Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro

Human esophageal cancers have been shown to express high levels of epidermal growth factor receptor (EGFR) and a relationship between high EGFR expression and local advance, the number of lymph node metastases, life expectancy, and sensitivity to chemo-radiotherapy has been demonstrated. We examined the use of gefitinib, an orally active EGFR-selective tyrosine kinase inhibitor, as a new strategy for treatment of esophageal carcinoma. The effects of gefitinib were evaluated in monotherapy and in combination with radiotherapy in human esophageal carcinoma cell lines. Gefitinib produced a dose-dependent inhibition of cellular proliferation in all of the 8 esophageal carcinoma cell lines examined, with IC50 values ranging from 5.7 microM to 36.9 microM. In combination, gefitinib and radiotherapy showed a synergistic effect in 2 human esophageal carcinoma cell lines and an additive effect in 5 cell lines. Western blotting demonstrated that gefitinib blocked activation of the EGFR-extracellular signal-regulated kinase (Erk) pathway and the EGFR-phosphoinositide-3 kinase (PI3K)-Akt pathway after irradiation. These results suggest that further evaluation of EGFR blockade as a treatment for esophageal cancer should be performed, and that radiotherapy combined with EGFR blockade may enhance the response of esophageal carcinoma to therapy.     

Contribution of Parenting Factors to the Developmental Attainment of 9-Month-Old Infants: Results From the Japan Children’s Study

Background

Child development integrates several interdependent domains, but few studies have attempted to identify the common factors that contribute to these different domains of development in infancy. The aim of the present study was to identify the factors that contribute to several domains of developmental attainment in 9-month-old infants.

Methods

We used data from the Japan Children’s Study, a prospective cohort study underway in Japan since 2005. Mothers completed questionnaires about their children’s temperament, coparenting behaviors, maternal parenting stress, and parenting behavior. The Kinder infant development scale was used to evaluate child development outcomes.

Results

A total of 270 children were included in this analysis. After adjusting for the children’s birth weight, gestational age, temperament, and other family environmental variables, multiple logistic regression analyses showed that greater maternal cognitive stimulation was associated with the development of receptive language, expressive language, social relationships, and feeding. Results also suggest that early supportive coparenting helped to promote development in manipulation, receptive language, and social relationships. Maternal parenting stress was stable between the infant ages of 4 and 9 months and was negatively correlated with scores for coparenting and maternal stimulation, which suggests an indirect effect of maternal parenting stress on child outcomes.

Conclusions

Supportive coparenting and maternal cognitive stimulation were the most important contributors to most domains of child development. Our findings suggest that educational interventions targeting young families would help parents establish and maintain an environment of successful coparenting and cognitive stimulation as their children grow.Key words: development, coparenting, maternal stimulation, parenting stress, prospective study     

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.     

The role of oxysterol binding protein‐related protein 5 in pancreatic cancer

The expression of oxysterol binding protein‐related protein (ORP) 5 is related to invasion and a poor prognosis in pancreatic cancer patients. ORP5 induced the expression of sterol response element binding protein (SREBP) 2 and activated the downstream gene of sterol response element. ChIP using SREBP2 antibody revealed that histone deacetylase 5 (HDAC5) was one of the downstream genes of SREBP2. The effect of HMG‐CoA reductase inhibitors (statins) were analyzed according to the expression level of ORP5. The invasion rate and growth was suppressed in cells that strongly expressed ORP5 in a time‐ and dose‐dependent manner, but had less effect in cells weakly expressing ORP5, suggesting that when the potential of invasion and growth relies on the cholesterol synthesis pathway, it becomes sensitive to HMG‐CoA reductase inhibitor. Furthermore, HDAC inhibitor, tricostatin A, induced the expression of phosphatase and tensin homolog as well when ORP5 was suppressed or the cells were treated with statin. Treatment with both statin and tricostatin A showed a synergistic antitumor effect in cells that highly expressed ORP5. Therefore, in some pancreatic cancers, continuous ORP5 expression enhances the cholesterol synthesis pathway and this signal transduction regulates phosphatase and tensin homolog through HDAC5 expression. This is the first report to detail how the signal transduction of cholesterol synthesis is related to cancer invasion and why statins can suppress invasion and growth. (Cancer Sci 2010; 101: 898–905)     

Topical efinaconazole: A promising therapeutic medication for tinea unguium

We treated tinea unguium (onychomycosis caused by dermatophytes) patients with efinaconazole 10% solution. All patients with tinea unguium who tested positive for fungi in fingernails and toenails, regardless of age or severity, were eligible for the treatment. The number of patients was 106, consisting of 43 men and 63 women with a mean age of 66.7 years. The patients were treated with efinaconazole for a mean treatment duration of 38.1 weeks. Therapeutic efficacy was rated on a 5‐point scale as follows: “cured”, “markedly improved”, “improved”, “slightly improved” or “no change”. A single nail was selected in each patient as the target nail. Selected nails were the big toenails with less than 50% involvement in 25 patients, the big toenails with 50% or more involvement in 52 patients, the fingernails in 10 patients and the second to fifth toenails in 19 patients with a mean treatment duration of 43.9, 38.1, 38.7 and 33.7 weeks, respectively. All groups showed an improvement in the percentage involvement from 30.6% to 9.8%, 77.6% to 35.7%, 82.7% to 17.6% and 80.3% to 15.5%, respectively (P < 0.01). The improvement rate (i.e. percentage of those rated as improved and better) was 76.0%, 65.4%, 80.0% and 89.5%, respectively. Efinaconazole 10% topical solution is beneficial for patients, regardless of age, severity or clinical type.     

Usefulness of simultaneous measurement of brain and muscle regional oxygen saturation in shock patients: A report of three cases

The regional oxygen saturation (rSO₂) values of brain and muscle tissues can be measured simultaneously even if blood pressure cannot be measured due to circulatory failure associated with shock and may continuously reflect the oxygen supply‐demand balance.