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Zhang K.,Tengzhou Central Peoples Hospital | Yuan Q.,Tengzhou Central Peoples Hospital
Journal of Cancer Research and Therapeutics | Year: 2016

Lung cancer continues to be a major health problem and the most common cancer-related mortality worldwide with about 80%-85% patients suffering from nonsmall cell lung cancer (NSCLC). More than 80% of NSCLC cases are often diagnosed as advanced stage and harbor epidermal growth factor receptor (EGFR) activating mutation. Although great success in initial response to EGFR-Tyrosine kinase inhibitors (EGFR-TKIs) are found in EGFR-mutant NSCLC patients, acquired resistance usually occurs on the continuous treatment. Here, we provide an overview on the mechanism of acquired resistance to EGFR-TKIs in NSCLC therapy as well as current preclinical and clinical evidence of new therapy strategies and inhibitors in the treatment of NSCLC. Many studies have shown that original or induced T790M mutation, human EGFR 2 amplification, and activated secondary signaling such as MET amplification or phosphatidylinositol 3-kinase mutation can lead to acquired resistance to EGFR-TKIs. In addition, transformation from NSCLC to SCLC or conferred epithelial to mesenchymal transition has also been identified as mechanisms of acquired resistance to EGFR-TKIs. Increasing evidence has proven that non-coding RNA including long noncoding RNAs and microRNAs or new EGFR mutation is involved in acquired resistance. Preclinical and clinical Phase 1-3 evidence on combination drug therapy or new generation inhibitors with different tumor-Targeting approaches have made those strategies the promising options for EGFR-TKI-resistant NSCLC therapy. This review aims to get deep insight into providing a state-of-The-Art overview of the recent advances in the mechanisms of acquired resistance and new strategies for targeted cancer therapy in EGFR-TKI-resistant NSCLC.


Liu X.-Y.,Capital Medical University | Liu X.-Y.,Tengzhou Central Peoples Hospital | Zhang T.,Beijing Normal University | Jia Y.-L.,Zaozhuang Municipal Hospital | And 2 more authors.
Investigative Ophthalmology and Visual Science | Year: 2011

PURPOSE. To investigate the therapeutic impact of perceptual learning on juvenile amblyopia that is no longer responsive to patching treatment (PT group) or was never patch treated (NPT group). METHODS. Ten PT and 13 NPT subjects aged 8 to 17 years were trained with a grating acuity task for 40 to 60 sessions. Half in each group were further trained with single or crowded tumbling E acuity tasks for 8 to 10 sessions. RESULTS. Training improved grating acuity by -2.1% in the PT eyes and 36.1% in the NPT eyes, along with a boost of single and crowded E acuities by 0.9 or 0.7 lines in the PT eyes and 1.5 and 1.2 lines in the NPT eyes, in contrast to a nearly 5-line improvement in the same PT eyes after previous patching treatment. Stereoacuity was improved in some PT and NPT eyes. The single and crowded E acuity improvements were not significantly dependent on the pretraining acuity. The single and crowded E acuity and stereoacuity improvements were uncorrelated with grating acuity improvement, suggesting some random training impacts on different tasks and individuals. Further direct single and crowded E acuity training generated an additional 0.2- and 0.2-line boost for PT eyes and a 0.4- and 0.5-line boost for NPT eyes, resulting in overall single and crowded E acuity gains of 1.4 and 1.0 lines for PT eyes and 2.2 and 1.8 lines for NPT eyes. CONCLUSIONS. Perceptual learning has a small but significant therapeutic impact on both PT and NPT juvenile eyes, which is most likely to have clinical values for eyes with mild amblyopia. Early diagnosis and treatment are most important and effective. © 2011 The Association for Research in Vision and Ophthalmology, Inc.


Wang T.,Xi'an Jiaotong University | Zhu H.,Tengzhou Central Peoples Hospital | Sun J.,Xi'an Jiaotong University | Cheng X.,Xi'an 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.


