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Mariele Feiffer Charão,1,2 Caroline Souto,2 Natália Brucker,1,2 Anelise Barth,1,2 Denise S Jornada,1,3 Daiandra Fagundez,4 Daiana Silva Ávila,4 Vera L Eifler-Lima,1,5 Silvia S Guterres,1,3 Adriana R Pohlmann,1,6 Solange Cristina Garcia1,21Post-Graduate Programme in Pharmaceutical Sciences, 2Laboratory of Toxicology (LATOX), Department of Analysis, Pharmacy Faculty, 3Department of Production and Control of Drugs, Pharmacy Faculty, Federal University of Rio Grande do Sul, Porto Alegre, 4Research Group in Biochemistry and Toxicology in Caenorhabditis elegans (GBToxCE), Federal University of Pampa – UNIPAMPA, Uruguaiana, 5Laboratory of Medical Synthesis Organic (LaSOM), Pharmacy Faculty, 6Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, RS, BrazilAbstract: Caenorhabditis elegans is an alternative in vivo model that is being successfully used to assess the pharmacological and toxic effects of drugs. The exponential growth of nanotechnology requires the use of alternative in vivo models to assess the toxic effects of theses nanomaterials. The use of polymeric nanocapsules has shown promising results for drug delivery. Moreover, these formulations have not been used in cases of intoxication, such as in treatment of paraquat (PQ) poisoning. Thus, the use of drugs with properties improved by nanotechnology is a promising approach to overcome the toxic effects of PQ. This research aimed to evaluate the absorption of rhodamine B-labeled melatonin (Mel)-loaded lipid-core nanocapsules (LNC) by C. elegans, the application of this model in nanotoxicology, and the protection of Mel-LNC against PQ damage. The formulations were prepared by self-assembly and characterized by particle sizing, zeta potential, drug content, and encapsulation efficiency. The results demonstrated that the formulations had narrow size distributions. Rhodamine B-labeled Mel-LNC were orally absorbed and distributed in the worms. The toxicity assessment of LNC showed a lethal dose 50% near the highest dose tested, indicating low toxicity of the nanocapsules. Moreover, pretreatment with Mel-LNC significantly increased the survival rate, reduced the reactive oxygen species, and maintained the development in C. elegans exposed to PQ compared to those worms that were either untreated or pretreated with free Mel. These results demonstrated for the first time the uptake and distribution of Mel-LNC by a nematode, and indicate that while LNC is not toxic, Mel-LNC prevents the effects of PQ poisoning. Thus, C. elegans may be an interesting alternative model to test the nanocapsules toxicity and efficacy.Keywords: C. elegans, nanotoxicology, rhodamine B-labeled polymer

Abstract Background We sought to investigate the relationships among the plasma levels of carotenoids, tocopherols, endogenous antioxidants, oxidative damage and lipid profiles and their possible effects on the cardiovascular risk associated with hemodialysis (HD) patients. Methods The study groups were divided into HD and healthy subjects. Plasma carotenoid, tocopherol and malondialdehyde (MDA) levels, as well as erythrocyte reduced glutathione (GSH), were measured by HPLC. Blood antioxidant enzymes, kidney function biomarkers and the lipid profiles were analyzed by spectrophotometric methods. Results Plasma lycopene levels and blood glutathione peroxidase (GPx) activity were significantly decreased in HD patients compared with healthy subjects. Total cholesterol, low-density lipoprotein cholesterol (LDL-c), creatinine, urea, MDA, GSH, superoxide dismutase (SOD) and catalase (CAT) were significantly increased in HD (p < 0.05). Lycopene levels were correlated with MDA (r = -0.50; p < 0.01), LDL-c (r = -0.38; p = 0.01) levels, the LDL-c/HDL-c index (r = -0.33; p = 0.03) and GPx activity (r = 0.30; p = 0.03). Regression models showed that lycopene levels were correlated with LDL-c (β estimated = -31.59; p = 0.04), while gender was correlated with the TC/HDL-c index and triglycerides. Age did not present a correlation with the parameters evaluated. GPx activity was negatively correlated with MDA levels and with the LDL-c/HDL-c and CT/HDL-c indexes. Conclusions Lycopene may represent an additional factor that contributes to reduced lipid peroxidation and atherogenesis in hemodialysis patients.

