Journal of internal medicine
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This review is largely based on a previous paper published in the journal Spinal Cord. The care of many patients undergoing long-term bladder catheterization is complicated by encrustation and blockage of their Foley catheters. This problem stems from infection by urease-producing bacteria, particularly Proteus mirabilis. ⋯ In this review, the ways in which biofilm formation on Foley catheters is initiated by P. mirabilis will be described. The implications of understanding these mechanisms for the development of an encrustation-resistant catheter will be discussed. Finally, the way forward for the prevention and control of this problem will be considered.
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Review
Tumour-induced immune suppression: role of inflammatory mediators released by myelomonocytic cells.
Tumour-induced immune dysfunction is a serious challenge to immunotherapy for cancer, and intact adaptive and innate cellular immunity is key to its success. Myelomonocytic cells have a central role in this immune suppression, and tumour-associated macrophages, eosinophils, neutrophils and myeloid-derived suppressor cells have all been shown to be of major importance. These myelomonocytic cells secrete a broad repertoire of inflammatory mediators providing them with powerful tools to inhibit tumour-reactive T cells and natural killer cells; free oxygen radicals including reactive oxygen species and NO, arginase, indoleamine 2,3-dioxygenase, prostaglandins, the pro-inflammatory heterodimer S100A8/9 and cytokines, such as granulocyte-macrophage colony-stimulating factor and transforming growth factor-β, have proven particularly potent in suppressing antitumour cellular immunity. Determining which of these factors prevail in individual cancer patients and designing methods aimed at neutralization or inhibition of their effects on target tissues have the potential to greatly enhance the clinical efficacy of immunotherapy.
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Cells within tumours have diverse genomes and epigenomes and interact differentially with their surrounding microenvironment generating intratumour heterogeneity, which has critical implications for treating cancer patients. Understanding the cellular and microenvironment composition and characteristics in individual tumours is critical to stratify the patient population that is likely to benefit from specific treatment regimens. ⋯ Comprehensive assessment of the molecular features of patients based on tumour specimen characterization (including intratumour spatial and temporal variations), ancillary noninvasive methods (such as circulating biomarkers and molecular imaging approaches) and the correct design of clinical trials are required to guide administration of targeted therapy and to control therapeutic resistance. Finding the means to accurately determine and effectively control tumour heterogeneity and translate these achievements into patient benefit are major goals in modern oncology.
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Stem cell function is regulated by intrinsic mechanisms, such as transcriptional and epigenetic regulators, as well as extrinsic mechanisms, such as short-range signals from the niche and long-range humoral signals. Interactions between these regulatory mechanisms and cellular metabolism are just beginning to be identified. In multiple systems, differentiation is accompanied by changes in glycolysis, oxidative phosphorylation and the levels of reactive oxygen species. ⋯ Some metabolic pathways appear to function differently in stem cells as compared with restricted progenitors and differentiated cells. They also appear to influence stem cell function by regulating signal transduction, epigenetic marks and oxidative stress. Studies to date illustrate the importance of metabolism in the regulation of stem cell function and suggest complex cross-regulation likely exists between metabolism and other stem cell regulatory mechanisms.
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The MYC proto-oncogene is an essential regulator of many normal biological programmes. MYC, when activated as an oncogene, has been implicated in the pathogenesis of most types of human cancers. MYC overexpression in normal cells is restrained from causing cancer through multiple genetically and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis and cellular senescence. ⋯ Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can lead to the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumour regression associated with tumour cells undergoing proliferative arrest, differentiation, senescence and apoptosis, as well as remodelling of the tumour microenvironment, recruitment of an immune response and shutdown of angiogenesis. Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host-dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis.