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Journal of International Translational Medicine
Journal of International Translational Medicine
JITM, ISSN 2227-6394
founded in 2012
Editor-in-chief:Feng Jifeng, China
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2013 Vol. 1, No. 4
Published: 30 December 2013

 
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Correlation between DAPK Promoter Methylation and Gefitinib Sensitivity in Non-small Cell Lung Cancer Hot!

Wu Weiqin, Zhang Xiaoyuan, Xu Haifeng, Xu Jing, Shen Jie, Lu Kaihua
Journal of International Translational Medicine, 2013, 1(4): 152-157
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Objective: To explore the correlation between DAPK promoter methylation and gefitinib sensitivity in human non-small cell lung cancer (NSCLC). Methods: Different concentrations of gefitinib were respectively used to act on two strains of NSCLC cells with epidermal growth factor receptor (EGFR) exon 19-deleted mutation (H1650 and PC9) and two strains with wild-type EGFR (A549 and H520). The cells were detected before and after 5-aza-CdR demethylation. The cell proliferation rate was determined by CCK-8 assay, apoptosis rate by flow cytometry (FCM), DAPK mRNA expression by fluorescent quatititive polymerase chain reaction (RT-PCR), and methylation status in the region of DAPK promoter by methylation-specific PCR. Results: Gefitinib had proliferation inhibition effects on four kinds of cell lines by varying degrees, and with its concentration increase, the proliferation of PC9 and A549 cells was inhibited obviously, whereas both H1650 and H520 cells presented drug-resistance. After 5-aza-CdR methylation, the sensitivity of H1650 cells with EGFR mutation and H520 cells with wild-type EGFR to gefitinib was enhanced compared with the previous. Among the cell lines not dealt with 5-aza-CdR, the gefitinib-sensitive cell lines PC9 and A549 displayed high expression of DAPK, with the gene promoter in a non-methylation status, but in gefitinib-resistant cell lines H1650 and H520, DAPK expression was low, with DAPK promoter in a high methylation status. DAPK gene expression and gefitinib sensitivity in H1650 and H520 cell lines apparently were increased compared to the previous after 5-aza-CdR was applied to remove the methylation of DAPK gene promoter region in gefitinib-non-sensitive cell lines H1650 and H520, with significant difference (P < 0.01). However, there were no significant changes in gefitinib-sensitive cell lines PC9 and A549 (P > 0.05). Conclusion: High methylation in the region of tumor suppressor gene DAPK promoter can reduce the sensitivity of gefitinib to NSCLC by down-regulating DAPK gene expression. Detecting the methylation status of DAPK gene may provide a new method for predicting the efficiency of gefitinib.
       

BAC Library Construction and Physical Mapping of Bacillus anthracis A16R Hot!

Zhang Da, Zhu Houchu, Huang Liuyu
Journal of International Translational Medicine, 2013, 1(4): 158-167
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Bacillus anthracis is an endospore-forming bacterium that causes severe inhalational anthrax, and bacillus anthracis A16R is an attenuated strain derived from Bacillus anthracis A16. The development of bacterial artificial chromosome (BAC) system has allowed the construction of large insert-size DNA libraries, and the bacterial artificial chromosomes (BACs) have become the preferred large insert cloning system for genomic analysis because such libraries are characteristically stable, high in fidelity and easy to handle. To facilitate genome studies of this bacterium, a bacterial artificial chromosome library (BAC) has been established from genome DNA of Bacillus anthracis A16R. This library consisted of 9 600 clones randomly selected from more than 15 000 recombinant clones carrying inserts in the plindigoBAC-5 vectors. The mean insert size was 56 kbp, representing an approximate 12-fold genome coverage, while end sequences were obtained from 700 randomly selected clones. Sequences were compared with Bacillus anthracis Ames and Bacillus cereus ATCC 14579 Genome Project databases using the NCBI BLASTN search project. And most BLASTN results showed high identities and that the sequences’ sites could be used as STSs. To construct this physical map, Excel was used for the array of STSs and some gaps of the map were filled up by PCR walking. Artemis-V4 was used in the construction of a genome-wide physical map with 93% genome coverage. The A16R BAC library proved to be a vital tool for the generation of a map that would not only allow the subsequent sequencing of defined areas of genome, but also provide immediate access to clones that were stable and convenient for functional genomic researches.
       

Expression and Significance of WT1 and Betacatenin Proteins in Non-small Cell Lung Cancer Hot!

