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1.  Ribosomal s6 protein kinase 4: a prognostic factor for renal cell carcinoma 
Fan, L | Li, P | Yin, Z | Fu, G | Liao, D J | Liu, Y | Zhu, J | Zhang, Y | Wang, L | Yan, Q | Guo, Y | Shao, C | Huang, G | Wang, Z
British Journal of Cancer  2013;109(5):1137-1146.
The expression and function of ribosomal s6 protein kinase 4 (RSK4) in renal cell carcinoma (RCC) are unknown.
Immunohistochemistry was used to detect the expression of RSK4 in RCC, and the relationship between RSK4 expression and clinicopathological features as well as prognosis of RCC patients was statistically analysed. Ectopic RSK4 expression in RCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability.
RSK4 was overexpressed in RCCs (P=0.003), compared with normal tissues, and the expression varied in different RCC subtypes (P=0.021), especially in two subtypes of papillary RCCs (P=0.001). RSK4 expression was positively correlated with high pT stage (P<0.001), high Fuhrman grade (P<0.001), lymph node involvement (P<0.001), and presence of distant metastasis (P=0.039), and could predict poor outcome in RCC patients. Molecular studies showed that overexpression of RSK4 could promote cell cycle progression and enhance the invasive and metastatic capability of RCC cell lines and vice versa.
The expression pattern and molecular mechanisms of RSK4 in RCCs indicate that it could be a potential independent prognostic factor and serve as a new potential therapeutic target for RCC patients.
PMCID: PMC3778307  PMID: 23942078
ribosomal s6 protein kinase 4; renal cell carcinoma; prognosis; invasion; metastasis
2.  Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein 
Shao, Y | Liu, Y | Shao, C | Hu, J | Li, X | Li, F | Zhang, L | Zhao, D | Sun, L | Zhao, X | Kopecko, DJ | Kalvakolanu, DV | Li, Y | Xu, DQ
Cancer gene therapy  2010;17(12):844-854.
The development of malignant prostate cancer involves multiple genetic alterations. For example, alterations in both survivin and p53 are reported to have crucial roles in prostate cancer progression. However, little is known regarding the interrelationships between p53 and survivin in prostate cancer. Our data demonstrate that the expression of survivin is inversely correlated with that of wtp53 protein (rs=0.548) in prostate cancer and in normal prostate tissues. We have developed a therapeutic strategy, in which two antitumor factors, small interfering RNA-survivin and p53 protein, are co-expressed from the same plasmid, and have examined their effects on the growth of PC3, an androgen-independent prostate cancer cell line. When p53 was expressed along with a survivin-specific short hairpin RNA (shRNA), tumor cell proliferation was significantly suppressed and apoptosis occurred. In addition, this combination also abrogated the expression of downstream target molecules such as cyclin-dependent kinase 4 and c-Myc, while enhancing the expression of GRIM19. These changes in gene expression occurred distinctly in the presence of survivin-shRNA/wtp53 compared with control or single treatment groups. Intratumoral injection of the co-expressed construct inhibited the growth and survival of tumor xenografts in a nude mouse model. These studies revealed evidence of an interaction between p53 and survivin proteins plus a complex signaling network operating downstream of the wtp53-survivin pathway that actively controls tumor cell proliferation, survival and apoptosis.
PMCID: PMC3915357  PMID: 20706288
prostate cancer; p53; survivin; siRNA
3.  Cytochrome-c mediated a bystander response dependent on inducible nitric oxide synthase in irradiated hepatoma cells 
He, M | Ye, S | Ren, R | Dong, C | Xie, Y | Yuan, D | Shao, C
British Journal of Cancer  2012;106(5):889-895.
Radiation-induced bystander effect (RIBE) has important implication in tumour radiotherapy, but the bystander signals are still not well known.
The role of cytochrome-c (cyt-c) and free radicals in RIBE on human hepatoma cells HepG2 was investigated by detecting the formation of bystander micronuclei (MN) and the generation of endogenous cyt-c, inducible nitric oxide (NO) synthase (iNOS), NO, and reactive oxygen species (ROS) molecules.
