Epidemiological evidence indicates that cadmium and arsenic exposure increase lung cancer risk. Cadmium and arsenic are environmental contaminants that act as endocrine disruptors (EDs) by activating estrogen receptors (ERs) in breast and other cancer cell lines but their activity as EDs in lung cancer is untested. Here, we examined the effect of cadmium chloride (CdCl2) and sodium arsenite (NaAsO2) on the proliferation of human lung adenocarcinoma cell lines. Results demonstrated that both CdCl2 and NaAsO2 stimulated cell proliferation at environmentally relevant nM concentrations in a similar manner to 17β-estradiol (E2) in H1793, H2073, and H1944 cells but not in H1792 or H1299 cells. Further studies in H1793 cells showed that 100 nM CdCl2 and NaAsO2 rapidly stimulated mitogen-activated protein kinase (MAPK, extracellular-signal-regulated kinases) phosphorylation with a peak detected at 15 min. Inhibitor studies suggest that rapid MAPK phosphorylation by NaAsO2, CdCl2, and E2 involves ER, Src, epidermal growth factor receptor, and G-protein coupled ER (GPER) in a pertussis toxin-sensitive pathway. CdCl2 and E2 activation of MAPK may also involve ERβ. This study supports the involvement of membrane ER and GPER signaling in mediating cellular responses to environmentally relevant nM concentrations of CdCl2 and NaAsO2 in lung adenocarcinoma cells.

In order to find out the normal values and to evaluate the effects of age, heart rate, sex, and haemodynamic and standard echocardiographic parameters on pulmonary venous flow velocity obtained by the transthoracic approach. Doppler pulmonary venous flow parameters were measured in 143 healthy subjects aged from 20 to 80 years. Doppler pulmonary venous flow parameters which had the best correlation with age were: the peak velocity of the systolic wave (r = 0.39) and its integral (r = 0.5), the peak velocity of the diastolic wave (r = -0.6) and its integral (r = -0.44); the systolic (r = 0.68) and diastolic fractions (r = -0.68); the systolic/diastolic peak velocity ratio (r = 0.73) and the systolic/diastolic integral ratio (r = 0.7). The atrial reversal wave did not correlate with age; the atrial reversal wave was more difficult and probably less reliable to measure than the systolic and diastolic waves. The correlations of pulmonary venous flow parameters with mitral flow parameters were also examined. This study showed that, in healthy subjects, despite an increase in the early and atrial waves from the annulus to the tips of the mitral leaflets, there is a similar association between pulmonary venous flow and mitral flow measured at the annulus or at the tips of the mitral leaflets. The intra-observer reproducibility of all the pulmonary venous flow parameters considered were found to be excellent. Moderate inter-observer variability was observed for the systolic, diastolic and atrial reversal wave peak velocities and integrals; however, the systolic/diastolic ratio improved the precision of the measurements. Multivariate analysis showed that age is the principal determinant of the Doppler parameters of pulmonary venous flow: heart rate, sex, body surface area, the size of the left atrium in systole and the left ventricular ejection fraction all influence the Doppler parameters of pulmonary venous flow, even if only slightly.

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Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.

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