Background: 5-Fluorouracil (5-FU) is essential in treating gastrointestinal cancers, but some patients show severe toxicity. The toxicity is exposure-related, which is linked to the enzyme dihydropyrimidine dehydrogenase (DPD) decoded by the DPYD gene. This study aimed to evaluate the possible toxicity related to 5-FU plasma levels, DPYD genotyping, and DPD phenotyping., Methods: Forty-seven gastrointestinal cancer patients receiving 5-FU were included in this study. 5-FU plasma levels and DPD phenotyping were analyzed by UPLC-MS/MS. DPYD genotyping was also assessed. The Common Terminology Criteria for Adverse Events (CTCAE) was used to classify the toxicity., Results: For hematological toxicity, 27.65% showed neutropenia, 78.72% anemia, and 29.78% thrombocytopenia. The area under the curve (AUC) of 5-FU calculated from the plasma was evaluated for three treatment cycles, and we observed that at the initial cycle, 48.93% were underexposed and 10.63% were overexposed, with a total of 59.56% of patients outside the therapeutic range. In the DPYD genotyping, 97.87% of patients had a wild-type genotype, and 2.12% had c.1236G>A mutation (E412E, rs56038477). A total of 82.97% of patients showed a phenotype compatible with normal DPD activity., Conclusion: These findings suggest that the evaluation of DPYD genotyping and DPD phenotyping in the Brazilian population still requires further study. Moreover, the analysis of the plasma AUC of 5-FU could contribute to clinical routine, being a very useful tool, especially for identifying patients outside the therapeutic range and thus guiding more individualized doses, or even in the intervention of possible toxicities related to overexposure., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Urbanization and agricultural activities increased environmental contaminants. Integrated analysis of water parameters and bioassays represents an essential approach to evaluating aquatic resource quality. This study aimed to assess water quality by microbiological and physicochemical parameters as well as the toxicological effects of water samples on the Ames test and Caenorhabditis elegans model. Samples were collected during (collection 1) and after (collection 2) pesticide application in the upper (S1), middle (S2), and lower (S3) sections of the Rolante River, southern Brazil. Metals were determined by GFAAS and pesticides by UPLC-MS/MS. Bioassays using the Ames test and the nematode C. elegans were performed. Levels of microbiological parameters, as well as Mn and Cu were higher than the maximum allowed limits established by legislation in collection 2 compared to collection 1. The presence of pesticide was observed in both collections; higher levels were found in collection 1. No mutagenic effect was detected. Significant inhibition of body length of C. elegans was found in collection 1 at S2 ( P  < 0.001) and S3 ( P  < 0.001) and in collection 2 at S2 ( P  = 0.004). Comparing the same sampling site between collections, a significant difference was found between the site of collection (F(3,6)=8.75, P  = 0.01) and the time of collection (F(1,2)=28.61, P  = 0.03), for the S2 and S3 samples. C. elegans model was useful for assessing surface water quality/toxicity. Results suggest that an integrated analysis for the surface water status could be beneficial for future approaches., Competing Interests: There are no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Therapeutic drug monitoring (TDM) of 5-Fluorouracil (5-FU) is strongly recommended because of its large inter-individual pharmacokinetic variability, narrow therapeutic window, and incidence of toxicity. However, there are several factors that limit the application of TDM in clinical settings. Considering the intrinsic advantages of dried microsamples, such as minimally invasive sampling, analyte stability, and cost-effective logistics, this study aimed to develop a method for the determination of 5-FU in dried blood spots (DBS) using ultra-high liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and to evaluate its clinical application. Sample preparation was based on an aqueous extraction followed by protein precipitation. Separation was performed in an Acquity UPLC® HSS C18 (150 ×2.1 mm, 1.8 µm), and the mobile phases were water and acetonitrile with 0.5% acetic acid. The total run time was 5.5 min. The method was linear from 100 to 2000 ng/mL, precise (maximum CV% of 7.5%), and accurate (98.3-115.4%). The average recovery was 70%. Blood hematocrit had a minimal impact on the assay. DBS samples were stable for 21 days at 4, 25, and 45 °C. A total of 40 paired samples of plasma, capillary DBS, and venous DBS were analyzed. Median 5-FU concentrations were 444.7, 637.0, and 499.7 ng/mL for plasma, capillary DBS, and venous DBS, respectively. Capillary and plasma concentrations were significantly correlated (r > 0.90), but there was a lack of agreement between the methods, as capillary DBS levels were on average 146% of plasma. Venous DBS corresponded to 110% of the measured plasma concentrations, with a strong correlation (r > 0.97) and agreement between the methods. Our study is the first to report the use of DBS samples to quantify 5-FU. Further studies are needed to establish whether capillary samples can replace plasma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Nifedipine (NIFE) is a calcium channel blocker drug used to treat cardiovascular diseases, angina, and hypertension. However, NIFE is photolabile, has a short biological half-life, low aqueous solubility, and undergoes an intense first-pass effect, compromising its oral bioavailability. Thus, this study aimed to develop NIFE-loaded nanocapsules for sublingual administration. Nanocapsule suspensions of Eudragit ® RS100 and medium chain triglycerides containing NIFE were prepared by the interfacial deposition of preformed polymer technique. The developed formulations showed particle size around 170 nm, polydispersity index below 0.2, positive zeta potential, and acid pH. The NIFE content was 0.98 ± 0.03 mg/mL, and the encapsulation efficiency was 99.9%. The natural light photodegradation experiment showed that the nanocapsules were able to provide NIFE photoprotection. The nanocapsules reduced the cytotoxicity of NIFE and showed no genotoxic effects in the Allium cepa model. Through the HET-CAM test, the formulations were classified as non-irritating. The developed nanocapsule suspension demonstrated a controlled release of NIFE and mucoadhesive potential. The in vitro permeation assay showed that the nanocapsules favored the NIFE permeation to the receptor compartment. In addition, the nanocapsules provided greater drug retention in the mucosa. Thus, the development of polymeric nanocapsule suspensions showed that this system could be a promising platform for NIFE sublingual administration.

Rural children are exposed to several chemicals. This study evaluated the environmental co-exposure of rural children to cholinesterase inhibitor insecticides and metals/metalloids, and the resulting oxidative stress and DNA damage. Seventy-two children (5 to 16 years old) were studied at two different moments: period 1, when agrochemicals were less used, and period 2, when agrochemicals were extensively used in agriculture. Biomonitoring was performed by evaluating butyrylcholinesterase (BuChE) activity in serum; arsenic (As), chromium (Cr), lead (Pb), and nickel (Ni) levels in blood; malondialdehyde (MDA) in plasma; glutathione peroxidase (GSH-Px) and glutathione S-transferase (GST) activities in whole blood; non-protein thiol levels in erythrocytes; and micronuclei (MN) assay in exfoliated buccal cells. Cr and As levels were higher than the reference values in both periods, and Ni levels were higher than the reference values in period 2 alone. BuChE activity was inhibited in period 2 compared with period 1. In period 2, there was an increase in endogenous antioxidants and a decrease in MDA, probably demonstrating a compensatory mechanism as a response to increasing xenobiotics. Also in period 2, the MN frequency increased and BuChE and As were positively associated, suggesting co-exposure. On the other hand, in period 1, it was observed that Cr, Ni, and Pb blood levels were negatively associated with GSH-Px and GST, while MDA was positively associated with As levels. Our findings demonstrated an imbalance in endogenous antioxidants, contributing to genotoxicity and lipoperoxidation, probably in response to exposure to xenobiotics, especially carcinogenic elements (Cr, As, and Ni)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Formaldehyde (FA) is a xenobiotic air pollutant and its universal distribution causes a widespread exposure to humans. This review aimed to bring updated information concerning FA toxicity in humans and animals based on in vitro and in vivo studies from 2013 to 2019. Researches were carried out in Pubmed, Scopus, and Science Direct databases to determine the effects of FA exposure on inflammation, oxidative stress and genotoxicity in experimental studies with animals (rats and mice) and humans. Besides, in vitro studies assessing FA cytotoxicity focusing on cell viability and apoptosis in different cell line cultures were reviewed. Studies with humans gave evidence regarding significant deleterious effects on health associated to chronic FA occupational exposure. Evaluations carried out in experimental studies showed toxic effects on different organs as lung, upper respiratory tract, bone marrow and brain as well as in cells. In summary, this study demonstrates that knowing the mechanisms underlying FA toxicity is essential to understand the deleterious effects that this xenobiotic causes on biological systems.