When HepG2 cells were cocultured with an equal number of irradiated HepG2 cells, the yield of MN in the nonirradiated bystander cells was increased in a manner depended on radiation dose and cell coculture time, but it was diminished when the cells were treated with cyclosporin A (CsA), an inhibitor of cyt-c release. Meanwhile the CsA treatment inhibited radiation-induced NO but not ROS. Both of the depressed bystander effect and NO generation in the CsA-treated cells were reversed when 5 μ cyt-c was added in the cell coculture medium. But these exogenous cyt-c-mediated overproductions of NO and bystander MN were abolished when the cells were pretreated with s-methylisothiourea sulphate, an iNOS inhibitor.
Radiation-induced cyt-c has a profound role in regulating bystander response through an iNOS-triggered NO signal but not ROS in HepG2 cells.
PMCID: PMC3305951  PMID: 22274409
ionising radiation; bystander effect; cytochrome-c; iNOS; ROS
5.  Radiation-induced intercellular signaling mediated by cytochrome-c via a p53-dependent pathway in hepatoma cells 
Oncogene  2010;30(16):1947-1955.
The tumor suppressor p53 has a crucial role in cellular response to DNA damage caused by ionizing radiation, but it is still unclear whether p53 can modulate radiation-induced bystander effects (RIBE). In the present work, three different hepatoma cell lines, namely HepG2 (wild p53), PLC/PRF/5 (mutation p53) and Hep3B (p53 null), were irradiated with γ-rays and then co-cultured with normal Chang liver cell (wild p53) in order to elucidate the mechanisms of RIBE. Results showed that the radiosensitivity of HepG2 cells was higher than that of PLC/PRF/5 and Hep3B cells. Only irradiated HepG2 cells, rather than irradiated PLC/PRF/5 or Hep3B cells, could induce bystander effect of micronuclei (MN) formation in the neighboring Chang liver cells. When HepG2 cells were treated with 20 μm pifithrin-α, an inhibitor of p53 function, or 5 μm cyclosporin A (CsA), an inhibitor of cytochrome-c release from mitochondria, the MN induction in bystander Chang liver cells was diminished. In fact, it was found that after irradiation, cytochrome-c was released from mitochondria into the cytoplasm only in HepG2 cells in a p53-dependent manner, but not in PLC/PRF/5 and Hep3B cells. Interestingly, when 50 μg/ml exogenous cytochrome-c was added into cell co-culture medium, RIBE was significantly triggered by irradiated PLC/PRF/5 and Hep3B cells, which previously failed to provoke a bystander effect. In addition, this exogenous cytochrome-c also partly recovered the RIBE induced by irradiated HepG2 cells even with CsA treatment. Our results provide new evidence that the RIBE can be modulated by the p53 status of irradiated hepatoma cells and that a p53-dependent release of cytochrome-c may be involved in the RIBE.
PMCID: PMC3070628  PMID: 21132005
irradiation; hepatoma cells; bystander effect; p53; cytochrome-c
6.  Role of TGF-β1 and nitric oxide in the bystander response of irradiated glioma cells 
Oncogene  2007;27(4):434-440.
The radiation-induced bystander effect (RIBE) increases the probability of cellular response and therefore has important implications for cancer risk assessment following low-dose irradiation and for the likelihood of secondary cancers after radiotherapy. However, our knowledge of bystander signaling factors, especially those having long half-lives, is still limited. The present study found that, when a fraction of cells within a glioblastoma population were individually irradiated with helium ions from a particle microbeam, the yield of micronuclei (MN) in the nontargeted cells was increased, but these bystander MN were eliminated by treating the cells with either aminoguanidine (an inhibitor of inducible nitric oxide (NO) synthase) or anti-transforming growth factor β1 (anti-TGF-β1), indicating that NO and TGF-β1 are involved in the RIBE. Intracellular NO was detected in the bystander cells, and additional TGF-β1 was detected in the medium from irradiated T98G cells, but it was diminished by aminoguanidine. Consistent with this, an NO donor, diethylamine nitric oxide (DEANO), induced TGF-β1 generation in T98G cells. Conversely, treatment of cells with recombinant TGF-β1 could also induce NO and MN in T98G cells. Treatment of T98G cells with anti-TGF-β1 inhibited the NO production when only 1% of cells were targeted, but not when 100% of cells were targeted. Our results indicate that, downstream of radiation-induced NO, TGF-β1 can be released from targeted T98G cells and plays a key role as a signaling factor in the RIBE by further inducing free radicals and DNA damage in the nontargeted bystander cells.
