Young adolescents' responsiveness to sexual communication with their mother: Distinguishing diverse intentions.

INTRODUCTION: It is unlikely that parents can have effective sexuality discussions with their adolescent if the adolescent is not responsive to their efforts. We evaluated young adolescents' intentions of being responsive to sexual communication with their mother and whether youths who were likely, ambivalent, or unlikely to be responsive differed on their characteristics, features of previous sexual communication, and features of the mother-adolescent relationship. METHODS: Participants were 259 Canadian adolescents (12-14 years; 53% girls) who received and returned a survey by mail. They completed measures of responsiveness intentions, expected outcomes of sexual communication, extent of past sexual communication, the frequency with which mothers encouraged questions and provided information about sexuality topics, open communication, and mothers' provision of warmth, structure, and autonomy support. RESULTS: We found that 37% of adolescents were likely to be responsive to sexual communication with their mother, 34% were ambivalent, and 29% were unlikely to be responsive. Youths' responsiveness intentions were general rather than topic-specific. A discriminant analysis showed that only features of previous sexual communication separated all three groups whereas specific mother-adolescent relationship features (open communication and structure) and one adolescent characteristic (expected outcomes) separated the unlikely group from the other groups. CONCLUSIONS: Young adolescents' intentions of being responsive to sexual communication from their mother are diverse yet general in nature. Mothers' engagement in sexual communication appears essential for youths' openness to these discussions. Enhancing specific mother-adolescent relationship features and youths' outcome expectations may shift adolescents who are resistant to sexuality discussions to being more sure.

Antitumor Properties of an IgG2-Enhanced Next-Generation MET Monoclonal Antibody That Degrades Wild-Type and Mutant MET Receptors.

A sound rationale exists for antibody targeting of the MET receptor tyrosine kinase, but therapeutic agents that can broadly block HGF ligand binding and exon 14-mutated or amplified MET to induce receptor degradation have yet to be reported. Here we report the identification of several MET monoclonal antibodies (mAb) that block MET-dependent signaling and tumor growth. In particular, the MET mAb KTN0073 and KTN0074 bind the Sema/PSI domain, at overlapping but distinct epitopes, preventing HGF interaction with MET and triggering receptor ubiquitination and degradation. Notably, both mAbs also triggered degradation of oncogenic MET exon 14 mutants, which propagate more durable MET signals due to a defect in receptor degradation. Mechanistic investigations showed that both mAbs engaged a pathway distinct from HGF-induced receptor degradation and protease-mediated shedding, independently of signaling driven by the exon 14-encoded sequences in the intracellular juxtamembrane region of the MET receptor. Grafting the mAb variable regions onto the IgG2 constant region dramatically enhanced the tumor inhibitory activities of KTN0073 but not KTN0074, suggesting a specific influence of antibody isotype of the epitopes for these two MET mAbs. Overall, our results highlight KTN0073 as a novel IgG2-based MET mAb that acts through exon 14-independent mechanisms to degrade the MET receptor, potentially offering a therapeutic tool to treat a broader range of human tumors where MET is exon 14 mutated or amplified. Cancer Res; 76(19); 5788-97. ©2016 AACR.

Phosphoproteomic characterization of PYK2 signaling pathways involved in osteogenesis.

The PYK2 tyrosine kinase is a negative regulator of bone formation, but aside from the requirement for PYK2 kinase activity there has been little progress toward understanding of the molecular mechanism involved in this function. To gain insight into the signaling pathways modulated by PYK2 we sought to identify PYK2 substrates. Challenges inherent to a quantitative phosphoproteomic analysis for non-receptor tyrosine kinases were overcome by employing an inducible PYK2 overexpression system in NIH3T3 cells in combination with a selective PYK2 inhibitor. The identification of a number of known PYK2 substrates and interacting partners validated the methodology. Results of the inducible cell system were extended to a cell model of osteogenesis, examining the effect of the PYK2 inhibitor on the phosphorylation state of targets identified in the phosphoproteomic study. Consistent with phosphoproteomic analysis, increased osteogenesis associated with a selective PYK2 inhibitor was accompanied by reduced phosphorylation of paxillin, Gab1 and p130(Cas), along with reduction of phosphorylation levels of the Met activation loop. These results further confirmed the utility of the methodology and point to a previously unknown bi-directional activation pathway between PYK2 and Met.

Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions.

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.