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Background: Extensive-disease small-cell lung cancer (ED-SCLC) is characterized by rapid progression and relapse, despite high initial response rates to chemotherapy. The primary objective of this trial was to demonstrate the non-inferiority of amrubicin and cisplatin (AP) combination therapy compared with the standard first-line regimen of etoposide and cisplatin (EP) for previously untreated ED-SCLC in a Chinese population. When non-inferiority was verified, the objective was switched from non-inferiority to superiority.Methods: From June 2008 to July 2010, 300 patients were enrolled and randomly assigned at a 1:1 ratio to AP and EP groups. AP-treated patients received cisplatin (60 mg/m(2), day 1) and amrubicin (40 mg/m(2), days 1-3) once every 21 days. EP-treated patients received cisplatin (80 mg/m(2), day 1) and etoposide (100 mg/m(2), days 1-3) once every 21 days. Treatment was continued for four to six cycles, except in cases of progressive disease or toxicity, and patient refusal.Results: Median overall survival (OS) for AP vs. EP treatment was 11.8 vs. 10.3 months (p = 0.08), respectively, demonstrating non-inferiority of AP to EP (AP group: 95% confidence interval for hazard ratio 0.63-1.03 months). Median progression-free survival and overall response rates for AP vs. EP groups were 6.8 vs. 5.7 months (p = 0.35) and 69.8% vs. 57.3%, respectively. Drug-related adverse events in both groups were similar, with neutropenia being the most frequent (AP 54.4%; EP 44.0%). Leukopenia, pyrexia, and fatigue were more prevalent in the AP group, but all were clinically reversible and manageable.Conclusions: AP therapy demonstrated non-inferiority to EP therapy, prolonging OS for 1.5 months, but this difference was not statistically significant; thus we propose AP as a promising treatment option for ED-SCLC in China.Trial Registration: This trial was registered on 10 April 2008 (ClinicalTrials.gov NCT00660504). [ABSTRACT FROM AUTHOR]

Purpose: The benefit of docetaxel-based therapy in the second-line treatment of advanced non-small cell lung cancer (NSCLC) is still unclear. The goal of this meta-analysis was to assess the efficacy and toxicity of docetaxel-based doublet compared with docetaxel alone for patients with advanced NSCLC who failed to improve with first-line treatment. Methods: Several databases were searched, including PubMed, Embase, and the Cochrane databases. The end points were overall survival, progression-free survival (PFS), objective response rate, disease control rate, and grade 3 or 4 adverse events. Data were extracted from the studies by 2 independent reviewers. The meta-analysis was performed by using Review Manager version 5.2. The pooled hazard ratio (HR) or odds ratio (OR) and 95% CIs were calculated by using fixed or random effects models depending on the heterogeneity of the included trials. Findings: Twelve eligible trials involving 2680 patients were identified. The intention-to-treatment analysis found that docetaxel-based therapy significantly improved overall survival (HR, 0.89 [95% CI, 0.83-0.96]; P < 0.01), PFS (HR, 0.79 [95%CI, 0.71-0.89]; Po0.01), objective response rate (OR, 1.73 [95% CI, 1.37-2.18; P < 0.01), and disease control rate (OR, 1.30 [95% CI, 1.09-1.55]; P < 0.01). In addition, a subgroup analysis based on type of combined drug showed that there were significant improvement in PFS and overall survival in combining docetaxel with targeted therapy. In addition, a higher incidence of grade 3 or 4 diarrhea and thrombocytopenia was observed in docetaxel-based doublet therapy. Implications: Based on the available evidence, docetaxel-based doublet therapy seems superior to docetaxel monotherapy as a second-line treatment for advanced NSCLC. More studies should focus on combining docetaxel with targeted therapy to identify patients who will most likely benefit from the appropriate combination targeted therapy. [ABSTRACT FROM AUTHOR]

Crocin is a carotenoid of the saffron extract that exhibits antitumor activity against many human tumors. However, the effects of crocin on HL-60 cells in vivo have not been evaluated. This study aimed to examine the effects of crocin on HL-60 cells in vitro and in vivo and investigate the underlying mechanisms. HL-60 cells were treated by crocin, and cell proliferation, apoptosis, and cell cycle profiles were examined by MTT assay, AO/EB staining, and flow cytometry, respectively. Furthermore, HL-60 cells were xenografted into nude mice and treated by crocin, the tumor weight and size were calculated, and the expression of Bcl-2 and Bax in xenografts was detected by immunohistochemical staining. The results showed that crocin (0.625-5 mg/mL) inhibited HL-60 cell proliferation and induced apoptosis and cell cycle arrest at G0/G1 phase, in a concentration and time-dependent manner. In addition, crocin (6.25,25 mg/kg) inhibited the tumor weight and size of HL-60 xenografts in nude mice, inhibited Bcl-2 expression, and increased Bax expression in xenografts. In summary, crocin inhibits the proliferation and tumorigenicity of HL-60 cells, which may be mediated by the induction of apoptosis and cell cycle arrest and the regulation of Bcl-2 and Bax expression. [ABSTRACT FROM AUTHOR]