PMCID: PMC3016606  PMID: 17621264
targeted irradiation; bystander signaling; TGF-β1; nitric oxide; glioma
7.  Genome-wide linkage analysis of heroin dependence in Han Chinese: Results from Wave Two of a multi-stage study 
Drug and alcohol dependence  2008;98(1-2):30-34.
Previously we reported the results of Wave One of a genome-wide search for heroin dependence susceptibility loci in Han Chinese families from Yunnan Province, China, near Asia’s “Golden Triangle”. Our initial analysis of 194 independent affected sibling-pairs from 192 families identified two regions with nonparametric linkage (NPL) Z-scores greater than 2.0, which were suggestive of linkage. Presently we have supplemented our sample with additional individuals and families, bringing the total number of genotyped individuals to 1513 and the number of independent sibling-pairs to 397. Upon repeating our analyses with this larger sample, we found that the evidence for linkage at our most strongly implicated locus from Wave One (marker D17S1880; 53.4 cM on 17q11.2; NPL Z = 2.36; uncorrected p = 0.009) was completely abolished (Z = -1.13; p = 0.900). In contrast, the evidence for linkage at the second-most strongly implicated locus from Wave One (D4S1644; 143.3 cM on 4q31.21; NPL Z = 2.19; uncorrected p = 0.014) increased in its magnitude and significance (Z = 2.64; uncorrected p = 0.004), becoming the most strongly implicated locus overall in our full sample. Other loci on chromosomes 1, 2, 4, 12, 16, and X also displayed nominally significant evidence for linkage (p ≤ 0.05). These loci appear to be entirely distinct from opioid-linked loci reported by other groups; however, meta-analyses of all available linkage data may reveal common sites of interest and promising candidate genes that can be further evaluated as risk factors for the illness.
PMCID: PMC2764288  PMID: 18538955
Affected sibling-pairs; Chromosome 4; Genome-wide linkage analysis; Heroin dependence; Opioid dependence
8.  Evaluation of OPRM1 Variants in Heroin Dependence by Family-Based Association Testing and Meta-Analysis 
Drug and alcohol dependence  2007;90(2-3):159-165.
OPRM1, which codes for the μ-opioid receptor, is the most frequently studied candidate gene for opioid dependence. Despite numerous allelic association studies, no definitive conclusion has been reached regarding the role of OPRM1 polymorphisms in determining risk for opioid dependence. We attempted to resolve this by conducting a family-based association study and meta-analysis which may be more robust and powerful, respectively, than traditional case-control analyses. First, we genotyped three single nucleotide polymorphisms (SNPs) of OPRM1 in 1208 individuals from 473 Han Chinese families ascertained on the basis of having two or more siblings with DSM-IV-defined opioid dependence. The Val6Ala and Arg111His SNPs were detected, but with low minor allele frequencies (0.002 and 0.001, respectively). The Asn40Asp SNP was more informative (minor allele frequency: 0.419), but no significant evidence was observed for either a dominant (p=0.810) or additive (p=0.406) effect of this polymorphism on risk for opioid dependence. In addition, a meta-analysis of case-control studies of opioid dependence was performed, and found a similar lack of evidence for an association with the Asn40Asp SNP (p=0.859). Although a role of OPRM1 polymorphisms in determining risk for opioid dependence cannot be entirely discounted, a major contribution of the Asn40Asp polymorphism seems unlikely. Further analysis is warranted in samples from specific ancestral groups. In addition, it is critical that other OPRM1 variants, including all haplotype-tagging and amino-acid-coding SNPs, be tested for an influence on risk for opioid dependence, since the Asn40Asp polymorphism is only one of several hundred known mutations in the gene.
