Anti-KDR monoclonal antibody

Background Aedes aegyptiis a primary vector of dengue, chikungunya and Zika infections in India. In the absence of specific drugs or safe and effective vaccines for these infections, their control relies mainly on vector control measures. The emergence of insecticide resistance in vectors, especially against pyrethroids, is a serious threat to the insecticide-based vector control programme. This study reports the presence of multiple knockdown resistance (kdr) mutations present in anAe. aegyptipopulation from Bengaluru (India), including a new mutation F1534L. Methods Aedes aegypticollected from Bengaluru were subjected to insecticide susceptibility tests with DDT, deltamethrin and permethrin. The DNA sequencing of partial domain II, III and IV of the voltage-gated sodium channel (VGSC) was performed to screenkdrmutations present in the population and PCR-based assays were developed for their detection. Genotyping ofkdrmutations was done using PCR-based assays, allelic frequencies were determined, and tests of genetic association ofkdrmutations with the insecticide resistance phenotype were performed. Results TheAe. aegyptipopulation was resistant to DDT, deltamethrin and permethrin. The DNA sequencing of the VGSC revealed the presence of fourkdrmutations, i.e. S989P and V1016G in domain II and two alternativekdrmutations F1534C and F1534L in domain III. Allele-specific PCR assays (ASPCR) were developed for the detection ofkdrmutations S989P and V1016G and an existing PCR-RFLP based strategy was modified for the genotyping of all three knownkdrmutations in domain III (F1534L, F1534C and T1520I). Genotyping ofAe. aegyptisamples revealed a moderate frequency of S989P/V1016G (18.27%) and F1534L (17.48%), a relatively high frequency of F1534C (50.61%) and absence of T1520I in the population. Mutations S989P and V1016G were in complete linkage disequilibrium in this population while they were in linkage equilibrium withkdrmutations F1534C and F1534L. The alleles F1534C and F1534L are genetically associated with permethrin resistance. Conclusions A newkdrmutation, F1534L, was found in anAe. aegyptipopulation from Bengaluru (India), co-occurring with the other three mutations S989P, V1016G and F1534C. The findings of a new mutation have implications for insecticide resistance management.

Angiosarcoma (AS) is the most frequent primary sarcoma of the breast but nevertheless remains uncommon, accounting for <0.05% of breast malignancies. Secondary mammary AS arise following radiation therapy for breast cancer, in contrast to primary AS which occur sporadically. Essentially all show aggressive clinical behavior independent of histologic grade and most are treated by mastectomy. MYC amplification is frequently identified in radiation-induced AS but only rarely in primary mammary AS (PMAS). As a heterogeneous group, AS from various anatomic sites have been shown to harbor recurrent alterations in TP53, MAP kinase pathway genes, and genes involved in angiogenic signaling including KDR (VEGFR2) and PTPRB. In part due to its rarity, the pathogenesis of PMAS has not been fully characterized. In this study, we examined the clinical, pathologic, and genomic features of ten cases of PMAS, including one patient with bilateral disease. Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites. Six tumors harbored a KDR p.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism (four with loss of heterozygosity and three with two aberrations). Of the seven tumors with PI3K alterations, six harbored pathogenic mutations other than in the canonical PIK3CA residues which are most frequent in breast cancer. Three AS were hypermutated (>= 10 mutations/megabase (Mb)); hypermutation was seen concurrent with KDR or PIK3CA mutations. The patient with bilateral disease demonstrated shared alterations, indicative of contralateral metastasis. No MYC or TP53 aberrations were detected in this series. Immunohistochemistry for VEGFR2 was unable to discriminate between KDR-mutant tumors and benign vascular lesions of the breast. These findings highlight the underrecognized frequency of KDR and PIK3CA mutation in PMAS, and a significant subset with hypermutation, suggesting a pathogenesis distinct from other AS.