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.
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.
Mast cells signal their importance in health and disease Olivera, Ana; Beaven, Michael A.; Metcalfe, Dean D.
Journal of allergy and clinical immunology,
August 2018, 2018-08-00, 20180801, Letnik:
142, Številka:
2
Journal Article
Recenzirano
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FcεRI is the primary receptor in mast cells that mediates allergic reactions by inducing rapid release of mediators, an adaptive immune response that might have evolved as a host defense against ...parasites and venoms. Yet it is apparent that mast cells are also activated through non-IgE receptors, the significance of which is just beginning to be understood. This includes the Mas-related G protein–coupled receptor X2, which might contribute to reactions to diverse antimicrobials and polybasic compounds, and the adhesion G protein–coupled receptor E2, variants of which are associated with familial vibratory urticaria and are activated by mechanical vibration. Similarly, mast cells have long been recognized as the main repository for histamine, heparin, and proteases. Recent evidence also points to new functions, modes of delivery, and mechanisms of action of mast cell proteases that add new dimensions to the roles of mast cells in human biology. In addition, exposure of mast cells to environmental cues can quantitatively and qualitatively modulate their responses and thus their effect on allergic inflammation. Illustrating this paradigm, we summarize a number of recent studies implicating the injury/tissue damage cytokine IL-33 as a modulator of allergen-induced mast cell responses. We also discuss the discovery of markers associated with transformed mast cells and new potential directions in suppressing mast cell activity.
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, Letnik:
125, Številka:
2
Journal Article
Recenzirano
Odprti dostop
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.
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, Letnik:
124, Številka:
4
Journal Article
Recenzirano
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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.
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.
The nuclear envelope represents a key barrier to successful nonviral transfection and gene therapy both in vitro and in vivo. Although the main purpose of the nuclear envelope is to partition the ...cell to maintain cytoplasmic components in the cytoplasm and nuclear components, most notably genomic DNA, in the nucleus, this function poses a problem for transfections in which exogenous DNA is delivered into the cytoplasm. After delivery to the cytoplasm, nucleic acids rapidly become complexed with cellular proteins that mediate interactions with the cellular machinery for trafficking. Thus, it is these proteins that, in essence, control the nuclear import of DNA, and we must also understand their activities in cells. In this review, we will discuss the principles of nuclear import of proteins and DNA-protein complexes, as well as the various approaches that investigators have used to improve nuclear targeting of plasmids. These approaches include complexation of plasmids with peptides, native and engineered proteins, ligands and polymers, as well as the inclusion of transcription factor-binding sites for general and cell-specific delivery.
nonviral gene transfermid R:plasmidmid R:nuclear pore complexmid R:importinmid R:nuclear localization signalmid R:karyopherin.
Seminal fluid proteins affect fertility at multiple stages in reproduction. In many species, a male's ejaculate coagulates to form a copulatory plug. Although taxonomically widespread, the molecular ...details of plug formation remain poorly understood, limiting our ability to manipulate the structure and understand its role in reproduction. Here I show that male mice knockouts for transglutaminase IV (Tgm4) fail to form a copulatory plug, demonstrating that this gene is necessary for plug formation and lending a powerful new genetic tool to begin characterizing plug function. Tgm4 knockout males show normal sperm count, sperm motility, and reproductive morphology. However, very little of their ejaculate migrates into the female's reproductive tract, suggesting the plug prevents ejaculate leakage. Poor ejaculate migration leads to a reduction in the proportion of oocytes fertilized. However, Tgm4 knockout males fertilized between 3-11 oocytes, which should be adequate for a normal litter. Nevertheless, females mated to Tgm4 knockout males for approximately 14 days were significantly less likely to give birth to a litter compared to females mated to wild-type males. Therefore, it appears that the plug also affects post-fertilization events such as implantation and/or gestation. This study shows that a gene influencing the viscosity of seminal fluid has a major influence on male fertility.
Hospitals under financial pressure may struggle to maintain quality and patient safety and have worse patient outcomes relative to well-resourced hospitals. Poor predictive validity may explain why ...previous studies on the association between finances and quality/safety have been equivocal. This manuscript employs principal component analysis to produce robust measures of both financial status and quality/safety of care, to assess our a priori hypothesis: hospital financial performance is associated with the provision of quality care, as measured by quality and safety processes, patient outcomes, and patient centered care.
This 2014 cross-sectional study investigated hospital financial condition and hospital quality and safety at acute care hospitals. The hospital financial data from the Centers for Medicare and Medicaid Services (CMS) cost report were used to develop a composite financial performance score using principal component analysis. Hospital quality and patient safety were measured with a composite quality/safety performance score derived from principal component analysis, utilizing a range of established quality and safety indicators including: risk-standardized inpatient mortality, 30-day mortality, 30-day readmissions for select conditions, patient safety indicators from inpatient admissions, process of care chart reviews, CMS value-based purchasing total performance score and patient experience of care surveys. The correlation between the composite financial performance score and the composite quality/safety performance score was calculated using linear regression adjusting for hospital characteristics.
Among the 108 New York State acute care facilities for which data were available, there is a clear relationship between hospital financial performance and hospital quality/safety performance score (standardized correlation coefficient 0.34, p<0.001). The composite financial performance score is also positively associated with the CMS Value Based Purchasing Total Performance Score (standardized correlation coefficient 0.277, p = 0.002); while it is negatively associated with 30 day readmission for all outcomes (standardized correlation coefficient -0.236, p = 0.013), 30-day readmission for congestive heart failure (standardized correlation coefficient -0.23, p = 0.018), 30 day readmission for pneumonia (standardized correlation coefficient -0.209, p = 0.033), and a decrease in 30-day mortality for acute myocardial infarction (standardized correlation coefficient -0.211, p = 0.027). Used alone, operating margin and total margin are poor predictors of quality and safety outcomes.
Strong financial performance is associated with improved patient reported experience of care, the strongest component distinguishing quality and safety. These findings suggest that financially stable hospitals are better able to maintain highly reliable systems and provide ongoing resources for quality improvement.
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