Dacomitinib improves chemosensitivity of cisplatin-resistant human ovarian cancer cells.

Drug resistance hinders effectiveness of human ovarian cancer (OC) therapies, such as cisplatin or paclitaxel therapy. Although dacomitinib, a novel anticancer agent is used against multiple types of cancers, such as non-small cell lung cancer, head and neck cancer, few studies report its effectiveness in drug-resistant human OC cells. In the present study, would healing, microplate spectrophotometer analysis, flow cytometry analysis, western blotting and Gene Expression Omnibus (GEO) analysis were used to detect the synergistic effect of dacomitinib and cisplatin in human OC SKOV-3 or OV-4 cells. Co-administration of dacomitinib and cisplatin significantly reduced viability and promoted cell apoptosis of drug resistant OC cells. In addition, dacomitinib increased Cadherin 1 (CDH1) levels and decreased P-glycoprotein (P-GP) levels in cisplatin-resistant OC cells. In addition, GEO analysis demonstrated that dacomitinib inhibited the epidermal growth factor receptor (EGFR) signaling pathway. In summary, dacomitinib improves chemosensitivity of cisplatin in human OC by regulating CDH1 and P-GP protein levels and inhibiting the EGFR signaling pathway.

Dacomitinib, a new pan-EGFR inhibitor, is effective in killing ovarian cancer cells.

OBJECTIVE: Aberrant epidermal growth factor receptor (EGFR) is involved in a variety of cancers and its inhibitors have been studied for over a decade. We aim to investigate the effects of dacomitinib, a second generation pan-EGFR inhibitor, on ovarian cancer cells. METHODS: By immunohistochemistry, we studied the clinical significance of EGFR expression in epithelial ovarian cancer (EOC). The correlations between EGFR expression and the clinicopathological variables of patients with EOC were assessed using Pearson's X2 test. Kaplan-Meier analysis was used to compare the postoperative survival between groups of patients with EOC with varying levels of EGFR expression. MTT, caspase assay, cell apoptosis analysis, autophagy analysis, cell cycle analysis, and western blotting were used to investigate various effects of dacomitinib in cell proliferation, apoptosis, and associated molecular pathways. RESULTS: High expression of EGFR was found to be associated with poor prognosis of patients with EOC. EGFR, P-AKT, and P-ERK were inhibited after treatment of dacomitinib in both SKOV3 and OV4 cells. Activations of caspase activities, apoptosis, and autophagy were also observed and confirmed by western blot: caspase 9, LC3, and Bax levels were elevated, while Bcl-2 and Bcl-xl were down-regulated. The percentage of cancer cells in the S and G2 phases of the cell cycle significantly decreased after treatment. Cdk1 and Cdk2 protein levels declined after dacomitinib treatment; epithelial-mesenchymal transition (EMT) was inhibited, which was confirmed by observing E-cadherin, N-cadherin, and slug inhibition. Additionally, dacomitinib significantly increased chemotherapy sensitivity in chemotherapeutic resistant ovarian cell lines, C13 and 2780CP. CONCLUSION: Our data showed that increased expression of EGFR is associated with poor prognosis of patients with EOC and dacomitinib may act as a novel, useful chemotherapy drug. Further studies are warranted.

A randomly-controlled study on the cardiac function at the early stage of return to the plains after short-term exposure to high altitude.

High altitude acclimatization and adaptation mechanisms have been well clarified, however, high altitude de-adaptation mechanism remains unclear. In this study, we conducted a controlled study on cardiac functions in 96 healthy young male who rapidly entered the high altitude (3700 m) and returned to the plains (1500 m) after 50 days. Ninety eight healthy male who remained at low altitude were recruited as control group. The mean pulmonary arterial pressure (mPAP), left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), cardiac function index (Tei index) were tested. Levels of serum creatine kinase isoform MB (CK-MB), lactate dehydrogenase isoenzyme-1 (LDH-1), endothelin-1 (ET-1), nitrogen oxide (NO), serum hypoxia-inducible factor-1α (HIF-1α), 8-iso-prostaglandin F(2α) (8-iso PGF(2α)), superoxide dismutase (SOD) and malonaldehyde (MDA) were measured at an altitude of 3700 m and 1500 m respectively. The results showed that after short-term exposure to high altitude mPAP and Tei index increased significantly, while LVEF and LVFS decreased significantly. These changes were positively correlated with altitude. On the 15(th) day after the subjects returned to low altitude, mPAP, LVEF and LVFS levels returned to the same level as those of the control subjects, but the Tei index in the returned subjects was still significantly higher than that in the control subjects (P<0.01). We also found that changes in Tei index was positively correlated with mPAP, ET-1, HIF-1α and 8-iso PGF(2α) levels, and negatively correlated with the level of NO, LVEF, LVFS, CK-MB and LDH-1. These findings suggest that cardiac function de-adapts when returning to the plains after short-term exposure to high altitude and the function recovery takes a relatively long time.

[Analysis of prognostic risk factors in the patients with acute exacerbation of chronic cor pulmonale and obstructive sleep apnea-hypopnea syndrome in high altitude area].

OBJECTIVE: To assess the prognostic risk factors in the patients with acute exacerbation of chronic cor pulmonale (AEHACCP) and obstructive sleep apnea-hypopnea syndrome (OSAHS) in high altitude area. METHODS: The relations between neck circumference (Nc), body mass index (BMI), arterial blood gases, polysomnography (PSG) parameters and prognosis from 66 patients with AEHACCP and OSAHS (31 survivors, 35 non-survivors) were studied by one variable analysis and multivariable Logistic regression analysis. RESULTS: The results of one variable analysis showed that in patients with AEHACCP and OSAHS, Nc> or =45 cm, BMI > or =28 kg/m(2) , arterial oxygen partial pressure (PaO(2))< or =40 mm Hg (1 mm Hg= 0.133 kPa), mean pulmonary arterial pressure (mPAP)> or =45 mm Hg, apnea-hypopnea index (AHI)> or = 40 times/h, sleep mean arterial oxygen saturation (MSaO(2))< or =0.70, percentage of the duration of SaO(2)<0.70 during sleep(T(70) )> or =50% and difference between basic and minimum SaO(2) during sleep(Delta SaO(2))> or = 0.20 were closely correlated with prognosis. The Logistic regression models showed that Nc> or =45 cm [odds ratio (OR)=6.781, 95% confidence interval (95%CI)=1.153-17.502, P=0.007], BMI> or =28 kg/m(2) (OR=7.562, 95%CI=1.012-23.457, P=0.004), mPAP> or =45 mm Hg (OR=6.991, 95%CI=1.353-20.155, P=0.003), AHI> or =40 times/h (OR=7.258, 95%CI=1.526-18.022, P=0.006), MSaO(2)< or =0.70 (OR=6.488, 95%CI=1.562-26.878, P=0.008), T(70) > or =50% (OR=5.593, 95%CI=1.265-21.589, P=0.008) and Delta SaO(2)> or =0.20 (OR=6.551, 95%CI=1.495-18.920, P=0.007) were independent significant risk factors in prognosis of patients with AEHACCP and OSAHS. CONCLUSION: The patients with AEHACCP and OSAHS, Nc> or =45 cm, BMI> or =28 kg/m(2), mPAP> or =45 mm Hg, AHI> or = 40 times/h, MSaO(2)< or =0.70, T(70) > or =50% and Delta SaO(2)> or =0.20 are risk factors leading to a rise in mortality. It is important to use these parameters to guide clinical therapy, and to judge the prognosis so as to reduce the mortality of patients with AEHACCP and OSAHS by monitoring the above risk factors in clinical practice.