Diagnostic DNA Methylation Biomarkers for Renal Cell Carcinoma:A Systematic Review

CONTEXT: The 5-yr survival of early-stage renal cell carcinoma (RCC) is approximately 93%, but once metastasised, the 5-yr survival plummets to 12%, indicating that early RCC detection is crucial to improvement in survival. DNA methylation biomarkers have been suggested to be of potential diagnostic value; however, their current state of clinical translation is unclear and a comprehensive overview is lacking. OBJECTIVE: To systematically review and summarise all literature regarding diagnostic DNA methylation biomarkers for RCC. EVIDENCE ACQUISITION: We performed a systematic literature review of PubMed, EMBASE, Medline, and Google Scholar up to January 2019, according to the Preferred Reporting Items for Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines. Included studies were scored according to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forest plots were generated to summarise diagnostic performance of all biomarkers. Level of evidence (LoE) and potential risk of bias were determined for all included studies. EVIDENCE SYNTHESIS: After selection, 19 articles reporting on 44 diagnostic DNA methylation biomarkers and 11 multimarker panels were included; however, only 15 biomarkers were independently validated. STARD scores varied from 4 to 13 out of 23 points, with a median of 10 points. Large variation in subgroups, methods, and primer locations was observed. None of the reported biomarkers exceeded LoE III, and the majority of studies reported inadequately. CONCLUSIONS: None of the reported biomarkers exceeded LoE III, indicating their limited clinical utility. Moreover, study reproducibility and further development of these RCC biomarkers are greatly hampered by inadequate reporting. PATIENT SUMMARY: In this report, we reviewed whether specific biomarkers could be used to diagnose the most common form of kidney cancer. We conclude that due to limited evidence and reporting inconsistencies, none of these biomarkers can be used in clinical practice, and further development towards clinical use is hindered

A dedicated computer system for FM-CW radar applications, Journal of Telecommunications and Information Technology, 2001, nr 4

In this paper, a DSP based computer system for FM-CW radar applications is described. Besides data acquisition and storage, the computer system will also be used for front-end data processing and system control. Processing includes filtering and clutter suppression. The radar for which the computer is designed is a multi parameter atmospheric profiler capable of doing Doppler and polarimetric measurements. The computer system will allow for a measurement of the full polarimetric scattering matrix over 512 range cells and 512 Doppler cells in 2 s. Radar system control includes the timing and the settings of the radar system together with linearity correction of the sweep oscillator

Monitoring SARS-CoV-2 Circulation and Diversity through Community Wastewater Sequencing, the Netherlands and Belgium

Severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has rapidly become a major global health problem, and public health surveillance is crucial to monitor and prevent virus spread. Wastewater-based epidemiology has been proposed as an addition to disease-based surveillance because virus is shed in the feces of ≈40% of infected persons. We used next-generation sequencing of sewage samples to evaluate the diversity of SARS-CoV-2 at the community level in the Netherlands and Belgium. Phylogenetic analysis revealed the presence of the most prevalent clades (19A, 20A, and 20B) and clustering of sewage samples with clinical samples from the same region. We distinguished multiple clades within a single sewage sample by using low-frequency variant analysis. In addition, several novel mutations in the SARS-CoV-2 genome were detected. Our results illustrate how wastewater can be used to investigate the diversity of SARS-CoV-2 viruses circulating in a community and identify new outbreaks

Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Funding Cancer Research UK, Medical Research Council

Droplet digital RT-PCR to detect SARS-CoV-2 signature mutations of variants of concern in wastewater

Wastewater surveillance has shown to be a valuable and efficient tool to obtain information about the trends of COVID-19 in the community. Since the recent emergence of new variants, associated with increased transmissibility and/or antibody escape (variants of concern), there is an urgent need for methods that enable specific and timely detection and quantification of the occurrence of these variants in the community. In this study, we demonstrate the use of RT-ddPCR on wastewater samples for specific detection of mutation N501Y. This assay enabled simultaneous enumeration of lineage B.1.351 (containing the 501Y mutati

Mobility and redox transformation of arsenic during treatment of artificially recharged groundwater for drinking water production

In this study we investigate opportunities for reducing arsenic (As) to low levels, below 1 μg/L in produced drinking water from artificially infiltrated groundwater. We observe that rapid sand filtration is the most important treatment step for the oxidation and removal of As at water treatment plants which use artificially recharged groundwater as source. Removal of As is mainly due to As co-precipitation with Fe(III)(oxyhydr)oxides, which shows higher efficiency in rapid sand filter beds compared to aeration and supernatant storage. This is due to an accelerated oxidation of As(III) to As(V) in the filter bed which may be caused by the manganese oxides and/or As(III) oxidizing bacteria, as both are found in the coating of rapid sand filter media grains by chemical analysis and taxonomic profiling of the bacterial communities. Arsenic removal does not take place in treatment steps such as granular activated carbon filtration, ultrafiltration or slow sand filtration, due to a lack of hydrolyzing iron in their influent and a lack of adsorption affinity between As and the filtration surfaces. Further, we found that As reduction to below 1 μg/L can be effectively achieved at water treatment plants either by treating the influent of rapid sand filters by dosing potassium permanganate in combination with ferric chloride or by treating the effluent of rapid sand filters with ferric chloride dosing only. Finally, we observe that reducing the pH is an effective measure for increasing As co-precipitation with Fe(III)(oxyhydr)oxides, but only when the oxidized arsenic, As(V), is the predominant species in water

Prevalence and circulation patterns of SARS-CoV-2 variants in European sewage mirror clinical data of 54 European cities

