mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment the antitumor activities of BETis in SCLC. We found that multiple drugs targeting the PI-3K-AKT-mTOR pathway synergize with BETis, among which mTOR inhibitors (mTORis) show the highest synergy. Using various molecular subtypes of the xenograft models derived from patients with SCLC, we confirmed that mTOR inhibition potentiates the antitumor activities of BETis in vivo without substantially increasing toxicity. Furthermore, BETis induce apoptosis in both in vitro and in vivo SCLC models, and this antitumor effect is further amplified by combining mTOR inhibition. Mechanistically, BETis induce apoptosis in SCLC by activating the intrinsic apoptotic pathway. However, BET inhibition leads to RSK3 upregulation, which promotes survival by activating the TSC2-mTOR-p70S6K1-BAD cascade. mTORis block this protective signaling and augment the apoptosis induced by BET inhibition. Our findings reveal a critical role of RSK3 induction in tumor survival upon BET inhibition and warrant further evaluation of the combination of mTORis and BETis in patients with SCLC.

Targeting ß-tubulin/CCT-ß complex induces apoptosis and suppresses migration and invasion of highly metastatic lung adenocarcinoma.

Metastasis, the movement of cancer cells from one site to another, is responsible for the highest number of cancer deaths, especially in lung cancer patients. In this study, we first identified a prognostic marker of lung adenocarcinoma, TCP-1 ß subunit (chaperonin-containing TCP-1ß; CCT-ß). We showed a compound that disrupted the interaction of CCT-ß with ß-tubulin killed a highly metastatic non-small cell lung cancer cell line CL1-5 through inducing Endoplasmic reticulum stress and caspases activation. Moreover, at the dosage of EC20, the compound inhibited migration and invasion of the lung cancer cells by suppressing matrix metalloproteinase (MMP)-2/9 and epithelial-mesenchymal transition (EMT)-related proteins through downregulating mitogen-activated protein kinases (MAPKs), Akt/ß-catenin and integrin-focal adhesion kinase signaling pathways. Unlike the anticancer drugs, such as Taxol, that target the adenosine triphosphate site of ß-tubulin, this study reveals a therapeutic target, ß-tubulin/CCT-ß complex, for metastatic human lung adenocarcinoma. The study demonstrated CCT-ß as a prognostic marker. Targeting ß-tubulin/CCT-ß complex caused apoptosis and inhibited invasion/migration of CCT-ß overexpressed, highly metastatic lung adenocarcinoma.

The influence of delay elimination communication on the prevalence of primary nocturnal enuresis-a survey from Mainland China.

AIMS: A pilot survey shows that primary nocturnal enuresis (PNE) prevalence has increased significantly during the past decade in Mainland China. Whether it is related to the delay of elimination communication (EC) is unclear. This study retrospectively investigated the influence of delayed EC on the PNE prevalence in children and adolescents in mainland China. METHODS: A cross-sectional study of PNE prevalence was performed by distributing 19 500 anonymous self-administered questionnaires to parents in five provinces of mainland China from July 2017 to October 2017. The questionnaires included sociodemographic data, family caregivers' information, and details about the disposable diapers (DD) usage, EC commencement date, psychological disorders, lower urinary tract symptoms, and family history of PNE in children and adolescents. The 2017 PNE prevalence was compared with that of 2006 in Mainland China. RESULTS: The total response rate was 97.04% (18 631 of 19 500) and 92.39% (18 016 of 19 500) qualified for statistical analysis. The PNE prevalence in 2017 has increased significantly compared to that of 2006 (7.30% vs 4.07%, P < 0.001). The PNE prevalence in children with EC starting before 6 months of age was significantly lower than those who start after 12 months of age. The longer DD were used and the later the beginning of EC, the higher the PNE prevalence was found. CONCLUSIONS: The PNE prevalence in Mainland China has increased significantly during the past 10 years. A longer use of DD and later onset of EC may be risk factors for PNE.

Perceived stress and depression amongst older stroke patients: Sense of coherence as a mediator?