Zhou Feng, Mao Guoxin
Journal of International Translational Medicine, 2013, 1(4): 168-176
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Objective: To investigate the expression, clinic-pathologic significance and the relevance of WT1 protein β-catenin protein in non-small cell lung cancer (NSCLC). Methods: A total of 48 paraffin-embedded tissue samples from patients with resected NSCLC were collected and none had received radiotherapy or chemotherapy before surgical resection. The expressions of WT1 and β-catenin proteins were detected with immunohistchemistry. All data were dealt with SPSS19.0 statistical software while the relationship between WT1 protein or β-catenin protein and each clinical pathological characteristic was tested by Pearson X2 and Fisher’s Exact Test, and X2 test of independence of two attributes was performed for the relevant analysis of the two indexes. Results: The positive expression rates of WT1 and aberrant β-catenin proteins were 62.5% (30/48) and 72.9% (35/48) in NSCLC, respectively. There was significant association between WT1 protein and lymph node metastasis (X2 = 4.480, df = 1, P = 0.034), but no obvious connection was observed between WT1 protein and genders, ages, tumor sizes, pathological patterns, differentiated degrees and pTNM stagings (P > 0.05). Aberrant expression of β-catenin protein was closely correlated with differentiation degrees (X2 = 8.224, df = 2, P = 0.016), and the results of further comparisons of differentiation degrees showed that there were significant differences between highly and moderately differentiated groups (P = 0.026), and between highly and lowly differentiated groups (P = 0.031), but the difference between moderately and lowly differentiated groups was not significant (P = 0.655). Similar to WT1 protein, there was no close relation between the aberrant expression of β-catenin protein and genders, ages, tumor sizes, pathological patterns, differentiated degrees and pTNM stagings (P > 0.05). The relationship between WT1 protein expression and aberrant expression of β-catenin protein was analyzed by Pearson chi-square independence test (X2 = 5.915, P = 0.015, r = 0.331), indicating that the aberrant expression of WT1 protein was closely associated with that of β-catenin protein in NSCLC. Conclusions: 1. The positive expression rate of WT1 protein expression is 62.5% in NSCLC. 2. The positive expression rate of aberrant β-catenin protein is 72.9% in NSCLC. 3. There is significant association between WT1 protein and lymph node metastasis. WT1 protein expression is higher in non- lymph node metastasis group than in lymph node metastasis group (P < 0.05); and there was no significant association between WT1 protein and genders, ages, tumor sizes, pathological patterns, differentiated degrees and pTNM stagings (P > 0.05). 4. Aberrant protein of β-catenin is in reverse relevance with differentiation degrees, and the higher the differentiation degree is, the lower aberrant expression of β-catenin protein will be observed, but there is no significant association between the aberrant expression of β-catenin protein and genders, ages, tumor sizes, pathological patterns, differentiated degrees and pTNM stagings (P > 0.05). 5. There is certain relevance between WT1 protein expression and the aberrant expression of β-catenin protein in NSCLC (P < 0.05). 6. WT1 protein and β-catenin proteins may play certain roles in early events of NSCLC.
       

Meta-Analysis of Cytochrome P2D6 Gene Polymorphisms and Susceptibility to Acute Leukemia Hot!

Ma Limin, Ruan Linhai
Journal of International Translational Medicine, 2013, 1(4): 177-184
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Objective: To provide a more robust assessment to the effect of cytochrome P2D6 (CYP2D6) polymorphisms on the risk of acute leukemia (AL), and to evaluate the association between the two most commonly studied CYP2D6 polymorphisms (CYP2D6*3 and CYP2D6*4) and AL risk by meta-analysis. Methods: All case-control studies investigating an association between the CYP2D6*3 or CYP2D6*4 polymorphisms and AL risk were included. Either fixed-effects or random-effects models were applied to combine odds ratios (ORs) and 95% confidence intervals (CIs) by RevMan 5.1. Q-statistic was used to evaluate the heterogeneity, and both Egger’s test and funnel plots were used to assess publication bias. Results: Six studies were included in the meta-analysis. The results we acquired were that the OR value and 95%CI of CYP2D6*4 wild type, heterozygous mutant and homozygous mutant were 0.94 (0.66-1.35), 1.04(0.74-1.45) and 1.63 (0.95-2.81), respectively with Z = 0.33, 0.23 and 1.76 (P > 0.05), indicating that there was no significant association between CYP2D6*4 polymorphism and the risk of AL. We also performed subgroup analysis by the AL immunophenotype for those groups with heterogeneity. The results of the combined analysis of CYP2D6*4 wild type, heterozygous mutant and acute lymphoblastic leukemia (ALL) were Z = 0.08, 0.08 (P > 0.05), for acute myeloblastic leukemia (AML) were Z = 0.17, 0.26 (P > 0.05), indicating that there was no significant association between CYP2D6*4 polymorphism and the development of both ALL and AML. Conclusion: CYP2D6 polymorphisms are not associated with AL risk.
       