Fu M.,Linyi Peoples Hospital | Shi W.,Linyi Tumor Hospital | Li Z.,Tengzhou Central Peoples Hospital | Liu H.,Linyi Peoples Hospital
Biochemical and Biophysical Research Communications | Year: 2016

Over-expression and aberrant activation of histone deacetylases (HDACs) are often associated with poor prognosis of hepatocellular carcinoma (HCC). Here, we evaluated the potential anti-hepatocellular carcinoma (HCC) cell activity by resminostat, a novel pan HDAC inhibitor (HDACi). We demonstrated that resminostat induced potent cytotoxic and anti-proliferative activity against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, resminostat treatment in HCC cells activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway, which was evidenced by physical association of cyclophilin-D and adenine nucleotide translocator 1 (ANT-1), mitochondrial depolarization, cytochrome C release and caspase-9 activation. Intriguingly, the mPTP blockers (sanglifehrin A and cyclosporine A), shRNA knockdown of cyclophilin-D or the caspase-9 inhibitor dramatically attenuated resminostat-induced HCC cell apoptosis and cytotoxicity. Reversely, HCC cells with exogenous cyclophilin-D over-expression were hyper-sensitive to resminostat. Intriguingly, a low concentration of resminostat remarkably potentiated sorafenib-induced mitochondrial apoptosis pathway activation, leading to a profound cytotoxicity in HCC cells. The results of this preclinical study indicate that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. © 2016 Elsevier Inc.


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.


Gai Z.,University of Zürich | Chu L.,Shandong University | Chu L.,Tengzhou Central Peoples Hospital | Hiller C.,University of Zürich | And 5 more authors.
American Journal of Physiology - Renal Physiology | Year: 2014

Although the kidney is believed to play a minor role in bile acid (BA) excretion, chronic renal failure (CRF) has been reported to be associated with increased serum bile acid levels and alterations in BA homeostasis. The mechanisms for elevated BA levels are poorly understood in both clinical and experimental studies. This study was designed to examine the effects of naturally progressing CRF of longer duration on the hepatic and renal mRNA and protein levels of the BA-synthesizing enzyme Cyp7a1 and the BA transporters Ntcp, Bsep, Mrp3, Ost-α, and Ost-β. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy) or to the sham-operated control group and were analyzed 8 wk after surgery. Results obtained in the CRF rats were compared with those obtained in rats that had undergone uninephrectomy (UNX). The CRF group exhibited significantly increased plasma cholesterol and BA concentrations. Hepatic Cyp7a1 mRNA and protein levels were almost identical in the two groups. Hepatic Mrp3, Ost-α, and Ost-β expression was increased, suggesting increased basolateral efflux of bile acids into the blood. However, no such changes in BA transporter expression were observed in the remnant kidney. In UNX rats, similar changes in plasma BA levels and in the expression of BA transporters were found. We hypothesize that the increase in plasma BA is an early event in the progression of CRF and is caused by increased efflux across the basolateral hepatocyte membrane. © 2014 the American Physiological Society.


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.


Sun Z.-Q.,Xinjiang Medical University | Sun Z.-Q.,Central South University | Han X.-N.,Xinjiang Medical University | Wang H.-J.,Xinjiang Medical University | And 6 more authors.
World Journal of Gastroenterology | Year: 2014

