Baorui Liu

Polymorphism of XRCC1 predicts overall survival of gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population

Pharmacogenetic advances in cancer chemotherapy have the potential to predict clinical benefit to particular regimens. Platinum agents have shown to be effective in the treatment of gastric cancer. We assessed whether single nucleotide polymorphisms (SNPs) in xeroderma pigmentosum group D (XPD), X-ray repair cross complementing group 1 (XRCC1) and glutathione S-transferase P1 (GSTP1) predicted overall survival in gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population. SNPs of XPD-751, XRCC1-399 and GSTP1-105 in 62 gastric cancer patients were evaluated using the TaqMan 5′ nuclease assay. Genotypes were correlated to survival. The median overall survival time was 322 days (range: 56–2058 days). The median survival times for patients with Arg/Arg or Arg/Gln genotypes of XRCC1 gene were significantly longer than others (P=0.03). For 58 patients with ECOG PS (Eastern Cooperative Oncology Group performance status)≤2, more obvious significance was demonstrated (P=0.002). Patients with XRCC1-399 Gln/Gln genotype demonstrated a significant worse survival. No significant association was found between SNPs of XPD-751, GSTP1-105 and survival (P=0.125, 0.475, respectively). XRCC1 genotyping might make tailor chemotherapy possible for gastric cancer patients treated with oxaliplatin-based chemotherapy.

Anticancer effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluids

OBJECTIVEnThe present study was designed to examine the effect of tetrandrine on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers.nnnMETHODSnPrimary cancer cells were isolated from the pleural fluids (n=13) or ascites (n=21) of patients. Compared with culture cell lines, the response of these cancer cells to tetrandrine and chemotherapeutic agents commonly used in clinical practice were determined by WST-8 assay. Tetrandrine-induced apoptosis in primary cancer cells was determined by Annexin V-FITC assay. Quantitative RT-PCR was used to examine the role of apoptotic associated genes in the anticancer effect of tetrandrine.nnnRESULTSnThe primary cancer cells isolated from effusions showed sensitivity to tetrandrine with IC50 values of 38.23+/-25.77microM, similar to the IC50 in established cell lines. Patients with gastric cancers were more sensitive to tetrandrine than patients with lung cancers (P=0.04). Four cancer cells isolated from effusions were resistant to tetrandrine, which also had increased tolerance to docetaxel, cisplatin and 5-fluorouracil. We also observed a weak but significant correlation between sensitivity to tetrandrine and cellular expression of bcl-2 (P=0.035, r=-0.364).nnnCONCLUSIONSnUsing cancer cells isolated from the ascites or pleural fluids, this study shows the potential anticancer effect of tetrandrine against primary cancer cells.

Synergistic interaction between tetrandrine and chemotherapeutic agents and influence of tetrandrine on chemotherapeutic agent-associated genes in human gastric cancer cell lines

PurposeTetrandrine (Tet), a bis-benzylisoquinoline alkaloid that was isolated from the dried root of Hang-Fang-Chi (Stephania tetrandra S. Moore), is well known as processing a marked antitumor effect in vitro and in vivo. The aim of this study was to assess the interaction between tetrandrine and chemotherapeutic agents widely used in gastric cancer treatment, and to investigate the influence of tetrandrine on chemotherapeutic agent-associated gene expression and apoptosis.MethodsSynergistic interaction on human gastric cancer BGC-823 and MKN-28 cells was evaluated using the combination index (CI) method. The double staining with both Annexin-V-FITC and PI was employed to distinguish the apoptotic cells from living cells. Expression of chemotherapeutic agent-associated genes, i.e., excision repair cross-complementing 1 (ERCC1), thymidylate synthase (TS), class III β-tubulin (β-tubulin III) and tau, of BGC-823 cells with or without tetrandrine treatment were measured by real-time quantitative PCR.ResultsTetrandrine had a synergistic effect on the cytotoxicity of chemotherapeutic agents in both two gastric cancer cell lines. The combination of tetrandrine and chemotherapeutic agents could also induce apoptosis in a synergistic manner. Tetrandrine could suppress the mRNA expression of ERCC1, TS, β-tubulin III and tau. Most prominently, ERCC1, TS and β-tubulin III mRNA levels were markedly suppressed at 0.29-, 0.12- and 0.60-fold, respectively, by the presentation of tetrandrine.ConclusionTetrandrine appears a promising candidate for combining with three chemotherapeutic agents. The possible mechanisms might be the synergistic apoptotic effect and the downregulation of chemotherapeutic agent-associated genes.

