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Fu M.,Linyi Peoples Hospital | Wan F.,Linyi Tumor Hospital | Li Z.,Tengzhou Central Peoples Hospital | Zhang F.,Linyi Peoples Hospital
Biochemical and Biophysical Research Communications | Year: 2016

The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation-inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells. © 2016 Elsevier Inc. All rights reserved. Source


Wan J.,Fudan University | Gai Y.,Tengzhou Central Peoples Hospital | Li G.,Fudan University | Tao Z.,Fudan University | Zhang Z.,Fudan University
Clinical Colorectal Cancer | Year: 2015

Background The incidence rates of colorectal cancer (CRC) in young individuals are increasing. There has been a significant improvement in overall survival in CRC because of advances in adjuvant chemotherapy and chemoradiotherapy over the past decades. However, these procedures may compromise the function of the reproductive system, and ovarian failure and premature menopause may occur. The objective of this analysis was to determine the incidence of long-term amenorrhea (≥ 12 months) in women with CRC aged 40 years and younger after adjuvant treatment. Patients and Methods The authors identified 162 premenopausal women with CRC aged 40 years or younger who were treated with adjuvant chemotherapy and chemoradiotherapy at Fudan University Shanghai Cancer Center from January 2008 to December 2012. One hundred twenty-three patients met all eligibility criteria and had sufficient follow-up for evaluation. The median age at diagnosis in patients with colon and rectal cancers was, respectively, 36 and 35 years (range, 17-40 and 24-40 years). Results All patients had regular menses before treatment; 3 patients with colon cancer (4.2%) experienced long-term amenorrhea, and 48 patients with rectal cancer (94.1%) experienced long-term amenorrhea. The incidence of amenorrhea was significantly lower in patients with colon cancer (4.2%; 3 of 72) than in patients with rectal cancer (94.1%; 48 of 51) (P <.01). Conclusion In this retrospective series, the incidence of amenorrhea in patients with colon and rectal cancers was 4.2% and 94.1%, respectively. We believe our data support the fact that young female patients with CRC, especially those with rectal cancer who are scheduled to undergo pelvic irradiation, should be counseled regarding fertility preservation options, including ovarian transposition and cryopreservation of ovarian tissue, embryo, or oocyte. © 2015 Elsevier Inc. Source


Lv Y.-L.,Southern Medical University | Yuan D.-M.,Nanjing University | Wang K.,Guangxi Medical University | Miao X.-H.,Nanjing University | And 4 more authors.
Journal of Thoracic Oncology | Year: 2011

Accurate clinical staging of mediastinal lymph nodes (MLNs) of patients with non-small cell lung cancer (NSCLC) is important in determining therapeutic options and prognoses. Integrated positron emission tomography and computed tomography (PET/CT) scanning is becoming widely used for MLN staging in patients with NSCLC. We performed a bivariate meta-analysis to determine the pooled sensitivity (SEN) and specificity (SPE) of this imaging modality. Methods: The PubMed/MEDLINE, Embase, and SpringerLink databases were searched for articles related to PET/CT for MLN staging in patients with NSCLC. SEN and SPE were calculated for every study. Hierarchical summary receiver operating characteristic curves were used to summarize overall test performance and assess study quality. Potential between-study heterogeneity was explored by subgroup analyses. Results: Fourteen of 330 initially identified reports were included in the meta-analysis. When we did not consider the unit of analysis, the pooled weighted SEN and SPE were 0.73 (95% confidence interval [CI]: 0.65-0.79) and 0.92 (95% CI: 0.88-0.94), respectively. In the patient-based data analysis, the pooled weighted SEN was 0.76 (95% CI: 0.65-0.84) and the pooled weighted SPE was 0.88 (95% CI: 0.82-0.92). In the MLN-based data analysis, the pooled SEN was 0.68 (95% CI: 0.56-0.78) and the pooled SPE was 0.95 (95% CI: 0.91-0.97). Conclusions: Integrated PET/CT is a relatively accurate noninvasive imaging technique, with excellent specificity for MLN staging in patients with NSCLC. Nevertheless, current evidence suggests that we should not depend on the results of PET/CT completely for MLN staging in patients with NSCLC. Copyright © 2011 by the International Association for the Study of Lung Cancer. Source