Inhalation of xenobiotics during manufacture process in chrome plating bath produce hazards to workers' health. Chromium (Cr) is a metal widely used by industry, and its hexavalent (VI) form has been classified as mutagenic and carcinogenic. This study aimed to evaluate the occupational risk of exposure to metals in chrome plating workers. Biological monitoring was performed through quantification of Cr, Pb, As, Ni, and V in blood by ICP-MS in 50 male chrome-plating workers from the exposed group and 50 male non-exposed workers. The inflammatory parameters assessed were β-2 integrin, intercellular adhesion molecule-1 (ICAM-1), and L-selectin expression in lymphocytes. The genotoxicity was evaluated with comet and micronucleus (MN) assays and as a biomarker of oxidative damage the lipid peroxidation (MDA) and protein carbonyl (PCO). The results demonstrated that Cr levels in blood and urine were increased in the exposed group compared to the non-exposed group. Although the biomarkers of exposure proved to be within the levels considered safe in exposed individuals, chrome plating workers presented significantly increase in the percentage of lymphocytes expressing β-2 integrin, ICAM-1, and L-selectin as well as DNA damage (comet assay) and plasmatic MDA and PCO levels. Therefore, it is possible also assign the injuries caused to lipids, proteins, and DNA assessed due to the increased presence of other metals such as Pb, As, Ni, and V in exposed subjects. These results suggest that exposure to xenobiotics present in the occupational environment in chrome plating industry could play a crucial role toward the inflammation, genetic, and oxidative damage.

Peripheral biomarkers are important tools for detecting occupational exposures to prevent the onset and/or progression of diseases. Studies that reveal early peripheral biomarkers are highly important to preserve the health of workers and can potentially contribute to diagnosing and/or prognosing occupational pathologies. Exposure to crystalline silica is a problem in several workplaces because it increases the risk of chronic obstructive pulmonary disease (COPD), tuberculosis, cancer, and pulmonary fibrosis, clinically defined as silicosis. Silicosis is diagnosed by chest radiography and/or lung tomography in advanced stages when there is a severe loss of lung function. Peripheral biomarkers can help in diagnosing early changes prior to silicosis and represent a highly important technical-scientific advance that is minimally invasive. This review aimed to investigate the biomarkers studied for evaluating occupational exposure to crystalline silica and to understand the recent advances in this area. Potential oxidative, inflammatory, and immunological biomarkers were reviewed, as well as routine biomarkers such as biochemical parameters. It was found that biomarkers of effect such as serum CC16 and l-selectin levels could represent promising alternatives. Additionally, studies have shown that neopterin levels in urine and serum can be used to monitor worker exposure. However, further studies are needed that include a greater number of participants, different times of exposure to crystalline silica, and a combination of silicosis patients and healthy volunteers. Evaluating the concentration of crystalline silica in occupational environments, its impact on biomarkers of effect, and alterations in lung function could contribute to revealing early health alterations in workers in a more robust manner., (© 2021 John Wiley & Sons, Ltd.)

Agriculture activities have increased the concentration of pesticides and metals in the environment. The excessive use of pesticides can generate an environmental impact and contribute to the development of human diseases. This study aimed to determine the presence of pesticides and metals in water samples collected in the Brazilian rural area in two different periods (before and after pesticide application) and to evaluate the alternative bioassays Lactuca sativa , Allium cepa , and Caenorhabditis elegans to monitoring toxicity in human drinking water samples. Eight sites in the rural area were selected and water samples were collected in two different periods of the year (before and after pesticide application). The presence of the pesticides was determinated by ultra-high performance liquid chromatography-tandem mass spectrometry and metals by inductively coupled plasma mass spectrometry. The potential toxicity of the water samples was performed with three different alternatives in vivo models ( L. sativa , A. cepa , and C. elegans ). Fifty-seven pesticides were analyzed and, according to the results, the most found ones were clomazone, atrazine, tebuconazole, metconazole, pyrimethanil, and carbofuran-3-hydroxide, which is a metabolic degradation product of insecticide carbofuran. The most detected metals were Cu, Cr, Mg, Fe, and Mn. The assays with L. sativa and A. cepa showed alterations in the period after pesticide application, while C. elegans presented changes in both periods compared to the same collection sites. These results indicate that bioassays, especially C. elegans , could be complementary and useful tools for monitoring the toxicity in drinking water samples., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Arsenic (As) causes health effects, especially cancer. Rice ( Oryza sativa L.) can contain high As concentrations. Using ICP-MS, we quantified the total As ( t As) levels in the main brands of rice ( n  = 103) and infant cereals ( n  = 27) consumed by Brazilians. The levels were compared to the maximum limits prescribed by regulatory agencies. We estimated the daily intake (EDI) of As by Brazilians by combining the mean As concentration determined in the white rice samples with per capita daily consumption divided by the average body weight as reported by the Brazilian Institute of Geography and Statistics in 2010. The possible health risk for consumers was assessed by calculating the margin of exposure (MOE) as prescribed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Moreover, t As was determined in 11 pesticides used by Brazilian farmers. The t As levels in the rice ranged from 0.003 to 1.3 mg kg -1 . Approximately 27% of the white rice contained t As levels above the limit set by Mercosul (0.3 mg kg -1 ) and 45% were above the limit set by the European Commission (0.2 mg kg -1 ). In the infant cereals, t As levels ranged from 0.003 to 0.243 mg kg -1 . In the pesticides, t As levels ranged from 0.005 to 0.315 mg L -1 . The EDI showed that, on average, Brazilians consume 4.13 µg As kg -1 BW weekly. In addition, a low MOE was observed, demonstrating that high use of rice presents a risk of high inorganic ( i As) exposure, which represents a public health concern.