Survival Model Established by Combined Serum Tumor Markers in Predicating the Effect of Erlotinib on Patients with Recurrent Non-small Cell Lung Cancer Hot!

Shao Lan, Hong Wei, Zhang Yiping
Journal of International Translational Medicine, 2013, 1(4): 185-193
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Objective: To investigate the relationship of serum pulmonary surfactant-associated pretein (SP-D), transforming growth factor-α (TGF-α), matrix metalloproteinases-9 (MMP-9), tissue polypeptide specific antigen (TPS) and lung adenocarcinoma-related antigen (KL-6) with the effect and survival of treating advanced recurrent non-small cell lung cancer (NSCLC), and to establish a survival predication model. Methods: ELISA was applied to detect peripheral serum SP-D, TGF-α, MMP-9, TPS and KL-6 levels in 114 patients with recurrent NSCLC, and to analyze their relationship with the effect of erlotinib by combining with clinical symptoms, while one-way and multi-way analysis of variances were analyzed with Kaplan-Meier survival curve and Cox multi-way survival analysis model in order to establish the survival predication model. Results: The total effective rate and stability rate of erlotinib in 114 patients were 22.8% and 72.8% with progression-free survival (PFS) and 1-year survival rate being 5.13 months and 69.3%, respectively, and they were higher in SP-D > 110 ng/mL group than in ≤ 110 ng/mL group (P= 0.011, P = 0.017). The stability rate in MMP-9 ≤ 535 ng/mL and TPS < 80 U/L groups were higher than in MMP-9 > 535 ng/mL (P = 0.009) and TPS ≥ 80 U/L groups (P = 0.002) respectively, while mPFS in SP-D > 110 ng/mL, MMP-9 ≤ 535 ng/mL, KL-6 < 500 U/mL and TPS < 80 U/L groups were longer than in SP-D ≤ 110 ng/mL (5.95 months vs. 3.25 months, P =0.009), MMP-9 > 535 ng/mL (5.83 months vs. 3.47 months, P = 0.046), KL-6 ≥ 500 U/mL (6.03 months vs. 3.40 months, P = 0.040) and TPS ≥ 80 U/L groups (6.15 months vs. 2.42 months, P= 0.014), respectively. Cox multi-way analysis showed that smoking history, wild EGFR genes, effective progression of terminal chemotherapy, free-of-rash during erlotinib treatment, increased LDH and TPS ≥ 80 U/L were independent risk factors for PFS. Additionally, patients were divided into 4 groups according to the predicative indexes in prognostic predication model: low risk group,medium-low risk group, medium risk group and high risk group, with PFS being 9.12, 6.88, 3.52 and 0.93 months, respectively, and there were significant differences (P = 0.000). Conclusion: The establishment of prognostic survival model by detecting TPS level in serum tumor markers combined with clinical symptoms is of great significance in guiding and predicating erlotinib treatment on patients with recurrent NSCLC in clinic.
       

Short-term Effect of Chemotherapy Concomitant with Multiple Autologous Immunocytes on Patients with Colorectal Carcinoma Hot!