OBJECTIVE: This study aimed to explore the relationship between perceived stress, sense of coherence, and depression among older stroke patients. METHODS: A demographic questionnaire, the Perceived Stress Scale (PSS), the Sense of Coherence Scale (SOC) and the Center for Epidemiologic Studies Depression Scale (CES-D) were distributed to 3000 older stroke patients from Neurology wards in six large general hospitals, and 2907 individuals completed the survey. Data analysis consisted of correlation, multiple linear regression, and structural equation modeling. RESULTS: The total score of the SOC and perceived stress showed a negative correlation (r = -0.80, P ＜ 0.01), the total SOC of coherence and depression also resulted in a negative correlation (r = -0.77, P ＜ 0.01), and the total score of the perceived stress and depression resulted in a positive correlation (r = 0.82, P ＜ 0.01). The results of multiple regression analyses indicated that SOC mediated the association between perceived stress and depression, and the influence of perceived stress on depression was decreased by 16.0%with in the sense of being out of control dimension and was decreased by 12.3% within the feeling of tension dimension when sense of coherence was added to the model. The structural equation model confirmed that the sense of coherence had a partial mediation effect between perceived stress and depression. CONCLUSION: SOC is the mediating variable between perceived stress and depression, and can reduce the influence of perceived stress on depression.

Highly sensitive fluorogenic sensing of L-Cysteine in live cells using gelatin-stabilized gold nanoparticles decorated graphene nanosheets.

A highly sensitive and selective fluorogenic sensing of L-Cysteine (L-Cys) was implemented based on gelatin stabilized gold nanoparticles decorated reduced graphene oxide (rGO/Au) nanohybrid. The rGO/Au nanohybrid was prepared by the one-pot hydrothermal method and well characterized by different physiochemical techniques. The nanohybrid exhibits a weak fluorescence of rGO due to the energy transfer from the rGO to Au NPs. The rGO/Au nanohybrid shows enhanced fluorescence activity due to the restoration of quenched fluorescence of rGO/Au nanohybrid in presence of L-Cys. The rGO/Au nanohybrid exhibits much lower detection limit of 0.51 nM for L-Cys with higher selectivity. The fluorescence sensing mechanism arose from the fluorescence recovery due to the stronger interaction between Au NPs and L-Cys, and consequently, the energy transfer was prevented between rGO and Au NPs. The practicability of rGO/Au sensor was implemented by invitro bioimaging measurements in Colo-205 (colorectal adenocarcinoma) and MKN-45 (gastric carcinoma) cancer live cells with excellent biocompatibility.

Psychometric Assessment of the Depressive Cognition Scale Among Older Chinese People.

The study aimed to translate the Depressive Cognition Scale (DCS) into Chinese and to test its reliability and validity among Chinese older people. Using a cross-sectional design, a demographic questionnaire and Chinese versions of the Depressive Cognition Scale (DCS-CHI) and the Center for Epidemiological Studies-Depression Scale (CES-D) were administered. The sample consisted of 1673 older people who were from communities and hospitals. The Cronbach's alpha (α) of DCS-CHI was 0.91, and the test-retest correlation coefficient was 0.91 (95% CI, 0.86-0.95, p<0.001). The Content Validity Index (CVI) was found to be good. Exploratory factor analysis (EFA) resulted in a single factor that explained 58.46% of the total variance and all 8 items had strong factor loadings ranging from 0.62 to 0.83; confirmatory factory analysis (CFA) indicated all measurements of the structural model exceeded the recommended criteria, and the single factor solution of DCS-CHI had a good fit (χ2/df=2.45, GFI=0.99, AGFI=0.97, CFI=0.99, TLI=0.99, RMSEA=0.04, RMR=0.01, PCLOSE=0.79). The strong correlation of 0.81 (p<0.01) between the DCS-CHI and CES-D suggested good concurrent validity. Specifying the CES-D as the criterion, the area under the receiver operator characteristic (ROC) curve of the DCS-CHI for the optimal cut-point was 0.941(95%CI:0.919-0.963, p=0.000), the sensitivity and the specificity were 84.7% and 90.7% respectively, suggesting good predictive validity. The findings support the reliability and validity of the DCS-CHI as a measure of depressive cognitions that typically proceed more serious depressive symptoms among Chinese older adults.