Abstract: We design and develop chitosan nanoparticles which load two different drugs simultaneously. Aspirin (acetylsalicylic acid, ASA), a hydrophilic drug and probucol (PRO), a hydrophobic drug, are chosen as typical drugs, which are widely used to treat restenosis. The drug loaded chitosan nanoparticles are prepared by gelation of chitosan with tripolyphosphate (TPP) by ionic cross-linking. The physicochemical properties of nanoparticles are investigated by FTIR, transmission electron microscope (TEM), scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The images show that these particles are spherical in shape with ASA being in the amorphous phase, while PRO is crystalline. The properties of chitosan nanoparticles such as encapsulation capacity and controlled release behaviors of ASA and PRO are evaluated. Experimental results indicate that the loading capacity (LC), encapsulation efficiency (EE) and ASA and PRO release behaviors are affected by several factors including pH, concentration of TPP, chitosan molecular weight (MW) and ASA initial concentration as well as PRO. In vitro release shows that the nanoparticles provide a continuous release. Entrapped ASA is released for more than 24h and PRO lasts longer for 120h. [Copyright &y& Elsevier]

Hepatic fibrosis is a reversible pathological process, in which fibrotic tissue is excessively deposited in the liver during the repair process that follows hepatic injury. Early prevention or treatment of hepatic fibrosis has great significance on the treatment of chronic hepatic diseases. Hydroxysafflor yellow A (HSYA) is a water-soluble monomer extracted from safflower, which serves numerous pharmacological roles. However, it remains to be elucidated how HSYA regulates hepatic fibrogenesis. The aim of the present study was to reveal the possible mechanisms underlying the effects of HSYA on the prevention and treatment of hepatic fibrosis. A rat model of hepatic fibrosis was established in the present study, and the rats were administered various doses of HSYA. The effects of HSYA on pathological alterations of the liver tissue in rats with hepatic fibrosis were observed using hematoxylin-eosin staining and Masson staining. In order to explore the anti-hepatic fibrosis effects and underlying mechanisms of HSYA, serum levels, and hepatic function and hepatic fibrosis indices were evaluated. The results demonstrated that HSYA can improve the general condition of rats with hepatic fibrosis and relieve cellular swelling of the liver, fatty degeneration, necrosis, inflammatory cell infiltration and fibroplastic proliferation. Subsequent to administration of HSYA, globulin was increased during hepatic fibrosis caused by tetrachloromethane. However, total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase and levels of hyaluronic acid, laminin, procollagen III N-terminal peptide, collagen type IV and hydroxyproline were significantly reduced. The results additionally demonstrated that HSYA could enhance superoxide dismutase activity and reduce malondialdehyde levels, inhibiting lipid peroxidation caused by free radicals. [ABSTRACT FROM AUTHOR]

Background: HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment.Methods: Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines.Results: Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and CHOP-dependent apoptosis as well as a partial activation of the ER stress response network via XBP1 and ATF6. This response appears to be a general feature of HER2/neu-positive breast cancer cells but not cells that overexpress only HER2/neu. Exogenous palmitate reduces HER2 and HER3 protein levels without changes in phosphorylation and sensitizes HER2/neu-positive breast cancer cells to treatment with the HER2-targeted therapy trastuzumab.Conclusions: Several studies have shown that HER2, FASN and fatty acid synthesis are functionally linked. Exogenous palmitate exerts its toxic effects in part through inducing ER stress, reducing HER2 expression and thereby sensitizing cells to trastuzumab. These data provide further evidence that HER2 signaling and fatty acid metabolism are highly integrated processes that may be important for disease development and progression. [ABSTRACT FROM AUTHOR]

Background: Radiation therapy is the method of choice for subjects with inoperable salivary gland malignancies. I-125 brachytherapy, delivering a high radiation dose to a tumor but sparing surrounding normal tissues, is supposed to be ideal modality for the treatment of salivary gland malignancies. We designed a randomised controlled clinical trial to compare the efficacy of I-125 permanent brachytherapy (PBT) versus intensity-modulated radiation therapy (IMRT) for inoperable salivary gland malignancies.Methods/design: In this study, inclusion criteria are subjects with inoperable salivary gland malignancies, aged 18-80 years, have provided informed consent, with at least one measurable tumor focus, be able to survive ≥3 months, Karnofsky performance status ≥60, have adequate hematopoietic function of bone marrow, have normal liver and kidney function, and are willing to prevent pregnancy. Exclusion criteria include a history of radiation or chemotherapy, a history of other malignant tumors in the past 5 years, receiving other effective treatments, participating in other clinical trials, with circulatory metastasis, cognitive impairment, severe cardiovascular and cerebrovascular diseases, acute infection, uncontrolled systemic disease, history of interstitial lungdisease, and being pregnant or breast feeding. The study will be conducted as a clinical, prospective, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 90 subjects. Subjects with inoperable salivary gland malignancies are randomised to receive either I-125 PBT or IMRT, with stratification by tumor size and neck lymph node metastasis. Participants in both groups will be followed up at 2, 4, 6, 9, 12, 15, 18, 21 and 24 months after randomization. The primary outcome is local control rate of the primary site (based on imaging findings and clinical examination, RECIST criteria) in 1 year. Secondary outcomes are progression-free survival, overall survival, quality of life (QOL) measured with the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30 and QLQ-H&N35) of Chinese version, and safety of treatment. Chi-squared test is used to compare the local control rates in both groups. The survival curves are estimated by the Kaplan-Meier method, and log-rank test is used to test the significant difference.Discussion: Only few observational studies have investigated the effect of I-125 PBT on inoperable salivary gland malignancies. To our knowledge, this is the first randomised controlled trial to investigate the efficacy of I-125 PBT for subjects with inoperable salivary gland malignancies, and will add to the knowledge base for the treatment of these subjects.Trial Registration: The study is registered to Clinical Trials.gov ( NCT02048254 ) on Jan 29, 2014. [ABSTRACT FROM AUTHOR]

