Cisplatin-induced activation of TGF-βsignaling contributes to drug resistance

Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.

A Scale of Parental Anxiety about Pediatric Emergency Medical Care Services of Japan: Development, Reliability, Validity, Generalizability and Usefulness

Aim: The purpose of this study was to develop a scale, “parental anxiety about pediatric emergency medical care services” (PAPEMCS), and to evaluate its psychometric properties. Methods: Participants were 14,510 parents with children 6 years old or younger in Kagawa Prefecture. Using each half of the participants, exploratory factor analysis was performed to generate items and factors for the PAPEMCS, and confirmatory factor analysis (CFA) was used to establish the construct validity. The generalizability of the PAPEMCS was evaluated by congruence tests and multigroup CFA. The usefulness of the PAPEMCS was established by the relationship between the PAPEMCS and non-urgent usage of pediatric emergency medical care services (PEMCS). Results: The PAPEMCS compromised 4 factors: “anxiety about quality of PEMCS”, “anxiety about PEMCS system”, “anxiety about public support”, and “anxiety about private support”. All reliability estimates (polychoric ordinal alpha coefficients, item-rest correlations), the item discrimination, 5 fit indices for CFA, the convergent validity (indicator reliabilities, composite reliabilities, average variance extracteds), and the discriminant validity fulfilled the acceptability thresholds. All generalizability estimates fulfilled the predetermined levels of acceptability (Tucker’s congruence coefficients, congruence tests, strict factorial invariance). The usefulness of the PAPEMCS was established by the higher scores of the PAPEMCS being related to non-urgent usage of PEMCS. Conclusions: The PAPEMCS demonstrated satisfactory reliability, validity, generalizability and usefulness. The PAPEMCS is useful to quantify the contents and extent of parental anxiety about PEMCS, and to clarify the mechanisms of non-urgent PEMCS usage.