PAMAM dendrimers for siRNA delivery: computational and experimental insights.

Short double-stranded RNAs, which are known as short interfering RNA (siRNA), can be used to specifically down-regulate the expression of the targeted gene in a process known as RNA interference (RNAi). However, the success of gene silencing applications based on the use of synthetic siRNA critically depends on efficient intracellular delivery. Polycationic branched macromolecules such as poly(amidoamine) (PAMAM) dendrimers show a strong binding affinity for RNA molecules and, hence, can provide an effective, reproducible, and relatively nontoxic method for transferring siRNAs into animal cells.

Activate and resist: L576P-KIT in GIST.

L576P is a rare KIT mutation often reported in cancers other than gastrointestinal stromal tumors (GIST). In GISTs, it correlates with features linked to an aggressive phenotype, eventually resulting in secondary mutations. In vitro findings point out that L576P/KIT is constitutively activated, and shows poor imatinib sensitivity.

T670X KIT mutations in gastrointestinal stromal tumors: making sense of missense.

Background: Chronic myeloid leukemia, gastrointestinal stromal tumors (GISTs), and idiopathic hypereosinophilic syndrome are associated with pathological deregulation of the tyrosine kinases BCR-ABL, KIT, and PDGFRA, respectively. Patients who become resistant to imatinib treatment often develop secondary mutations, the most common of which results in a substitution of isoleucine for threonine at the same location in the ATP-binding domain in all three kinases (in KIT this occurs at amino acid 670). We sought to determine why Thr is always replaced by Ile.