Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis.

Podoplanin (PDPN) enhances tumor metastases by eliciting tumor cell-induced platelet aggregation (TCIPA) through activation of platelet C-type lectin-like receptor 2 (CLEC-2). A novel and non-cytotoxic 5-nitrobenzoate compound 2CP was synthesized that specifically inhibited the PDPN/CLEC-2 interaction and TCIPA with no effect on platelet aggregation stimulated by other platelet agonists. 2CP possessed anti-cancer metastatic activity in vivo and augmented the therapeutic efficacy of cisplatin in the experimental animal model without causing a bleeding risk. Analysis of the molecular action of 2CP further revealed that Akt1/PDK1 and PKCµ were two alternative CLEC-2 signaling pathways mediating PDPN-induced platelet activation. 2CP directly bound to CLEC-2 and, by competing with the same binding pocket of PDPN in CLEC-2, inhibited PDPN-mediated platelet activation. This study provides evidence that 2CP is the first defined platelet antagonist with CLEC-2 binding activity. The augmentation in the therapeutic efficacy of cisplatin by 2CP suggests that a combination of a chemotherapeutic agent and a drug with anti-TCIPA activity such as 2CP may prove clinically effective.

Synthesis and characterization of one-dimensional Ag-doped ZnO/Ga-doped ZnO coaxial nanostructure diodes.

In the pursuit of high injection current diode nanodevices, entire one-dimensional (1D) ZnO coaxial nanostructures with p-n homojunctions is one of the ideal structures. In this study, we synthesized entire 1D ZnO-based coaxial homojunction diodes with p-type Ag-doped ZnO (SZO) nanostructure shells covering n-type Ga-doped ZnO (GZO) nanopagoda (NPG) cores by a metal-organic chemical vapor deposition (MOCVD) technique. The entire 1D SZO-GZO and SZO-ZnO coaxial nanostructures exhibit better diode characteristics, such as lower threshold voltage, better rectification ratios, and better ideality factor n, than that reported for either 2D or 2D-1D p-n heterojunction and/or homojunction diodes. The binding energies of Ga and Ag were evaluated by low-temperature and temperature-dependent photoluminescence. In comparison, the SZO-GZO coaxial p-n nanostructures display better diode performance than the SZO-ZnO ones.

High-resolution melting analysis is a more effective approach for screening TSC genes mutations.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with a prevalence of 1 in 95,136 in Taiwan. TSC is characterized by hamartomatous lesions in multiple organ systems. Genetic defects in TSC1 and TSC2 genes are the main causes of TSC. A molecular screening protocol using denaturing high-performance liquid chromatography (dHPLC) followed by DNA sequencing is currently performed to locate the genetic lesions in many clinical laboratories. The current screening approach is time consuming and inefficient. In this study, we analyzed all coding exons of TSC1 and TSC2 genes of 30 TSC patients and 47 unaffected family members using the traditional dHPLC protocol and our recently developed diagnostic platform based on high-resolution melting analysis (HRM) followed by bidirectional DNA sequencing. Data indicated that 20 mutations, including 5 mutations in TSC1 (2 sporadic, 1 familial mutation, and 2 of uncertain origin) and 15 mutations in TSC2 (14 sporadic and 1 familial mutation), 8 single-nucleotide polymorphisms (SNPs, including 3 SNPs found in irrelevant individuals without TSC phenotypes studied in the control group), and 3 variants with undetermined significance were identified, including 4 novel mutations. The sensitivities of HRM and dHPLC for TSC mutation screening were estimated as 95% and 75%, respectively. The specificities of HRM and dHPLC for TSC mutation screening were evaluated as 91% and 98%. In addition, results suggested our novel HRM screening protocol to be more economical. In conclusion, we successfully developed a superior approach for TSC genes mutation screening for clinical application.