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Subcellular localization of beta-arrestin1 and its prognostic value in lung adenocarcinoma
Li, XW;Che, KY;Wang, LG;Zhang, TH;Wang, GH;Pang, ZF;Shen, HC;Du, JJ
MEDICINE 2017年 96卷45期
NUCLEAR EXPORT SIGNAL; BETA-ARRESTINS; HIGH EXPRESSION; BREAST-CANCER; UNFAVORABLE PROGNOSIS; PROSTATE-CANCER; POOR-PROGNOSIS; P300; GROWTH; PROGRESSION
-Arrestins play important roles in cancer progression, and the subcellular localization of -arrestin1 has been receiving increasingly more attention. Intriguingly, several studies, including some of our previous work, showed that the effects of -arrestin1 on outcomes of cancer patients were controversial.Specimens were obtained from 133 patients with lung adenocarcinoma. Immunohistochemistry was used to detect the expression of -arrestin1 and p300 in the collected tissues. The Kaplan-Meier analysis and Cox proportional hazards regression were used to examine the relationship between -arrestin1 and patient survival.We found no significant association between -arrestin1 and clinicopathological variables. The Kaplan-Meier plot showed that patients with high expression of -arrestin1 (especially in the nucleus) had a poorer overall survival (OS) and shorter disease-free survival (DFS) (P=.026, P=.015). Additionally, high p300 expression also resulted in worse OS (P=.039). Following the univariate analysis, high expressions of nuclear -arrestin1 and p300 were classed as poor prognostic factors for both OS (P=.016) and DFS (P=.025).The expression of -arrestin1 in the nucleus is associated with increased malignant tendency of lung adenocarcinoma, and the predictive value of -arrestin1 may be optimized by combining information about the expression of p300 acetyltransferase.
Weekly versus biweekly bortezomib given in patients with indolent non-Hodgkin lymphoma: A meta-analysis
Yuan, T;Zhang, F;Yao, QM;Liu, YX;Zhu, XJ;Wang, X
PLOS ONE 2017年 12卷5期 影响因子:3.057
REFRACTORY FOLLICULAR LYMPHOMA; MANTLE CELL LYMPHOMA; PROTEASOME INHIBITOR BORTEZOMIB; NATIONAL-CANCER-INSTITUTE; CLINICAL-TRIALS GROUP; PHASE-II; RITUXIMAB; CYCLOPHOSPHAMIDE; DOXORUBICIN; PREDNISONE
Background;-;Bortezomib is recently studied as a novel agent in indolent lymphoma. The optimal schedule of bortezomib used in indolent lymphoma is still uncertain.;-;Methods;-;We did a systematic review and meta-analysis of the clinical trials comparing the efficacy and toxicity of the weekly and biweekly schedules of bortezomib in patients with indolent lymphoma. We searched Pubmed, Cochrane Library and Emabase from inception to July 29, 2016. The primary outcome was the overall response rate including the complete response rate and the partial response rate. The secondary outcomes were the proportions of patients in each group experiencing the adverse events including the neutropathy, fatigue, diarrhea, nausea and neutropenia.;-;Findings;-;After final screening, six trials were considered eligible for analysis. The results showed that the overall response rate of biweekly schedule was higher than that of weekly schedule in indolent lymphoma (OR 1.691; 95% CI 1.02-2.80). Furthermore, there were no significant differences between the two schedules of bortezomib for the main adverse events.;-;Interpretation;-;The biweekly schedule of bortezomib was more effective than the weekly schedule in indolent lymphoma, with similar proportion of toxicities.
Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy
Qu, X;Wu, ZA;Dong, W;Zhang, TH;Wang, LG;Pang, ZF;Ma, W;Du, JJ
ONCOTARGET 2017年 8卷17期 页码:29501-29518 影响因子:5.008
METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; GROWTH-FACTOR RECEPTOR; PLACEBO-CONTROLLED PHASE-2; FACTOR-I RECEPTOR; OPEN-LABEL; MONOCLONAL-ANTIBODIES; PANCREATIC-CANCER; DOUBLE-BLIND; III TRIAL
Background: Prognostic studies of insulin-like growth factor-1 receptor( IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R signalling was crucial in cancer cells growth. However, the conclusion of later clinical trials revealed a dim future for IGF-1R inhibitors to treat cancer. We conducted this analysis to figure out how IGF-1R inhibitors acted in clinical cancer therapy. Material and Methods: We searched up-to-date studies about the single agent of IGF-1R inhibitors or combination with other therapies in solid tumor. Five IGF-1R anti-agents were involved. The primary endpoint was progression- free survival (PFS). The secondary endpoint was overall survival (OS). Result: 17studies were enrolled. The results was not significant in overall survival (I-2= 37.1%, P= 0.080, HR=1.08, 95% CI= 0.97-1.21) and in progression- free survival (I-2= 0.0%, P= 0.637, HR= 1.05, 95% CI= 0.98-1.12). OS for dalotuzumab, breast cancer, colorectal cancer, and PFS for prostate cancer even indicated harmful effects. Conclusion: So far, anti-IGF-1R mono-antibodies did not make significant differences in solid tumor prognosis. On the contrary, pessimistic effects were shown in the dalotuzumab, breast cancer, colorectal cancer and prostate cancer subgroups. Further studies of IGF-1R anti-agents were needed, but unwarranted in unselected patients by predictive biomarkers.
ARRB1 enhances the chemosensitivity of lung cancer through the mediation of DNA damage response
Shen, HC;Wang, LG;Zhang, JG;Dong, W;Zhang, TH;Ni, Y;Cao, HX;Wang, K;Li, Y;Wang, YB;Du, JJ
ONCOLOGY REPORTS 2017年 37卷2期 页码:761-767
FLOW-CYTOMETRY; BETA-ARRESTINS; CELL; CARCINOMA; APOPTOSIS; BETA-ARRESTIN-1; EXPRESSION; PROGNOSIS; THERAPY; ASSAY
ARRB1 (also known as beta-arresting) serves as a multifunctional adaptor contributing to the regulation of signaling pathways. ARRB1 may be involved in DNA damage accumulation; however the underlying mechanism involved is unclear. In the present study, non-small cell lung cancer (NSCLC) cell lines (H520 and SK-MES-1) were transfected with ARRB1 plasmids or small interfering ribonucleic acid (siRNA) and received treatment with DNA-damaging agents (cisplatin and etoposide). A mouse xenograft model was used to assess the impact of ARRB1 on the efficacy of cisplatin in vivo. A total of 30 surgically resected NSCLC patients were recruited for the present study and qRT-PCR was performed to determine the mRNA levels in cancer tissues compared with para-carcinoma tissues. Our data showed that DNA damage was abrogated in the ARRB1-knockdown cells and enhanced in the ARRB1-overexpressing cells. ATR and Chk1 were more activated in the ARRB1-overexpressing cells compared to the ARRB1-knockdown cells, followed by increased H2AX phosphorylation. DNA damage and apoptosis were increased in the ARRB1-overexpressing cells treated with cisplatin. These data provided strong evidence that ARRB1 contributes to the response of NSCLC to DNA-damaging agents and is essential for DNA damage response (DDR). ARRB1 may enhance the efficacy of DNA-damaging agents in NSCLC.
Role of quality control circle in sustained improvement of hand hygiene compliance: an observational study in a stomatology hospital in Shandong, China
Chen, P;Yuan, T;Sun, QF;Jiang, LL;Jiang, HM;Zhu, ZK;Tao, ZX;Wang, HY;Xu, AQ
ANTIMICROBIAL RESISTANCE AND INFECTION CONTROL 2016年 5卷
HEALTH-CARE WORKERS; PERCEPTIONS; GUIDELINES
Background: Hand hygiene is an important element of the WHO multimodal strategy for healthcare-associated infection control, whereas compliance of hand hygiene among healthcare workers (HCWs) remains a challenge to sustain. In order to increase the hand hygiene compliance of HCWs, a quality control circle (QCC) program was carried out in our hospital, and the plan-do-check-act (PDCA) method was applied for 12 months.;-;Findings: Hand hygiene compliance rates improved over time, with significant improvement between preintervention (60.1%) and postintervention (97.2%) periods (P < 0.001). Nurses (88.3%) exhibited higher compliance than dentists (87.3%), and female (88.4%) HCWs were more likely to perform hand hygiene than males (85.6%), both P < 0.001. Overall hand hygiene compliance and observance of the five indications exhibited significant linear increases over time (P < 0.005).;-;Conclusion: This study highlights the success of a multifaceted intervention, conducted by QCC program and PDCA method, which led to a significant improvement of hand hygiene compliance. Though training is the most basic intervention element, surveillance, evaluation and feedback should be explored as additional interventions to ensure that hand hygiene compliance is achieved and sustained at high levels.
Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations
Wang, YH;Singh, R;Wang, LG;Nilsson, M;Goonatilake, R;Tong, P;Li, LR;Giri, U;Villalobos, P;Mino, B;Rodriguez-Canales, J;Wistuba, I;Wang, J;Heymach, JV;Johnson, FM
ONCOTARGET 2016年 7卷30期 页码:47998-48010 影响因子:5.008
EPITHELIAL-MESENCHYMAL TRANSITION; STRAND BREAK REPAIR; TYROSINE KINASE; EGFR-TKI; ERLOTINIB-RESISTANCE; PI3K INHIBITORS; DRUG TARGETS; DNA-DAMAGE; PHASE-I; ADENOCARCINOMA
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial-mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.
The Effect of Diabetes Mellitus on Lung Cancer Prognosis A PRISMA-compliant Meta-analysis of Cohort Studies
Zhu, LH;Cao, HX;Zhang, TH;Shen, HC;Dong, W;Wang, LG;Du, JJ
MEDICINE 2016年 95卷17期
METAANALYSIS; SURVIVAL; INHIBITION; RISK; MORTALITY; IGF-1R; IMPACT; GROWTH; STRATEGIES; THERAPY
Previous studies suggested that diabetes mellitus (DM) was associated with risk and mortality of cancer, but studies investigating the correlation between DM and lung cancer prognosis remain controversial. Herein, a meta-analysis was performed to derive a more precise estimate of the prognostic role of DM in lung cancer.;-;Medline and Embase were searched for eligible articles from inception to October 25, 2015. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) was calculated to evaluate the correlation between DM and lung cancer prognosis. Subgroup meta-analysis was performed based on the histology and the treatment methods.;-;A total of 20 cohort studies from 12 articles were included in the meta-analysis. Also, 16 studies investigated the overall survival (OS) and 4 studies investigated the progression-free survival (PFS). DM was significantly associated with the inferior OS of lung cancer with the pooled HR 1.28 (95% CI: 1.10-1.49, P = 0.001). The association was prominent in the nonsmall cell lung cancer (NSCLC) subgroup (HR 1.35, 95% CI: 1.14-1.60, P = 0.002), whereas the association was not significant in the small cell lung cancer (SCLC) subgroup (HR 1.33, 95% CI: 0.87-2.03, P = 0.18). When NSCLC patients were further stratified by treatment methods, DM had more influence on the surgically treated subgroup than the nonsurgically treated subgroup. There was no obvious evidence for publication bias by Begg's and Egger's test.;-;The results of this meta-analysis exhibit an association of DM with inferior prognosis amongst lung cancer patients, especially the surgically treated NSCLC patients. Given the small number of studies included in this meta-analysis, the present conclusion should be consolidated with more high-quality prospective cohort studies or randomized controlled trials.
Epithelial-Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor-Mediated Apoptosis in Non-Small Cell Lung Cancer
Ferrarotto, R;Goonatilake, R;Yoo, SY;Tong, P;Giri, U;Peng, SH;Minna, J;Girard, L;Wang, YH;Wang, LG;Li, LR;Diao, LX;Peng, DH;Gibbons, DL;Glisson, BS;Heymach, JV;Wang, J;Byers, LA;Johnson, FM
CLINICAL CANCER RESEARCH 2016年 22卷7期 页码:1674-1686
ADVANCED SOLID TUMORS; VOLASERTIB BI 6727; BREAST-CANCER; PHASE-I; CHROMOSOMAL INSTABILITY; THERAPEUTIC TARGET; PANCREATIC-CANCER; DRUG-SENSITIVITY; DOSE-ESCALATION; STEM-CELLS
Purpose: To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development.;-;Experimental Design: To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines.;-;Results: The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all three inhibitors. PLK1 inhibition led to G(2)-M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial-mesenchymal transition (EMT) gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than epithelial lines (P < 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (P < 0.01). Induction of an epithelial phenotype by expression of the miRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, KRAS mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC.;-;Conclusions: In this first reported large-scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that EMT leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies. (C) 2015 AACR.
