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Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, such as leukemia and glioma, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2-HG]. Elucidation of the role of IDH mutations and (R)-2-HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. It has been recently reported that a canonical IDH1 mutant, IDH1 R132H, promoted cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2-HG, but not (S)-2-HG, despite the fact that (S)-2-HG more potently inhibits enzymes previously linked to the pathogenesis of IDH mutant tumors, such as the 5'-methylcytosine hydroxylase TET2. This paradox is perhaps due to the ability of (S)-2-HG, but not (R)-2-HG, to inhibit the EglN prolyl hydroxylases. 2-HG has also been shown to inhibit the activity of multiple other a-KG-dependent dioxygenases, including the JmjC domain-containing histone demethylases (KDMs).

How to Use:

In vitro:? (R)-2-HG was used at 100-250 μM final concentration in vitro and in cellular assays.

In vivo: ?n/a?

Reference:

1. 1. Losman JA, et al.? (R)-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible. (2013) Science. 339(6127):1621-5.
2. 2. Ye D, et al. R-2-Hydroxyglutarate as the Key Effector of IDH Mutations Promoting Oncogenesis. (2013) Cancer Cell. 23(3):274-6.?

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