PMCID: PMC2012941  PMID: 17416470
allelic association; genetic polymorphism; mu-opioid receptor gene; opiate dependence; opioid dependence
9.  Genome-wide Linkage Analysis of Heroin Dependence in Han Chinese: Results from Wave One of a Multi-Stage Study 
The contribution of genes to the etiology of heroin dependence is greater than for any other illicit drug. The specific genes mediating this effect remain unknown, despite several candidate gene association studies of the condition. Here we report the results of a genome-wide search for heroin dependence susceptibility loci using multipoint linkage analysis. In phase I, we ascertained 207 independent affected sibling pairs from 202 Han Chinese families from Yunnan Province, China (near Asia's “Golden Triangle”). After data-cleaning, 194 fully independent sibling pairs (i.e., with no overlapping individuals) from 192 families were genotyped on 404 short tandem-repeat markers spaced at an average inter-marker distance of 9cM. Although none of our findings achieved genome-wide significance, we found two regions with nonparametric linkage (NPL) Z-scores greater than 2.0. An NPL Z-score of 2.19 (uncorrected p-value = 0.014) was observed at D4S1644, located at 143.3 cM on chromosomal region 4q31.21. The highest NPL Z-score of 2.36 (uncorrected p-value = 0.009) was observed at 53.4 cM on chromosomal region 17q11.2 at marker D17S1880. This is among the first published reports of a genome-wide linkage analysis of heroin dependence. Forthcoming results from other groups and from two additional waves of ascertainment (one planned, one currently ongoing) for our own study should be able to support or refute the putative susceptibility loci we have identified, after which positional candidate genes can be further evaluated as risk factors for the illness.
PMCID: PMC2562776  PMID: 16856125
affected sibling-pairs; chromosome 17; genome-wide linkage analysis; heroin dependence; opioid dependence
10.  Differential Requirements for Actin Polymerization, Calmodulin, and Ca2+ Define Distinct Stages of Lysosome/Phagosome Targeting 
Molecular Biology of the Cell  2006;17(4):1697-1710.
Fusion of phagosomes with late endocytic organelles is essential for cellular digestion of microbial pathogens, senescent cells, apoptotic bodies, and retinal outer segment fragments. To further elucidate the biochemistry of the targeting process, we developed a scintillation proximity assay to study the stepwise association of lysosomes and phagosomes in vitro. Incubation of tritium-labeled lysosomes with phagosomes containing scintillant latex beads led to light emission in a reaction requiring cytosol, ATP, and low Ca2+ concentrations. The nascent complex was sensitive to disruption by alkaline carbonate, indicating that the organelles had “docked” but not fused. Through inhibitor studies and fluorescence microscopy we show that docking is preceded by a tethering step that requires actin polymerization and calmodulin. In the docked state ongoing actin polymerization and calmodulin are no longer necessary. The tethering/docking activity was purified to near homogeneity from rat liver cytosol. Major proteins in the active fractions included actin, calmodulin and IQGAP2. IQGAPs are known to bind calmodulin and cross-link F-actin, suggesting a key coordinating role during lysosome/phagosome attachment. The current results support the conclusion that lysosome/phagosome interactions proceed through distinct stages and provide a useful new approach for further experimental dissection.
PMCID: PMC1415291  PMID: 16452628
11.  Prevalence of and risk indicators for STIs among women seeking induced abortions in two urban family planning clinics in Shandong province, People's Republic of China 
Methods: Women seeking induced abortions were recruited in two urban family planning clinics in Jinan, Shandong in a cross sectional study. A standardised questionnaire was used to collect demographic characteristics, obstetric and abortion history, condom use, and sexual risk behaviours. Vaginal and cervical samples were taken for the diagnosis of STIs and blood samples were collected for the testing of syphilis and HIV. Univariate and multivariate ORs and 95% CIs of risk factors for several STIs were determined using logistic regression.
