The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NFκB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NFκB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration, and invasion. In addition, CBM-dependent activation of NFκB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NFκB signaling in AGTR1 breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NFκB signaling pathways to improve the treatment of this breast cancer subset. These findings offer a mechanistic rationale to explore the repurposing of drugs that target angiotensin action to improve the treatment of AGTR1-expressing breast cancers. .

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This study of 52 undergraduates of English as a foreign language (EFL) involves an empirical assessment of the pedagogical suitability of data-driven learning (DDL) in three Taiwanese grammar classes. One class (16 students) was taught using a traditional deductive approach (TDA), and the others (one of 17 and one of 19 students) were taught using blends of DDL and TDA. The participants’ performance in grammar and their judgments of the teaching effects of DDL were both collected for analysis. Using a covariance analysis, the study results indicate no significant differences between the three classes in grammar proficiency, although paired-sample t-tests reveal significant gains for each class. However, the results of quantifying participants’ perceptions of the treatments over time show clear changes as the experiment proceeded; there was a growing preference for DDL-integrated treatments but a disinclination towards the TDA. Although it seems premature to claim DDL’s pedagogical suitability here, the overall results lend support to the legitimacy of practicing DDL in different educational areas. This is particularly notable for Taiwan’s EFL context, given that most of its grammar classrooms are still employing conventional approaches, including the Grammar Translation method, even if they are not inclined towards them. The article concludes with a discussion of DDL’s effects on future EFL grammar classes and possible avenues for further studies.

The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.

hCG exhibits a considerable heterogeneity in blood during pregnancy. The overall charge of the isoforms of hCG has been shown to be more negative in the early than in the latter part of pregnancy. The present study analyzes the change in median charge and the charge heterogeneity as pregnancy progresses. The hCG activity in sera from 76 women from weeks 6-43 of gestation was measured with a noncompetitive time-resolved sandwich fluoroimmunoassay. The median charge and degree of charge heterogeneity of the isoforms of hCG in each serum was determined by electrophoresis in 0.10% agarose suspension. Median charge was expressed as median electrophoretic mobility. Electrophoresis with a high resolution revealed that the number of isoforms of hCG in a serum specimen from week 36 of gestation was 20-30. A change in median charge was found to occur at a limited time period of gestation, around the 13th week. All 16 sera from weeks 6-10 had isoforms of hCG with a more negative median charge than that of hCG in 21 sera from weeks 16-43 of gestation. The change in charge was accompanied by an increased degree of charge heterogeneity. There was a significant (P < 0.01) correlation between median mobility and the concentration of hCG during weeks 11-15 of gestation, but not before or after this period. There was no relationship between the sex of the fetus and the median charge of the isoforms of hCG. The data show that a change in the isoforms of hCG, revealed by a change in median charge of hCG, occurs at a limited time around the 13th week of gestation. This change occurs when the hCG concentration in blood decreases, and the placental production of estradiol and progesterone rapidly increases.