Disrupting CCT-ß : ß-tubulin selectively kills CCT-ß overexpressed cancer cells through MAPKs activation.

We have previously demonstrated the ability of I-Trp to disrupt the protein-protein interaction of ß-tubulin with chaperonin-containing TCP-1ß (CCT-ß). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT-ß overexpression. In this study, we screened a panel of cancer cell lines, finding CCT-ß overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45. Thus, I-Trp killed these cancers with sub- to low-µM EC50, whereas it was non-toxic to MCF-10A. We then synthesized analogs of I-Trp and evaluated their cytotoxicity. Furthermore, apoptotic mechanism investigations revealed the activation of both protein ubiquitination/degradation and ER-associated protein degradation pathways. These pathways proceeded through activation of MAPKs at the onset of CCT-ß : ß-tubulin complex disruption. We thus establish an effective strategy to treat CCT-ß overexpressed cancers by disrupting the CCT-ß : ß-tubulin complex.

Synergistic inhibition of leukemia WEHI-3 cell growth by arsenic trioxide and Hedyotis diffusa Willd extract in vitro and in vivo.

Arsenic trioxide (ATO) is clinically used to treat acute promyelocytic leukemia (APL); however, the therapeutic dose of ATO may prompt critical cardiac side effects. Combination therapy may be used to improve the therapeutic efficiency. To evaluate this possibility, the present study determined the combined effects of Hedyotis diffusa Willd (HDW) extract and ATO in leukemic WEHI-3 cells. The results demonstrated that co-treatment of HDW with ATO resulted in a synergistic augmentation of cytotoxicity in cells at the concentration tested. In order to investigate the potential therapeutic application for leukemia, the combined effects of HDW and ATO were analyzed on the WEHI-3 cell-induced orthotopic leukemia animal model in vivo. The WEHI-3 cells in mice with leukemia were established by injecting murine WEHI-3 cells into BALB/c mice, and treating them with HDW and/or combined with ATO. The results indicated that HDW alone or HDW combined with ATO promoted the total survival rate of mice with leukemia, and these effects are dose-dependent. HDW alone or HDW combined with ATO did not affect the body weight, decreased the spleen weight and did not affect the liver weight. Furthermore, the results demonstrated that HDW alone or HDW combined with ATO resulted in a synergistic augmentation of apoptosis in WEHI-3 cells at the concentration tested. In order to further reveal the detailed mechanism of this synergistic effect on apoptosis, apoptosis-related proteins were also evaluated. The data revealed that HDW alone or HDW combined with ATO induced the expression of death receptor 4 (DR4) and DR5 and the activation of poly adenosine diphosphate ribose polymerase, caspase-3, -8 and -9. Furthermore, HDW alone or HDW combined with ATO decreased the expression levels of B-cell lymphoma 2, B-cell lymphoma-extra large and survivin, and increased the expression levels of Bak and t-Bid. Altogether, the results indicate that the combination of HDW with ATO may be a promising strategy used to increase the clinical efficacy of ATO in the treatment of APL.

Psychometric properties of the Chinese version of the Self-Efficacy for Appropriate Medication Use Scale in patients with stroke.

BACKGROUND: It has been reported that stroke has a higher incidence and mortality rate in the People's Republic of China compared to the global average. These conditions can be managed by proper medication use, but ensuring medication adherence is challenging. OBJECTIVE: To translate the Self-Efficacy for Appropriate Medication Use Scale into Chinese and test its validity and reliability in patients with stroke. METHODS: Instrument performances were measured from January 15, 2015 to April 28, 2015 on a convenience sample of 400 patients with stroke recruited at four neurology departments of the First Affiliated Hospital of Zhengzhou University. Questionnaires included the Chinese versions of the Self-Efficacy for Appropriate Medication Use Scale (C-SEAMS) and the General Self-Efficacy Scale (C-GSE). Construct validity, convergent validity, internal consistency, and test-retest reliability were measured. RESULTS: Item analysis showed that item-to-total correlations were in the range of 0.362-0.672. Exploratory factor analysis revealed two factors (which accounted for 60.862% of total variance), with factor loading ranging from 0.534 to 0.756. Confirmatory factor analysis was performed to support the results, with an acceptable fit (χ (2)=73.716; df=64; P<0.01; goodness-of-fit index =0.902; adjusted goodness-of-fit index =0.897; comparative fit index =0.865; root-mean-square error of approximation =0.058). The convergent validity of the C-SEAMS correlated well with the validated measure of the C-GSE in measuring self-efficacy (r=0.531, P<0.01). Good internal consistency (Cronbach's alpha ranged from 0.826 to 0.915) and test-retest reliability (Pearson's correlation coefficient r=0.642, P<0.01) were found. CONCLUSION: The C-SEAMS is a brief and psychometrically sound measure for evaluating self-efficacy for medication adherence in the Chinese population with stroke.

