GM-CSF in inflammation Hamilton, John A
The Journal of experimental medicine,
01/2020, Letnik:
217, Številka:
1
Journal Article
Recenzirano
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor ...cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.
Pre-clinical models and clinical trials demonstrate that targeting the action of the cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), can be efficacious in ...inflammation/autoimmunity reinforcing the importance of understanding how GM-CSF functions; a significant GM-CSF-responding cell in this context is likely to be the monocyte. This article summarizes critically the literature on the downstream cellular pathways regulating GM-CSF interaction with monocytes (and macrophages), highlighting some contentious issues, and conclusions surrounding this biology. It also suggests future directions which could be undertaken so as to more fully understand this aspect of GM-CSF biology. Given the focus of this collection of articles on monocytes, the following discussion in general will be limited to this population or to its more mature progeny, the macrophage, even though GM-CSF biology is broader than this.
Although they were originally defined as haematopoietic-cell growth factors, colony-stimulating factors (CSFs) have been shown to have additional functions by acting directly on mature myeloid cells. ...Recent data from animal models indicate that the depletion of CSFs has therapeutic benefit in many inflammatory and/or autoimmune conditions and as a result, early-phase clinical trials targeting granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor have now commenced. The distinct biological features of CSFs offer opportunities for specific targeting, but with some associated risks. Here, I describe these biological features, discuss the probable specific outcomes of targeting CSFs in vivo and highlight outstanding questions that need to be addressed.
Methane is an important greenhouse gas and its atmospheric concentration has almost tripled since pre-industrial times. It plays a central role in atmospheric oxidation chemistry and affects ...stratospheric ozone and water vapour levels. Most of the methane from natural sources in Earth's atmosphere is thought to originate from biological processes in anoxic environments. Here we demonstrate using stable carbon isotopes that methane is readily formed in situ in terrestrial plants under oxic conditions by a hitherto unrecognized process. Significant methane emissions from both intact plants and detached leaves were observed during incubation experiments in the laboratory and in the field. If our measurements are typical for short-lived biomass and scaled on a global basis, we estimate a methane source strength of 62–236 Tg yr-1 for living plants and 1–7 Tg yr-1 for plant litter (1 Tg = 1012 g). We suggest that this newly identified source may have important implications for the global methane budget and may call for a reconsideration of the role of natural methane sources in past climate change.
The colony stimulating factors (CSFs), granulocyte macrophage-CSF (GM-CSF), macrophage-CSF (M-CSF or CSF-1) and granulocyte-CSF (G-CSF) were first identified as in vitro hematopoietic growth factors. ...They have since been shown to regulate myeloid cell numbers and function at steady state and during inflammation. Preclinical data suggest that targeting CSFs might be beneficial in autoimmune and inflammatory disease, and manipulation of CSF biology is now being tested in clinical trials. Here, we examine recent insights into CSF function, at steady state and during pathology, as provided by CSF or CSF receptor neutralization/deletion studies or from CSF administration. We discuss controversies regarding the role of CSFs in controlling specific myeloid cell populations and highlight how the newly identified M-CSF receptor ligand, interleukin (IL)-34, is necessitating a reassessment of the field.
This paper contributes to the literature on maintenance of institutions by analyzing the case of an old profession—Scottish advocates. Drawing on the neo-institutional perspective on professions, we ...address the question, what role does organizational space play in institutional maintenance? We draw on our ethnographic study to make a three-fold contribution. Firstly, our case study shows how spaces, and how institutional actors interacting with them, have a stabilizing effect on the institution, which leads to two important outcomes: maintenance of closure and reproduction of the status order. Secondly, we show how three spatial phenomena underpinning this stabilizing process are intertwined, thus enabling the process of institutional maintenance: (1) emplacement, (2) enactment of space, and (3) enchantment of space. Thirdly, by foregrounding the role of enchantment evoked by organizational spaces, we highlight the importance of the emotional and aesthetic aspects of institutional maintenance.
