Journal articles on the topic 'Copper – Toxicity testing'
To see the other types of publications on this topic, follow the link: Copper – Toxicity testing.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Copper – Toxicity testing.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Richards, Laura, Stephanie Walsh, Carmen Shultz, and Marilyne Stuart. "ASSESSMENT OF THE EFFECT OF WATER QUALITY ON COPPER TOXICITY INHYALELLA AZTECA." AECL Nuclear Review 4, no. 1 (June 1, 2015): 83–90. http://dx.doi.org/10.12943/anr.2015.00040.
Full textAbstract:
The objective of this study was to test the hypothesis that when standard artificial media 5-salt culture water (SAM-5S) is used to test sediment toxicity of much lower ionic-strength aquatic ecosystems, the resulting toxicity estimates are lower than if the tests had been conducted in water of comparable ionic strength. Results showed that this concern was unfounded for testing of copper toxicity to Hyalella azteca (H. azteca) in Ottawa River water. Sediment testing is often conducted using a standard water that is prepared in the laboratory. However, this water may have an ionic strength that is different than local water bodies. It follows that laboratory results using the standard water may be unrepresentative. A study was undertaken to assess the copper tolerance of 2 strains of H. azteca in SAM-5S, diluted SAM-5S (similar in electrical conductivity to Ottawa River water), and Ottawa River water. Acute (96 h) copper toxicity tests were conducted with 9–16 day-old H. azteca. For a given water type, the 2 strains of H. azteca yielded comparable responses to copper. The highest copper tolerance was found in Ottawa River water (closely followed by SAM-5S), whereas the lowest copper tolerance was found in diluted SAM-5S. Our results suggest that sediment toxicity is not lowered by the higher ionic strength of SAM-5S and that sediment toxicity tests of Ottawa River sediments, conducted with SAM-5S, can be used to estimate the in situ toxicity of the sediments.
2
Ivorra, Núria, Michiel H. S. Kraak, and Wim Admiraal. "Use of lake water in testing copper toxicity to desmid species." Water Research 29, no. 9 (September 1995): 2113–17. http://dx.doi.org/10.1016/0043-1354(95)00019-h.
Full text
3
Jacobson, Peter J., Donald S. Cherry, Jerry L. Farris, and Richard J. Neves. "Juvenile freshwater mussel (bivalvia: unionidae) responses to acute toxicity testing with copper." Environmental Toxicology and Chemistry 12, no. 5 (May 1993): 879–83. http://dx.doi.org/10.1002/etc.5620120512.
Full text
4
Zizzo, John. "Toxicity effects of Cubic Cu2O nanoparticles on defecation rate and length in C. Elegans." Biomedical Research and Therapy 7, no. 10 (October 31, 2020): 4045–51. http://dx.doi.org/10.15419/bmrat.v7i10.639.
Full textAbstract:
Introduction: The increased presence of radiation and toxins in the atmosphere has given rise to fuel cells and nanoparticle technology with the ability to catalyze reactions at favorable energy levels. The purpose of this experiment was to determine the lasting effects of a synthesized catalyst on a model organism, Caenorhabditis (C.) elegans.
Methods: Copper sulfate was tested alongside copper(I) oxide (i.e. Cu2O) to dissociate the copper composition effects from those of the nanoparticles themselves. The prospect of testing both defecation rate and size differences allowed for C. elegans to be utilized due to their low maintenance costs, mapped neuronal pathways, and short-generation times.
Results: The results indicated significant toxicity effects in wild-type worms as witnessed by the decreases in nematode defecation rate and length by copper sulfate, with similar results in SMF-1 and PCS-1 mutants by Cu2O catalysts in cubic synthesized form.
Conclusion: These outcomes reinforce the known effects of metal oxides on pollutants and highlight the need for further testing with additional variables such as varying pH and temperature.
5
Apte, Simon C., Graeme E. Batley, Karl C. Bowles, Paul L. Brown, Nicola Creighton, Leigh T. Hales, Ross V. Hyne, et al. "A Comparison of Copper Speciation Measurements with the Toxic Responses of Three Sensitive Freshwater Organisms." Environmental Chemistry 2, no. 4 (2005): 320. http://dx.doi.org/10.1071/en05048.
Full textAbstract:
Environmental Context.A rapid Chelex resin method is shown to be a valuable speciation screening tool for use in a tiered risk assessment of copper toxicity in fresh waters. It is a more conservative measure than toxicity testing with sensitive biota, but a better indicator of toxicity than a dissolved copper measurement. Abstract.Twelve natural fresh waters with similar pH and hardness, but varying dissolved organic carbon (DOC) and copper concentrations, were assessed for (a) toxicity to an alga (Chlorella sp. 12), a cladoceran (Ceriodaphnia cf. dubia) and a bacterium (Erwinnia sp.), and (b) copper speciation using a rapid Chelex extraction method, diffusive gradients in thin films (DGT) and anodic stripping voltammetry (ASV). In synthetic fresh water with no added DOC, at pH 7.0 and low hardness, the toxic responses (EC/IC50) of all three organisms to copper were similar. However, in the toxicity of copper added to natural water samples exhibited a negative linear relationship to DOC (r2 = 0.82–0.83), with respective slopes for algae, cladocerans and bacteria decreasing in the ratio 7.4 : 3.5 : 1. The marked difference in responses in the presence of natural dissolved organic matter indicated that not all of the organisms conformed to the free ion activity model (FIAM). This was confirmed by copper ion selective electrode measurement of copper ion activity. Copper toxicity to algae in the presence of DOC was overestimated by free ion activity possibly due to surface binding of DOC. Copper toxicity to the bacteria was greater than predicted and was shown to be a result of bioavailability of some copper complexes formed with organic matter. Cladocerans appear to more closely follow FIAM predictions. These findings have important implications for attempts to extend predictive models of metal toxicity beyond fish to more sensitive freshwater species. The measured labile copper concentrations of copper-spiked natural waters varied from 0 to 70% of total copper concentrations. There was no clear relationship between the three measurement techniques. Good correlations were obtained between both algal and bacterial growth inhibitions measured on copper-spiked natural waters and the corresponding Chelex-labile copper concentrations. A single natural water sample was manipulated to different pH and hardness values, spiked with copper, and tested using the above three organisms with the Chelex method. Toxicity test results generally agreed with studies performed in synthetic fresh waters, showing that the relationships between toxicity, pH and hardness were organism-specific. Chelex-labile copper was always over-predictive of toxicity but significantly better (P ≤ 0.05) than dissolved copper concentrations, as it only detects the fraction of total copper that is reactive over biologically-relevant timescales. Colloidally-bound copper and copper associated with strong ligands are not detected. The Chelex method is therefore useful as a measure where speciation is accepted in water quality regulations.
6
MacRae, Russell K., Ann S. Maest, and Joseph S. Meyer. "Selection of an organic acid analogue of dissolved organic matter for use in toxicity testing." Canadian Journal of Fisheries and Aquatic Sciences 56, no. 8 (August 1, 1999): 1484–93. http://dx.doi.org/10.1139/f99-090.
Full textAbstract:
Uncontaminated stream waters in the vicinity of a Co mine in Idaho were titrated with Cu to determine the Cu-binding characteristics of natural dissolved organic matter (DOM) and suspended particles. Nonlinear regressions of bound versus free Cu concentrations were consistent with a two-ligand model for DOM complexation of Cu, in which the conditional stability constants (log K) and complexation capacities (CC) were log K1 = 7.26, CC1 = 0.21 µmol Cu·mg dissolved organic carbon (DOC)-1 and log K2 = 5.13, CC2 = 2.89 µmol Cu·mg DOC-1. Copper-binding constants were similar in filtered (0.45 µm) and unfiltered water samples. Calcium, Mg, and Co did not compete appreciably with Cu for DOM complexation at concentrations present in site waters. Copper binding to amorphous iron oxide flocs also was not important at the Fe concentrations present in the stream waters. We selected a mixture of three organic acids, dipicolinic, oxalic, and malonic, to mimic the Cu-binding properties of this DOM. Geochemical models were developed to estimate Cu speciation and evaluate its bioavailability in companion fish toxicity tests using the DOM analogue (Marr et al. 1999. Can. J. Fish. Aquat. Sci. 56: 1471-1483).
7
Nalewajko, Czeslawa, and Mary M. Olaveson. "Differential responses of growth, photosynthesis, respiration, and phosphate uptake to copper in copper-tolerant and copper-intolerant strains of Scenedesmus acutus (Chlorophyceae)." Canadian Journal of Botany 73, no. 8 (August 1, 1995): 1295–303. http://dx.doi.org/10.1139/b95-141.
Full textAbstract:
We detected significant differences in copper toxicity to growth and several physiological processes (e.g., photosynthesis, respiration, and phosphate uptake) in three strains of Scenedesmus acutus f. alternans demonstrating differential sensitivity to copper. The copper-intolerant strain (designated X-72) and the two copper-tolerant strains (designated X-Cu and B-4) were tested in long-term (5-day) growth bioassays and short-term (< 24 h) physiological experiments under both nutrient-sufficient and nutrient-limited conditions. The three strains showed the same pattern of sensitivity to copper for growth and for all physiological processes examined: the copper-intolerant strain, X-72, showed the greatest sensitivity, followed by X-Cu. B-4 was most tolerant. Under nutrient-sufficient conditions, growth was more sensitive to copper than photosynthesis or respiration. Depression of the growth rate to 50% of control occurred at 25, 56, and 175 nmol Cu/106 cells in X-72, X-Cu, and B-4, respectively. Photosynthesis and respiration were inhibited in cultures that were preexposed to algistatic copper dosages for 20 h prior to testing. Both processes were equally inhibited in X-72 (to about 8.5% of controls) and in X-Cu (to about 32% of controls), but respiration was more inhibited than photosynthesis in B-4 (to 47.7 vs. 67.1% of control rates). L-buthionine-S,R-sulfoximine (BSO), a known inhibitor of phytochelatin synthesis, significantly reduced the tolerance of photosynthesis to copper in X-72 but not in X-Cu or B-4. Short-term responses among several physiological processes were also examined under phosphorus and nitrogen limitation. In P-limited cultures, phosphate uptake was depressed by 50% at 3 nmol Cu/106 cells in X-72, and at 5.8 nmol Cu/106 cells in X-Cu and B-4. In N-limited cultures, photosynthesis was more tolerant to copper than in nutrient-sufficient conditions in both X-72 and X-Cu but less tolerant in B-4. Key words: copper toxicity, growth, nutrient limitation, nitrogen, phosphate uptake, photosynthesis, respiration, Scenedesmus.
8
Bogomolov, D. M., S. K. Chen, R. W. Parmelee, S. Subler, and C. A. Edwards. "An ecosystem approach to soil toxicity testing: a study of copper contamination in laboratory soil microcosms." Applied Soil Ecology 4, no. 2 (September 1996): 95–105. http://dx.doi.org/10.1016/0929-1393(96)00112-6.
Full text
9
Colvin, Marienne A., Katherine R. Kowal, Nicholas T. Hayman, Chris Stransky, Jeff VanVoorhis, Steve Carlson, and Gunther Rosen. "Pulsed exposure toxicity testing: Baseline evaluations and considerations using copper and zinc with two marine species." Chemosphere 277 (August 2021): 130323. http://dx.doi.org/10.1016/j.chemosphere.2021.130323.
Full text
10
Mohd Mansor, Ahmad Fairuzabadi, Phirdaous Abbas, Taufik Hakim Hamdan, Yumi Zuhanis Has-Yun Hashim, and Anis Nurashikin Nordin. "Toxicity studies of agarwood essential oil in vero cells using electrical impedance sensor." Malaysian Journal of Fundamental and Applied Sciences 13, no. 4-2 (December 17, 2017): 540–45. http://dx.doi.org/10.11113/mjfas.v13n4-2.841.