UVB radiation-mediated inflammation and the oxidative process involve the transient receptor potential vanilloid 1 (TRPV1) channel activation in neuronal and non-neuronal cells. Once diosmetin has been identified as a novel TRPV1 antagonist, we evaluated the action of diosmetin from the inflammatory [ear oedema, myeloperoxidase (MPO) activity, histological changes, and cytokines levels] and oxidative [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and SOD activities] parameters in mice exposed to UVB radiation (0.5 j/cm 2 ). We also verified the action of diosmetin on UVB radiation-induced inflammatory parameters after cutaneous nerve fibers denervation by RTX (50 µg/kg s.c.). The topical treatment with the novel TRPV1 antagonist, diosmetin (1%; 15 mg/ear), reduced ear oedema, MPO activity, and MIP-2 and IL-1β cytokines levels by 82 ± 8%, 59 ± 10%, 40 ± 12%, and 85 ± 9%, respectively. The action of diosmetin on ear oedema and inflammatory cell infiltration was histologically confirmed. Topical diosmetin (1%) also reduced NADPH oxidase activity by 67 ± 10% and reverted SOD activity by 81 ± 13%. After cutaneous nerve fibers denervation using RTX, diosmetin reduced ear oedema, but not the inflammatory cell infiltration in mice exposed to UVB radiation. Diosmetin can be a promising molecule against skin inflammatory disorders as a result of sunburn induced by UVB radiation exposure.

What Is Known and Objective: Meropenem, a carbapenem antibiotic, is widely prescribed for the treatment of life-threatening infections. The main parameter associated with its therapeutic success is the percentage of time that the levels remain above the minimum inhibitory concentration. Inadequate levels of meropenem can lead to therapeutic failure and increase the possibility of microbial resistance. The employment of strategies involving dose regimens and drug pharmacodynamics has become increasingly important to optimize therapies. In the present study, we conducted a review with the purpose of assembling information about the clinical use of meropenem and therapeutic drug monitoring., Methods: A literature review emphasizing the application of therapeutic drug monitoring (TDM) of meropenem in clinical practice has been done. To identify articles related to the topic, we performed a standardized search from January 21, 2020 to December 21, 2020, using specific descriptors in PubMed, Lilacs and Embase., Results and Discussion: In total, 35 studies were included in the review. The daily dose of meropenem commonly ranged from 3 to 6 g/day. Critically ill patients and those with impaired renal function appear to be the most suitable patients for the application of meropenem TDM, in order to guide therapy. We observed that most of the studies recommend TDM and that, in nine locations, the TDM of meropenem and of other beta-lactams is a routine practice. TDM data can help to maximize the clinical outcomes of the treatment with meropenem. It can also improve the patient care by providing suitable levels of meropenem, guiding the most appropriate dose regimens, which is the main parameter associated with therapeutic success., What Is New and Conclusion: The findings from this review suggest that the therapeutic monitoring of meropenem can be beneficial, since it adjusts the treatment and aids clinical outcomes. It does so by indicating the appropriate dosage and preventing failure, toxicity and possible antimicrobial resistance. The multidisciplinary effort, basic knowledge and communication among the medical team are also essential., (© 2021 John Wiley & Sons Ltd.)

Abstract: Immune checkpoint inhibition has improved the clinical outcomes for numerous patients with cancer. However, the downside is a whole new spectrum of immune-related adverse events. We report a 68-year-old man with a history of nonsmall cell lung cancer presenting with a spontaneous corneal perforation in the right eye after 22 cycles of pembrolizumab. In addition, a chronic central nonhealing epithelial defect developed after performing a penetrating keratoplasty. Treatment with autologous serum drops resulted in complete healing of the corneal ulcer, where other conventional therapies had no effect. One month after reinitiating pembrolizumab therapy, our patient presented again with a corneal perforation in the fellow eye. This case describes relapsing sterile ulcerations associated with pembrolizumab use and presents an unexpected cure., Competing Interests: A. Sandrine has received speakers fees from BMS, Roche, Astra Zeneca, Merck, Pfizer, and Novartis. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The study aimed to evaluate the potential effects of the chronic exposure to chemical agents from air pollution on phenotypic and genotypic expressions of peripheral biomarkers and tumor-related proteins in mononuclear cells. This study evaluates 85 taxi drivers (outdoor workers) and 55 non-occupationally exposed persons (NOE) to air pollution (indoor workers). The biomarkers were urinary 1-hydroxypyrene (1-OHP), for organic agents, and blood As and Ni, for inorganic agents. Oxidative stress biomarkers; protein expression of ICAM-1 (CD54), β2-integrin, L-selectin (CD62-L), and MCP1; gene expression of ICAM-1, p53 and CD26 were performed. Urinary 1-OHP and blood As and Ni levels were increased in taxi drivers and were associated with inflammatory and oxidative stress biomarkers. These exposure biomarkers were also associated with each other, suggesting a common source of exposure. The gene expression of p53, CD26 and ICAM-1 were decreased in taxi drivers and were strongly associated between them, indicating a commom regulation point. The antioxidant non-protein thiols and lycopene were negatively associated with inflammatory biomarkers, maybe regulating the immune-response. We demonstrated, for the first time, that in occupational exposure to air pollution chemicals, oxidative and inflammatory processes are involved in the immune-regulatory process, and indirectly contribute to suppressing the p53 and CD26 expressions, increasing the risk of cancer development. On the other hand, antioxidants could contribute to improving the immune-regulation, but more studies are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Formaldehyde (FA) exposure has been proven to increase the risk of asthma and cancer. This study aimed to evaluate for 28 days the FA inhalation effects on oxidative stress, inflammation process, genotoxicity, and global DNA methylation in mice as well as to investigate the potential protective effects of melatonin. For that, analyses were performed on lung, liver and kidney tissues, blood, and bone marrow. Bronchoalveolar lavage was used to measure inflammatory parameters. Lipid peroxidation (TBARS), protein carbonyl (PCO), non-protein thiols (NPSH), catalase activity (CAT), comet assay, micronuclei (MN), and global methylation were determined. The exposure to 5-ppm FA resulted in oxidative damage to the lung, presenting a significant increase in TBARS and NO levels and a decrease in NPSH levels, besides an increase in inflammatory cells recruited for bronchoalveolar lavage. Likewise, in the liver tissue, the exposure to 5-ppm FA increased TBARS and PCO levels and decreased NPSH levels. In addition, FA significantly induced DNA damage, evidenced by the increase of % tail moment and MN frequency. The pretreatment of mice exposed to FA applying melatonin improved inflammatory and oxidative damage in lung and liver tissues and attenuated MN formation in bone marrow cells. The pulmonary histological study reinforced the results observed in biochemical parameters, demonstrating the potential beneficial role of melatonin. Therefore, our results demonstrated that FA exposure with repeated doses might induce oxidative damage, inflammatory, and genotoxic effects, and melatonin minimized the toxic effects caused by FA inhalation in mice., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To compare the prognostic value and reproducibility of visual versus AI-assisted analysis of lung involvement on submillisievert low-dose chest CT in COVID-19 patients., Materials and Methods: This was a HIPAA-compliant, institutional review board-approved retrospective study. From March 15 to June 1, 2020, 250 RT-PCR confirmed COVID-19 patients were studied with low-dose chest CT at admission. Visual and AI-assisted analysis of lung involvement was performed by using a semi-quantitative CT score and a quantitative percentage of lung involvement. Adverse outcome was defined as intensive care unit (ICU) admission or death. Cox regression analysis, Kaplan-Meier curves, and cross-validated receiver operating characteristic curve with area under the curve (AUROC) analysis was performed to compare model performance. Intraclass correlation coefficients (ICCs) and Bland- Altman analysis was used to assess intra- and interreader reproducibility., Results: Adverse outcome occurred in 39 patients (11 deaths, 28 ICU admissions). AUC values from AI-assisted analysis were significantly higher than those from visual analysis for both semi-quantitative CT scores and percentages of lung involvement (all P<0.001). Intrareader and interreader agreement rates were significantly higher for AI-assisted analysis than visual analysis (all ICC ≥0.960 versus ≥0.885). AI-assisted variability for quantitative percentage of lung involvement was 17.2% (coefficient of variation) versus 34.7% for visual analysis. The sample size to detect a 5% change in lung involvement with 90% power and an α error of 0.05 was 250 patients with AI-assisted analysis and 1014 patients with visual analysis., Conclusion: AI-assisted analysis of lung involvement on submillisievert low-dose chest CT outperformed conventional visual analysis in predicting outcome in COVID-19 patients while reducing CT variability. Lung involvement on chest CT could be used as a reliable metric in future clinical trials., Competing Interests: Conflicts of interest: none declared, (2020 by the Radiological Society of North America, Inc.)