Background/Aims: This study determined the role and mechanism of action of transcription factor EB (TFEB) in H2O2-induced neuronal apoptosis. Methods: SH-SY5Y cells were treated with Akt inhibitor/activator and different concentrations of H2O2. Cell apoptosis was detected by flow cytometric analysis. Akt and TFEB phosphorylation and PARP cleavage were determined by Western blotting. HEK293T cells were transfected with different truncated TFEB mutants and HA-Akt-WT; SH-SY5Y cells were transfected with Flag-vector, Flag-TFEB, Flag-TFEB-S467A or Flag-TFEB-S467D; and TFEB interaction with Akt was determined by co-immunoprecipitation and GST pull-down assays. Results: A low concentration of H2O2 induces TFEB phosphorylation at Ser467 and nuclear translocation, facilitating neuronal survival, whereas a high concentration of H2O2 promotes SH-SY5Y cell apoptosis via suppressing TFEB Ser467 phosphorylation and nuclear translocation. The TFEB-S467D mutant is more easily translocated into the nucleus than the non-phosphorylated TFEB-S467A mutant. Further, Akt physically binds to TFEB via its C-terminal tail interaction with the HLH domain of TFEB and phosphorylates TFEB at Ser467. Mutation of TFEB-Ser467 can prevent the phosphorylation of TFEB by Akt, preventing inhibition of oxidative stress-induced apoptosis. Conclusions: Oxidative stress induces neuronal apoptosis through suppressing TFEB phosphorylation at Ser467 by Akt, providing a novel therapeutic strategy for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Importance: Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects.Objective: To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet.Design, Setting, and Participants: A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015.Interventions: Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily.Main Outcomes and Measures: The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting.Results: The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5% (95% CI, -17.5% to -3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%).Conclusions and Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety.Trial Registration: clinicaltrials.gov Identifier: NCT1896232. [ABSTRACT FROM AUTHOR]

Objective: To investigate the functional mechanism of microRNA-182 (miR-182) in head and neck squamous cell carcinoma (HNSCC). Design: HNSCC and normal samples were used to check both p53 and miR-182 expression. Two cancer cell lines with overexpression of miR-182 were used to check cell proliferation and migration. In vivo role of miR-182 was assessed using mouse xenograft tumor model. b-TrCP2 was found to be direct target of miR-182 by luciferase reporter assay. Results: Overexpression of miR-182 was closely related with overproduction of p53 in HNSCC. Overexpression of miR-182 promoted cell proliferation and migration and its oncogenic effect was also confirmed in vivo. b-TrCP2 acted as direct target of miR-182 and its overexpression can reverse the miR-182 induced cell proliferation and migration. Conclusion: Overexpression of TP53 mutation-associated miR-182 may promote tumor cell proliferation and migration in HNSCC and suggest possible biomarker for the prediction of tumor recurrence. [ABSTRACT FROM AUTHOR]

Background: To observe the impact of application of bio-amniotic membrane immersed in 5-fluorouracil solution in trabeculectomy on the retina in a rabbit model. Materials and Methods: Healthy white New Zealand rabbits were randomly assigned into three groups with 20 in each group. Bio-amniotic membranes of 4 × 5 mm immersed in either physiological saline/water for 10 min, or 25 mg/mL 5-fluorouracil solution for 5 and 10 min, respectively, were applied on rabbit eyes during trabeculectomy. At 7, 14, 21, and 28 days of postoperation, five rabbits from each group were examined with electroretinogram (ERG). After being examined for eye pressure and bleb morphology, rabbits were sacrificed by air embolism and their retinas were collected and examined by transmission electron microscopy (TEM). In addition, 5-fluorouracil amount in bio-amniotic membranes was measured using high-performance liquid chromatography. Results: Each bio-amniotic membrane could absorb 59.004 μg and 75.828 μg 5-fluorouracil after being immersed in 5-fluorouracil solution for 5 and 10 min, respectively. Application of these bio-amniotic membranes in trabeculectomy could promote the formation of well-functioning bleb and maintain intraocular pressure, although it had no effect on retina structures as examined with ERG and TEM. Conclusion: Application of 5-FU soaked bio-amniotic membrane in rabbit eye trabeculectomy is effective and safe. [ABSTRACT FROM AUTHOR]