Full textAbstract:
Natural products have traditionally been used for medicinal purposes in Asian communities. Toxicity studies typically use animal testing to predict the harmfulness of a particular substance to human health. For this study, in lieu of animal testing, we utilize cell-based biosensors to evaluate the toxicity of natural products. The cell-based biosensors are fabricated on a printed circuit board with copper electrodes and are equipped with PDMS cell culture chambers. Two different electrodes (interdigitated and circular) were designed. Vero cells were used to represent normal healthy cells. The cells are first cultured on biosensors and then are inoculated with natural products, Taxol (chemo drug – positive control) and DMSO (negative control). Impedances of these biosensors were then recorded at six-hour intervals for 80 hours to determine the growth of the cells. It was found that compared to Taxol, natural products has a very low toxicant values.
11
Bhutra, Renu, Rashmi Sharma, and Arun Kumar Sharma. "Antimicrobial Studies and Characterization of Copper Surfactants Derived from Various Oils Treated at High Temperatures by P.D.A. Technique." Open Pharmaceutical Sciences Journal 5, no. 1 (November 14, 2018): 36–44. http://dx.doi.org/10.2174/1874844901805010036.
Full textAbstract:
Introduction:Biologically potent compounds are one of the most important classes of materials for the upcoming generations. Increasing number of microbial infectious diseases and resistant pathogens create a demand and urgency to develop novel, potent, safe and improved variety of antimicrobial agents. This initiates a task for current chemistry to synthesize compounds that show promising activity as therapeutic agents with lower toxicity. Therefore, a substantial research is needed for their discovery and improvement. Chemistry of present era aims to build a pollution free environment. For the same, it targets to create some alternativeswhich are eco-friendly and nature loving. Present research work is a step towards achieving such alternatives.Method:For this the metallic soaps of copper (derived from common edible oils) were synthesized. The synthesized copper soaps have been confirmed by elemental analysis, UV, and IR spectroscopic technique. The fungicidal activities of copper soaps derived from soyabean, sesame oils have been evaluated by testing against Alternaria alternate and Aspergillus niger by P.D.A. technique.Result:The fungi toxicity results indicate that the strain of fungal species are susceptible towards these soaps and suggests that with the increase in concentration of copper soap it may increase further. The transition metallic soaps showed good antifungal activity because chelation increases the anti-microbial potency.
12
Karekar, Neha, Anik Karan, Elnaz Khezerlou, Neela Prajapati, Chelsea D. Pernici, Teresa A. Murray, and Mark A. DeCoster. "Self-Assembled Metal–Organic Biohybrids (MOBs) Using Copper and Silver for Cell Studies." Nanomaterials 9, no. 9 (September 8, 2019): 1282. http://dx.doi.org/10.3390/nano9091282.
Full textAbstract:
The novel synthesis of metal-containing biohybrids using self-assembly methods at physiological temperatures (37 °C) was compared for copper and silver using the amino acid dimer cystine. Once assembled, the copper containing biohybrid is a stable, high-aspect ratio structure, which we call CuHARS. Using the same synthesis conditions, but replacing copper with silver, we have synthesized cystine-capped silver nanoparticles (AgCysNPs), which are shown here to form stable colloid solutions in contrast to the CuHARS, which settle out from a 1 mg/mL solution in 90 min. Both the copper and silver biohybrids, as synthesized, demonstrate very low agglomeration which we have applied for the purpose of applications with cell culture methods, namely, for testing as anti-cancer compounds. AgCysNPs (1000 ng/mL) demonstrated significant toxicity (only 6.8% viability) to glioma and neuroblastoma cells in vitro, with concentrations as low as 20 ng/mL causing some toxicity. In contrast, CuHARS required at least 5 μg/mL. For comparative purposes, silver sulfate at 100 ng/mL decreased viability by 52% and copper sulfate at 100 ng/mL only by 19.5% on glioma cells. Using these methods, the novel materials were tested here as metal–organic biohybrids (MOBs), and it is anticipated that the functionalization and dynamics of MOBs may result in building a foundation of new materials for cellular applications, including cell engineering of both normal and diseased cells and tissue constructs.
13
Santos, Maria Alice, Regina T. R. Monteiro, Christian Blaise, François Gagné, Kimberly Bull, and Jean-François Férard. "Influence of Sediment Grain Size on Elutriate Toxicity of Inorganic Nanomaterials." Water Quality Research Journal 44, no. 3 (August 1, 2009): 201–10. http://dx.doi.org/10.2166/wqrj.2009.022.
Full textAbstract:
Abstract Knowledge concerning the ecotoxic effects of nanomaterials, chemical structures with novel properties owing to their small sizes (1 to 100 nm), is wanting and deserves to be documented more fully. In this study we conducted testing with the MARA (microbial array for risk assessment) assay-an 11 microbial species 96-well microplate toxicity test measuring growth inhibition-to determine the toxic potential of four metallic nanopowders (MNPs): copper zinc iron oxide, samarium (III) oxide, erbium (III) oxide, and holmium (III) oxide. MTC (microbial toxicity concentration) endpoint values showed a range of toxicity responses generated by individual strains that was MNP-specific. Cluster analysis undertaken with the (n = 11) MTC values of the four MNPs, reflecting a toxic fingerprint proper to each nanochemical, indicated that their modes of action may be different. Experiments were also conducted with an artificial sediment, composed of varying concentrations of silica sand and kaolin (fine particles < 0.004 mm), spiked with each MNP to assess the contribution of fine particles on the resulting elutriate toxicity. The latter was shown to increase as fines contents decreased, except for CuZnFeO where no particular trends were observed. Toxicity testing was then undertaken with each MNP spiked into natural Saint Lawrence River freshwater sediments displaying low, medium, and high fines contents. Once again, analogous results to those obtained with the artificial sediment experiments were observed for MNP elutriate toxicity. Overall, MARA bioassay data indicate that MNP toxicity can be modulated by sediment grain size and that resulting adverse effects on aquatic biota will in part depend on such sediment characteristics.
14
Marr, J. CA, J. Lipton, D. Cacela, J. A. Hansen, J. S. Meyer, and H. L. Bergman. "Bioavailability and acute toxicity of copper to rainbow trout (Oncorhynchus mykiss) in the presence of organic acids simulating natural dissolved organic carbon." Canadian Journal of Fisheries and Aquatic Sciences 56, no. 8 (August 1, 1999): 1471–83. http://dx.doi.org/10.1139/f99-089.
Full textAbstract:
Copper bioavailability and toxicity to early life stage rainbow trout (Oncorhynchus mykiss) were evaluated by laboratory toxicity testing performed using organic acid mixtures. Geochemical modeling was used to design exposure solutions that simulate dissolved organic carbon (DOC) of a natural aquatic system and to determine the fractions of total Cu present as inorganic species (e.g., Cu2+) and as individual Cu-organic complexes. Failure time modeling indicated that mortality was best predicted by a combination of total inorganic Cu and distinct Cu-organic complexes. The Cu-organic complexes that contributed to toxicity are characterized as low-affinity Cu-ligands, and our results support the hypothesis that Cu toxicity in nature is a function of the binding characteristics of individual ligands. Estimates of time-independent median lethal concentration thresholds determined at widely varying equivalent concentrations of DOC (0-16 mg/L) were constant (7.9-8.6 µg Cu/L) when modeled using the sum of inorganic Cu and Cu bound to the two low-affinity ligands as predictors of toxicity. Our results indicate that Cu bound to organic complexes may be available to fish and that acute toxicity of Cu is determined by the binding affinities of specific DOC components relative to Cu-binding affinity of fish gill.
15
Brierley, James A., and M. C. Kuhn. "From Laboratory to Application Heap Bioleach or not." Advanced Materials Research 71-73 (May 2009): 311–17. http://dx.doi.org/10.4028/www.scientific.net/amr.71-73.311.
Full textAbstract:
The importance of comprehensive laboratory evaluation for development of an ore body to commercial processing using biohydrometallurgy cannot be understated. Laboratory evaluation for a biohydrometallurgical process must include the microbiological component and definition of operating parameters for the engineers to design the commercial plant. Failure to meet commercial production at a mine site can be a consequence of incomplete understanding of biohydrometallurgical technologies for processing a specific ore. One example is the inability of a copper bioleach process to meet the design criteria in part because of lack of sufficient testing to demonstrate the ramifications of fluoride toxicity to the microbial component of the bioleach process. Laboratory research has demonstrated toxicity of low levels of fluoride to Acidithiobacillus species. However, laboratory determined toxicity values are not always relevant to field conditions at commercial bioleach operations. This is the case with fluoride toxicity where complexing reactions increase the amount of fluoride required for toxicity. Consequently, the toxic fluoride concentrations at field sites can be significantly higher than toxic levels reported in the laboratory, but still achieve concentration inhibitory for the microorganisms.
16
Eklund, Britta T., and Lena Kautsky. "Review on toxicity testing with marine macroalgae and the need for method standardization––exemplified with copper and phenol." Marine Pollution Bulletin 46, no. 2 (February 2003): 171–81. http://dx.doi.org/10.1016/s0025-326x(02)00225-4.
Full text
17
Marchenko, Tatyana A., Tatyana V. Izvekova, Andrey A. Gushchin, Vladimir I. Grinevich, and Elena A. Golovkina. "WATER QUALITY IN TRIBUTARIES OF VOLGA RIVER IN WATER AREA OF GORKY WATER-STORAGE BASIN." IZVESTIYA VYSSHIKH UCHEBNYKH ZAVEDENIY KHIMIYA KHIMICHESKAYA TEKHNOLOGIYA 59, no. 5 (July 12, 2018): 89. http://dx.doi.org/10.6060/tcct.20165905.5393.
Full textAbstract:
In article the results of complex study of water quality for tributaries of Volga river in a water area of Gorky water-storage basin. Study methods included both the chemical and biological methods of pollution level control. For all water flows the excess of MPC on heavy metals (by 1-27 times), partially on copper by 1-27, on iron –by 3-9, on manganese by 1-8, as well as on ammonium cations – by 1-6, and difficult-oxidizing organic compounds (COD)-by 2-4 is observed. It was established by the bio-testing method (test-objects are the chlorella algae and Daphnia) that water samples taken in the region of river mouths of Gorky water-storage basin (Sunzha, Kazokha, Elnat, Kineshemka) don’t posses acute toxicity but they are slightly toxicity.
18
Bálint, A. F., G. Kovács, and J. Sutka. "Comparative studies on the seedling copper tolerance of various hexaploid wheat varieties and of spelt in soil with a high copper content and in hydroponic culture." Acta Agronomica Hungarica 51, no. 2 (July 1, 2003): 199–203. http://dx.doi.org/10.1556/aagr.51.2003.2.8.
Full textAbstract:
On areas used for agriculture copper toxicity is one of the most important forms of heavy metal pollution, especially where field crops are to be grown in fields previously used as orchards or vineyards, treated for a long period with pesticides containing copper. Only varieties with good tolerance of soil with a high copper content should be grown on such areas. The selection of copper-tolerant varieties is complicated, however, by the fact that it is difficult to study copper tolerance under field conditions. Heavy metal tolerance is generally tested in hydroponic cultures, in which interfering factors can be minimised, but it is impossible to test a large number of genotypes or segregating generations using this method. Another problem in such experiments is that the conditions existing in hydroponic cultures bear little resemblance to those found in the field, so little information is obtained on the real adaptation of the varieties. The aim of the present experiments was thus to elaborate a soil-based technique suitable for determining the copper tolerance of various genotypes and allowing the simultaneous testing of a large number of genotypes under conditions approaching those found in the field. The results indicate that the copper tolerance of seedlings can be determined by growing them to an age of 2 weeks in soil containing 1000-1500 mg/kg CuSO4 × 5 H2O, since genetic differences in copper tolerance could be clearly distinguished under these conditions. The copper tolerance of plants grown in copper-containing soil exhibited a close correlation with the results obtained in physiological tests in hydroponic culture.