There is a well-recognized association between environmental air pollution exposure and several human diseases. However, the relationship between diseases related to occupational air pollution exposure on roads and high levels of traffic-related air pollutants (TRAPs) is less substantiated. Biomarkers are essential tools in environmental and occupational toxicology, and studies on new biomarkers are increasingly relevant due to the need to determine early biomarkers to be assessed in exposure conditions. This review aimed to investigate the main advances in the biomonitoring of subjects occupationally exposed to air pollution, as well as to summarize the biomarkers of exposure, effect, and susceptibility. Furthermore, we discuss how biomarkers could be used to complement the current application of methods used to assess occupational exposures to xenobiotics present in air pollution. The databases used in the preparation of this review were PubMed, Scopus, and Science Direct. Considering the significant deleterious effects on health associated with chronic occupational exposure to xenobiotics, this topic deserves attention. As it is difficult to avoid occupational exposure to TRAPs, biomonitoring should be applied as a strategy to reduce the toxic effects of workplace exposure., (© 2020 John Wiley & Sons, Ltd.)

Amikacin (AMI) is an aminoglycoside antibiotic widely used in the treatment of severe infections caused by multi-resistant bacteria, with established exposition targets in therapeutic drug monitoring (TDM). The usual specimen for AMI concentration measurement is plasma or serum. The access to TDM of AMI in Developing Countries is constrained by the limited availability of laboratories performing the quantitation of this drug. In this context, the use of dried microsamples, such as dried plasma spots (DPS) could be an alternative to allow reduced specimen transportation and storage costs in resource-limited settings, increasing the access to TDM of AMI. This study aimed to develop and validate the first report of simultaneous determination of AMI and creatinine (CRE) in DPS, using UHPLC-MS/MS. Precision, accuracy and stability assays showed acceptable results. AMI was stable in DPS for 14 days at 6 °C, 2 days at 22 °C, and one day at 42 °C. CRE was stable during 14 days at all tested temperatures. AMI and CRE concentrations in DPS and plasma were compared by Passing-Bablok regression and Bland and Altmann plots and presented comparable results. Estimates of patient's clearance, volume of distribution and suggested doses of AMI were also similar using DPS or plasma concentrations. The assay provides a useful logistic alternative to allow more widespread access to dose individualization of AMI in limited resources settings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Gasoline is a complex mixture of saturated and unsaturated hydrocarbons, in which aromatic compounds, such as BTX (benzene, toluene, and xylene) feature as the main constituents. Simultaneous exposure to these aromatic hydrocarbons causes a significant impact on benzene toxicity. In order to detect early alterations caused in gasoline station attendants exposed to BTX compounds, immunological, inflammatory, and oxidative stress biomarkers were evaluated., Methods: A total of 66 male subjects participated in this study. The gasoline station attendants (GSA) group consisted of 38 gasoline station attendants from Rio Grande do Sul, Brazil. The non-exposed group consisted of 28 subjects who were non-smokers and who had no history of occupational exposure. Environmental and biological monitoring of BTX exposure was performed using blood and urine., Results: The GSA group showed increased BTX concentrations in relation to the non-exposed group (p < 0.001). The GSA group showed elevated protein carbonyl (PCO) levels and pro-inflammatory cytokines, decreased expression of CD80 and CD86 in monocytes, and reduced glutathione S-transferase (GST) activity compared to the non-exposed group (p < 0.05). BTX levels and trans,trans-muconic acid levels were positively correlated with pro-inflammatory cytokines and negatively correlated with interleukin-10 contents (p < 0.001). Increased levels of pro-inflammatory cytokines were accompanied by increased PCO contents and decreased GST activity (p < 0.001). Furthermore, according to the multiple linear regression analysis, benzene exposure was the only factor that significantly contributed to the increased pro-inflammatory cytokines (p < 0.05)., Conclusions: Taken together, these findings show the influence of exposure to BTX compounds, especially benzene, on the immunological, inflammatory, and oxidative stress biomarkers evaluated. Furthermore, the data suggest the relationship among the evaluated biomarkers of effect, which could contribute to providing early signs of damage to biomolecules in subjects occupationally exposed to BTX compounds.

