Lack of effective therapeutics for pancreatic cancer at the present time underscores the dire need for safe and effective agents for the treatment of this malignancy. In the present study, we have evaluated the anticancer activity and the mechanism of action of pristimerin (PM), a quinonemethide triterpenoid, against MiaPaCa-2 and Panc-1 pancreatic ductal adenocarcinoma (PDA) cell lines. Treatment with PM inhibited the proliferation and induced apoptosis in both cell lines as characterized by the increased Annexin V-binding and cleavage of PARP-1 and procaspases -3, -8 and -9. PM also induced mitochondrial depolarization and the release of cytochrome c from the mitochondria. The induction of apoptosis by PM was associated with the inhibition of the pro-survival Akt, NF-κB and mTOR signaling proteins and their downstream intermediaries such as Foxo-3α and cyclin D1 (Akt); Cox-2 and VEGF (NF-κB); p-S6K1 and p-4E-BP1 (mTOR) as well as PKCɛ. Treatment with PM also inhibited the expression of anti-apoptotic Bcl-2 and survivin but not Bcl-xL. The downregulation of Bcl-2 by PM was not due to proteasomal or lysosomal proteolytic degradation of Bcl-2, since treatment with PM in the presence of proteasomal inhibitors MG132 or lactacystin (LAC) or calpain inhibitor MG101 failed to block the downregulation of Bcl-2 by PM. On the other hand, RT-PCR analysis showed the inhibition of Bcl-2 mRNA by PM in a dose-related manner, indicating that inhibition of Bcl-2 by PM is mediated through the suppression of Bcl-2 gene expression. Thus, the mechanistic understanding of the antitumor activity of pristimerin could facilitate in vivo efficacy studies of pristimerin for pancreatic cancer.
Biotinidase deficiency is an inherited disorder in which the vitamin, biotin, is not recycled. Individuals with biotinidase deficiency can develop neurological and cutaneous symptoms if they are not treated with biotin. Biotinidase deficiency screening has been incorporated into essentially all newborn screening programs in the United States and in many countries. We now report 140 known mutations in the biotinidase gene (BTD) that cause biotinidase deficiency. All types of mutations have been found to cause biotinidase deficiency. Variants have been identified throughout the coding sequence. Essentially all the variants result in enzymatic activities with less than 10% of mean normal enzyme activity (profound biotinidase deficiency) with the exception of the c.1330G>C (p.D444H) mutation, which results in an enzyme having 50% of mean normal serum activity. The putative three-dimensional structure of biotinidase has been predicted by homology to that of nitrilases/ amidases. The effect of the various missense mutations can be predicted to affect various important sites within the structure of the enzyme. This compilation of variants causing biotinidase deficiency will be useful to clinical laboratories that are performing mutation analysis for confirmational testing when the enzymatic results are equivocal for children identified through newborn screening. Hum Mutat 31:983-991,
This individual exemplifies the need to include biotinidase deficiency in the differential diagnosis of patients with extensive myelopathy and/or bilateral optic neuropathy and argues for newborn screening for the disorder.
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