19
Thummeepak, Rapee, Renuka Pooalai, Christian Harrison, Lucy Gannon, Aunchalee Thanwisai, Narisara Chantratita, Andrew D. Millard, and Sutthirat Sitthisak. "Essential Gene Clusters Involved in Copper Tolerance Identified in Acinetobacter baumannii Clinical and Environmental Isolates." Pathogens 9, no. 1 (January 15, 2020): 60. http://dx.doi.org/10.3390/pathogens9010060.
Full textAbstract:
Copper is widely used as antimicrobial in agriculture and medicine. Copper tolerance mechanisms of pathogenic bacteria have been proven to be required for both copper tolerance and survival during bacterial infections. Here, we determined both copper-tolerant phenotype and genotype in A. baumannii originated from clinical and environmental samples. Using copper susceptibility testing, copper-tolerant A. baumannii could be found in both clinical and environmental isolates. Genotypic study revealed that representative copper-related genes of the cluster A (cueR), B (pcoAB), and D (oprC) were detected in all isolates, while copRS of cluster C was detected in only copper-tolerant A. baumannii isolates. Moreover, we found that copper-tolerant phenotype was associated with amikacin resistance, while the presence of copRS was statistically associated with blaNDM-1. We chose the A. baumannii strain AB003 as a representative of copper-tolerant isolate to characterize the effect of copper treatment on external morphology as well as on genes responsible for copper tolerance. The morphological features and survival of A. baumannii AB003 were affected by its exposure to copper, while whole-genome sequencing and analysis showed that it carried fourteen copper-related genes located on four clusters, and cluster C of AB003 was found to be embedded on genomic island G08. Transcriptional analysis of fourteen copper-related genes identified in AB003 revealed that copper treatment induced the expressions of genes of clusters A, B, and D at the micromolar level, while genes of cluster C were over-expressed at the millimolar levels of copper. This study showed that both clinical and environmental A. baumannii isolates have the ability to tolerate copper and carried numerous copper tolerance determinants including intrinsic copper tolerance (clusters A, B, and D) and acquired copper tolerance (cluster C) that could respond to copper toxicity. Our evidence suggests that we need to reconsider the use of copper in hospitals and other medical environments to prevent the selection and spread of copper-tolerant organisms.
20
Karasavvas, Nicos, Juan M. Cárcamo, George Stratis, and David W. Golde. "Vitamin C protects HL60 and U266 cells from arsenic toxicity." Blood 105, no. 10 (May 15, 2005): 4004–12. http://dx.doi.org/10.1182/blood-2003-03-0772.
Full textAbstract:
AbstractAlthough there is no compelling evidence that vitamin C has antitumor activity in humans, clinical trials are testing the hypothesis that ascorbic acid (AA) will enhance the efficacy of arsenic trioxide (As2O3) in myeloma. In vitro, AA cytotoxicity depends on its interaction with free transition metal ions in culture media leading to the generation of H2O2 and other reactive oxygen species (ROSs). Therefore, to circumvent the extracellular in vitro pro-oxidant effects of AA, we loaded HL60, U266, and RPMI-8226 cells with vitamin C by incubation with dehydroascorbic acid (DHA). Loading cells in this manner resulted in prominent, dose-dependent protection of As2O3-treated cells as measured by viability, colony formation, and apoptosis assays. Glutathione depletion enhanced cell sensitivity to the cytotoxic effects of As2O3 and vitamin C loading provided protection. AA was found to generate cytotoxic concentrations of H2O2 in culture medium without cells and copper/iron chelators inhibited this reaction. However, AA did not generate H2O2 in simple buffer or human plasma. Direct incubation with AA resulted in increased intracellular ROSs, whereas DHA incubation decreased it. These results clarify an apparent paradox and indicate that vitamin C loading in HL60, U266, and RPMI-8226 cells ameliorates As2O3 cytotoxicity.
21
da Silva, Luís, Zhaochu Yang, Nuno Pires, Tao Dong, Hans-Christian Teien, Trond Storebakken, and Brit Salbu. "Monitoring Aquaculture Water Quality: Design of an Early Warning Sensor with Aliivibrio fischeri and Predictive Models." Sensors 18, no. 9 (August 29, 2018): 2848. http://dx.doi.org/10.3390/s18092848.
Full textAbstract:
A novel toxicity-warning sensor for water quality monitoring in recirculating aquaculture systems (RAS) is presented. The design of the sensor system mainly comprises a whole-cell biosensor. Aliivibrio fischeri, a luminescent bacterium widely used in toxicity analysis, was tested for a mixture of known fish-health stressors, namely nitrite, un-ionized ammonia, copper, aluminum and zinc. Two toxicity predictive models were constructed. Correlation, root mean squared error, relative error and toxic behavior were analyzed. The linear concentration addition (LCA) model was found suitable to ally with a machine learning algorithm for prediction of toxic events, thanks to additive behavior near the limit concentrations for these stressors, with a root-mean-squared error (RMSE) of 0.0623, and a mean absolute error of 4%. The model was proved to have a smaller relative deviation than other methods described in the literature. Moreover, the design of a novel microfluidic chip for toxicity testing is also proposed, which is to be integrated in a fluidic system that functions as a bypass of the RAS tank to enable near-real time monitoring. This chip was tested with simulated samples of RAS water spiked with zinc, with an EC50 of 6,46E-7 M. Future work will be extended to the analysis of other stressors with the novel chip.
22
De Laender, F., K. A. C. De Schamphelaere, C. R. Janssen, and P. A. Vanrolleghem. "An ecosystem modelling approach for deriving water quality criteria." Water Science and Technology 56, no. 6 (September 1, 2007): 19–27. http://dx.doi.org/10.2166/wst.2007.582.
Full textAbstract:
Ecological effects of chemicals on ecosystems are the result of direct effects of the chemical, determined in single-species toxicity testing, and indirect effects due to ecological interactions between species. Current experimental methods to account for such interactions are expensive. Hence, mathematical models of ecosystems have been proposed as an alternative. The use of these models often requires extensive calibration, which hampers their use as a general tool in ecological effect assessments. Here we present a novel ecosystem modelling approach which assesses effects of chemicals on ecosystems by integrating single-species toxicity test results and ecological interactions, without the need for calibration on case-specific data. The methodology is validated by comparing predicted ecological effects of copper in a freshwater planktonic ecosystem with an experimental ecosystem data set. Two main effects reflected by this data set (a decrease of cladocerans and an increase of small phytoplankton) which were unpredictable from single-species toxicity test results alone, were predicted accurately by the developed model. Effects on populations which don't interact directly with other populations, were predicted equally well by single-species toxicity test results as by the ecosystem model. The small amount of required data and the high predictive capacity can make this ecosystem modelling approach an efficient tool in water quality criteria derivation for chemicals.
23
Suratno, Suratno, Rachma Puspitasari, Triyoni Purbonegoro, and Dieni Mansur. "Copper and Cadmium Toxicity to Marine Phytoplankton, Chaetoceros gracilis and Isochrysis sp." Indonesian Journal of Chemistry 15, no. 2 (July 13, 2015): 172–78. http://dx.doi.org/10.22146/ijc.21211.
Full textAbstract:
In Copper (Cu) based antifouling (AF) paints Cu was largely used as booster biocide after organotin was banned. Cu is micronutrient which is important in photosynthesis process because Cu is an essential metal as component of enzyme and electron transport chain. But in certain dosage, Cu could be toxic to marine organism. Chaetoceros gracilis and Isochrysis sp. are dominant microalgae in aquatic ecosystem. In this study the effect of Cu and Cadmium (Cd) on two marine microalgae, C. gracilis and Isochrysis sp. were compared. Toxicity test was based on American Standard for Testing Material (ASTM). IC50-96 h of Cd as reference toxicant was 2,370 mg.L-1 for C. gracilis and 490 mg.L-1 for Isochrysis sp. IC50-96 h of Cu to growth of C. gracilis was 63.75 mg.L-1 and Isochrysis sp. was 31.80 mg.L-1. Both Cd and Cu were inhibited growth of microalgae. Based on IC50-96 h value, it could be concluded that Cu was more toxic than Cd. Toxicity of Cu was 37 times stronger than Cd for C. gracilis and 15 times for Isochrysis sp. It was estimated that at concentration 10 mg.L-1 Cu does not show observable effect (NOEC) to C. gracilis and 5 mg.L-1 to Isochrysis sp. The lowest observable effect of Cu (LOEC) to C. gracilis was at concentration 17 mg.L-1 and 10 mg.L-1 for Isochrysis sp.
24
Beaumont, M., P. Butler, and E. Taylor. "Plasma ammonia concentration in brown trout in soft acidic water and its relationship to decreased swimming performance." Journal of Experimental Biology 198, no. 10 (October 1, 1995): 2213–20. http://dx.doi.org/10.1242/jeb.198.10.2213.
Full textAbstract:
Adult brown trout (300­600 g) were acclimated for 2 weeks to an artificial soft water (Ca2+, 50 µmol l-1) and maintained at either 5 °C (October to March) or 15 °C (May to August). Following insertion of a cannula into the dorsal aorta under MS-222 anaesthesia and a recovery period of 2 days, the fish were exposed to a 4 day episode of sub-lethal copper levels at pH 5 or kept at control conditions of pH 7 without copper. The copper concentrations had been predetermined by toxicity testing and were approximately 0.47 µmol l-1 at 5 °C and 0.08 µmol l-1 at 15 °C. At 5 °C, a group of fish was also exposed to approximately 0.08 µmol l-1 copper at pH 5. Plasma total ammonia (Tamm) concentration was significantly elevated by exposure to copper and pH 5. In resting trout exposed to the appropriate sub-lethal copper concentration at pH 5, Tamm was six and 7.5 times greater at 5 and 15 °C, respectively, than those of control trout at the respective temperatures. Although unconfirmed, an elevation of ammonia production alone seems unlikely to account for such substantial increases. From previous studies, there is little evidence of impairment of respiratory gas exchange in trout exposed to these copper concentrations and yet, in the acidic test waters, the gradient of NH3 partial pressure between fish and water was 5.5­6 times greater than that under control conditions. Swimming performance determined by the critical swimming speed (Ucrit) was reduced by copper and acid exposure, and a significant relationship existed between Ucrit and the plasma ammonia concentration of exercised trout. Ammonium ions influence several key enzymes involved in energy metabolism, and elevated ammonia levels might, therefore, reduce the capacity of muscle to exercise. Alternatively, ammonia may have affected the nervous coordination of exercise either centrally or by disrupting peripheral motor innervation.
25
Ivsic-Bajceta, Dragana, Zeljko Kamberovic, Marija Korac, and Milorad Gavrilovski. "A solidification/stabilization process for wastewater treatment sludge from a primary copper smelter." Journal of the Serbian Chemical Society 78, no. 5 (2013): 725–39. http://dx.doi.org/10.2298/jsc120716125i.
