Over the past few years, substantial advances have been made in understanding the pathogenesis, evolution, and complexity of mast cell neoplasms. New diagnostic and prognostic parameters and novel ...therapeutic targets with demonstrable clinical impact have been identified. Several of these new markers, molecular targets, and therapeutic approaches have been validated and translated into clinical practice. At the same time, the classification of mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO). As a result, more specific therapies tailored toward prognostic subgroups of patients have been developed. Emerging treatment concepts use drugs directed against KIT and other relevant targets in neoplastic mast cells and will hopefully receive recognition by health authorities in the near future. This article provides an overview of recent developments in the field, with emphasis on the updated WHO classification, refined criteria, additional prognostic parameters, and novel therapeutic approaches. Based on these emerging concepts, the prognosis, quality of life, and survival of patients with advanced mastocytosis are expected to improve in the coming years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mast cells have been recognized for well over 100 years. With time, human mast cells have been documented to originate from CD34+ cells, and have been implicated in host responses in both innate and ...acquired immunity. In clinical immunology, they are recognized for their central role in IgE-mediated degranulation and allergic inflammation by virtue of their expression of the high-affinity receptor for IgE and release of potent proinflammatory mediators. In hematology, the clinical disease of mastocytosis is characterized by a pathologic increase of mast cells in tissues, often associated with mutations in KIT, the receptor for stem cell factor. More recently, and with increased understanding of how human mast cells are activated through receptors including the high-affinity receptor for IgE and KIT, specific tyrosine kinase inhibitors have been identified with the potential to interrupt signaling pathways and thus limit the proliferation of mast cells as well as their activation through immunoglobulin receptors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Road runoff is an important vector for the transport of chemicals originating from tire wear into receiving waters. In this study, samples of surface water were collected in the summer of 2020 from ...two rivers near high-traffic corridors in the Greater Toronto Area (GTA) in Canada. These samples were analyzed for two additives used in tire production, 1,3-diphenyl guanidine (DPG) and hexamethoxymethylmelamine (HMMM), as well 26 of the transformation compounds of HMMM. In addition, samples were analyzed for 6PPD-quinone (6PPD-q), an oxidation by-product of a tire additive that was recently identified as a candidate compound responsible for mass mortalities of Coho salmon (Oncorhynchus kisutch) in spawning streams in the USA. Grab and composite samples were collected during rain events (i.e., wet events) at both locations. Grab samples were collected from the Don River upstream, downstream and at the point of discharge from a municipal wastewater treatment plant (WWTP) during a period of dry weather. Of the target analytes, 6PPD-q, DPG and HMMM, as well as 15 of the transformation compounds of HMMM, were detected at concentrations above limits of quantitation. The concentrations of 6PPD-q in the receiving waters during wet events were within the range of the LC50 for adult Coho salmon. One of the transformation products (TPs) of HMMM, dimethoxymethylmelamine was detected in a composite sample from Highland Creek at an estimated concentration greater than 10 μg/L, indicating that more research is needed to evaluate the potential hazards to the aquatic environment from this compound. Sampling in the Don River during a dry period showed that discharges of wastewater from WWTPs are also continuous sources of the TPs of HMMM. This study contributes to the growing literature showing that chemicals derived from tire wear are ubiquitous in urban watersheds and may be a significant hazard to aquatic organisms.
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•Compounds derived from tire wear were detected in rivers in the Greater Toronto Area.•Hexamethoxymethyl-melamine and 17 transformation compounds were detected.•A toxic by-product of 6PPD (6PPD-quinione) and diphenylguanidine were also detected.•Estimated concentrations of 6PPD-quinone approached toxic thresholds.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This paper presents results from two large-scale natural field experiments that tested the effect of social norm messages on tax compliance. Using administrative data from >200,000 individuals in the ...United Kingdom, we show that including social norm messages in standard reminder letters increases payment rates for overdue tax. This result offers a rare example of social norm messages affecting tax compliance behavior in a real world setting. We find no evidence that loss framing is more effective than gain framing. Descriptive norms appear to be more effective than injunctive norms. Messages referring to public services or financial information also significantly increased payment rates. The field experiments accelerated the collection of tax revenue at little cost.