AIM: To investigate the prognostic significance of preoperative fibrinogen levels in colon cancer patients. METHODS: A total of 255 colon cancer patients treated at the Affiliated Tumor Hospital of Xinjiang Medical University from June 1st2005 to June 1st2008 were enrolled in the study. All patients received radical surgery as their primary treatment method. Preoperative fibrinogen was detected by the Clauss method, and all patients were followed up after surgery. Preoperative fibrinogen measurements were correlated with a number of clinicopathological parameters using the Student t test and analysis of variance. Survival analyses were performed by the Kaplan-Meier method and Cox regression modeling to measure 5-year disease-free survival (DFS) and overall survival (OS). RESULTS: The mean preoperative fibrinogen concentration of all colon cancer patients was 3.17 ± 0.88 g/L. Statistically significant differences were found between preoperative fibrinogen levels and the clinicopathological parameters of age, smoking status, tumor size, tumor location, tumor-node-metastasis (TNM) stage, modified Glasgow prognostic scores (mGPS), white blood cell (WBC) count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and carcino-embryonic antigen (CEA) levels. Univariate survival analysis showed that TNM stage, tumor cell differentiation grade, vascular invasion, mGPS score, preoperative fibrinogen, WBC, NLR, PLR and CEA all correlated with both OS and DFS. Alpha-fetoprotein (AFP) and body mass index correlated only with OS. Kaplan-Meier analysis revealed that both OS and DFS of the total cohort, as well as of the stage II and III patients, were higher in the hypofibrinogen group compared to the hyperfibrinogen group (all P < 0.05). In contrast, there was no significant difference between OS and DFS in stage I patients with low or high fibrinogen levels. Cox regression analysis indicated preoperative fibrinogen levels, TNM stage, mGPS score, CEA, and AFP levels correlated with both OS and DFS. CONCLUSION: Preoperative fibrinogen levels can serve as an independent prognostic marker to evaluate patient response to colon cancer treatment. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Zhao L.L.,Xuzhou Medical College | Hu G.C.,University of Illinois at Chicago | Zhu S.S.,Xuzhou Medical College | Li J.F.,Tengzhou Central Peoples Hospital | Liu G.J.,Xuzhou Medical College
Brazilian Journal of Medical and Biological Research | Year: 2014

The aim of this study was to investigate the effect of propofol pretreatment on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway in this procedure. Survival was determined 48 h after LPS injection. At 1 h after LPS challenge, the lung wet- to dry-weight ratio was examined, and concentrations of protein, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method or ELISA. Lung injury was assayed via lung histological examination. PI3K and p-Akt expression levels in the lung tissue were determined by Western blotting. Propofol pretreatment prolonged survival, decreased the concentrations of protein, TNF-α, and IL-6 in BALF, attenuated ALI, and increased PI3K and p-Akt expression in the lung tissue of LPS-challenged rats, whereas treatment with wortmannin, a PI3K/Akt pathway specific inhibitor, blunted this effect. Our study indicates that propofol pretreatment attenuated LPS-induced ALI, partly by activation of the PI3K/Akt pathway. © 2014, Associacao Brasileira de Divulgacao Cientifica. All rights reserved.


Ma Y.,Tengzhou Central Peoples Hospital | Gai Y.,Tengzhou Central Peoples Hospital | Yan J.,Tengzhou Central Peoples Hospital | Li J.,Zaozhuang Municipal Hospital | Zhang Y.,Tengzhou Central Peoples Hospital
Medical Science Monitor | Year: 2016

Background: Puerarin has protective effects on ischemia-reperfusion injury, but the underlying mechanisms are not fully revealed. This study explored the effect of puerarin on the expression of Bcl-2 associated athanogene 3 (BAG3) in an in vitro model of anoxia/reoxygenation injury (A/RI) in neonate rat primary cardiomyocytes and the functions of BAG3 in A/RI. Material/Methods: BAG3 expression in cardiomyocytes with or without puerarin pre-treatment was quantified using qRT-PCR and Western blot analysis. The effects of BAG3 on A/RI were studied by measuring the activity of lactate dehydrogenase (LDH) and creatine phosphate kinase (CPK), the concentration of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). The effects of BAG3 on autophagy and apoptosis of the cardiomyocytes after A/RI were further studied. Results: Puerarin significantly promoted BAG3 expression in the rat primary cardiomyocytes after A/RI. Enforced BAG3 expression presented similar effects as puerarin pre-treatment in attenuating A/RI in terms of CPK, LDH, MDA, SOD, GSH-Px, ROS generation, and cell viability. BAG3 overexpression significantly stimulated autophagy in cardiomyocytes after A/RI, which presented protective effects on A/RI in terms of cell viability and apoptosis. Autophagy inhibition partly abrogated the protective effects of BAG3. Conclusions: Puerarin can directly increase BAG3 transcription and translation in cardiomyocytes after A/RI. The elevated BAG3 expression presents protective effects on A/RI at least through enhancing autophagy and reducing apoptosis, which is a novel protective mechanism of puerarin in ARI. © Med Sci Monit, 2016.

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