Evaluating ECG-aided tip localization of peripherally inserted central catheter in patients with cancer.

OBJECTIVE: To evaluate ECG-aided tip localization of peripherally inserted central catheter (PICC) in the patients with cancer. METHODS: Between September and December 2014, 170 patients undergoing PICC were divided into observation group and control group (each group with 85 patients). In observation group, patients received ECG-aided tip localization of PICC. In control group, PICC was performed with conventional method. After PICC was performed, all patients took orthophoria chest radiograph (OCR) to check whether the tip position of PICC was appropriate. Finally, successful rate of the first PICC was compared between the two groups. RESULTS: In observation group, OCR showed that the tip of PICC was located in middle and low one-third of superior vena cava in 85 patients. In control group, OCR showed that the tip of PICC was located between superior vena cava and right atrium in 75 patients. The successful rate of the first PICC was significantly higher in observation group than in control group (P < 0.05). CONCLUSION: ECG-aided tip localization of PICC is accurate and safe, and is worth clinically recommending.

Comparison of Pressure- and Volume-Controlled Ventilation in Laparoscopic Surgery: A Meta-analysis of Randomized Controlled Trial.

PURPOSE: Volume-controlled ventilation (VCV) has been the traditional mechanical ventilation mode in laparoscopic surgery. Pressure-controlled ventilation (PCV) has been used more frequently in recent years, especially for patients with complicated conditions; however, evidence on whether PCV is superior to VCV is still lacking. A meta-analysis was used to compare the effects of PCV and VCV on respiratory and hemodynamic parameters during laparoscopic surgery. METHODS: PubMed and Embase were each searched from their inception to December 2014 for randomized controlled trials comparing the effects of PCV and VCV on respiratory and hemodynamic parameters during laparoscopic surgery. Standard mean difference (SMD) with 95% confidence interval (CI) was calculated using a random effect model. Outcomes were assessed at three times: preoperative (T1), intraoperative (T2) and postoperative (T3). Respiratory mechanics (including peak airway pressure, plateau pressure, mean airway pressure, compliance, airway resistance, minute volume, end-tidal CO2 tension and tidal volume) and hemodynamic parameters (including heart rate and mean arterial pressure) were calculated. RESULTS: Eight randomized controlled trials with a total of 428 participants, 214 cases using PCV and 214 cases using VCV, were included in the meta-analysis. No significant differences were detected between the groups in terms of hemodynamic parameters. In contrast, with respiratory mechanics, PCV was slightly but significantly associated with lower peak airway pressure, higher compliance, lower airway resistance at T1, lower peak airway pressure, higher compliance, higher mean airway pressure at T2, lower peak airway pressure, lower mean airway pressure and higher end-tidal CO2 tension at T3. For the rest of respiratory parameters, there were no statistical differences between the groups. Subgroup analysis by morbidly obese, type of operations and quality of studies, showed similar results. CONCLUSIONS: Our meta-analysis suggests that hemodynamic parameters are similar in patients who underwent laparoscopic surgery with PCV and VCV, but patients who had PCV exhibited mildly better respiratory data.

Computed tomography image analysis before and after treatment of anti-neutrophil cytoplasmic antibody-associated pulmonary interstitial fibrosis in 8 patients.