Loss of beta-arrestin1 expression predicts unfavorable prognosis for non-small cell lung cancer patients
Ma, HH;Wang, LG;Zhang, TH;Shen, HC;Du, JJ
TUMOR BIOLOGY 2016年 37卷1期 页码:1341-1347
PROTEASE-ACTIVATED RECEPTOR-2; BETA-ARRESTIN; MAPK ACTIVATION; DOWN-REGULATION; EMERGING ROLES; PROLIFERATION; CENTROSOME; TRAFFICKING; PROGRESSION; CHEMOTAXIS
We aimed to study the expression status of beta-arrestin1 in non-small cell lung cancer (NSCLC) specimens and its clinicopathologic significance. The correlation between beta-arrestin1 and the tumor migration biomarker E-cadherin, as well as smoking index were studied. A total of 152 patients with NSCLC who undergone surgery were enrolled. Altogether, 88 lung squamous cell lung cancer (SCC) specimens and 64 adenocarcinoma (ADC) specimens were tested for immunohistochemistry. Patients' survival was analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine independent prognostic factors. Spearman rank correlation test was used to show data associations. For SCC patients, the expression of beta-arrestin1 was either lost (56 of 88, 63.6 %) or low (32 of 88, 36.4 %), which was significantly and negatively associated with E-cadherin expression (P = 0.017). The similar correlation existed between smoking index and beta-arrestin1 expression (P = 0.044). For ADC patients, the deletion of beta-arrestin1 expression was rare (4 of 64, 6.3 %). Loss of beta-arrestin1 expression indicated poorer survival for both SCC (P = 0.026) and ADC patients (P = 0.006). beta-arrestin1 expression was detected in the other ADC specimens but showed no significant correlation with survival. In SCC patients, the loss expression of beta-arrestin1 was frequently observed, and beta-arrestin1 expression was significantly correlated with the smoking index and E-cadherin expression, which all indicated beta-arrestin1's significant clinicopathologic role. However, beta-arrestin1 was expressed in most ADC patients, but its clinicopathologic role seemed to be obscure and might need further exploration.
Angiotensin-(1-7) enhances the effects of angiotensin II on the cardiac sympathetic afferent reflex and sympathetic activity in rostral ventrolateral medulla in renovascular hypertensive rats
Li, P;Zhang, F;Sun, HJ;Zhang, F;Han, Y
JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION 2015年 9卷11期 页码:865-877
PARAVENTRICULAR NUCLEUS MEDIATE; CHRONIC KIDNEY-DISEASE; BLOOD-PRESSURE; OXIDATIVE STRESS; NERVOUS-SYSTEM; HEART-FAILURE; ACTIVATION; SYMPATHOEXCITATION; RECEPTORS; PATHOGENESIS
Excessive sympathetic activity propels the pathogenesis and progression of organ damage in hypertension. Enhanced cardiac sympathetic afferent reflex (CSAR) is involved in sympathetic activation in hypertension. Given the important role of the renin-angiotensin (Ang) system in regulating sympathetic outflow and cardiovascular activity, the present study aimed to investigate the roles of Ang-(1-7) in Ang II-induced CSAR and the sympathetic activation responses in the rostral ventrolateral medulla (RVLM) of hypertensive rats. The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension. Responses of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to epicardial application of capsaicin were used to evaluate the CSAR in sinoaortic-denervated and cervical-vagotomized rats with anesthesia. Both Ang II and Ang(1-7) in the RVLM caused greater increases in RSNA and MAP in 2K1C rats than in sham-operated (sham) rats and enhanced CSAR independently. RVLM pretreatment with Ang-(1-7) dose dependently augmented the effects of Ang 11011 RSNA, MAP, and CSAR in 2K1C rats. Mas receptor antagonist A-779 in the RVLM exhibited more powerful inhibitory effects on RSNA, MAP, and CSAR than the Ang II type 1 (AT(1)) receptor antagonist losartan. The expression of both the AT(1) receptor and Mas receptor proteins in the RVLM increased, but neither the Ang II nor Ang-(1-7) levels in the RVLM changed significantly in the 2K1C rats compared with the sham rats. These results indicate that Ang-(1-7) in the RVLM enhances the CSAR and sympathetic output not only by itself but also through enhancing the effects of Ang II in renovascular hypertensive rats. Both endogenous Ang-(1-7) and Ang 11 in the RVLM contribute to the enhanced CSAR and sympathetic activation in renovascular hypertension. (C) 2015 American Society of Hypertension. All rights reserved.
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