Wang T.,Xian Jiaotong University | Zhu H.,Tengzhou Central Peoples Hospital | Sun J.,Xian Jiaotong University | Cheng X.,Xian Jiaotong University | And 7 more authors.
International Journal of Antimicrobial Agents | Year: 2014

The aim of this study was to determine an optimum voriconazole target concentration, to study the influence of CYP2C19 gene status on metabolism of voriconazole and to identify a dose-adjustment strategy for voriconazole according to CYP2C19 polymorphism in patients with invasive fungal infections. A total of 328 voriconazole trough plasma concentrations (Cmin) were collected and monitored from 144 patients. Information on efficacy and safety was obtained. Voriconazole therapy was effective in 81.9% of patients (118/144), and 12.5% (18/144) exhibited signs of hepatotoxicity. The relationships between voriconazole Cmin and clinical response and hepatotoxicity were explored using logistic regression, and a target clinical Cmin range of 1.5-4 mg/L was identified. Values of voriconazole Cmin and the ratio of Cmin to concentration of voriconazole-N-oxide (Cmin/CN) of poor metabolisers (PMs) were significantly higher than extensive metabolisers and intermediate metabolisers. Model-based simulations showed that PM patients could be safely and effectively treated with 200 mg twice daily orally or intravenously, and non-PM patients with 300 mg twice daily orally or 200 mg twice daily intravenously. This study highlighted that voriconazole Cmin and Cmin/CN are strongly influenced by CYP2C19 polymorphism, and gene-adjusted dosing is important to achieve therapeutic levels that maximise therapeutic response and minimise hepatotoxicity. © 2014 Elsevier B.V. and the International Society of Chemotherapy. Source


Gao W.,Shandong University | Dong J.,Shandong University | Liu J.,Shandong University | Li Y.,Shandong University | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2014

Aims: We reviewed randomized controlled trials (RCTs) to compare the efficacy and safety of initial dipeptidyl peptidase-IV (DPP-IV) inhibitors and metformin combination therapy with equal-dosage metformin monotherapy in type 2 diabetes. Methods: We conducted a systematic review of English articles using MEDLINE and EMBASE. Search terms included randomized controlled trial, controlled clinical trial, random allocation, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, duotogliptin and dipeptidyl peptidase IV inhibitor. Double-blinded RCTs comparing DPP-IV inhibitors initially combined with metformin and metformin monotherapy in non-pregnant drug-naive adults with type 2 diabetes were included for this study. Extraction of articles was performed by two authors using predefined data fields. Meta-analysis was used when studies were homogeneous enough, and data were shown and not combined if no formal meta-analysis was performed. Results: Five RCTs met the inclusion criteria. By analysis of different outcomes, patients receiving initial combination of DPP-IV inhibitors and metformin showed a greater reduction in haemoglobinA1c (HbA1c) from baseline [weighted mean difference (WMD), -0.55%; 95% confidence interval (CI), -0.63 to -0.46%], a higher rate of achieving target of HbA1c<7% [risk ratio (RR), 1.55; 95% CI, 1.43-1.67], a significantly lower fasting plasma glucose (FPG) (WMD, -0.97mmol/l; 95% CI, -1.26 to -0.68mmol/l),while the initial combination therapy and monotherapy did not show a significant difference in incidence of total adverse events (AEs, 51.8 vs. 53.7%, respectively; RR, 0.96; 95% CI, 0.91-1.02), gastrointestinal AEs (18.2 vs. 19.4%, respectively; RR, 0.94; 95% CI, 0.82-1.07), drug-related AEs (RR, 0.88; 95% CI, 0.74-1.03) and discontinuation due to AEs (RR, 0.85; 95% CI, 0.61-1.20). The following outcomes were not included for meta-analysis: change from baseline in postprandial glycaemia, β-cell function, insulin sensitivity and body weight as well as incidence of hypoglycaemia. The analyses of these trials revealed that the change from baseline of the postprandial glycaemia and index of β-cell function were greater while the RRs for incidence of hypoglycaemia and body weight increase had no statistical significance. Conclusions: Compared with equal-dosage metformin monotherapy, the initial combination of metformin and DPP-IV inhibitors were more effective in glycaemic control without additional risk of AEs, therefore it can be considered as a beneficial therapeutic regimen for drug-naive type 2 diabetes patients. © 2013 John Wiley & Sons Ltd. Source

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