Background Systemic inflammation is associated with skeletal muscle atrophy and metabolic dysfunction. Although the nucleotide-binding oligomerization domain-like receptor family pyrin domain... Show moreBackground Systemic inflammation is associated with skeletal muscle atrophy and metabolic dysfunction. Although the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cytokine production in immune cells, its role in skeletal muscle is poorly understood. Here, we studied the link between inflammation, NLRP3, muscle morphology, and metabolism in in vitro cultured C2C12 myotubes, independent of immune cell involvement.Methods Differentiated C2C12 myotubes were treated with lipopolysaccharide (LPS; 0, 10, and 100-200 ng/mL) to induce activation of the NLRP3 inflammasome with and without MCC950, a pharmacological inhibitor of NLRP3-induced IL-1 ss production. We assessed markers of the NLRP3 inflammasome, cell diameter, reactive oxygen species, and mitochondrial function.Results NLRP3 gene expression and protein concentrations increased in a time-dependent and dose-dependent manner. Intracellular IL-1 ss concentration significantly increased (P < 0.0001), but significantly less with MCC950 (P = 0.03), suggestive of moderate activation of the NLRP3 inflammasome in cultured myotubes upon LPS stimulation. LPS suppressed myotube growth after 24 h (P = 0.03), and myotubes remained smaller up to 72 h (P = 0.0009). Exposure of myotubes to IL-1 ss caused similar alterations in cell morphology, and MCC950 mitigated these LPS-induced differences in cell diameter. NLRP3 appeared to co-localize with mitochondria, more so upon exposure to LPS. Mitochondrial reactive oxygen species were higher after LPS (P = 0.03), but not after addition of MCC950. Myotubes had higher glycolytic rates, and mitochondria were more fragmented upon LPS exposure, which was not altered by MCC950 supplementation.Conclusions LPS- induced activation of the NLRP3 inflammasome in cultured myotubes contributes to morphological and metabolic alterations, likely due to its mitochondrial association. Show less
Tumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances... Show moreTumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances using soluble molecules and hijack non-neoplastic cells (such as immune cells) in distant organs for their own benefit, thus maximising their metastatic potential. The phenotype of immune cells in tumors and in systemic environments is therefore a key determinant of cancer progression and response to therapy.This thesis aims to understand what governs the tumor-immune ecosystem. We argue that cancer-intrinsic genetic aberrations have a dominant role in determining the tumor immune contexture, as well as systemic inflammatory activation. Understanding the intricate connection between the genetics of breast cancer and anti-tumor immune responses will help develop personalised immune intervention strategies for cancer, tailored to the genetic makeup of a patient’s tumor. Furthermore, we examine in detail the role of neutrophils in cancer-induced systemic inflammation, and how they influence the progression and spread of breast cancer. While tumors can be highly heterogeneous in nature, we show that neutrophils themselves also have a tremendous phenotypic diversity. Mapping this heterogeneity in neutrophil phenotypes may help to utilise these cells in cancer immunotherapy. Show less
Marques, P.; Vries, F. de; Dekkers, O.M.; Furth, W.R. van; Korbonits, M.; Biermasz, N.R.; Pereira, A.M. 2020
Objective Full blood count (FBC) and serum inflammation-based scores reflect systemic inflammation and predict outcomes in cancer, but little is known in pituitary adenomas (PAs). We aimed to... Show moreObjective Full blood count (FBC) and serum inflammation-based scores reflect systemic inflammation and predict outcomes in cancer, but little is known in pituitary adenomas (PAs). We aimed to characterise FBC and inflammation-based scores in PA patients and investigate their usefulness in predicting challenging disease course. Methods We studied 424 PA patients first operated at our centre with available pre-operative biochemical data. Patients with infection, malignancies, autoimmune or haematological conditions were excluded. Inflammation-based scores studied: Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic Immune-Inflammation Index (SII), Neutrophil-Platelet Score (NPS), Prognostic Nutrition Index (PNI), and Glasgow Prognostic Score (GPS). Results Cushing's disease patients had more platelets, leucocytes, neutrophils and monocytes, and higher NLR, NPS and SII. Serum inflammation-based scores didn't differ among non-Cushing PA subtypes. The glucocorticoid excess severity influenced leucocyte, eosinophil, basophil and platelet counts, and GPS in Cushing's disease. Patients with functioning non-Cushing PAs with suprasellar extension, cavernous sinus invasion and hypopituitarism had GPS >= 1, while NPS >= 1 was associated with suprasellar extension. More invasive and difficult to treat corticotrophinomas were associated with fewer platelets pre-operatively (< 299.5 x 10(9)/L predicting multimodal treatment). Non-functioning PA patients who suffered apoplexy had more leucocytes, neutrophils and monocytes, higher GPS >= 1 and fewer platelets; re-operated cases had fewer lymphocytes, higher NLR and PLR. Conclusions Serum inflammation-based scores may predict invasive/refractory PAs: GPS and PNI in non-functioning and functioning non-Cushing PAs; NPS in functioning non-Cushing PAs; NLR and PLR in non-functioning PAs. Platelets < 299.5 x 10(9)/L predict multimodal treatment in Cushing's disease. Further studies are needed to confirm these observations. Show less
The most important risk factor for atherosclerotic cardiovascular disease is increased levels of LDL-C. Statins have long been the most potent LDL-C lowering drugs on the market. However,... Show moreThe most important risk factor for atherosclerotic cardiovascular disease is increased levels of LDL-C. Statins have long been the most potent LDL-C lowering drugs on the market. However, statin treatment is complicated by the fact that a considerable number of patients is unable to tolerate full therapeutic doses, or can be classified as statin low or non-responders. In >25% of patients at (very) high risk for cardiovascular disease, statin efficacy is too limited to achieve current guideline-mandated LDL-C target goals, and aggressive statin therapy decreases relative risk for ASCD by only 30-35%, leaving an unacceptable residual relative risk of 65-70% for life-threatening events. It is clear that on-treatment LDL-C levels and on-treatment measures of systemic inflammation are of equal importance in this residual risk. Both for residual cholesterol risk and residual inflammatory risk, effective drug therapy has been lacking for decades. In this thesis, we describe the first clinical studies with novel compounds based on increased LDL-C levels and inflammation (including the required methodology), and present the methodology that may be useful to develop future compounds based on dysfunctional endothelial barrier function resulting in subendothelial cholesterol accumulation and subsequent atheroma formation. Show less
Erp, S. van; Ercan, E.; Breedveld, P.; Brakenhoff, L.; Ghariq, E.; Schmid, S.; ... ; Meulen-de Jong, A. van der 2017
This thesis consists of three parts. Part A describes in chapter 2 the complex diagnosis of asthma in the morbidly obese, and especially focuses on underdiagnosis and overdiagnosis of asthma in... Show moreThis thesis consists of three parts. Part A describes in chapter 2 the complex diagnosis of asthma in the morbidly obese, and especially focuses on underdiagnosis and overdiagnosis of asthma in this patient group. Part B investigates bronchial and systemic inflammation. It starts in chapter 3 with a review on the association between obesity and asthma, where the metabolic syndrome __ as state of systemic inflammation - is mentioned as possible explanation for the association between obesity and asthma. In chapter 4 systemic inflammation and the metabolic syndrome and impaired lung function in morbidly obese subjects are discussed. This is followed by chapter 5, in which the presence and possible relationship between bronchial and systemic inflammation in morbidly obese asthma subjects are discussed. Part C focuses on bariatric surgery, first pulmonary function testing and complications of bariatric surgery are discussed in chapter 6. In chapter 7 the effect of bariatric surgery on asthma is described. And finally, in chapter 8, a summary and general discussion of these studies is presented. Show less
Hoogland, I.C.M.; Houbolt, C.; Westerloo, D.J. van; Gool, W.A. van; Beek, D. van de 2015