Background: Melatonin has been described in the literature as a potent antioxidant. However, melatonin presents variable, low bioavailability and a short half-life. The use of polymeric nanoparticulated systems has been proposed for controlled release. Thus, the purpose of this study was to investigate the action of melatonin-loaded lipid-core nanocapsules (Mel-LNC) in the antioxidant system of Caenorhabditis elegans, and the possible protective effect of this formulation against lipid peroxidation caused by paraquat (PQ)., Methods: The suspensions were prepared by interfacial deposition of the polymer and were physiochemically characterized. C. elegans N2 wild type and transgenic worm CF1553, muls84 [sod-3p::gfp; rol6(su1006)] were obtained from the Caenorhabditis Genetics Center (CGC). The worms were divided into 5 groups: Control, PQ 0.5 mM, PQ 0.5 mM + Mel-LNC 10 μg/mL, PQ + unloaded lipid-core nanocapsules (LNC), and PQ + free melatonin (Mel) 10 μg/mL. The lipid peroxidation was assessed through thiobarbituric acid (TBARS) levels and the fluorescence levels of the transgenic worms expressing GFP were measured., Results: The LNC and Mel-LNC presented a bluish-white liquid, with pH values of 5.56 and 5.69, respectively. The zeta potential was - 6.4 ± 0.6 and - 5.2 ± 0.2, respectively. The mean particle diameter was 205 ± 4 nm and 203 ± 3 nm, respectively. The total melatonin content was 0.967 mg/ml. The TBARS levels were significantly higher in the PQ group when compared to the control group (p < 0.001). Mel-LNC reduced TBARS levels to similar levels found in the control group. Moreover, only Mel-LNC significantly enhanced the SOD-3 expression (p < 0.05). Mel-LNC was capable of protecting C. elegans from lipid peroxidation caused by PQ and this was not observed when free melatonin was used. Moreover, Mel-LNC increased the fluorescence intensity of the transgenic strain that encodes the antioxidant enzyme SOD-3, demonstrating a possible mechanism of protection from PQ-induced damage., Conclusion: These findings demonstrated that melatonin, when associated with nanocapsules, had improved antioxidant properties and the protective activity against PQ-induced lipid peroxidation could be associated with the activation of antioxidant enzymes by Mel-LNC in C. elegans.

Background: Amikacin (AMI) and vancomycin (VAN) are antibiotics largely used in intensive care in the empiric treatment of severe infections by multi-resistant gram-negative and gram-positive bacteria. AMI and VAN are eliminated untransformed by glomerular filtration, showing depuration ratio highly correlated with creatinine (CRE) clearance. AMI, VAN and CRE are highly polar structures, presenting poor retention in reversed-phase liquid chromatography when using conventional stationary phases., Objective: This study aimed to develop and validate a simple UPLC-MS/MS method for simultaneous determination of AMI, VAN, and CRE in human plasma for therapeutic drug monitoring., Results: Samples were prepared by protein precipitation, followed by dilution. Heptafluorobutyric acid (HFBA) was added to the mobile phase at low concentration (0.01%), and separation was performed in an ultra-performance reversed-phase column (particle diameter of 1.8 μm). These conditions allowed retention times of 0.92, 0.93, 2.12, 2.17 and 2.27 min for CRE, CRE-D3, AMI, KAN and VAN, respectively. The assay was linear from 0.5 to 100 mg L -1 for AMI and VAN and 5 to 100 mg L -1 . Precision, accuracy and stability assays were acceptable according to bioanalytical validation guidelines. Suitable results. Matrix effects were in the range of +10.5 to +11.6% for AMI, -4.3 to -4.5% for VAN, and - 1.7 to +0.7 for CRE., Conclusion: The first assay for the simultaneous determination of AMI, VAN and CRE in plasma by liquid chromatography-tandem mass spectrometry was reported. This assay allows the obtention of the necessary analytical data for the clinical application of population pharmacokinetic methods for therapeutic drug monitoring of AMI and VAN., (Copyright © 2019 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

The most commonly used solution in chrome plating bath is chromic acid (hexavalent Cr), and a considerable amount of mists is released into the air and consequently produce hazards to workers. Thus, the aim of this study was to evaluate whether the biomarker of exposure to metals, specially Cr levels, presents associations with hematological and biochemical parameters and if they can alter the activity of enzymes that contain thiol groups such as pyruvate kinase, creatine kinase, adenylate kinase, and δ-aminolevulinate dehydratase. Fifty male chrome plating workers were used for exposed group and 50 male non-exposed workers for control group. For that, biological monitoring was performed through quantification of metals on total blood and urine by inductively coupled plasma mass spectrometry (ICP-MS) and enzyme activity was performed by spectrometry in erythrocytes. In addition, chromium levels in water was quantified and ecotoxicology assay was performed with Allium cepa test. The results demonstrated that blood and urinary chromium levels in exposed group were higher than the control group (p < 0.0001). Furthermore, decreased activity of enzymes was found in those that contain thiol groups from exposed group when compared with the control group (p < 0.001). The water analysis did not present a statistical difference between control and exposed groups (p > 0.05), demonstrating that water did not seem to be the source of contamination. In summary, our findings indicated some toxicology effects observed in the exposed group, such as thiol enzyme inhibition, mainly associated with occupational exposure in chrome plating and besides the presence of other metals, and Cr demonstrated to influence the activity of the enzymes analyzed in this research.