Full textAbstract:
Wastewater treatment sludge from primary copper smelter is characterized as hazardous waste that requires treatment prior disposal due to significant amount of heavy metals and arsenic. The aim of the presented study was to investigate the feasibility and the effectiveness of solidification/stabilization process of the sludge using fly ash and lime as binders. The effectiveness of the process was evaluated by Unconfined Compressive Strength (UCS) testing, leaching tests (EN 12457-4 and Toxicity Characteristic Leaching Procedure (TCLP)) and Acid Neutralization Capacity (ANC) test. All samples reached target UCS of 0.35 MPa. Calcium to silicon concentration ratio (cCa/cSi), determined by X-Ray Fluorescence (XRF) analysis, was identified as main factor governing strength development. Inductively coupled plasma-optical emission spectrometry (ICP-OES) analyses of solutions after leaching tests showed excellent stabilization of Cu, Ni, Pb and Zn (above 99 %) and arsenic (above 90 %) in samples with high Ca(OH)2 content. Results of ANC test indicated that buffering capacity of solidified material linearly depended on Ca concentration in FA and lime. Sample with 20 % of binder heaving 50 % of FA and 50 % of lime met all requirements to be safely disposed.
26
Gheorghe, Stefania, Gabriela Geanina Vasile, Cristina Gligor, Irina Eugenia Lucaciu, and Mihai Nita Lazar. "Metallic Elements (Cu, Zn, Ni and Mn) Toxicity Effects Determination on a Fresh Water Fish Cyprinus Carpio (Common Carp) Laboratory Acclimatized." Revista de Chimie 68, no. 8 (September 15, 2017): 1711–15. http://dx.doi.org/10.37358/rc.17.8.5750.
Full textAbstract:
Metallic elements copper (Cu), zinc (Zn), nickel (Ni) and manganese (Mn) are some of the most commonly found in water and sediment samples collected from the Danube - Danube Delta. These elements are important as essential micronutrients, being normally present at low concentrations in biological organisms, but in high concentrations they become toxic with immediate and delayed effects. The role of this metals is still controversial, that�s why bioconcentration potential is so important. In this non-clinical study, we tested in vitro effect of heavy metals on carp, Cyprinus carpio, reproducing in vivo presence of Cu, Zn, Ni and Mn in the Romanian�s surface water. The toxicity tests were performed according to OECD 203 by detecting the average (50%) lethal concentration - LC50 on aquatic organisms (freshwater fish) at 96h. The results pointed out that, copper value for LC 50 at 96h was estimated as 3.4 mg/L (concentrations tested in the range of 0.1 - 4.75 mg/L). Zinc value for LC 50 at 96h was estimated as 20.8 mg/L (concentrations tested in the range of 0.028 � 29.6 mg/L). Nickel value for LC 50 at 96h was estimated as 40.1 mg/L (concentrations tested in the range of 0.008 - 84.5 mg/L). For manganese the mortality effects has recorded at LC 50 at 96h at estimated value higher than 53 mg/L (concentrations tested in the range of 0.04 - 53.9 mg/L). The accuracy of the testing metals concentration was insured by the screening of the dilution water, as well as food and control fish, acclimated in laboratory conditions.
27
Juganson, Katre, Angela Ivask, Irina Blinova, Monika Mortimer, and Anne Kahru. "NanoE-Tox: New and in-depth database concerning ecotoxicity of nanomaterials." Beilstein Journal of Nanotechnology 6 (August 25, 2015): 1788–804. http://dx.doi.org/10.3762/bjnano.6.183.
Full textAbstract:
The increasing production and use of engineered nanomaterials (ENMs) inevitably results in their higher concentrations in the environment. This may lead to undesirable environmental effects and thus warrants risk assessment. The ecotoxicity testing of a wide variety of ENMs rapidly evolving in the market is costly but also ethically questionable when bioassays with vertebrates are conducted. Therefore, alternative methods, e.g., models for predicting toxicity mechanisms of ENMs based on their physico-chemical properties (e.g., quantitative (nano)structure-activity relationships, QSARs/QNARs), should be developed. While the development of such models relies on good-quality experimental toxicity data, most of the available data in the literature even for the same test species are highly variable. In order to map and analyse the state of the art of the existing nanoecotoxicological information suitable for QNARs, we created a database NanoE-Tox that is available as Supporting Information File 2. The database is based on existing literature on ecotoxicology of eight ENMs with different chemical composition: carbon nanotubes (CNTs), fullerenes, silver (Ag), titanium dioxide (TiO2), zinc oxide (ZnO), cerium dioxide (CeO2), copper oxide (CuO), and iron oxide (FeO x ; Fe2O3, Fe3O4). Altogether, NanoE-Tox database consolidates data from 224 articles and lists altogether 1,518 toxicity values (EC50/LC50/NOEC) with corresponding test conditions and physico-chemical parameters of the ENMs as well as reported toxicity mechanisms and uptake of ENMs in the organisms. 35% of the data in NanoE-Tox concerns ecotoxicity of Ag NPs, followed by TiO2 (22%), CeO2 (13%), and ZnO (10%). Most of the data originates from studies with crustaceans (26%), bacteria (17%), fish (13%), and algae (11%). Based on the median toxicity values of the most sensitive organism (data derived from three or more articles) the toxicity order was as follows: Ag > ZnO > CuO > CeO2 > CNTs > TiO2 > FeO x . We believe NanoE-Tox database contains valuable information for ENM environmental hazard estimation and development of models for predicting toxic potential of ENMs.
28
Saleem, Haleema, and Syed Javaid Zaidi. "Recent Developments in the Application of Nanomaterials in Agroecosystems." Nanomaterials 10, no. 12 (December 2, 2020): 2411. http://dx.doi.org/10.3390/nano10122411.
Full textAbstract:
Nanotechnology implies the scientific research, development, and manufacture, along with processing, of materials and structures on a nano scale. Presently, the contamination of metalloids and metals in the soil has gained substantial attention. The consolidation of nanomaterials and plants in ecological management has received considerable research attention because certain nanomaterials could enhance plant seed germination and entire plant growth. Conversely, when the nanomaterial concentration is not properly controlled, toxicity will definitely develop. This paper discusses the role of nanomaterials as: (1) nano-pesticides (for improving the plant resistance against the biotic stress); and (2) nano-fertilizers (for promoting the plant growth by providing vital nutrients). This review analyzes the potential usages of nanomaterials in agroecosystem. In addition, the adverse effects of nanomaterials on soil organisms are discussed. We mostly examine the beneficial effects of nanomaterials such as nano-zerovalent iron, iron oxide, titanium dioxide, nano-hydroxyapatite, carbon nanotubes, and silver- and copper-based nanomaterials. Some nanomaterials can affect the growth, survival, and reproduction of soil organisms. A change from testing/using nanomaterials in plants for developing nanomaterials depending on agricultural requirements would be an important phase in the utilization of nanomaterials in sustainable agriculture. Conversely, the transport as well as ecological toxicity of nanomaterials should be seriously examined for guaranteeing its benign usage in agriculture.
29
Yanagihara, Miina, Fumiyuki Nakajima, and Tomohiro Tobino. "Effect of Control Sediment Composition on the Metabolomic Responses of Grandidierella japonica during Toxicity Testing Using Copper at an Acutely Toxic Level." Journal of Water and Environment Technology 17, no. 6 (2019): 386–94. http://dx.doi.org/10.2965/jwet.18-104.
Full text
30
Harrison, Joe J., Raymond J. Turner, Daniel A. Joo, Michelle A. Stan, Catherine S. Chan, Nick D. Allan, Helen A. Vrionis, Merle E. Olson, and Howard Ceri. "Copper and Quaternary Ammonium Cations Exert Synergistic Bactericidal and Antibiofilm Activity against Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 52, no. 8 (June 2, 2008): 2870–81. http://dx.doi.org/10.1128/aac.00203-08.
Full textAbstract:
ABSTRACT Biofilms are slimy aggregates of microbes that are likely responsible for many chronic infections as well as for contamination of clinical and industrial environments. Pseudomonas aeruginosa is a prevalent hospital pathogen that is well known for its ability to form biofilms that are recalcitrant to many different antimicrobial treatments. We have devised a high-throughput method for testing combinations of antimicrobials for synergistic activity against biofilms, including those formed by P. aeruginosa. This approach was used to look for changes in biofilm susceptibility to various biocides when these agents were combined with metal ions. This process identified that Cu2+ works synergistically with quaternary ammonium compounds (QACs; specifically benzalkonium chloride, cetalkonium chloride, cetylpyridinium chloride, myristalkonium chloride, and Polycide) to kill P. aeruginosa biofilms. In some cases, adding Cu2+ to QACs resulted in a 128-fold decrease in the biofilm minimum bactericidal concentration compared to that for single-agent treatments. In combination, these agents retained broad-spectrum antimicrobial activity that also eradicated biofilms of Escherichia coli, Staphylococcus aureus, Salmonella enterica serovar Cholerasuis, and Pseudomonas fluorescens. To investigate the mechanism of action, isothermal titration calorimetry was used to show that Cu2+ and QACs do not interact in aqueous solutions, suggesting that each agent exerts microbiological toxicity through independent biochemical routes. Additionally, Cu2+ and QACs, both alone and in combination, reduced the activity of nitrate reductases, which are enzymes that are important for normal biofilm growth. Collectively, the results of this study indicate that Cu2+ and QACs are effective combinations of antimicrobials that may be used to kill bacterial biofilms.
31
Expósito, Nora, Roberta Carafa, Vikas Kumar, Jordi Sierra, Marta Schuhmacher, and Gemma Giménez Papiol. "Performance of Chlorella Vulgaris Exposed to Heavy Metal Mixtures: Linking Measured Endpoints and Mechanisms." International Journal of Environmental Research and Public Health 18, no. 3 (January 25, 2021): 1037. http://dx.doi.org/10.3390/ijerph18031037.
Full textAbstract:
Microalgae growth inhibition assays are candidates for referent ecotoxicology as a fundamental part of the strategy to reduce the use of fish and other animal models in aquatic toxicology. In the present work, the performance of Chlorella vulgaris exposed to heavy metals following standardized growth and photosynthesis inhibition assays was assessed in two different scenarios: (1) dilutions of single heavy metals and (2) an artificial mixture of heavy metals at similar levels as those found in natural rivers. Chemical speciation of heavy metals was estimated with Visual MINTEQ software; free heavy metal ion concentrations were used as input data, together with microalgae growth and photosynthesis inhibition, to compare different effects and explain possible toxicity mechanisms. The final goal was to assess the suitability of the ecotoxicological test based on the growth and photosynthesis inhibition of microalgae cultures, supported by mathematic models for regulatory and decision-making purposes. The C. vulgaris algae growth inhibition test was more sensitive for As, Zn, and Pb exposure whereas the photosynthesis inhibition test was more sensitive for Cu and Ni exposure. The effects on growth and photosynthesis were not related. C. vulgaris evidenced the formation of mucilaginous aggregations at lower copper concentrations. We found that the toxicity of a given heavy metal is not only determined by its chemical speciation; other chemical compounds (as nutrient loads) and biological interactions play an important role in the final toxicity. Predictive mixture effect models tend to overestimate the effects of metal mixtures in C. vulgaris for both growth and photosynthesis inhibition tests. Growth and photosynthesis inhibition tests give complementary information, and both are a fast, cheap, and sensitive alternative to animal testing. More research is needed to solve the challenge of complex pollutant mixtures as they are present in natural environments, where microalgae-based assays can be suitable monitoring tools for pollution management and regulatory purposes.
32
Peterson, H. G., N. Nyholm, M. Nelson, R. Powell, P. M. Huang, and R. Scroggins. "Development of aquatic plant bioassays for rapid screening and interpretive risk assessments of metal mining liquid waste waters." Water Science and Technology 33, no. 6 (March 1, 1996): 155–61. http://dx.doi.org/10.2166/wst.1996.0092.