Results: Out of 2020 women seeking induced abortions in two family planning clinics, the prevalence of STIs was 4.8% for Chlamydia trachomatis, 0.4% Neisseria goorrhoeae, 2.5% trichomoniasis. Bacterial vaginosis was found in 3.4%. Five (1%) out of 503 women tested for syphilis had a positive TPPA and one of 787 women tested for HIV was seropositive. Although some risk factors were associated with the infections in logistic regression models, the positive predictive value was poor in this "low risk" population of women.
Conclusions: Women attending for induced abortions could be a targeted group for STIs, especially for chlamydial infection. Since most infections are asymptomatic and no criteria for screening can be used in practice, other strategies to detect these genital infections need to be developed.
PMCID: PMC1744460
12.  Novel Cyanobacterial Biosensor for Detection of Herbicides 
Applied and Environmental Microbiology  2002;68(10):5026-5033.
The aim of this work was to generate a cyanobacterial biosensor that could be used to detect herbicides and other environmental pollutants. A representative freshwater cyanobacterium, Synechocystis sp. strain PCC6803, was chromosomally marked with the luciferase gene luc (from the firefly Photinus pyralis) to create a novel bioluminescent cyanobacterial strain. Successful expression of the luc gene during growth of Synechocystis sp. strain PCC6803 cultures was characterized by measuring optical density and bioluminescence. Bioluminescence was optimized with regard to uptake of the luciferase substrate, luciferin, and the physiology of the cyanobacterium. Bioassays demonstrated that a novel luminescent cyanobacterial biosensor has been developed which responded to a range of compounds including different herbicide types and other toxins. This biosensor is expected to provide new opportunities for the rapid screening of environmental samples or for the investigation of potential environmental damage.
PMCID: PMC126403  PMID: 12324353
13.  Genetic study of indirect inguinal hernia. 
Gong, Y | Shao, C | Sun, Q | Chen, B | Jiang, Y | Guo, C | Wei, J | Guo, Y
Journal of Medical Genetics  1994;31(3):187-192.
We performed a genetic analysis of 280 families with congenital indirect inguinal hernia ascertained in Shandong province. The multifactorial threshold model and segregation analysis were applied to these families to investigate the mode of inheritance of congenital indirect inguinal hernia. Our results indicate that congenital indirect inguinal hernia is not compatible with a multifactorial threshold model, and the frequent vertical transmission and high segregation ratio suggest autosomal dominant inheritance with incomplete penetrance and sex influence. Through further pedigree analysis of the multiple case families with at least two closely related affected members, we noted preferential paternal transmission of the disease gene, which might suggest the role of genomic imprinting in the aetiology of this condition.
PMCID: PMC1049739  PMID: 8014965
14.  Childhood sexual abuse and the risk for recurrent major depression in Chinese women 
Psychological Medicine  2011;42(2):409-417.
Studies in Western countries have repeatedly shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in China?
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression and regression coefficients by linear or Poisson regression.
Any form of CSA was significantly associated with recurrent MD [OR 3.26, 95% confidence interval (CI) 1.95–5.45]. This association strengthened with increasing CSA severity: non-genital (OR 2.47, 95% CI 1.17–5.23), genital (OR 2.77, 95% CI 1.32–5.83) and intercourse (OR 13.35, 95% CI 1.83–97.42). The association between any form of CSA and MD remained significant after accounting for parental history of depression, childhood emotional neglect (CEN), childhood physical abuse (CPA) and parent–child relationship. Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes and an increased risk for generalized anxiety disorder (GAD; OR 1.92, 95% CI 1.39–2.66) and dysthymia (OR 2.16, 95% CI 1.52–3.09).
In Chinese women CSA is strongly associated with MD and this association increases with greater severity of CSA. Depressed women with CSA have an earlier age of onset, longer depressive episodes and increased co-morbidity with GAD and dysthymia. Although reporting biases cannot be ruled out, our results are consistent with the hypothesis that, as in Western countries, CSA substantially increases the risk for MD in China.
PMCID: PMC3250087  PMID: 21835095
Childhood sexual abuse; co-morbidity; major depression

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