Security Hamilton, John T
06/2013, Letnik:
34
eBook
From national security and social security to homeland and cyber-security, "security" has become one of the most overused words in culture and politics today. Yet it also remains one of the most ...undefined. What exactlyarewe talking about when we talk about security? In this original and timely book, John Hamilton examines the discursive versatility and semantic vagueness of security both in current and historical usage. Adopting a philological approach, he explores the fundamental ambiguity of this word, which denotes the removal of "concern" or "care" and therefore implies a condition that is either carefree or careless. Spanning texts from ancient Greek poetry to Roman Stoicism, from Augustine and Luther to Machiavelli and Hobbes, from Kant and Nietzsche to Heidegger and Carl Schmitt, Hamilton analyzes formulations of security that involve both safety and negligence, confidence and complacency, certitude and ignorance. Does security instill more fear than it assuages? Is a security purchased with freedom or human rights morally viable? How do security projects inform our expectations, desires, and anxieties? And how does the will to security relate to human finitude? Although the book makes clear that security has always been a major preoccupation of humanity, it also suggests that contemporary panics about security and the related desire to achieve perfect safety carry their own very significant risks.
Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for ...many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with pathologies of multiple joint tissues. Inflammation is associated with both OA pain and disease outcome and is therefore a major treatment target for OA and OA pain. Unlike TNF inhibitors and IL-1 inhibitors, established drugs such as glucocorticoids and methotrexate can reduce OA pain. Although central nociceptive pathways contribute to OA pain, crosstalk between the immune system and nociceptive neurons is central to inflammatory pain; therefore, new therapies might target this crosstalk. Newly identified drug targets, including neurotrophins and the granulocyte-macrophage colony-stimulating factor (GM-CSF)-CC-chemokine ligand 17 (CCL17) chemokine axis, offer the hope of better results but require clinical validation.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF; also known as CSF1), granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3) can ...each play a part in the host response to injury and infection, and there is burgeoning interest in targeting these CSFs in inflammatory and autoimmune disorders, as well as in cancer. For success in clinical medicine, therapeutic targeting will need to be delineated from current strategies. The individual CSFs have unique biological roles, suggesting that they could be used to target specific conditions. This Review compares the CSFs, with a focus on how they could be targeted, discusses the relevant clinical trial data and summarizes the potential clinical applications of targeting each CSF. Importantly, we discuss the novelty of CSF biology and attempt to clarify some of the surrounding misconceptions and issues that can affect therapeutic decisions.
The concurrent development of high-throughput genotyping platforms and next generation sequencing (NGS) has increased the number and density of genetic markers, the efficiency of constructing ...detailed linkage maps, and our ability to overlay recombination and physical maps of the genome. We developed an array for tomato with 8,784 Single Nucleotide Polymorphisms (SNPs) mainly discovered based on NGS-derived transcriptome sequences. Of the SNPs, 7,720 (88%) passed manufacturing quality control and could be scored in tomato germplasm. The array was used to generate high-density linkage maps for three interspecific F(2) populations: EXPEN 2000 (Solanum lycopersicum LA0925 x S. pennellii LA0716, 79 individuals), EXPEN 2012 (S. lycopersicum Moneymaker x S. pennellii LA0716, 160 individuals), and EXPIM 2012 (S. lycopersicum Moneymaker x S. pimpinellifolium LA0121, 183 individuals). The EXPEN 2000-SNP and EXPEN 2012 maps consisted of 3,503 and 3,687 markers representing 1,076 and 1,229 unique map positions (genetic bins), respectively. The EXPEN 2000-SNP map had an average marker bin interval of 1.6 cM, while the EXPEN 2012 map had an average bin interval of 0.9 cM. The EXPIM 2012 map was constructed with 4,491 markers (1,358 bins) and an average bin interval of 0.8 cM. All three linkage maps revealed an uneven distribution of markers across the genome. The dense EXPEN 2012 and EXPIM 2012 maps showed high levels of colinearity across all 12 chromosomes, and also revealed evidence of small inversions between LA0716 and LA0121. Physical positions of 7,666 SNPs were identified relative to the tomato genome sequence. The genetic and physical positions were mostly consistent. Exceptions were observed for chromosomes 3, 10 and 12. Comparing genetic positions relative to physical positions revealed that genomic regions with high recombination rates were consistent with the known distribution of euchromatin across the 12 chromosomes, while very low recombination rates were observed in the heterochromatic regions.
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