Full textAbstract:
The use of non-photosynthetic organisms alone to describe environmental impact has been recognized by regulatory agencies, industry, and academia as being insufficient both in Europe and North America. Lack of adequate testing methods for photosynthetic aquatic organisms is considered as a major impediment to the successful regulation and safe use of pesticides and waste discharges and is of even more concern to the metal mining industry due to the non-biodegradable nature of its waste streams. This work shows that the chemical effluent limits set in the “Metal mining liquid effluent regulations and guidelines” provide variable protection of aquatic photosynthetic organisms. Aquatic effects of the more toxic metals (e.g., copper, nickel, and zinc) may occur at levels that are one to two orders of magnitude lower than present limits. To establish adequate protection of receiving water bodies it may be necessary to establish site-specific criteria taking into consideration toxicity modifying factors of individual sites. If the establishment of such criteria is determined with a host of ecologically relevant organisms, it will be possible to design effective environmental protection at the least possible cost.
33
Du, Yunpeng, Xiong Tong, Xian Xie, Wenjie Zhang, Hanxu Yang, and Qiang Song. "Recovery of Zinc and Silver from Zinc Acid-Leaching Residues with Reduction of Their Environmental Impact Using a Novel Water Leaching-Flotation Process." Minerals 11, no. 6 (May 31, 2021): 586. http://dx.doi.org/10.3390/min11060586.
Full textAbstract:
Zinc-leaching residue (ZLR) is a strongly acidic hazardous waste; it has poor stability, high heavy metal levels, and releases toxic elements into the environment. ZLR has potential as a valuable resource, because it contains elevated levels of zinc and silver. In this paper, the recovery of zinc (Zn) and silver (Ag) from ZLR wastes from zinc hydrometallurgy workshops using water leaching followed by flotation was studied. During water leaching experiments, the zinc and copper recovery rates were 38% and 61%, respectively. Thereafter, various flotation testing parameters were optimized and included grinding time, reagent dosages, pulp density, flotation time, and type of adjuster. Experimental results demonstrated this flotation method successfully recycled Ag and Zn. A froth product containing more than 9256.41 g/t Ag and 12.26% Zn was produced from the ZLR with approximately 80.32% Ag and 42.88% Zn recoveries. The toxicity characteristic leaching procedure (TCLP) results indicated the water-leaching flotation process not only recycled valuable metals such as zinc and silver in zinc-containing hazardous wastes but lowered the hazardous waste levels to those of general wastes and recycled wastes in an efficient, economical, and environmentally friendly way.
34
KUMAR, YOGENDRA. "Nanofertilizers and their role in sustainable agriculture." Annals of Plant and Soil Research 23, no. 3 (August 1, 2021): 238–55. http://dx.doi.org/10.47815/apsr.2021.10067.
Full textAbstract:
Enhancing nutrient use efficiency (NUE) with minimal threat to environment has become critical for our agriculture food production systems (FPS) to sustain the burgeoning population. Nanotechnology with nanoscale inputs for production of nano agri-inputs (NAIPs) has emerged as an innovative solution for addressing issue of low or declining nutrient use efficiency (NUE) with minimal environment footprint. Nanotechnology is a promising field of research which has the potential to offer sustainable solutions to ever pressing challenges confronting our modern intensive agriculture. Nanotechnology employs nanomaterials which typically have small size (1–100 nm) which imparts unique characteristics and benefits. In addition to numerous other benefits, large surface area to volume ratio offers opportunity for better and effective interaction of nanoparticles to target sites. Nano-fertilizers hold potential to fulfil plant nutrition requirements along with imparting sustainability to crop production systems and that too without compromising the crops yield. Indian Farmers Fertilizer Cooperative Limited (IFFCO) - the farmers’ own fertilizer cooperative has been in the forefront for promotion of agro-technologies and novel agri-inputs to mitigate problems faced by the farmers. It has indigenously innovated at its Nano Biotechnology Research Centre (NBRC) at Kalol, Gujarat and succeeded in R& D and manufacturing of proprietary nano-fertilizers viz. nano urea, nano zinc, and nano copper. These nano-fertilizers utilize the dynamics of shape, size, surface area and bio-assimilation. There efficacy was evaluated on the basis of multi-location multi-crop trials under varying crop seasons, both by the research institutes and also on the progressive farmers’ fields across 11,000 locations on 94 crops across India. Independently, nano nitrogen, nano zinc, and nano copper have also been tested for bio-efficacy- bio safety- toxicity and environment suitability. IFFCO nano-fertilizers meet alll the current national and international guidelines related to nano technology or nano scale agri-inputs.They are in sync with OECD testing guidelines (TGs) and “Guidelines for Testing of NAIPs and Food Products” released by the Department of Biotechnology, Government of India. Harvested produce of crops applied with IFFCO nano-Urea, nano-zinc, and nano-copper have been found fit for consumption with no adverse effect. This paper reviews the benefits of nanofertilizers (Nano N, Nano Zn and Nano Cu) towards increasing nutrient use efficiency and crop productivity and produce quality in general and the journey of IFFCO nano-fertilizers (IFFCO’s Nano Urea, Nano Zn and Nano Cu) from conception to PILOT to PLANT stage has also been covered in this paper.
35
Modica-Napolitano, Bharath, Hanlon, and Hurley. "The Anticancer Agent Elesclomol Has Direct Effects on Mitochondrial Bioenergetic Function in Isolated Mammalian Mitochondria." Biomolecules 9, no. 8 (July 24, 2019): 298. http://dx.doi.org/10.3390/biom9080298.
Full textAbstract:
Elesclomol ((N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide)); formerly STA-4783) is a mitochondria-targeted chemotherapeutic agent that has demonstrated efficacy in selective cancer cell killing in pre-clinical and clinical testing. The biologically active form of elesclomol is a deprotonated copper chelate (elesclomol:copper; E:C), which has been shown to enhance reactive oxygen species (ROS) production and induce a transcriptional gene profile characteristic of an oxidative stress response in vitro. Previous studies suggest that E:C interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and ultimately induce cell death. The purpose of this study was to further explore the mechanism of cellular and mitochondrial toxicity of E:C by examining its direct effect on mitochondrial bioenergetic function. The results obtained indicate that E:C treatment in whole cells of non-tumorigenic origin at high concentrations (40 M and higher) induces a rapid and substantial increase in mitochondrial superoxide levels and dissipation of mitochondrial membrane potential. Furthermore, similar higher concentrations of E:C act as a direct uncoupler of oxidative phosphorylation and generalized inhibitor of electron transport activity in isolated, intact mitochondria, and induce a dose-dependent inhibition of mitochondrial NADH-ubiquinone oxidoreductase activity in freeze-thawed mitochondrial preparations. The results of this study are important in that they are the first to demonstrate a direct effect of the E:C chelate on bioenergetic function in isolated mammalian mitochondria, and suggest the possibility that the increase in ROS production and cytotoxicity induced by E:C may in part be due to uncoupling of mitochondrial oxidative phosphorylation and/or inhibition of electron transport activity. These results also provide important information about the mechanisms of mitochondrial and cellular toxicity induced by E:C and will ultimately contribute to a better understanding of the therapeutic potential of elesclomol as an anticancer compound.
36
Sánchez-Marín, Paula. "A review of chemical speciation techniques used for predicting dissolved copper bioavailability in seawater." Environmental Chemistry 17, no. 7 (2020): 469. http://dx.doi.org/10.1071/en19266.
Full textAbstract:
Environmental contextCopper (Cu) is a metal of ecotoxicological concern in contaminated coastal areas. Cu present as the free ion is considered the most bioavailable fraction of the metal, and there is a need for the correct measurement or estimation of free Cu-ion concentrations in seawater. I review studies that have combined a biological measure of Cu bioavailability with chemical speciation measurements, and critically assess the ability of current methods to predict Cu bioavailability in contaminated coastal ecosystems. AbstractCopper (Cu) is an essential metal, but it is also toxic at concentrations reached in polluted coastal areas. In seawater, the speciation of this metal is largely controlled by the presence of dissolved organic matter (DOM), which binds Cu ions decreasing the concentration of inorganic and free forms of the metal. This is important to aquatic life, given that the bioavailability of dissolved metals is generally expected to be determined by the free ion concentration according to bioavailability models such as the free ion activity model and biotic ligand model (FIAM/BLM). The analytical determination of free metal concentrations in seawater is a challenging task that is needed (in combination with toxicity tests or other means of testing bioavailability) in order to test the applicability of the FIAM/BLM in particular systems and also for its application in monitoring and risk assessment of metals. This review summarises the studies that combine a biological measure of Cu bioavailability with the use of a chemical speciation technique for the measurement of Cu speciation in seawater, and it presents a critical examination of the results of those studies in order to determine which techniques are more suitable for the prediction of Cu bioavailability in seawater and to highlight research needs in the field. The technique showing the highest level of agreement with bioavailability data is anodic stripping voltammetry (ASV). Cathodic stripping voltammetry (CSV), aluminium hydroxide coated exchange resin (ALSA), and diffusion gradients in thin films (DGT) are also promising in this regard, although DGT slightly overestimates bioavailable Cu. More research is needed comparing the performance of different chemical speciation techniques with Cu bioavailability in seawater, especially at environmentally relevant concentrations of Cu.
37
Lamb, J. C. "Reproductive Toxicity Testing: Evaluating and Developing New Testing Systems." Journal of the American College of Toxicology 4, no. 2 (March 1985): 163–71. http://dx.doi.org/10.3109/10915818509014511.
Full textAbstract:
Reproductive toxicity testing systems are used by national and international regulatory agencies. Protocols have not been standardized between agencies or even within certain agencies. Although there have been efforts at standardization, a certain amount of the differences between testing protocols is a reflection of the needs of the particular agency. New developments in in vitro techniques might lead to new test systems, but reproductive function is dependent upon the interaction of various cells and organs that cannot presently be copied in the test tube; this makes whole-animal testing systems a necessity. The present whole-animal models used by the Food and Drug Administration include the 3 segment reproduction studies used for testing drug safety and the multigeneration studies used for food additives. The Environmental Protection Agency has adopted 2 similar versions of a 2-generation study for the Office of Pesticide Programs and the Office of Toxic Substances. The National Toxicology Program, although not a regulatory agency, has taken a prominent role in reproductive toxicity testing, test system development, and test system evaluation. A new testing system, Fertility Assessment by Continuous Breeding (FACB), is currently being studied as a cost-effective and reliable alternative test system. The FACB protocol houses male and female mice as breeding pairs and removes offspring as soon as they are born during the first 14 weeks to allow continuous mating. Each breeding pair normally has up to 5 litters, and the last litter is saved to evaluate the second generation. The efficiency, reliability, and expense of the protocol are being compared to the existing testing systems.
38
Ivanyutin, N. M., and S. V. Podovalova. "USING AN INTEGRATED APPROACH TO ASSESS THE CURRENT ENVIRONMENTAL STATE OF THE BESHTEREK RIVER." Water and Ecology 25, no. 3 (2020): 41–49. http://dx.doi.org/10.23968/2305-3488.2020.25.3.41-49.