Objectives: In patients with refractory or recurrent non-small-cell lung cancer (NSCLC) after first line chemotherapy, phase III trials showed superiority of nivolumab, an IgG4 programmed death-1 immune-checkpoint-inhibitor antibody, over docetaxel. We evaluated case mix, effectiveness and safety of nivolumab upon implementation in general practice., Materials and Methods: In 20 general hospitals, all consecutive NSCLC patients treated with nivolumab within the medical need program (inclusion period 12 months) in Flanders - Belgium were evaluated., Results: There were 267 patients, Eastern Cooperative Oncology Group (ECOG) score was 2 in 24% and 0-1 in 76%. In 48%, two or more systemic regimens were given before nivolumab. The median overall survival was 7.8 months (95% confidence interval (CI) 6.3-9.3). At one year, the overall survival rate was 36.5±0.34%. Median progression-free survival was 3.7 months (95% CI 2.9-4.5). An objective response was obtained in 23.2%. ECOG score 2 and presence of liver metastasis strongly correlated with worse survival (p<0.00001). Treatment related adverse events grade 3 or 4 were reported in 21%, colitis (4%) and pneumonitis (7%) were most frequent., Conclusion: Upon implementation of nivolumab therapy in general hospitals, the case mix was characterized by a more heavily pretreated population with a substantial fraction of patients with ECOG score 2. The median overall survival is slightly inferior to what was published in the randomized phase III trials. An ECOG score 2 and the presence of liver metastasis correlated strongly with a worse survival. We report a high prevalence of serious adverse events., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study aimed to evaluate which xenobiotic (As, Hg, Pb or pyrenes) is primarily responsible for the inflammatory process in taxi drivers. Multiple regression analysis showed that Hg is the main xenobiotic responsible for the increase of cytokine levels. These associations suggest that co-exposure to pollutants could be a risk factor for health effects.

The aging phenomenon is associated with oxidative stress damage in biomolecules, especially DNA. 5-Methyltetrahydrofolate (5-MTHF), the active folate form, plays a pivotal role in maintaining genomic integrity. However, recently it was associated with cancer development. In Brazil, there are folic acid enriched foods, such as flour, making the general population chronically exposed to folates. Therefore, the aim of this study was to investigate whether erythrocytes 5-MTHF levels were associated with age-related DNA damage in two groups (elderly and young subjects). Additionally, a study in Caenorhabditis elegans , an in vivo alternative model, was performed to verify if 5-MTHF presents a pro-oxidant effect. A total of 50 elderly and 25 young subjects participated in this study, which analyzed whole blood DNA damage, plasma carbonyl proteins (PCO), and erythrocytes 5-MTHF levels. In addition, ROS and RNS production, survival rate, and lifespan were performed in C. elegans exposed to 5-MTHF. Blood 5-MTHF levels and DNA damage were increased in the elderly compared to the young group. A positive association was found between 5-MTHF levels and DNA damage, and between DNA damage and PCO levels, suggesting an oxidative cause of damage associated with the active folate form. In an experimental study it was observed that 5-MTHF increased ROS production in C. elegans , in a dose dependent manner, while survival rate and life span were not affected at the test doses. These findings suggest that 5-MTHF, the active folate form, may be involved in DNA damage in the elderly. This damage could be a result of oxidative stress, as observed in the in vivo alternative model; however, more studies are necessary to prove our present results.

Women are employed in increasing numbers as gasoline station attendants, a work category with risk of exposure to benzene. We have assessed the effect of gender on biomarkers of occupational benzene exposure. Gasoline station attendants (20 men and 20 women) and 40 control individuals (20 men and 20 women) with no history of occupational benzene exposure were evaluated. Benzene exposure was monitoring by environmental and biological measurements. Urinary trans,trans-muconic acid levels, well-known genetic and hematological alterations linked to benzene exposure, and non-cancer effects on the immune, hepatic, and renal systems were investigated. Our results suggest a potential effect of gender on some effects of occupational benzene exposure, particularly the hematological parameters and trans,trans-muconic acid levels. Despite limitations of our study, our findings provide important considerations about occupational exposure of women to benzene and may contribute to the development of occupational protection standards., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Children may be environmentally exposed to several hazards. In order to evaluate the health of children living in a tobacco-producing region, different biomarkers of exposure and effect, as well as hematological parameters, were evaluated. Biomarkers of exposure to the following xenobiotics were assessed: pesticides, nicotine, toxic elements, and organic solvents. Oxidative damage markers malondialdehyde (MDA) and protein carbonyls (PCO), vitamin C, microalbuminuria (mALB) levels, and N-acetyl-β-D-glucosaminidase (NAG) activity were also evaluated. Peripheral blood samples and urine were collected from 40 children (6-12 years), at two different crop periods: in the beginning of pesticide applications (period 1) and in the leaf harvest (period 2). The Wilcoxon signed-rank test for paired data was used to evaluate the differences between both periods. Biomarkers of exposure cotinine in urine and blood chromium (Cr) levels were increased in period 1 when compared to period 2. Moreover, a significant reduced plasmatic activity of butyrylcholinesterase (BuChE) was observed in period 2 in relation to period 1. Blood Cr levels were above the recommended by WHO in both evaluations. The biomarkers MDA and PCO as well as the kidney dysfunction biomarker, mALB, presented levels significantly increased in period 1. Additionally, decreased lymphocytes and increased basophils were also observed. Cotinine was positively associated with PCO, and Cr was positively associated with PCO and MDA. The increased Cr levels were associated with decreased lymphocytes and increased basophils. Our findings demonstrate that children environmentally exposed to xenobiotics in rural area may present early kidney dysfunction, hematological alterations, as well as lipid and protein damages, associated with co-exposure to different xenobiotics involved in tobacco cultivation.

Environmental exposure to pollutants, especially polycyclic aromatic hydrocarbons (PAHs), could lead to carcinogenesis development. However, there is a gap on the mechanisms involved in this effect. Therefore, the aim of this study was to investigate the potential relationship between exposure to environmental air pollution and inflammation process in DNA damage in taxi drivers. This study included 45 taxi drivers and 40 controls; non-smokers composed both groups. Biological monitoring was performed through quantification of urinary 1-hydroxypyrene (1-OHP). ICAM-1 (CD54) expression, NTPDase activity, inflammatory cytokine (IL-1β, IL-6, IL-10, TNF-α and IFN-γ) levels, and comet and micronucleus assays were evaluated. The results demonstrated that 1-OHP levels, ICAM-1 expression, NTPDase activity, and DNA damage biomarkers (% tail DNA and micronucleus frequency) were increased in taxi drivers compared to the control group (p < 0.01). Moreover, significant associations were found between 1-OHP levels and ICAM-1 expression, % tail DNA, and micronucleus frequency (p < 0.05). Besides, pro-inflammatory cytokine levels were positively correlated to % tail DNA and micronucleus frequency (p < 0.001). Our findings suggest an important association between environmental exposure to air pollution with increase of ICAM-1 expression and NTPDase activity in taxi drivers. Additionally, the multiple regression linear-analysis demonstrated association between IL-6 and DNA damage. Thus, the present study has provided important evidence that, in addition to environmental exposure to air pollutants, the inflammation process may contribute to DNA damage.

Environmental exposure to manganese (Mn) results in several toxic effects, mainly neurotoxicity. This study investigated associations among Mn exposure, neuropsychological performance, biomarkers of oxidative damage and early kidney dysfunction in children aged 6-12 years old. Sixty-three children were enrolled in this study, being 43 from a rural area and 20 from an urban area. Manganese was quantified in blood (B-Mn), hair (H-Mn) and drinking water using inductively coupled plasma mass spectrometry (ICP-MS). The neuropsychological functions assessed were attention, perception, working memory, phonological awareness and executive functions - inhibition. The Intelligence quotient (IQ) was also evaluated. The biomarkers malondialdehyde (MDA), protein carbonyls (PCO), δ-aminolevulinate dehydratase (ALA-D), reactivation indexes with dithiothreitol (ALA-RE/DTT) and ZnCl2 (ALA-RE/ZnCl2), non-protein thiol groups, as well as microalbuminuria (mALB) level and N-acetyl-β-D-glucosaminidase (NAG) activity were assessed. The results demonstrated that Mn levels in blood, hair and drinking water were higher in rural children than in urban children (p<0.01). Adjusted for potential confounding factors, IQ, age, gender and parents' education, significant associations were observed mainly between B-Mn and visual attention (β=0.649; p<0.001). Moreover, B-Mn was negatively associated with visual perception and phonological awareness. H-Mn was inversely associated with working memory, and Mn levels from drinking water with written language and executive functions - inhibition. Rural children showed a significant increase in oxidative damage to proteins and lipids, as well as alteration in kidney function biomarkers (p<0.05). Moreover, significant associations were found between B-Mn, H-Mn and Mn levels in drinking water and biomarkers of oxidative damage and kidney function, besides between some oxidative stress biomarkers and neuropsychological tasks (p<0.05). The findings of this study suggest an important association between environmental exposure to Mn and toxic effects on neuropsychological function, oxidative damage and kidney function in children., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Patients with ST-segment elevation (STEMI) have totally occluded vessels, while patients with non-ST-segment elevation (NSTEMI) present partial vessel occlusion, which may generate different levels of Reactive Oxygen Species (ROS). Objectives: The aim of this study was to compare the oxidative profile in AMI patients with ST segment elevation and non-STEMI as well as control subjects., Methods: This study was carried with 46 AMI patients divided into STEMI and NSTEMI. The control group consisted of 40 healthy subjects. Oxidative stress profile was evaluated analyzing carbonyl protein (PCO), lipid peroxidation (TBARS), ischemia-modified albumin (IMA), vitamin C (VIT C), superoxide dismutase (SOD) and catalase (CAT)., Results: Serum PCO (p < 0.001), plasma TBARS (p < 0.01), serum IMA (p < 0.0001) levels, erythrocytes CAT (p < 0.001), and SOD activities (p < 0.05) were significantly higher in STEMI patients when compared with the control group (p < 0.001). No difference in the IMA levels and oxidative stress parameters was observed between conditions of AMI. Only plasma VIT C in STEMI patients was significantly lower when compared with NSTEMI patients and control group (p < 0.001)., Conclusions: Results suggest that the oxidative profile generated by STEMI and NSTEMI is similar regardless of the size of arterial occlusion generated by thrombus.

Undoubtedly, the most important advance in the environmental regulatory monitoring of elements of the last decade is the widespread introduction of ICP-mass spectrometry (ICP-MS) due to standards developed by the European Committee for Standardization. The versatility of ICP-MS units as a tool for the determination of major, minor and trace elements (Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, P, Pb, Sb, Se, Sn, Ti, V and Zn) in surface water, groundwater, river sediment, topsoil, subsoil, fine particulates and atmospheric deposition is illustrated in this paper. Ranges of background concentrations for major, minor and trace elements obtained from a regional case study (Flanders, Belgium) are summarized for all of these environmental compartments and discussed in the context of a harmonized implementation of European regulatory monitoring requirements. The results were derived from monitoring programs in support of EU environmental quality directives and were based on a selection of (non-polluted) background locations. Because of the availability of ICP-MS instruments nowadays, it can be argued that the main hindrance for meeting the European environmental monitoring requirements is no longer the technical feasibility of analysis at these concentration levels, but rather (i) potential contamination during sampling and analysis, (ii) too limited implementation of quality control programs, validating the routinely applied methods (including sampling and low level verification) and (iii) lack of harmonization in reporting of the chemical environmental status between the individual member states.

ABSTRACT  In the past decade, the approach to patients with metastatic non-small-cell lung cancer has relied on chemotherapy and on targeted agents for molecularly selected subgroups of patients. Recent work has introduced immunotherapy as another area of progress, and likely as a new treatment paradigm in the near future. While the large Phase III studies with cancer vaccination with the current technologies remain at present disappointing, the immunomodulation strategies with immune checkpoint inhibitors have delivered remarkable results in expanded Phase I studies and are now intensively studied in large Phase III studies. This review summarizes the past decade of immunotherapy for non-small-cell lung cancer, gives an updated overview of trials in this field, and the context of future development in this exciting field.