Genotypephenotype Correlation

The reciprocal t(9;22)(q34;q11) translocation is probably the initial transforming event in the development of CML.

This translocation yields a shortened chromosome 22 that is the Philadelphia (Ph) chromosome. With the translocation, two distinct genes are fused: 1) BCR that encodes a cytoplasmic protein of uncertain function with oligomerization, serine threonine kinase, and GTPase-activating domains; and 2) ABL that encodes a non-receptor tyrosine kinase normally localized to the nucleus.[1] The resultant chimeric gene and fusion transcript yield a protein with constitutively heightened tyrosine kinase activity that is relocated from the nucleus to the cytoplasm and phosphorylates a variety of cellular substrates with consequent proliferative, growth factor independent, antiapoptotic, and defective adhesive properties in the transformed cells.

The subsequent occurrence of specific cytogenetic and molecular genetic events, in addition to t(9;22), heralds disease progression prior to hematological and/or clinical manifestations. The acquisition of +Ph, isochromosome 17q, and +8 commonly indicates an impending blast crisis while molecular abnormalities associated with disease progression include overexpression of BCR-ABL, upreg-ulation of the EVI1 gene, mutations in tumor suppressor genes P16, P53, CDKN2A, and RB1, and aberrant DNA methylation of the translocated ABL allele.[2,3] Deletion of the derivative chromosome 9 is an independent poor prognosticator that predicts rapid progression to blast crisis with shortened survival.[4]

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Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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