PURPOSE: The purpose of this study was to observe the treatment response of anti-neutrophil cytoplasmic antibody (ANCA)-associated pulmonary interstitial fibrosis in 8 patients before and after glucocorticoid or immunosuppressive therapy. METHODS: The clinical features and computed tomography imaging findings of the 8 patients in our hospital from October 2011 to October 2013, were retrospectively analyzed. FINDINGS: Mean age of the 8 patients was 72.6 (range 60-80) years. Five patients exhibited cough, sputum, and chest tightness, including 2 patients with fever. One patient developed hemoptysis, 1 patient exhibited abnormal urinalysis and developed renal insufficiency, and 1 patient developed limb pain. Two patients exhibited high urine erythrocytes and 2 patients had renal dysfunction and urinary abnormalities. One of the latter patients, upon renal biopsy, had focal proliferative necrotizing glomerulonephritis (consistent with vasculitis damage) with stage II to III mild nephropathy. Seven cases were anti-myeloperoxidase-ANCA, and 1 case was anti-proteinase 3-ANCA. All 8 cases exhibited streaks and grid shadows in chest imaging; 2 cases exhibited limited ground-glass patches; 1 case displayed multiple large patches of exudative shadows, indicating diffuse alveolar hemorrhage; 2 cases exhibited obvious honeycomb manifestations; and 1 case exhibited significant traction bronchiectasis. The ground-glass opacities disappeared after corticosteroid or immunosuppressive therapy; however, for streaks and grid shadows, no significant changes in the images were observed after treatment from 2 weeks to 10 months. IMPLICATIONS: ANCA-associated pulmonary interstitial fibrosis most often in elderly patients with many complications. In these patients ground-glass opacities in computed tomography images, corticosteroid or immunosuppressant therapy may be effective. Clinicians should consider the poor efficacy and side effects of these therapies in the fibrosis stage of the disease.

CCT327 enhances TRAIL-induced apoptosis through the induction of death receptors and downregulation of cell survival proteins in TRAIL-resistant human leukemia cells.

Tumor necrosis factor-related apoptosis­inducing ligand (TRAIL) has potential application in cancer therapy and it has the ability to selectively kill cancer cells without affecting normal cells. However, the development of resistance to TRAIL in cancer cells cannot be avoided. This study investigated the effects of 2-(5-methylselenophen­2­yl)­6,7­methylenedioxyquinolin­4-one (CCT327), an analogue of quinolin-4-one, on the sensitization of cancer cells to TRAIL and on TRAIL­induced apoptosis in TRAIL­resistance human leukemia cells (HL60­TR). We found that CCT327 enhanced TRAIL­induced apoptosis through upregulation of death receptors DR4 and DR5. In addition to upregulating DRs (death receptors), CCT327 suppressed the expression of decoy receptor DcR1 and DcR2. CCT327 significantly downregulated the expression of FLICE inhibitory protein (cFLIP) and other antiapoptotic proteins. We also demonstrated that CCT327 could activate p38 and JNK. Moreover, CCT327-induced induction of DR5 and DR4 was mediated by reactive oxygen species (ROS), and N-acetylcysteine (NAC) blocked the induction of DRs by CCT327. Taken together, these results showed that CCT327 combined with TRAIL treatment may provide an effective therapeutic strategy for cancer.

Hypolipidemic activity of Taraxacum mongolicum associated with the activation of AMP-activated protein kinase in human HepG2 cells.

This study investigated the hypolipidemic effect and potential mechanisms of T. mongolicum extracts. T. mongolicum was extracted by refluxing three times with water (TM-1), 50% ethanol (TM-2) and 95% ethanol (TM-3). TM-2 contained components with the most effective hypolipidemic potentials in HepG2 cells. Extended administration of TM-2 stimulated a significant reduction in body weight and levels of serum triglyceride LDL-C and total cholesterol in rats. To evaluate the bioactive compounds, we successively fractionated TM-2 with n-hexane (TM-4), dichloromethane (TM-5), ethyl acetate (TM-6), and water (TM-7). TM-4 fraction had the most effective hypolipidemic potential in HepG2 cells, and it decreased the expression of fatty acid synthase (FASN) and inhibited the activity of acetyl-coenzyme A carboxylase (ACC) through the phosphorylation of AMP-activated protein kinase (AMPK). Linoleic acid, phytol and tetracosanol are bioactive compounds identified from TM-4. These results suggest that T. mongolicum is expected to be useful for hypolipidemic effects.