Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions ...of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.
Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, ...although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.
Compartmentalization of biochemical processes is essential for cell function. Although membrane‐bound organelles are well studied in this context, recent work has shown that phase separation is a key ...contributor to cellular compartmentalization through the formation of liquid‐like membraneless organelles (MLOs). In this Minireview, the key mechanistic concepts that underlie MLO dynamics and function are first briefly discussed, including the relevant noncovalent interaction chemistry and polymer physical chemistry. Next, a few examples of MLOs and relevant proteins are given, along with their functions, which highlight the relevance of the above concepts. The developing area of active matter and non‐equilibrium systems, which can give rise to unexpected effects in fluctuating cellular conditions, are also discussed. Finally, our thoughts for emerging and future directions in the field are discussed, including in vitro and in vivo studies of MLO physical chemistry and function.
Phase separation and active matter: Liquid–liquid phase separation has been shown to play a major role in compartmentalization of cellular biochemistry. The key conceptual and mechanistic underpinnings of this phenomenon, including weak noncovalent interactions and polymer physics principles, and biological examples are discussed.
Abstract Background Allostatic load (AL) relates to the neural and bodily “wear and tear” that emerge in the context of chronic stress. This paper aims to provide clinicians with a comprehensive ...overview of the role of AL in patophysiology of bipolar disorder (BD) and its practical implications. Methods PubMed searches were conducted on English-language articles published from 1970 to June 2011 using the search terms allostatic load, oxidative stress, staging, and bipolar disorder cross-referenced with cognitive impairment, comorbidity, mediators, prevention. Results Progressive neural and physical dysfunction consequent to mood episodes in BD can be construed as a cumulative state of AL. The concept of AL can help to reconcile cognitive impairment and increased rates of clinical comorbidities that occur over the course of cumulative BD episodes. Conclusions Data on transduction of psychosocial stress into the neurobiology of mood episodes converges to the concept of AL. Mood episodes prevention would not only alleviate emotional suffering, but also arrest the cycle of AL, cognitive decline, physical morbidities and, eventually, related mortality. These objectives can be achieved by focusing on effective prophylaxis from the first stages of the disorder, providing mood-stabilizing agents and standardized psychoeducation and, potentially, addressing cognitive deficits by the means of specific medication and neuropsychological interventions.
In the last ten to fifteen years there has been much research in using amorphous and polycrystalline semiconductors as x-ray photoconductors in various x-ray image sensor applications, most notably ...in flat panel x-ray imagers (FPXIs). We first outline the essential requirements for an ideal large area photoconductor for use in a FPXI, and discuss how some of the current amorphous and polycrystalline semiconductors fulfill these requirements. At present, only stabilized amorphous selenium (doped and alloyed a-Se) has been commercialized, and FPXIs based on a-Se are particularly suitable for mammography, operating at the ideal limit of high detective quantum efficiency (DQE). Further, these FPXIs can also be used in real-time, and have already been used in such applications as tomosynthesis. We discuss some of the important attributes of amorphous and polycrystalline x-ray photoconductors such as their large area deposition ability, charge collection efficiency, x-ray sensitivity, DQE, modulation transfer function (MTF) and the importance of the dark current. We show the importance of charge trapping in limiting not only the sensitivity but also the resolution of these detectors. Limitations on the maximum acceptable dark current and the corresponding charge collection efficiency jointly impose a practical constraint that many photoconductors fail to satisfy. We discuss the case of a-Se in which the dark current was brought down by three orders of magnitude by the use of special blocking layers to satisfy the dark current constraint. There are also a number of polycrystalline photoconductors, HgI(2) and PbO being good examples, that show potential for commercialization in the same way that multilayer stabilized a-Se x-ray photoconductors were developed for commercial applications. We highlight the unique nature of avalanche multiplication in a-Se and how it has led to the development of the commercial HARP video-tube. An all solid state version of the HARP has been recently demonstrated with excellent avalanche gains; the latter is expected to lead to a number of novel imaging device applications that would be quantum noise limited. While passive pixel sensors use one TFT (thin film transistor) as a switch at the pixel, active pixel sensors (APSs) have two or more transistors and provide gain at the pixel level. The advantages of APS based x-ray imagers are also discussed with examples.
