
Cancer discovery,
10/2017, Letnik:
7, Številka:
10
Journal Article
Odprti dostop
A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the ...relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis-from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on "onco-ribosomes" as an Achilles' heel of cancer cells and a promising target for further therapeutic intervention.
The recent discovery of somatic mutations in ribosomal proteins in several cancers has strengthened the link between ribosome defects and cancer progression, while also raising the question of which cellular mechanisms such defects exploit. Here, we discuss the emerging molecular mechanisms by which ribosomes support oncogenesis, and how this understanding is driving the design of novel therapeutic strategies.
Satellite telemetry is an increasingly utilized technology in wildlife research, and current devices can track individual animal movements at unprecedented spatial and temporal resolutions. However, ...as we enter the golden age of satellite telemetry, we need an in-depth understanding of the main technological, species-specific and environmental factors that determine the success and failure of satellite tracking devices across species and habitats. Here, we assess the relative influence of such factors on the ability of satellite telemetry units to provide the expected amount and quality of data by analyzing data from over 3,000 devices deployed on 62 terrestrial species in 167 projects worldwide. We evaluate the success rate in obtaining GPS fixes as well as in transferring these fixes to the user and we evaluate failure rates. Average fix success and data transfer rates were high and were generally better predicted by species and unit characteristics, while environmental characteristics influenced the variability of performance. However, 48% of the unit deployments ended prematurely, half of them due to technical failure. Nonetheless, this study shows that the performance of satellite telemetry applications has shown improvements over time, and based on our findings, we provide further recommendations for both users and manufacturers.
Summary Background Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated ...with bone mineral density. Methods In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. Findings We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10−8 ). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10−12 for lumbar spine and p=1·9×10−4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio OR 1·3, 95% CI 1·09–1·52, p=0·002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10−10 for lumbar spine and p=3·3×10−8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10−6 ). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10−17 ). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density. Interpretation Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening. Funding Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.
Objectives
Physical activity (PA) is associated with health-related quality of life (HRQL). The specific PA types that provide beneficial effects in an older population remain unclear. We assessed ...the association of total PA, walking, cycling, domestic work, sports and gardening with HRQL in middle-aged and elderly adults.
Design
Cross-sectional study.
Setting
Rotterdam, the Netherlands.
Participants
5,554 participants, with a mean age of 69 years.
Measurements
Total PA was categorized in five groups to evaluate the dose-response effect of PA and specific PA types were categorized in tertiles. HRQL was measured with the EuroQoL 5-dimension. The outcome of every HRQL domain (i.e. mobility, self-care, daily activities, pain and mood) was expressed as having any problems versus not having problems. Logistic and linear regression analyses were used, adjusting for confounders, to examine associations of total PA and PA types with HRQL domains.
Results
In both middle-aged (<65 years) and elderly adults (>65 years), we found a dose-response association between total PA and better HRQL (i.e. lower odds of having problems in HRQL domains). In the middle-aged, sports was the only PA type associated with lower odds of having problems with all HRQL domains. In the elderly, all PA types were associated with less problems with HRQL domains, but cycling contributed most to the beneficial effect.
Conclusions
Total PA was associated with better HRQL. Sports and cycling were the activity types that contributed most to this association in the middle-aged and elderly, respectively. Since PA levels tend to decline with aging, cycling and sports should be promoted with the aim to improve HRQL.
Outcome after Complicated Minor Head Injury Smits, M; Hunink, M.G.M; van Rijssel, D.A ...
American journal of neuroradiology : AJNR,
03/2008, Letnik:
29, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Functional outcome in patients with minor head injury with neurocranial traumatic findings on CT is largely unknown. We hypothesized that certain CT findings may be predictive of poor functional ...outcome.
All patients from the CT in Head Injury Patients (CHIP) study with neurocranial traumatic CT findings were included. The CHIP study is a prospective, multicenter study of consecutive patients, > or =16 years of age, presenting within 24 hours of blunt head injury, with a Glasgow Coma Scale (GCS) score of 13-14 or a GCS score of 15 and a risk factor. Primary outcome was functional outcome according to the Glasgow Outcome Scale (GOS). Other outcome measures were the modified Rankin Scale (mRS), the Barthel Index (BI), and number and severity of postconcussive symptoms. The association between CT findings and outcome was assessed by using univariable and multivariable regression analysis.
GOS was assessed in 237/312 patients (76%) at an average of 15 months after injury. There was full recovery in 150 patients (63%), moderate disability in 70 (30%), severe disability in 7 (3.0%), and death in 10 (4.2%). Outcome according to the mRS and BI was also favorable in most patients, but 82% of patients had postconcussive symptoms. Evidence of parenchymal damage was the only independent predictor of poor functional outcome (odds ratio = 1.89, P = .022).
Patients with neurocranial complications after minor head injury generally make a good functional recovery, but postconcussive symptoms may persist. Evidence of parenchymal damage on CT was predictive of poor functional outcome.
PDF
