Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current hypothesis for the pathogenesis of myelofibrosis involves the intramedullary release of growth factors from defective or abnormal megakaryocytes. We describe a case of an acute micromegakaryocytic leukaemia, in a patient with chronic myelofibrosis, that provides additional evidence for this concept. The micromegakaryocytes, which reached 223 x 10(9)/l, were characterized morphologically by both light and electron microscopy, immunocytochemically and by platelet peroxidase activity. The cells were shown to have a mature cytoplasm, containing alpha granules and the associated proteins; vWF:Ag, fibrinogen, fibronectin and protein S. DNA analysis, by both a Seescan Solitaire Plus image analysis system and flow cytometry, revealed nuclear immaturity, with 92% of cells being diploid. Serum markers of connective tissue synthesis, namely carboxy terminal peptide of procollagen I (PICP), procollagen terminal peptide III (PIIIP) and laminin all increased significantly following transformation and were associated with an increase in platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). These observations support the current hypothesis for bone marrow fibrosis formation and provide, for the first time, a link between in vivo growth factor release, bone marrow stromal turnover and megakaryocyte mass. In addition, the release of biologically active TGF-beta may explain both the increased fibronectin and angiogenesis characteristic of myelofibrotic bone marrow.
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PMID:Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis. 843 38

Liver injury causes vascular disorganization and local tissue hypoxia starting early in disease course. In this context, hypoxia acts not only as an aggravating factor of cell damage and inflammation, but also as an inhibitor of liver regeneration, a major stimulus of angiogenesis and fibrogenesis, and a promoter of liver carcinogenesis. Many of the effects of hypoxia are mediated by hypoxia-inducible factor-1alpha (HIF-1alpha), an oxygen-sensitive transcription factor. Compared to cells in the periportal area, intralobular hepatic stellate cells (HSCs) are more responsive to hypoxia and like other pericytes play a key role in angiogenesis through interactions with endothelial cells VIA platelet-derived growth factor (PGDF) and vascular endothelial growth factor (VEGF) signaling, at the leading edge of fibrotic septa. Although required for successful liver repair, angiogenesis in cirrhosis may be inefficient because of the immaturity and permeability of VEGF-induced neo-vessels, and thereby may fail to correct liver hypoxia. The multiple receptor tyrosine kinase inhibitors, acting on VEGF and PDGF receptors, initially designed for cancer treatment, show in addition to therapeutic efficacy in patients with hepatocellular carcinoma, beneficial effects on many aspects of the progression of liver diseases, including, fibrosis, inflammation and portal hypertension.
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PMID:Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. 2066 78