Lack of association of single nucleotide polymorphism in LRCH1 with knee osteoarthritis susceptibility

AbstractA genetic association of knee osteoarthritis (OA) and a C/T transition single nucleotide polymorphism (SNP) (rs912428) located in intron 1 of the LRCH1 gene has recently been reported in European Caucasians; however, the results are inconsistent. Our objective was to evaluate the association in different knee OA populations. Three case-control association studies were conducted in Han Chinese, Japanese, and Greek Caucasian populations. The LRCH1 SNP was genotyped in patients who had primary symptomatic knee OA with radiographic confirmation and in matched controls, and the association was examined. We performed a meta-analysis for the studies together with results of two previous papers using the DerSimonian–Laird procedure and calculated the power of the pooled studies by the software R. A total of 1,145 OA patients and 1,266 controls were genotyped. No significant difference was detected in genotype or allele frequencies between knee OA and control groups in the three populations (all P > 0.05). Association was not observed even after stratification by gender and Kellgren/Lawrence (K/L) scores. Meta-analysis also supported the lack of association between LRCH1 and knee OA. The strong heterogeneity between original and replication studies was detected in Caucasian populations. However, a tendency for the increase of TT genotype was observed in the European populations (OR = 1.46, P = 0.06). The powers for European and Asian replication studies were less than 0.8. Our results suggest that there is no association between LRCH1 and knee OA. However, lack of association should be concluded by further replication studies.

Association of single-nucleotide polymorphisms in RHOB and TXNDC3 with knee osteoarthritis susceptibility: two case-control studies in East Asian populations and a meta-analysis

IntroductionConflicting findings on the association of single nucleotide polymorphisms (SNPs) in RHOB and TXNDC3 with susceptibility to knee osteoarthritis (OA) have been reported in European Caucasians. To examine the associations of these SNPs with OA in East Asian populations and to evaluate their global significance, we conducted two case-control studies in 955 Chinese and 750 Japanese patients.MethodsWe genotyped the previously implicated SNPs rs585017 (in RHOB) and rs4720262 (in TXNDC3) in patients with primary symptomatic knee OA with radiographic confirmation and in matched control individuals, and analyzed their associations. We further conducted a meta-analysis of the study findings together with those of previously reported European studies using the DerSimonian-Laird procedure.ResultsA significant association of RHOB with knee OA was observed in male Chinese patients (P = 0.02). No significant associations were found for RHOB in any other comparisons in the East Asian populations. The association of TXNDC3 was replicated in Chinese female (P = 0.04) and Japanese (P = 0.03) patients, although none of these associations persisted after Bonferroni correction. Significant association (P = 0.02 for the allelic frequency) with nonsignificant heterogeneity was found in the East Asian replication study. No significant association was found in any comparison in the meta-analysis for all studies.ConclusionOur study replicates the association, previously reported in European Caucasians, of TXNDC3 with knee OA susceptibility in an East Asian population.