Full textAbstract:
Introduction. The problem of restoring and preserving the environmental state of watercourses with an increase in anthropogenic load has recently become more urgent, but the use of only one method or approach does not allow us to judge the current state of a river, so there is a need to combine various methods aimed at obtaining integrated information. The purpose of this study was to analyze the environmental state of the water bodies in the Beshterek River Basin (Republic of Crimea). Methods. The studies were carried out during 2018–2019 and included: visual observations of the watercourse state, water-protection zone, channel ponds; water flow measurement; sampling for the study of water chemistry; calculation of the water pollution index (WPI) and the integrated indicator of ecological condition (IIEC); study of water toxicity by means of bio-assay techniques using wheat and cress seeds; development of environmental measures. Results. The studies have found that the main pollutants in river water are sulfates, phosphates as well as heavy metals: Cd, Pb, Cu, Zn. The concentration of sulfates increased from 0.15–0.22 MAC (upper river) to 1.5–2.4 MAC (mouth of the river), which indicates the ingress of domestic wastewater into the watercourse. The content of phosphates in the middle reaches exceeded the standards by 1.9–11.1 times. The heavy metal content exceeding the MAC was recorded at all river stations: zinc (station No. 1 — 2.1 MAC), cadmium (station No. 3 — 1.24 MAC), lead (station No. 4 — 1.23 MAC) and copper (station No. 4 — 1.5–10 MAC). The water quality in terms of the WPI was II and III (“clean” and “moderately polluted”) in the river and II, III and IV (“polluted”) in the channel ponds. The bio-assay testing showed no toxic effect on the test cultures. Conclusion. Among the priorities, the following can be distinguished: the need to establish a permanent monitoring network for the observation of the qualitative and quantitative characteristics of the river flow, and develop a program for sewage handling in villages located in the river valley.
39
Roth, William L., and John F. Young. "Use of Pharmacokinetic Data Under the FDA's Redbook II Guidelines for Direct Food Additives." International Journal of Toxicology 17, no. 3 (April 1998): 355–81. http://dx.doi.org/10.1080/109158198226620.
Full textAbstract:
Experience with food additive petitions submited after publication of the Food and Drug Administration's Redbook I (U. S. FDA, 1982) guide lines indicated a number of areas in which improvements were needed, and advances in toxicol-ogy testing during the last decade required additional rev is ions. In March 1993, the FDA's Center for Food Safety and Applied Nutrition (CFSAN) distributed copies of a draft of Redbook II for public comment. Since that time, revisions have been made based on comments received on the initial draft. This article describes the rationale for Redbook II guidance on the design of pharm acoki-netic studies and discusses some common problems the FDA has encountered in reviewing pharmacokine tic data submitted as part of food additive petitions. Points emphasized are that (1) pharmaco kinetic information is needed for the interpretation of toxicity studies and is most use ful when conducted before major toxicity studies, (2) the use of whole-body autoradiography is encouraged as a means to select tissues of interest, and as a substitute for dissection and tis-sue sampling, (3) kinetic and mechanistic studies conducted with blood compo-nents, tissue slices, hepatocytes, and othercell types in vitro ofien provide more useful information on the fate of chemicals in specific tissues than information extracted from whole-animal studies. The intention of th e new guide lines for pharmaco kinetic studies is to increase the information content of data gathered and to encourage the use of pharmaco kinetic models and results in the selection of doses for subchronic, chronic, and developmental toxicity studies.
40
Wang, Hui, Vinitha Ebenezer, and Jang-Seu Ki. "Photosynthetic and biochemical responses of the freshwater green algae Closterium ehrenbergii Meneghini (Conjugatophyceae) exposed to the metal coppers and its implication for toxicity testing." Journal of Microbiology 56, no. 6 (June 2018): 426–34. http://dx.doi.org/10.1007/s12275-018-8081-8.
Full text
41
Borthakur, Gautam, Hagop M. Kantarjian, Courtney D. DiNardo, Naval Daver, Elias J. Jabbour, Tapan Kadia, Guillermo Garcia-Manero, et al. "Phase II Study of CPX-351 (Cytarabine: Daunorubicin) Liposome Injection in Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) at High Risk for Induction Mortality." Blood 130, Suppl_1 (December 7, 2017): 892. http://dx.doi.org/10.1182/blood.v130.suppl_1.892.892.
Full textAbstract:
Abstract Background: CPX-351 is a liposomal formulation of 5:1 molar combination of cytarabine and daunorubicin (Leukemia research 2010; 34: 1214). Subset analysis in a Phase II study reported improved outcomes in first relapse AML pts with European Prognostic Index defined poor-risk disease (Cancer 2015; 121: 234). In a phase 3 randomized study among fit pts, 60-75 years (yrs) of age with high-risk AML, that compared induction CPX-351 (100 U/m2, days 1, 3, 5) and vs 7+3; CPX-351 significantly improved response, event free and overall survival (Journal of Clinical Oncology 2016; 34(15_suppl): 7000). Observations from the Phase I study of responses occurring at dose levels of one third to one half the MTD (32 to 43 U/m2), suggest that doses of 75 and 50 units/m2 may still be effective and better tolerated among pts at high risk for toxicity. Hypothesis: Reduced dose CPX-351 as induction therapy may improve the outcome of pts with AML at high risk for 60-day mortality and not ordinarily offered induction therapy. Design: We designed an open-label, phase II trial of CPX-351 administered on days 1, 3, and 5 at 50 (arm 1) or 75 (arm 2) units/m2 as induction. Fifteen pts each were to be randomly assigned to these two arms. As these doses are below the original MTD dose of 100 units/m2, a cohort of 15 pts were to be studied at 100 units/m2 provided the first two dose levels were safe. At the end of the study a single dose level was to be chosen based on efficacy and safety i.e. dose limiting toxicity (DLT) <33%. Bayesian method was used for futility and toxicity monitoring. Observation of ≤3 CR/CRp/CRi among 15 pts (<20%) defines lack of efficacy. An expansion cohort of 10 pts were to be treated at the selected dose for evaluation for safety and efficacy. The primary objective is to assess preliminary efficacy (CR/CRp/ CRi within 2 induction cycles) in pts with newly diagnosed AML at high risk for induction mortality, defined as 30-50% predicted risk of death by Day 60, and to select the most promising dose level for further efficacy testing. To be considered at high risk for induction mortality pts ≥60 yrs must have at least 1 and pts <60 yrs must have at least 2 risk factors that include antecedent hematological disorder, therapy related AML (T-AML), AML with MDS-related changes or MDS-associated karyotype, age ≥70 yrs, Performance Status ≥2, serum creatinine >1.3 g/dL. Pts with ejection fraction <50%, history of copper-metabolism disorder, uncontrolled infection or who received chemotherapy within 2 weeks of start were excluded. Responders could receive up to 4 consolidation courses of CPX-351 administered at 65 units/m2 on days 1 and 3. Results: Based on safety of 2 dose levels (50 units/m2 and 75 units/m2) of CPX-351, one additional cohort with a dose of 100 units/m2 was opened. Fifty-two pts (15 at 50 U/m2, 25 at 75 U/m2 and 12 at 100 U/m2) have been treated (4 screen failures). Median age is 68 yrs (range 54-84) and 19 (37%) pts are females. Ninety percent of pts had prior MDS or T-AML, 81% had therapies for MDS and 54% had adverse cytogenetics. Patient characteristics are outlined in Table 1. Median number of cycles to response has been 1 (range 1-2) and median number of cycles administered is 2 (range 1-5). Twenty (38%) pts have responded; 15 achieving CR, 3 CRi, 2 CRp. Six of 15 pts with CR were MRD negative at response. Responses (CR/CRp/CRi) are, arm 1=3/0/0 (20%), arm 2= 6/2/2 (40%) and arm 3= 6/0/1 (47%). With median follow up of 5.3 months, median survival in the entire cohort is 5.9 months and median remission (CR/CRp) duration 5.3 months (Fig 1a and b). Median time to recovery of counts for responding patients was 35 day (range, 16-153 days). Response rate trended to be lower among pts with mutant TP53 (20% vs 46%, p=.08), therapy related AML (0% versus 48%, p=.02) and younger than <65 yrs of age (21% vs 48%, p=.5). Deaths within 60 days were 11 (21%), all due to sepsis, multi-organ failure or disease progression; 5 in arm 1 (33%), and 3 each in arms 2 (12%) and 3 (25%). Most frequent grade 3-5 toxicities, irrespective of attribution, were febrile neutropenia (38%) and respiratory failure (17%). Conclusion : In a very high-risk elderly cohort of newly diagnosed pts with AML, CPX-351 induction yielded promising remission rates at all 3 doses tested. The efficacy, toxicity and early mortality profile favors the use of CPX-351 at 75u/m2 on days 1, 3 and 5 as the preferred induction schedule. Presence of TP53 mutation or T-AML potentially defines groups with low probabilities of response. Disclosures Kantarjian: Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. DiNardo: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Daver: Bristol-Myers Squibb Company: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Incyte Corporation: Honoraria, Research Funding; Kiromic: Research Funding; Immunogen: Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Daiichi-Sankyo: Research Funding; Pfizer Inc.: Consultancy, Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy. Pemmaraju: LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; cellectis: Research Funding; Incyte Corporation: Consultancy, Honoraria; novartis: Consultancy, Honoraria, Research Funding; roche diagnostics: Consultancy, Honoraria; abbvie: Research Funding. Wierda: Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Kite: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding; Juno: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jain: Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Incyte: Research Funding. Cortes: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.
42
Engelmann, Cornelius, Martina Sterneck, Karl Heinz Weiss, Silke Templin, Steffen Zopf, Gerald Denk, Dennis Eurich, et al. "Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers." Journal of Clinical Medicine 9, no. 8 (July 23, 2020): 2352. http://dx.doi.org/10.3390/jcm9082352.
Full textAbstract:
Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3–6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.
43
Brickelmaier, Margot, Alexey Lugovskoy, Ramya Kartikeyan, Marta M. Reviriego-Mendoza, Norm Allaire, Kenneth Simon, Richard J. Frisque, and Leonid Gorelik. "Identification and Characterization of Mefloquine Efficacy against JC Virus In Vitro." Antimicrobial Agents and Chemotherapy 53, no. 5 (March 2, 2009): 1840–49. http://dx.doi.org/10.1128/aac.01614-08.
Full textAbstract:
ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEΔ), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.
44
Sloane, Hillary, Evgeny Izumchenko, Austin Mattox, Rifat Hasina, Aashay Patel, Frederick Jones, Hannah Quinn, et al. "Ultra-sensitive detection and quantification of HPV DNA in the plasma of patients with oropharyngeal squamous cell carcinoma (OPSCC) enrolled in the OPTIMA 2 treatment de-escalation trial." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 6048. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.6048.
Full textAbstract:
6048 Background: Human papillomavirus (HPV) infection is a primary factor driving the increasing incidence of OPSCC. As patients with HPV+ OPSCC show significantly improved treatment response and prognosis, there is an urgent need to de-escalate treatment of HPV+ OPSCC that optimizes oncologic control while minimizing treatment-related toxicity. Cell-free HPV DNA (cfHPV-DNA) from plasma specimens represents a promising noninvasive surrogate of disease burden in these patients. To enable cfHPV-DNA analysis as a strategy to monitor response to therapy and guide treatment de-escalation, we developed a highly sensitive assay for HPV16/18 detection and quantification in plasma, based on the SafeSEQ next-generation sequencing (NGS) technology. Methods: Longitudinal plasma samples were collected from patients with locoregional HPV+ OPSCC treated on our institutional de-escalation protocol of induction chemoimmunotherapy followed by risk/response stratified de-escalated locoregional therapy, OPTIMA 2 (NCT03107182). Neck CT or MRI was obtained for all patients at baseline and following induction chemoimmunotherapy; radiographic response to induction therapy was assessed per RECIST 1.1 criteria. cfHPV-DNA was quantified in plasma samples collected at baseline and at the end of induction therapy. Changes in cfHPV-DNA levels were correlated with radiographic response. Results: The SafeSEQ HPV assay demonstrates high analytical sensitivity, with ability to detect a single copy of HPV DNA. Replicate testing of contrived samples containing HPV 16/18 DNA at defined levels revealed robust quantitative detection across a dynamic range over 5 orders of magnitude. The assay showed a low level of background signal ( < 0.04 copies per sample) across 20 healthy donor samples, indicating high specificity. In plasma samples collected at baseline from patients enrolled in OPTIMA 2, cfHPV-DNA was detected at levels ranging from 1 to > 30,000 copies/ml. A high correlation was observed between dynamic changes in patients’ cfHPV-DNA levels and radiographic responses following induction therapy. Furthermore, in samples collected longitudinally during induction therapy, changes in cfHPV-DNA levels accurately tracked radiographic responses to therapy. Conclusions: We have developed a highly sensitive and specific cfHPV-DNA detection assay based on SafeSEQ NGS technology and have successfully applied it to monitor therapeutic response in HPV+ OPSCC patients. The assay exhibits robust quantitative detection of HPV across a broad range of levels, even when only a few copies are present, enabling high-resolution molecular monitoring. Prospective studies are underway to further evaluate the kinetics of cfHPV-DNA as a predictor of response to therapy in order to more precisely guide the management of patients with HPV+ OPSCC.