Liu Junquan, Zhu Yun, Zhang Nanzheng, Chen Fuxing, Chen Ling, Zhang Song, Yang Wanying, Zhou Zhonghai, Lv Xiaoting
Journal of International Translational Medicine, 2013, 1(4): 194-200
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Objective: To compare the differences of cellular immunological functional changes and survival time of chemotherapy concomitant with multiple autologous immunocytes with single chemotherapy on patients with colorectal carcinoma (CRC). Methods: Of the 83 CRC patients, 43 were treated with single chemotherapy (single chemotherapy group) while the other 40 were given chemotherapy concomitant with multiple autologous immunocytes (combined chemotherapy group). Blood cell separator was applied to collect autologous peripheral blood mononuclear (PBMC) which was used to induce the cultures of peripheral blood CD3AK cell, CIK cell, dendritic cell (DC), γδT cell and NK cell based on routine approaches. Peripheral blood CD3+, CD4+, CD8+, CD19+, CD16+, CD56+, CD4/CD8 and γδT cell ratio as well as the positive expression rates of perforin, granular enzyme B and CD107a in PBMC were determined by flow cytometer. Same chemotherapy (oxaliplatin + CF + 5-FU) was intravenously given to both groups, while in combination group, 4, 6, 9, 11 and 10 patients received 3, 6, 7, 10 and > 16 courses of treatment, respectively. Results: Subgroup of immunocytes and absolute value in combined chemotherapy group were evidently higher than in single chemotherapy group, but there was no significant difference in Karnofsky score. In addition, combined chemotherapy group was apparently higher after treatment than treatment before and single chemotherapy group in the results of perforin, granular enzyme B (GranB) and CD107a in PBMC. Additionally, 1-, 2- and 5-year survival rates in combined chemotherapy group (in phases Ⅱ , Ⅲ and Ⅳ ) were 70.0% (28/40), 20.0% (8/40) and 10.0% (4/40), higher than those in single chemotherapy group [23.2% (10/43), 7.0% (3/43) and 4.6% (2/43)], respectively, in which the differences in phases Ⅱ and Ⅲ were more significant (P <0.05), but no difference was observed between two groups in 5-year survival rate in patients in phase Ⅳ . Conclusion: Chemotherapy concomitant with multiple autologous immunocytes can improve the immunological function and prolong survival time for patients with advanced colorectal carcinoma.
       

Influences of Resveratrol on the Proliferation of Cholangiocarcinoma Cells and Expression of p21 and p27 Proteins Hot!

Liu Yong, Qian Huaxiang, Zhuo Ma, Xu Jianzhong
Journal of International Translational Medicine, 2013, 1(4): 201-204
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Objective: To explore the effects of resveratrol on the proliferation of cholangiocarcinoma cells and expression of p21 and p27 proteins. Methods: The influences of resveratrol on the proliferation of cholangiocarcinoma cells and expression of p21 and p27 proteins were detected by methyl thiazolyl tetrazolium (MTT) method and Western blotting method, respectively. Results: Resveratrol had a conspicuous inhibitory effect on the proliferation of cholangiocarcinoma QBC939 cells, and was concentration- and time-dependant (P < 0.05). In addition, it could up regulate the expression of p21 and p27 proteins obviously, and was concentration-dependant (P <0.05). Conclusion: Resveratrol can significantly inhibit the proliferation of cholangiocarcinoma QBC939 cells, which may be related to regulation of p21 and p27 expression and negative regulation to cell cycles.
       

Clinical Study of Pemetrexed as the First-line Treatment in Elderly Patients with Advanced Non-squamous Non-small Cell Lung Cancer Hot!

Pu Xiaolin, Wang Jun, Li Wei, Lu Binbin, Wang Zhaoxia, Yang Min, Fan Weifei
Journal of International Translational Medicine, 2013, 1(4): 205-209
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Objective: To evaluate the efficacy and adverse reactions of pemetrexed as the first-line treatment in elderly patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: The elderly patients with advanced non-squamous NSCLC received pemetrexed as the first-line treatment were retrospectively analyzed. All of them were intravenously injected 500 mg/ m2 pemetrexed, and 21 days were as one cycle. The efficiency was evaluated every two cycles till the disease progressed or sever adverse reactions occurred. The condition of adverse reactions as well as final outcome were observed. Results: Eighty-seven patients were enrolled in the research, totally receiving 392 cycles of chemotherapy, and the mean for 1 patient being 4.5 cycles. After 2 cycles of chemotherapy, partial response (PR) and stable disease (SD) were respectively 39 and 18 cases. The response rate and disease control rate were 44.8% and 65.5%, respectively. The median overall survival (OS) of all patients was 16.1 months, and median progression-free survival (PFS) was 3.2 months. Twenty-five patients completed 4 cycles of chemotherapy, and 32 patients completed 6 cycles of chemotherapy at least. The median OS of patients > 4 cycles of chemotherapy was 17.4 months, while those ≤ 4 cycles was 13.6 months, and the difference had statistical significance (χ2 = 4.374, P = 0.036). The major adverse reactions included myelosuppression, fatigue and gastrointestinal reactions, mainly at grades 1 ~ 2. No treatment-related deaths occurred. Conclusion: The efficiency of pemetrexed is definite as the first-line treatment in elderly patients with advanced non-squamous NSCLC, and the incidence of adverse reactions is low. The prognosis of patients is associated with cycles of pemetrexed chemotherapy.
       

Effect of MicroRNA-335 on the Metastasis, Invasion and Proliferation of Cells in Patients with Non-small Cell Lung Cancer Hot!