For community-level monitoring, the European Commission under the EU Sewage Sentinel System recommends wastewater-based SARS-CoV-2 surveillance. Tracking SARS-CoV-2 variants in a community is pivotal for appropriate public health response. Genome sequencing of SARS-CoV-2 in wastewater samples for tracking variants is challenging, often resulting in low coverage genome sequences, thereby impeding the detection of the SARS-CoV-2 mutations. Therefore, we aimed at high-coverage SARS-CoV-2 genome sequences from sewage samples which we successfully accomplished. This first pan-European surveillance compared the mutation profiles associated with the variants of concerns: B.1.1.7, P.1, B.1.351 and B.1.617.2 across 20 European countries, including 54 municipalities. The results highlight that SARS-CoV-2 variants detected in the wastewater samples mirror the variants profiles reported in clinical data. This study demonstrated that >98% coverage of SARS-CoV-2 genomic sequences is possible and can be used to track SARS-CoV-2 mutations in wastewater to support identifying variants circulating in a city at the community level

Mobility and redox transformation of arsenic during treatment of artificially recharged groundwater for drinking water production

In this study we investigate opportunities for reducing arsenic (As) to low levels, below 1 μg/L in produced drinking water from artificially infiltrated groundwater. We observe that rapid sand filtration is the most important treatment step for the oxidation and removal of As at water treatment plants which use artificially recharged groundwater as source. Removal of As is mainly due to As co-precipitation with Fe(III)(oxyhydr)oxides, which shows higher efficiency in rapid sand filter beds compared to aeration and supernatant storage. This is due to an accelerated oxidation of As(III) to As(V) in the filter bed which may be caused by the manganese oxides and/or As(III) oxidizing bacteria, as both are found in the coating of rapid sand filter media grains by chemical analysis and taxonomic profiling of the bacterial communities. Arsenic removal does not take place in treatment steps such as granular activated carbon filtration, ultrafiltration or slow sand filtration, due to a lack of hydrolyzing iron in their influent and a lack of adsorption affinity between As and the filtration surfaces. Further, we found that As reduction to below 1 μg/L can be effectively achieved at water treatment plants either by treating the influent of rapid sand filters by dosing potassium permanganate in combination with ferric chloride or by treating the effluent of rapid sand filters with ferric chloride dosing only. Finally, we observe that reducing the pH is an effective measure for increasing As co-precipitation with Fe(III)(oxyhydr)oxides, but only when the oxidized arsenic, As(V), is the predominant species in water.</p

Development and validation of an analytical method using UPLC–MS/MS to quantify everolimus in dried blood spots in the oncology setting

While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated. An 7.5 mm disk from the central part of the DBS was punched, followed by the extraction of everolimus from the DBS by methanol/acetonitrile (80/20%) spiked with deuterium-labelled everolimus as internal standard. Subsequently, everolimus was separated and analyzed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The UPLC–MS/MS method was validated according to the European Medicine Agency (EMA) guideline. Everolimus concentrations could be quantified over the range of 3–75 μg/L. The intra- and inter-assay precision and accuracy of the method were shown to be acceptable (coefficient of variation ≤10.7% and relative error ≤4.4%, respectively). The matrix effects appeared to be influenced by the hematocrit effect. The hematocrit effect was tested in a range of 0.20–0.50 L/L, at which hematocrit accuracy and precision were satisfactory at values ≥0.25 L/L. However, at 0.20 L/L hematocrit in combination with high everolimus concentrations of 20 and 40 μg/L, the precision was adequate (≤7.4%), but the accuracy was &gt;15% of the nominal concentration. Everolimus was stable in DBS for at least 80 days at 2–8 °C. Given these results, the everolimus DBS method has been successfully developed and validated. Special attention is necessary for cancer patients with both a 0.20 L/L hematocrit in combination with everolimus concentrations ≥20 μg/L. A clinical validation for the use of everolimus DBS in cancer patients is currently being undertaken.</p

Monitoring the integrity of reverse osmosis membranes using novel indigenous freshwater viruses and bacteriophages

High pressure membranes are increasingly used for the treatment of contaminated water for various purposes including irrigation and drinking water. The lack of a fast and easy to implement membrane integrity test method with a log removal value (LRV) &gt;3 hampers the implementation of these membranes. Current on-line methods include conductivity, TOC (total organic carbon) and turbidity measurements and can monitor a maximum LRV of 3. Furthermore, challenge tests using chemical or bacteriological virus surrogates such as bacteriophage MS2 show that RO and NF systems can reach LRVs of 6-7, but dosing of these surrogates is not feasible and desirable in full scale drinking water plants. This study describes the identification and use of indigenous viruses, naturally present in surface waters to monitor the integrity of RO membranes in a pilot installation. Natural viruses were identified from fresh source water using metagenomics and qPCR primers developed for a selected set of viruses that were present in high numbers in surface water. The qPCR assays were used to determine the number of gene copies of these viruses in the feed and permeate of the pilot RO installation, and the LRV of these natural viruses was compared with the LRV of spiked MS2 and with on-line conductivity. The concentration of the selected natural viruses in the source water was sufficient to demonstrate a LRV of &gt;7 and was comparable to the results of the spiked MS2 bacteriophage. Furthermore, after inflicting damage to the membrane element by drilling small holes of 1 and 4 mm, both MS2 and the natural viruses detected the damage to the membrane with a nearly identical decrease of LRV, while conductivity lacked sensitivity to monitor any integrity loss. This novel method enables monitoring of the RO membrane integrity at a high sensitivity (LRV &gt; 7), without the addition of chemical or biological virus surrogates. Furthermore, the high concentration of viruses in source water simplifies detection without laborious sample concentration procedures. The implementation of this method facilitates monitoring of the integrity of RO membranes in full scale operation with a much higher sensitivity than current methods.Sanitary Engineerin