Mathematical Modelling as a Proof of Concept for MPNs as a Human Inflammation Model for Cancer Development

<p><b>Left:</b> Typical development in stem cells (top panel A) and mature cells (bottom panel B). Healthy hematopoietic cells (full blue curves) dominate in the early phase where the number of malignant cells (stipulated red curves) are few. The total number of cells is also shown (dotted green curves). When a stem cell mutates without repairing mechanisms, a slowly increasing exponential growth starts. At a certain stage, the malignant cells become dominant, and the healthy hematopoietic cells begin to show a visible decline. Finally, the composition between the cell types results in a takeover by the malignant cells, leading to an exponential decline in hematopoietic cells and ultimately their extinction. The development is driven by an approximately exponential increase in the MPN stem cells, and the development is closely followed by the mature MPN cells. <b>Right:</b> B)The corresponding allele burden (7%, 33% and 67% corresponding to ET, PV, and PMF, respectively) defined as the ratio of MPN mature cells to the total number of mature cells.</p

ICAR: endoscopic skull‐base surgery

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A role for mitogen-activated protein kinase and Ets-1 in the induction of interleukin-10 transcription by human immunodeficiency virus-1 Tat

The human immunodeficiency virus (HIV) Tat protein has multiple regulatory roles, including trans-activation of the HIV genome and regulation of immune signalling processes, including kinase activation and cytokine expression. We recently demonstrated that HIV-1 Tat induces the expression of interleukin (IL)-10 via p38 mitogen-activated protein kinase (MAPK) activation. We further delineated that the Tat-responsive element of the IL-10 promoter was located within 625 to 595 bp upstream from the transcription start site. Using electrophoretic mobility shift assays, the transcription factors Ets-1 and Sp-1 were shown to bind to the IL-10 promoter to activate transcription of the gene. Furthermore, sequential deletional mutations of the Ets-1- and Sp-1-binding sites in the −625/−595 region reduced the DNA binding and transcription activity of the IL-10 promoter. Our results also showed that both the Tat-induced and Ets-1-regulated IL-10 promoter-driven luciferase activity can be abrogated by inhibitors of the p38 MAPK activity. In conclusion, the coordinated activities of p38 MAPK and the transcription factors, Ets-1 and Sp-1, may play an important role in the HIV-1 Tat-induced IL-10 transcription