The transition of chronic pancreatic fibroinflammatory disease to neoplasia is a primary example of the paradigm linking inflammation to carcinogenesis. However, the cellular and molecular mediators ...bridging these entities are not well understood. Because TLR4 ligation can exacerbate pancreatic inflammation, we postulated that TLR4 activation drives pancreatic carcinogenesis. In this study, we show that lipopolysaccharide accelerates pancreatic tumorigenesis, whereas TLR4 inhibition is protective. Furthermore, blockade of the MyD88-independent TRIF pathway is protective against pancreatic cancer, whereas blockade of the MyD88-dependent pathway surprisingly exacerbates pancreatic inflammation and malignant progression. The protumorigenic and fibroinflammatory effects of MyD88 inhibition are mediated by dendritic cells (DCs), which induce pancreatic antigen-restricted Th2-deviated CD4(+) T cells and promote the transition from pancreatitis to carcinoma. Our data implicate a primary role for DCs in pancreatic carcinogenesis and illustrate divergent pathways in which blockade of TLR4 signaling via TRIF is protective against pancreatic cancer and, conversely, MyD88 inhibition exacerbates pancreatic inflammation and neoplastic transformation by augmenting the DC-Th2 axis.
During the last decade, a multitude of experimental evidence has accumulated showing that low-dose radiation therapy (single dose 0.5-1 Gy) functionally modulates a variety of inflammatory processes ...and cellular compounds including endothelial (EC), mononuclear (PBMC) and polymorphonuclear (PMN) cells, respectively. These modulations comprise a hampered leukocyte adhesion to EC, induction of apoptosis, a reduced activity of the inducible nitric oxide synthase, and a lowered oxidative burst in macrophages. Moreover, irradiation with a single dose between 0.5-0.7 Gy has been shown to induce the expression of X-chromosome linked inhibitor of apoptosis and transforming growth factor beta 1, to reduce the expression of E-selectin and L-selectin from EC and PBMC, and to hamper secretion of Interleukin-1, or chemokine CCL20 from macrophages and PMN. Notably, a common feature of most of these responses is that they display discontinuous or biphasic dose dependencies, shared with "non-targeted" effects of low-dose irradiation exposure like the bystander response and hyper-radiosensitivity. Thus, the purpose of the present review is to discuss recent developments in the understanding of low-dose irradiation immune modulating properties with special emphasis on discontinuous dose response relationships.
Since July 2007 prospective life-long follow-up (FU) for unrelated (URD) and related donors (RD) is mandatory in Switzerland and data on every allogeneic haematopoietic progenitor cell (HPC) donation ...are collected prospectively. We report the real-world experience of HPC donation during a 10-year study period (01.07.2007-30.06.2017) with basic characteristics and FU data. 1105 donors underwent 1155 HPC donation procedures. Eighty percent of first donations performed by 802 (73%) RDs and 303 (27%) URDs were peripheral blood stem cells (PBSC), 20% bone marrow (BM). Male donors were over-represented as URD (60% male vs 40% female). Main differences between RDs and URDs concerned age and pre-existing health disorders. RDs were significantly older at first donation (median age 48 years) compared to URD (34 years, p < 0.0001) and had more pre-existing health problems: 25% vs 9% in URD (p < 0.0001). No fatal complications occurred, collection related severe adverse events (SAE) after first donation were not significantly different between groups (RD 1.2%, URD 0.99%), incidence rates for neoplastic and autoimmune diseases did not exceed the rates of the general population. RDs are a more heterogeneous and potentially more vulnerable group, but if donor evaluation is performed appropriately, HPC donation is still safe.
Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can ...become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.
Increasing evidence suggests that community-level responses to human-induced biodiversity loss start with a decrease of interactions among communities and between them and their abiotic environment. ...The structural and functional consequences of such interaction losses are poorly understood and have rarely been tested in real-world systems. Here, we analysed how 5 years of progressive, size-selective exclusion of large, medium, and small vertebrates and invertebrates-a realistic scenario of human-induced defaunation-impacts the strength of relationships between above- and belowground communities and their abiotic environment (hereafter ecosystem coupling) and how this relates to ecosystem functionality in grasslands. Exclusion of all vertebrates results in the greatest level of ecosystem coupling, while the additional loss of invertebrates leads to poorly coupled ecosystems. Consumer-driven changes in ecosystem functionality are positively related to changes in ecosystem coupling. Our results highlight the importance of invertebrate communities for maintaining ecological coupling and functioning in an increasingly defaunated world.
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