Plasma mRNA expression levels of BRCA1 and TS as potential predictive biomarkers for chemotherapy in gastric cancer

ObjectivePersonalized chemotherapy based on predictive biomarkers can maximize efficacy. However, tumor tissue obtained at the time of initial diagnosis will not reflect genetic alterations observed at the time of disease progression. We have examined whether plasma mRNA levels can be a surrogate for tumor levels in predicting chemosensitivity.MethodsIn 150 gastric cancer patients, mRNA levels of BRCA1 and TS were assessed in plasma and paired tumor tissue. The Mann-Whitney U-test was used to compare mRNA expression levels between tumor samples exhibiting in vitro sensitivity or resistance to docetaxel and pemetrexed. All statistical tests were two-sided.ResultsThere were significant correlations between plasma and tumor mRNA levels of BRCA1 (rhou2009=u20090.696, Pu2009<u20090.001) and TS (rhou2009=u20090.620, Pu2009<u20090.001). BRCA1 levels in plasma (docetaxel-sensitive: 1.25; docetaxel-resistant: 0.50, Pu2009<u20090.001) and tumor (docetaxel-sensitive: 8.81; docetaxel-resistant: 4.88, Pu2009<u20090.001) were positively associated with docetaxel sensitivity. TS levels in plasma (pemetrexed-sensitive: 0.90; pemetrexed-resistant: 1.82, Pu2009<u20090.001) and tumor (pemetrexed-sensitive: 6.56; pemetrexed-resistant: 16.69, Pu2009<u20090.001) were negatively associated with pemetrexed sensitivity.ConclusionsPlasma mRNA expression levels mirror those in the tumor and may have a promising role as potential predictive biomarkers for chemotherapy.

Selection of DNA aptamer that specific binding human carcinoembryonic antigen in vitro

Abstract Objective To select the specific aptamer of carcinoembryonic antigen (CEA), one of the most attractive molecule for cancer target therapy and imaging. Methods Seven rounds in vitro selection were performed against the purified CEA protein. Ligand-mediated target purification and Co-immunoprecipitation were adopted to verify the specific binding of the aptamer to the purified and native protein separately. Results The CEA-specific aptamer which can bind both the purified and native protein with the high specificity was obtained. Conclusion This is the first time the CEA specific apatmer was produced. The results in this study provides the preliminary evidence for further investigation and application of CEA-aptamer in the future.

RNA-electroporated CD40-activated B cells induce functional T-cell responses against HepG2 cells

Hepatocellular carcinoma (HCC) is one of the incurable tumours in the world. Cell-based immunotherapy, in which antigen-loaded antigen-presenting cells (APCs) are able to elicit T cell responses, has become an alternative treatment for liver cancer. Here, we used HepG2 cells total RNA-electroporated CD40 ligand-activated B (CD40-B) cells as alternative APC for induction of specific CD8+ T-cell responses. The antigen-presenting ability of CD40-B cells was determined by phenotypic analysis, showing a polyclonal, strongly activated B-cell population with high expression of co-stimulatory molecules. To demonstrate the ability of total RNA extracted from HepG2 cells electroporated CD40-B cells to induce CD8+ T-cell responses, these RNA-loaded cells were co-cultured with autologous peripheral blood mononuclear cells for 7 days followed by analysis of T-cell antigen specificity. These experiments showed that CD40-B cells electroporated with HepG2 cells total RNA are capable of activating antigen-specific interferon-gamma-producing CD8+ T cells, and these T cells activated by CD40-B cells show a killing effect on HepG2 cells. These findings demonstrated that the carcinoma cell derived total RNA-electroporated CD40-B cells could be used as alternative APC for the induction of antigen-specific CD8+ T-cell responses, which might be used in HCC immunotherapy.

Molecular biomarkers for predicting chemotherapy response in lung cancer

BACKGROUNDnChemotherapy in non-small-cell lung cancer (NSCLC) has reached a plateau, with no evidence of substantial improvement in survival. However, recent advances in the management of lung cancer have paved the way for the optimization of treatment. Several lines of evidence indicate that multiple genetic disturbances found in human cancer cell lines and in the tumors of NSCLC patients have a role as predictive markers for response and survival with chemotherapy regimens now in use.nnnOBJECTIVEnThis review highlights relevant translational research findings on potential predictive markers in lung cancer with therapeutic impact in both the near and distant future.nnnCONCLUSIONnThe next step is to develop clinical trials that will prospectively validate the benefits of customizing chemotherapy, which should translate into an improvement in outcome in NSCLC patients.