Wang He, Liu Zhili, Wang Zhaoxia
Journal of International Translational Medicine, 2013, 1(4): 210-214
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Objective: To investigate the effect of microRNA-335 on the metastasis, invasion and proliferation of cells in patients with non-small-cell lung cancer (NSCLC). Methods: Real-time PCR was performed to detect the expression differences of microRNA-335 between 12 pairs of NSCLC and normal cancerous peripheral tissues, and between SPCA-1 cells of NSCLC and 16HBE of normal pulmonary epithelial cells, while miR-335 expression in SPCA- 1 cells were down-regulated and proved by Lipofectamine 2000 transient transfection and realtime PCR, respectively. Scratch test, Transwell invasion assay as well as MTT and clone formation assays were applied to respectively determine the effect of miR-335 on the metastasis, invasion and proliferation of SPCA-1 cells. Results: Compared with para-carcinoma tissues and 16HBE cells, miR-335 expression was evidently higher in NSCLC and SPCA-1 cells. However, it decreased remarkably after transient transfection of anti-miR-335 by SPCA-1 cells with Lipofectamine 2000 for 24 h. Metastasis and invasion of SPCA-1 cells could be inhibited by suppressing miR-335 expression with suppression rates being (42.8±2.7)% and (73.25±4.4)% , respectively. However, the inhibition of miR-335 expression had no effect on the proliferation of SPCA-1 cells. Conclusion: miR-335 expresses highly in NSCLC and its low expression can obviously inhibit the metastasis and invasion of SPCA-1 cells, but has no effect on the proliferation.
       

Detection of Soluble B7-H4 Molecules in Serum of Patients with Breast Cancer and its Clinical Significance Hot!

Chen Junjun, Shi Hongbing, Zheng Xiao, Cheng Gui, Xie Jun, Chen Lujun, Jiang Jingting, Wu Changping
Journal of International Translational Medicine, 2013, 1(4): 215-218
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Objective: To investigate the expression of soluble B7-H4 molecules (soluble B7-H4, sB7-H4) in serum of patients with breast cancer and its clinical significance. Methods: Seventy patients with breast cancer, 41 patients with benign breast disease and 28 healthy females were respectively selected as breast cancer group, benign control group and healthy control group. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the content of serum sB7-H4 in three groups, and the clinical correlation with content of serum sB7-H4 in patients with breast cancer was analyzed. Besides, the expression of B7-H4 mRNA and proteins in breast cancer tissue and normal tissue adjacent to cancer was detected respectively with polymerase chain reaction (PCR) and immunohistochemical method. Results: The content of serum sB7-H4 in breast cancer group was obviously higher than in benign control group (U = 844.0, P < 0.01) and healthy control group (U = 727.0, P < 0.05). The content of sB7-H4 in serum of patients with breast cancer was significantly associated with lymph node metastasis (χ2 = 6.944, P < 0.01), not with other clinical pathological parameters. The expression of B7-H4 mRNA and proteins was detectable in breast cancer tissue and normal tissue adjacent to cancer. Conclusion: In serum of patients with breast cancer, the content of sB7-H4 is increased notably and related to lymph node metastasis, hence it can be considered as a potential serum marker in the diagnosis and treatment of breast cancer.
       

Application of Evidence-based Medicine and Systems Biology Mediated by Translational Medicine in TCM Study Hot!

Gong Xiangwen, Zhang Jinwen, Yang Qinhe, Yan Haizhen, Zhang Yupei, Liu Yizhen, Xu Yongjian, Wang Hong, Lin Chunmei
Journal of International Translational Medicine, 2013, 1(4): 219-225
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The core of translational medicine means that the effective relationship between science researchers of basic medicine and clinical doctors makes basic medicine research transform into diagnosis, prevention and treatment of diseases to compensate for the wide gap between basic and clinical application. Translational medicine was introduced into traditional Chinese medicine (TCM) study, and evidence-based medicine capable of improving the accuracy and reliability of TCM clinical research transforming into basic research and systems biology capable of enhancing the systematicness and integrality of basic research to make it transform into clinical application better were as major technical support, hence, the application of evidence-based medicine and systems biology mediated by translational medicine in TCM will have far-reaching significance for the development of TCM modernization. In this article, the application of evidence-based medicine and systems biology mediated by translational medicine in TCM study is illustrated in terms of TCM in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD) and its clinical and basic bidirectional transformation, literature mining, translational medicine platform and team building.
 
 
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