45
Jacobson, Jeffrey M., Jacob P. Lalezari, Melanie A. Thompson, Carl J. Fichtenbaum, Michael S. Saag, Barry S. Zingman, Paul D'Ambrosio, et al. "Phase 2a Study of the CCR5 Monoclonal Antibody PRO 140 Administered Intravenously to HIV-Infected Adults." Antimicrobial Agents and Chemotherapy 54, no. 10 (July 26, 2010): 4137–42. http://dx.doi.org/10.1128/aac.00086-10.
Full textAbstract:
ABSTRACT The anti-CCR5 antibody PRO 140 has shown potent and prolonged antiretroviral activity in subjects infected with CCR5-tropic (R5) HIV-1. Prior studies have examined single intravenous doses ranging up to 5 mg/kg of body weight or up to three subcutaneous doses ranging up to 324 mg. Here we report the results of a randomized, double-blind, placebo-controlled trial that examined the antiviral activity, tolerability, and pharmacokinetics of single 5-mg/kg and 10-mg/kg intravenous infusions of PRO 140 in 31 treated subjects. Eligibility criteria included HIV-1 RNA levels of >5,000 copies/ml, CD4+ cell counts of >300/μl, no antiretroviral therapy for ≥12 weeks, and detection of only R5 HIV-1 in the original Trofile assay. Following poststudy testing with an enhanced-sensitivity Trofile assay, one subject treated with 10 mg/kg was reclassified as having dual/mixed-tropic virus at screening, and the data for that subject were censored from efficacy analyses. The mean maximum reduction of the HIV-1 RNA level from the baseline level was 1.8 log10 units for both the 5-mg/kg and 10-mg/kg doses (P < 0.0001 relative to placebo). Viral loads reached their nadir at day 12 posttreatment and remained significantly (P < 0.01) reduced through day 29 for both PRO 140 dose groups. Treatment was generally well tolerated, with no dose-limiting toxicity being observed. Peak serum concentrations and overall exposures increased proportionally with dose. In summary, single 5-mg/kg and 10-mg/kg doses of PRO 140 exhibited potent, long-lived antiviral activity and were generally well tolerated. The findings further delineate the safety and antiviral properties of this novel, long-acting antiretroviral agent.
46
Milano, Filippo, Steven Pergam, Hu Xie, Jonathan Gutman, Ivy Riffkin, Victor Chow, Laura Newell, Michael Boeckh, and Colleen Delaney. "Pre-Transplant Ganciclovir and High-Dose Valacyclovir Prophylaxis Decrease Incidence of CMV Reactivation In High-Risk Seropositive UCBT Recipients." Blood 116, no. 21 (November 19, 2010): 678. http://dx.doi.org/10.1182/blood.v116.21.678.678.
Full textAbstract:
Abstract Abstract 678 Background: Umbilical cord blood transplant (UCBT) recipients are high risk for cytomegalovirus (CMV) complications due to delayed and insufficient immune reconstitution. Since CMV viral load has been shown to be associated with the development of disease, an intensified prevention strategy was adopted at the FHCRC (Seattle, WA) which consists of pre-transplant ganciclovir (from day -8 to day -2), and high-dose acyclovir ([HDA] 2 gm valacyclovir 3 times daily) with preemptive bi-weekly monitoring for CMV DNA in serum from day 0 until day +100. Methods: We set out to compare rates of CMV reactivation and disease through day +100 in high-risk CMV seropositive UCBT recipients who received either the intensified strategy (G+HDA) or standard dose of acyclovir/valacyclovir (SDA, acyclovir 800 mg or valacyclovir 500 mg twice daily). All patients underwent weekly plasma testing for CMV by polymerase chain reaction (PCR). Our primary outcomes of interest were any CMV reactivation or disease by day 100. Risk factors for CMV reactivation were assessed using a multivariate Cox proportional hazards model. Results: Of the 105 UCBT recipients transplanted at the FHCRC between 1/2006 and 12/2009, 61 (58%) were CMV seropositive and eligible for inclusion in the cohort. In total, 31/61 (51%) received SDA and 30 (49%) G+HDA. The median patient age was lower in the SDA group 21.3 (interquartile range [IQR] 14.8–46.7) years and 30.1 (IQR 10.1–41.8) for G+HDA group, but other demographic factors were similar. Overall, the cumulative incidence of CMV reactivation was significantly lower in the G+HDA group (60% vs. 96.7; p=0.001 [Gray's test]) (Figure 1). In patients receiving G+HDA, the median time to first positive CMV PCR occurred later (27 days [IQR 11–35]) when compared to those given SDA prophylaxis (17 days [IQR 8–25]) (p=0.26). Additionally, the G+HDA group had significantly lower initial (71 copies/mL [IQR 47–110] vs. 235 [IQR 63–760], p=0.006) and maximum PCR viral loads (VL) (170 copies/ml [IQR 88–310] vs. 3200 [1400-11000], p<0.001) when compared to those receiving SDA prophylaxis. In multivariate analyses, the G+HDA prophylactic strategy was also associated with a significant reduction in CMV reactivation (HR 0.31; 95% CI 0.16–0.58; p<0.001). Over the first 100 days following transplant, there were fewer episodes of invasive CMV disease in the G+HDA group (1/30, 3% [1 pneumonia]) than under SDA prophylaxis (5/31, 16% [1 disseminated, 2 pneumonia, and 2 GI]) (p=0.09). In the SDA group 2/5 (40%) patients died secondary to CMV disease, and an additional 2 patients developed fatal CMV pneumonia after day 100 (day 165 & 191); no CMV related death or cases of late disease developed in the group receiving G+HDA prophylaxis. There was no evidence of increased toxicity by either median and maximum creatinine levels or days to engraftment when comparing the two regimens. Conclusions: Our study demonstrates that G+HDA was effective in preventing CMV complications in UCBT recipients. This intensified prevention strategy was associated with a decreased rate of CMV reactivation and appeared to significantly alter CMV replication dynamics. Importantly, the increased valacyclovir exposure did not alter the risk for developing either renal or hematologic toxicity. Disclosures: No relevant conflicts of interest to declare.
47
Castellarin, Mauro, Joseph A. Fraietta, Jihyun Lee, John Scholler, Yangbing Zhao, and Carl H. June. "A Novel Small Animal Model to Test on-Target Off-Tumor Cytoxicity of Adoptive Immune Therapies." Blood 126, no. 23 (December 3, 2015): 5432. http://dx.doi.org/10.1182/blood.v126.23.5432.5432.
Full textAbstract:
Abstract Chimeric antigen receptor (CAR) engineered T cells have been used clinically to improve outcomes in patients with hematopoietic malignancies owing to the ability of CAR T cells to recognize tumor antigens and kill malignant cells. CAR T cells possess the antigen recognizing capability of an antibody through the single chain variable fragment (scFv) and their cytotoxicity is enhanced through signaling via the intracellular domains of T cell receptors and co-activating receptors such as CD3zeta and 4-1BB, respectively. Thus, CAR expressing T cells are able to detect cancer cells through tumor antigens and can become activated to unleash their cytotoxic potentials in a non-MHC restricted manner. Therapeutic side-effects can occur when T-cell receptor targeting is misdirected to the incorrect tissue causing potentially serious on-target off-tumor cytotoxicity. Factors that influence CAR targeting include expression levels of tumor-associated antigen in normal tissue and the binding affinities of scFvs. Our first step in developing an in vivo, on target, off-tumor, CAR T cell toxicity model was to generate mice with tunable expression of a human tumor antigen in normal tissue. NSG mice were IV injected with recombinant adeno-associated virus serotype 8 (rAAV8) to deliver a truncated human ErbB2 (Her2/neu or CD340) gene and a Katushka fluorescent reporter that were driven by the liver-specific promoter, thyroxine binding globulin (TBG). AAV8 genomic copies (GCs) were injected at varying dilutions of 1.5 x 1012 GC/mouse, 7.25 x 1011 GC/mouseand 1.5x1010 GC/mouse to induce a range of expression of ErbB2 in the liver. Katushka expression was visualized in vivo using the IVIS small animal imager. ErbB2 gene expression was detected using reverse transcription polymerase chain reaction (qRT-PCR) and the ErbB2 protein was detected using western blots and immunohistochemistry (IHC). Our data has shown that expression levels of ErbB2 and the Katushka reporter positively correlated with the number of AAV8 GCs that were injected. This enabled us to obtain ErbB2 expression levels in the liver comparable to the levels seen in either ErbB2High tumors (eg. SK-OV3) or ErbB2Low tumors (eg. PC3 and HEK293T). To determine if affinity tuning of scFvs will allow CAR T cells to discriminate between high and low ErbB2 expression in the liver, T cells were engineered to co-express the click beetle red (CBR) reporter and either a high-affinity scFv, anti-ErbB2 CAR (4D5) or a low-affinity scFv, anti-ErbB2 CAR (4D5-5). These T cells were then IV injected into NSG mice that had either high or low ErbB2-expressing livers. Although these experiments were ongoing at the time of abstract submission, we will show our results on T cell trafficking in the liver, which will be visualized by IHC and by in vivo imaging using the IVIS small animal imager. Liver toxicity will be assessed by histological examination and by measuring liver function via standard enzymatic testing of blood. Furthermore, we aim to show whether affinity tuning of scFvs will allow CAR T cells to selectively recognize and target ErbB2High tumors while sparing ErbB2Low normal tissue. This will be performed by inoculating ErbB2high SK-OV3 tumor cells into mice with ErbB2Low livers followed by IV injection with either 4D5 or 4D5-5 CAR T cells. We expect that the low-affinity anti-ErbB2 CAR (4D5-5) T cells will target the ErbB2High SK-OV3 tumor cells and cause tumor regression while preserving function in the ErbB2Low liver. If so, then we will have shown that our pre-clinical mouse model can be used to identify on-target off-tumor CAR T cell toxicity, which will aid in improving the safety profile and clinical outcomes of future CAR T cell therapies. Disclosures Scholler: Novartis: Patents & Royalties. Zhao:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding.
48
Verger, Emmanuelle, Bruno Cassinat, Annalisa Andreoli, Elodie Lesteven, Christoph Klade, Oleh Zahriychuk, Christine Chomienne, and Jean-Jacques Kiladjian. "AOP2014/P1101, a Novel Peg-Proline-Interferon Alpha (IFNa) 2b, Specifically Targets JAK2V617F-Positive Polycythemia Vera (PV) Cells." Blood 122, no. 21 (November 15, 2013): 1611. http://dx.doi.org/10.1182/blood.v122.21.1611.1611.
Full textAbstract:
Abstract Background Pegylated Interferon alpha (PEG-IFNa) has proven clinical and molecular efficacy in the treatment of Bcr-Abl negative myeloproliferative neoplasms. Indeed PEG-IFNa induces complete hematological remissions but also molecular responses demonstrated by the reduction of the JAK2V617F (JAK2VF) allele burden. AOP2014/P1101 is a next generation long-acting PEG-IFNa-2b, recently shown to be safe and well tolerated in phase I-II studies in PV patients (pts) (Gisslinger at al, 2012). In addition, molecular responses (MR) were reported in these early phase trials with 50% of pts achieving partial MR at month 18. Furthermore, one pt with a baseline JAK2VF allelic burden of 22% achieved complete MR after 36 weeks of therapy suggesting a specific effect of AOP2014/P1101 on JAK2VF-positive cells. Aim To study the differential impact of AOP2014/P1101 on the proliferation and differentiation of wild type versus JAK2VF hematopoietic cells. Materials and methods We studied the effects of AOP2014/P1101 at different concentrations consistent with assumed exposure in patients (0.5 and 2µg/ml), compared with standard recombinant interferon alpha-2a (rIFNa-2a) at 700 U/ml in human cell lines in liquid suspension assay, and in normal and PV samples in methylcellulose assays. A) Two different human JAK2VF cell lines were studied: HEL characterized by the presence of multiple copies of JAK2VF, and UKE-1 which harbors 2 copies of JAK2VF. Cell lines were grown in presence or absence of drugs and living cells were counted each day during 3 days. B) Normal hematopoietic progenitors derived from cord blood and primary cells from 4 PV patients were studied in clonogenic assays (Methocult, Stemcell technologies©). In PV pts samples the presence of endogenous erythroid colonies (EECs) was determined in cultures without erythropoietin (EPO). Genotyping of the colonies was performed by picking the colonies, extracting the DNA and testing for the presence of JAK2VF using the JAK2 Mutascreen kit (Qiagen©). Results In both HEL and UKE-1 JAK2 mutated cell lines AOP2014/P1101 exhibited a dose-dependent anti-proliferative effect which was comparable to that of rIFNa-2a. AOP2014/P1101 at 0.5µg/ml and 2µg/ml induced a 9%, and 41% inhibition of HEL cells proliferation, respectively (resp). Same doses induced an 18% and 35% inhibition of UKE-1 cells proliferation, resp. A similar antiproliferative effect was observed with rIFNa-2a with 38%, and 36% inhibition of HEL, and UKE-1 cells proliferation, resp. In normal CD34+ hematopoietic progenitors derived from cord blood, AOP2014/P1101 induced a small decrease in the number of erythroid colonies (median reduction by 7%, 15% and 14% with AOP2014/P1101 0.5 µg/ml, 2 µg/ml, and rIFNa-2a, resp). Myeloid colonies were almost unaffected by AOP2014/P1101 (no modification at 0.5µg/ml, and 9% reduction at 2µg/ml) while a reduction by 18% was obtained using rIFNa-2a, confirming the low level of toxicity of AOP2014/P1101 on normal hematopoietic progenitors. In contrast, AOP2014/P1101 drastically reduced the growth of JAK2VF erythroïd progenitors in all the PV samples tested. A 41%, and 62% median reduction of the number of EPO-stimulated colonies was observed with AOP2014/P1101 0.5µg/ml, and 2µg/ml, respectively. A more striking effect was observed on colonies grown in the absence of EPO: the number of EECs was reduced by 82% with AOP2014/P1101 2µg/ml compared to untreated cells. This result suggested that AOP2014/P1101 inhibited more efficiently JAK2-mutant hematopoietic progenitors. This hypothesis was confirmed by the study of the JAK2 genotype at the clonogenic level: a median 2-fold increase in the ratio of wild type to mutant colonies with 2µg/ml AOP2014/P1101 was observed, suggesting that AOP2014/P1101 does specifically target PV erythroid progenitors harboring the JAK2VF mutation. In addition, in one patient with both homozygous and heterozygous JAK2VF colonies, eradication of homozygous colonies was achieved with AOP2014/P1101, suggesting that JAK2VF homozygous progenitors are even more sensitive to AOP2014/P1101. Conclusion Our results show that AOP2014/P1101, a novel form of PEG-IFNa-2b, can specifically target PV JAK2VF hematopoietic progenitors while sparing wild type cells. These results are in line with the clinical efficacy with low hematologic toxicity reported in early phase trials with AOP2014/P1101. Disclosures: Cassinat: AOP Orphan: Research Funding. Klade:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Kiladjian:AOP Orphan: Honoraria, Research Funding.
49
Schambach, Axel, Bernhard Schiedlmeier, Jens Bohne, Dorothee von Laer, Geoff Margison, and Christopher Baum. "High Level Expression of a Membrane-Anchored Inhibitor of HIV Infection in Murine Hematopoietic Stem and Progenitor Cells Does Not Pertubate Serial Multilineage Repopulation." Blood 104, no. 11 (November 16, 2004): 1758. http://dx.doi.org/10.1182/blood.v104.11.1758.1758.
Full textAbstract:
Abstract T20 is a 36-amino-acid peptide that binds to HIV-1 gp41 and thereby acts as a fusion inhibitor, thus mediating potent and selective inhibition of HIV-1 entry in vitro and in vivo. An extended peptide expressed as an artificial, membrane-bound molecule (mbC46) efficiently inhibits HIV infection of primary human T-cells following retroviral vector mediated gene transfer (Egelhofer et al., J Virol, 2004). To develop an even more stringent approach to HIV gene therapy, we targeted hematopoietic stem cells. In 3 experimental groups of C57BL/6 mice (9 animals/group), we investigated the long-term toxicity of murine bone marrow cells transduced with M87o, a therapeutic vector designed to coexpress mbC46 and an HIV-derived RNA RRE-decoy to inhibit HIV replication. As controls we used the same vector containing an inactive C46 peptide and mock-transduced cells. Blood samples were collected monthly. Donor chimerism and transgene expression in multiple lineages were determined by FACS analysis and transgene integration was measured by real time PCR. Six months after transplantation, 4 mice per group were sacrificed and the remaining 5 mice per group were observed for another 6 months. In addition to the parameters mentioned above, we performed complete histopathology, blood counts and clinical biochemistry. Donor chimerism in all groups ranged from 82 – 94% (day 190 and day 349). In the M87o group, 60% of donor cells expressed mbC46. FACS data showed persisting transgene expression in T-cells (CD4, CD8, 65%), B-cells (B220, 46%), myeloid cells (CD11b, 68%), platelets (CD41, 19%), and RBC (60%) of the peripheral blood and bone marrow cells. Highly sustained gene marking (2–4 copies/genome) was noticed on day 190. To reveal latent malignant clones potentially originating from side effects of the genetic manipulation, 1x106 bone marrow cells from 4 primary recipients were transplanted into lethally irradiated secondary recipients (3 recipients/primary mouse) and these mice were observed for 8 months. All together, we could not observe any evidence for leukemogenic capacity. Analysis of peripheral blood and bone marrow showed a similar transgene expression pattern compared to the primary mice. To generate a complete chimerism of transgenic cells, we chose the human drug resistance gene methylguanine-methyltransferase (MGMT, P140K) to select for mbC46-transduced stem cells in vitro and in vivo. Different coexpression strategies were tested. Function of the MGMT protein was confirmed in a quantitative alkyltransferase assay and in a cytotoxicity assay using BCNU or temozolomide. In vitro selection of transduced 32D and PM1 cells with benzylguanine and BCNU showed >95% positive cells with evidence of polyclonal survival. Transduced PM1 cells underwent an HIV challenge assay. In vivo experiments in a murine bone marrow transplantation setting are ongoing to determine the potency and safety of combined retroviral expression of mbC46 and MGMT in relevant preclinical models. Successful conclusion of these studies will hopefully result in a phase I clinical trial testing the concept of generating an HIV-resistant autologous hematopoiesis.
50
Castagnetti, Fausto, Francesco Di Raimondo, Antonio de Vivo, Antonio Spitaleri, Gabriele Gugliotta, Francesco Fabbiano, Isabella Capodanno, et al. "A Population-Based Study of Chronic Myeloid Leukemia Treated with Imatinib in First Line." Blood 128, no. 22 (December 2, 2016): 3076. http://dx.doi.org/10.1182/blood.v128.22.3076.3076.
Full textAbstract:
Abstract Background. Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapies. However these clinical trials included patients selected according to different inclusion and exclusion criteria, particularly age and comorbidities, and with specific treatment obligations. In daily clinical practice (real life), no inclusion and exclusion criteria do exist, and treatment outcomes depend not only on choice of the first-line TKI, but also on doctor- and patient-choice of second- and third-line TKIs. Aims. To investigate the response and the outcome on first-line imatinib, with switch to 2nd generation TKIs in case of failure or toxicity, in BCR-ABL1+ CML patients enrolled in a population-based registry (real-life setting). Methods. We report here the results from a prospective study, enrolling all newly diagnosed patients (N = 236, median age 60 years) living in two Italian regions, that were registered according to population-based criteria and treated front-line with imatinib. The decision to switch to second-line treatment was up to the Local Investigator (no predefined criteria) Definitions: major molecular response (MMR or MR3.0): BCR-ABL1IS ratio <0.1%; deep molecular response (MR4.0): BCR-ABL1IS ratio <0.01% with >10,000 ABL1 copies; failure and suboptimal response: according to 2009 European LeukemiaNet (ELN) criteria; progression: transformation to advanced phases according to ELN criteria; leukemia-related death (LRD): death after progression. Results. Median age was 60 years at diagnosis and 64 years at last contact, with a median follow up of 48 months (range 2-86 months). High risk patients according to Sokal score and new EUTOS long-term survival (ELTS) score were 23% and 18%, respectively. A switch from imatinib to a second generation TKI was reported in 14% of patients for side-effects, and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The median time to switch was 8 months for toxicity and 20 months for failure. At 12 months, 55% of all evaluable patients were in MR3.0 or better. At last contact, 75% of all evaluable patients were in MR3.0 or better and 48% were in MR4.0 or better. The molecular response of patients switching for failure or suboptimal response was evaluable in 61/63 patients: improved in 57%, not modified in 38%, worsened by at least 1 log in 5% of patients. Overall, the treatment switch was associated with a remarkable increase of MR3.0 rate: from 10% at the time of switching to 52% at last qPCR. Overall, 33% achieved a stable MR4.0, of whom 22% with imatinib alone, and 11% after switching to a second generation TKI (Table 1). The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively. Twenty-seven patients (11%) died, of whom 13 (6%) of leukemia, after disease progression and 14 (6%) of "other" causes, without any evidence of progression. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients who received nilotinib in second-line. OS was not affected by age in the interval between 18 and 69 years (5-year OS 92%, ranging from 89% to 95 % in the different decades), but 5-year OS probabilities of elderly (70-79 years) and very elderly patients (≥ 80 years) were significantly lower (78%, P = 0.003, and 34%, P < 0.0001, respectively). The probability of LRS was not affected by age. The Sokal score predicted OS, but not LRS. The ELTS score clearly separated low, intermediate, and high risk patients for OS and also for LRS. Conclusions. The results of this prospective population-based study emphasize the importance of second-line treatment in the clinical practice: the CML management with the 3 available TKIs in the period 2008-2012, according to current treatment recommendations for switching and without any predefined obligation, resulted in response rates and outcomes, that are in the high range of prospective interventional studies investigating the efficacy and the safety of a single TKI in selected patients. This study provides a robust dataset on the results of CML treatment with TKI in clinical practice, that will be important for interpreting and evaluating the results of the next prospective studies, arguably limited to selected patients. Disclosures Castagnetti: Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Marasca:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy. Martinelli:Genentech: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Ariad: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.