Inactivating mutations in one of the two parental GATA2 genes lead to a reduction, i.e. a haploinsufficiency, in the cellular levels of the genes product, the GATA2 transcription factor, and thereby to a rare autosomal dominant genetic disease, GATA2 deficiency. This disease is associated with a highly variable set of disorders including the myelodysplastic syndrome, acute myeloid leukemia, and CMML. GATA2-deficiency-induced CMML, like other types of CMML, is commonly preceded by monocytosis. Diagnosis
Blood films display a range of abnormalities. A monocyte count of >1x109/L is essential for a diagnosis of CMML. Other features may include; leukocytosis (50% of cases); left shift and dysplasia of monocytes and granulocytes; presence of metamyelocytes, myelocytes and promonocytes; monocytes with hypersegmented/abnormal shaped nuclei, increased cytoplasmic basophilia and/or the presence of cytoplasmic granules; eosinophilia (in cases of CMML with eosinophilia); and spherocytosis (in cases of direct Coombs test, DCT, positive haemolytic anaemia). Platelet counts may be reduced, increased or normal. Haemoglobin levels are usually reduced with normocytic and normochromic red blood cells. Autoantibodies and cold agglutinins may be present and 10% of CMML is DCT positive.Bone marrow aspirates will display hypercellularity with increased counts of granulocytic and monocytic cells. Bone marrow core biopsies may show a predominance of myelocytic and monocytic cells, abnormal localisation of immature precursors and dysplastic megakaryocytes.
Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity. Semisynthesis
Anidulafungin is manufactured via semi-synthesis. The starting material is echinocandin B (a lipopeptide fermentation product of Aspergillus nidulans or the closely related species, A. rugulosus), which undergoes deacylation (cleavage of the linoleoyl side chain) by the action of a deacylase enzyme from the bacterium Actinoplanes utahensis; in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin is synthesized. History
Anidulafungin was originally discovered at Lilly laboratories by Turner and Debono and licensed to Vicuron Pharmaceuticals who submitted it to the FDA. Pfizer acquired the drug upon its acquisition of Vicuron in the fall of 2005. Pfizer gained approval by the Food and Drug Administration (FDA) on February 21, 2006. == References ==