•We present results from two large natural field experiments that use data from 200,000 individuals in the United Kingdom.•Including social norms and public services messages in official reminder letters increased payment rates for overdue tax.•This low-cost intervention offers a rare example of social norm messages increasing tax compliance in a real world setting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The term mast cell activation syndrome (MCAS) is finding increasing use as a diagnosis for subjects who present with signs and symptoms involving the dermis, gastrointestinal track, and ...cardiovascular system frequently accompanied by neurologic complaints. Such patients often have undergone multiple extensive medical evaluations by different physicians in varied disciplines without a definitive medical diagnosis until the diagnosis of MCAS is applied. However, MCAS as a distinct clinical entity has not been generally accepted, nor do there exist definitive criteria for diagnosis. Based on current understanding of this disease “syndrome” and on what we do know about mast cell activation and resulting pathology, we will explore and propose criteria for its diagnosis. The proposed criteria will be discussed in the context of other disorders involving mast cells or with similar presentations and as a basis for further scientific study and validation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Prompted by a recent report that 6PPD-quinone (6PPD-q), a by-product of a common tire manufacturing additive that is present in road runoff, is toxic to coho salmon (
Oncorhynchus kisutch
), extracts ...of water samples collected from an urban river were re-analyzed to determine if this compound was present in stormwater-influenced flows. In addition, extracts were analyzed for 1,3-diphenylguanidine (DPG), which is also used in tire manufacturing. Samples were originally collected in the fall of 2019 and winter of 2020 in the Greater Toronto Area of Canada from the Don River, a highly urbanized watershed in close proximity to several major multi-lane highways. These target compounds were analyzed using ultra-high pressure liquid chromatography with high resolution mass spectrometric detection with parallel reaction monitoring. Both 6PPD-q and DPG were detected above limits of quantification (i.e., 0.0098 µg/L) in all extracts. Maximum concentrations for 6PPD-quinone of 2.30 ± 0.05 µg/L observed in the river during storm events exceeded the LC
50
for this compound for coho salmon (i.e., > 0.8 µg/L). In composite samples collected at intervals throughout one rain event, both compounds reached peak concentrations a few hours after initiation of the event (i.e., 0.52 µg/L for DPG and 2.85 µg/L for 6PPD-q), but the concentrations of 6PPD-q remained elevated above 2 µg/L for over 10-h in the middle of the event. Estimates of cumulative loads of these compounds in composite samples indicated that kg amounts of these compounds entered the Don River during each hydrological event, and the loads were proportional to the amounts of precipitation. This study contributes to the growing literature indicating that potentially toxic tire-wear compounds are present at elevated levels and are transported via road runoff into urban surface waters during rain events.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In 2005 and 2010 the Amazon basin experienced two strong droughts, driven by shifts in the tropical hydrological regime possibly associated with global climate change, as predicted by some global ...models. Tree mortality increased after the 2005 drought, and regional atmospheric inversion modelling showed basin-wide decreases in CO2 uptake in 2010 compared with 2011 (ref. 5). But the response of tropical forest carbon cycling to these droughts is not fully understood and there has been no detailed multi-site investigation in situ. Here we use several years of data from a network of thirteen 1-ha forest plots spread throughout South America, where each component of net primary production (NPP), autotrophic respiration and heterotrophic respiration is measured separately, to develop a better mechanistic understanding of the impact of the 2010 drought on the Amazon forest. We find that total NPP remained constant throughout the drought. However, towards the end of the drought, autotrophic respiration, especially in roots and stems, declined significantly compared with measurements in 2009 made in the absence of drought, with extended decreases in autotrophic respiration in the three driest plots. In the year after the drought, total NPP remained constant but the allocation of carbon shifted towards canopy NPP and away from fine-root NPP. Both leaf-level and plot-level measurements indicate that severe drought suppresses photosynthesis. Scaling these measurements to the entire Amazon basin with rainfall data, we estimate that drought suppressed Amazon-wide photosynthesis in 2010 by 0.38 petagrams of carbon (0.23-0.53 petagrams of carbon). Overall, we find that during this drought, instead of reducing total NPP, trees prioritized growth by reducing autotrophic respiration that was unrelated to growth. This suggests that trees decrease investment in tissue maintenance and defence, in line with eco-evolutionary theories that trees are competitively disadvantaged in the absence of growth. We propose that weakened maintenance and defence investment may, in turn, cause the increase in post-drought tree mortality observed at our plots.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Mast cells have long been recognized for their role in the genesis of allergic inflammation; and more recently for their participation in innate and acquired immune responses. Mast cells ...reside within tissues including the skin and mucosal membranes, which interface with the external environment; as well as being found within vascularized tissues next to nerves, blood vessels and glandular structures. Mast cells have the capability of reacting both within minutes and over hours to specific stimuli, with local and systemic effects. Mast cells express the high affinity IgE receptor (FcɛRI) and upon aggregation of FcɛRI by allergen‐specific IgE, mast cells release and generate biologically active preformed and newly synthesized mediators which are involved in many aspects of allergic inflammation. While mast cells have been well documented to be essential for acute allergic reactions, more recently the importance of mast cells in reacting through pattern recognition receptors in innate immune responses has become recognized. Moreover, as our molecular understanding of the mast cell has evolved, novel targets for modulation have been identified with promising therapeutic potential.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
IgE, mast cells, basophils, and eosinophils Stone, Kelly D., MD, PhD; Prussin, Calman, MD; Metcalfe, Dean D., MD
Journal of allergy and clinical immunology,
02/2010, Volume:
125, Issue:
2
Journal Article
Peer reviewed
Open access
IgE, mast cells, basophils, and eosinophils are essential components of allergic inflammation. Antigen-specific IgE production, with subsequent fixation of IgE to FcϵRI receptors on mast cells and ...basophils, is central to the initiation and propagation of immediate hypersensitivity reactions. Mast cells, basophils, and eosinophils are central effector cells in allergic inflammation, as well as in innate and adaptive immunity. This review highlights what is known about these components and their roles in disease pathogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mechanisms of mast cell signaling in anaphylaxis Metcalfe, Dean D., MD; Peavy, Richard D., PhD; Gilfillan, Alasdair M., PhD
Journal of allergy and clinical immunology,
10/2009, Volume:
124, Issue:
4
Journal Article
Peer reviewed
Open access
The recent development of a consensus definition and proposed diagnostic criteria for anaphylaxis offers promise for research efforts and a better understanding of the epidemiology and pathogenesis ...of this enigmatic and life-threatening disease. This review examines basic principles and recent research advances in the mechanisms of mast cell signaling believed to underlie anaphylaxis. The unfolding complexity of mast cell signaling suggests that the system is sensitive to regulation by any of several individual signaling pathways and intermediates and that complementary pathways regulate mast cell activation by amplified signals. The signaling events underlying anaphylactic reactions have largely been identified through experiments in genetically modified mice and supported by biochemical studies of mast cells derived from these mice. These studies have revealed that signaling pathways exist to both upregulate and downregulate mast cell responses. In this review we will thus describe the key molecular players in these pathways in the context of anaphylaxis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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