Paraoxonase (PON1) polymorphisms Q192R and L55M are not associated with human longevity: A meta-analysis.

BACKGROUND: Genetic mutations in the paraoxonase 1 (PON1) encoding gene have been considered to affect mortality and of these the functional promoter region polymorphisms Q192R and L55M are among the most widely studied. OBJECTIVE: The aim of this study was to determine whether the Q192R and L55M polymorphisms of PON1 can increase susceptibility to longevity. A meta-analysis was performed to obtain a comprehensive estimation of the association between Q192R and L55M and longevity in long-lived individuals (LLIs) aged 80 years or more. MATERIAL AND METHODS: A search was carried out in the PubMed database (from January 2001 to May 2014) to obtain data on the role of PON1 polymorphisms in longevity and a pooled odds ratio (OR) with a 95% confidence interval (CI) was used to assess the associations. RESULTS: The meta-analysis was based on 9 studies of PON1 Q192R and 5 studies of PON1 L55M that covered a total of 5086 LLIs and 4494 controls. Overall, significantly increased risks were not observed for either Q192R or L55M. The results of the statistical calculations were as follows: R vs. Q (additive model): OR = 1.080, 95% CI = 0.989-1.179, p = 0.088 and RR + RQ vs. QQ (dominant model): OR = 1.099, 95% CI = 0.975-1.240, p = 0.124; M vs. L (additive model): OR = 0.946, 95% CI = 0.862-1.039, p = 0.245 and MM + ML vs. LL (dominant model): OR = 0.951, 95% CI = 0.836-1.081, p = 0.442 for Q192R and L55M, respectively. The results did not change with an age cut-off among the LLIs of ≥ 93 years. CONCLUSION: No evidence that the Q192R and L55M polymorphisms of PON1 impacted on the probability of reaching extreme ages was found although this cannot be completely ruled out; however, the possibility of population-specific effects due to the influence of and interaction between different genes or environmental factors could not be ruled out.

Association of longevity with TNF-α G308A and IL-6 G174C polymorphic inflammatory biomarkers in Caucasians: a meta-analysis.

BACKGROUND: Mutations in genes encoding tumor necrosis factor (TNF)-α and interleukin (IL)-6 were previously shown to affect mortality. Single nucleotide polymorphisms (SNPs) in the functional promoter regions of TNF-α (G308A) and IL-6 (G174C) are among the most widely studied. OBJECTIVES: To determine whether TNF-α G308A and IL-6 G174C SNPs confer susceptibility to longevity, we performed a meta-analysis to comprehensively estimate the association between these SNPs and longevity in long-lived individuals (LLI, aged ≥ 80 years). MATERIALS AND METHODS: Studies addressing the role of TNF-α and IL-6 SNPs in longevity were identified from the PubMed database. Pooled ORs with 95 % confidence intervals (CIs) were used to assess the association between SNPs and longevity. RESULTS: The meta-analysis was based on four studies of TNF-α G308A and nine of IL-6 G174C, covering a total of 2945 LLI individuals and 2992 controls. Overall, no significantly increased risks were observed for G308A [A vs. G (additive model): OR = 0.98, 95 % CI = 0.79-1.22, p = 0.852; AA + AG vs. GG (dominant model): OR = 0.97, 95 % CI = 0.75-1.24, p = 0.791] or for G174C [C vs. G (additive model): OR = 1.07, 95 % CI = 0.94-1.22, p = 0.293; CC + CG vs. GG (dominant model): OR = 1.09, 95 % CI = 0.93-1.28, p = 0.299]. There was no change in the significance when a cutoff age of ≥ 90 years was introduced. CONCLUSIONS: We found no evidence that the TNF-α G308A and IL-6 G174C SNPs affected the probability of reaching an advanced age in Caucasians, and that they have little effect on delaying the onset and progression of age-related diseases, but this does not rule out the possibility of population-specific effects caused by different genes and/or environmental factors and their interactions.

Triterpenes from the aerial parts of Cimicifuga yunnanensis and their antiproliferative effects on p53(N236S) mouse embryonic fibroblasts.

Nine new triterpene derivatives, yunnanterpenes A-F (1-6), 15,16-seco-cimiterpenes A and B (7, 8), and cimilactone C (9), and 15 known analogues (10-24) were isolated from the aerial parts of Cimicifuga yunnanensis. The new structures were established using a combination of MS, NMR, and single-crystal X-ray diffraction techniques. WT MEFs (wild-type mouse embryonic fibroblasts) and tumorigenic cell lines p53(-/-)+H-RasV12 and p53(-/-)+p53(N236S)+H-RasV12 were used for evaluating active structures, targeting p53(N236S) (corresponding to p53(N239S) in humans) mutation. Compound 5 showed nonselective activities against these cell lines, with IC50 values of 5.8, 8.6, and 6.0 µM, respectively. Compound 4 exhibited greater selectivity against the p53(-/-)+p53(N236S)+H-RasV12 cells (IC50 5.5 µM) than against the WT MEFs cells (IC50 14.3 µM).

[The regulation of anoikis in tumor invasion and metastasis].

As a barrier to metastasis of cancer, cells that lost contact with the neighbouring cells or extracellular matrix(Extracellular matrix, ECM) will be subjected to apoptosis. This cell death process has been termed "anoikis". When normal epithelial cells or solid tumor cells without metastatic potential detach from the primary site, and then enter into the circulatory system, the anoikis mechanism will be activated. The significance of anoikis is to prevent the shedding cells from growing and implanting into other inappropriate sites. Tumor cells, especially several malignant cells that is prone to transfer to distant sites, have properties of anti-anoikis, which facilitates metastasis as well as invasion of tumor cells. The studies found that tumor cells can resist anoikis through multiple mechanisms: the pro-survival pathways are activated by cells autocrine growth factors and paracrine factors derived from neighboring cells; cells change the pattern of integrin expression so that they can receive survival signals from new environment; reactive oxygen species (ROS) activates growth factor receptors in a ligand-independent way to avoid apoptosis; and epithelial-mesenchymal transformation(EMT) is activated etc.. All of these mechanisms lead to activation of survival signals and inhibition of apoptotic pathways, and ultimately cause resistance to anoikis as well as metastasis. This paper summarizes the key mechanisms of the current studies on metastasis, which also suggest important targets for cancer therapy.

[Differentiation of rat bone marrow mesenchymal stem cells into adipocytes and blockage of the differentiation].

OBJECTIVE: To explore the pathogenesis of tumors by blocking the normal differentiation process of stem cells. METHODS: Bone marrow mesenchymal stem cells (BMSCs) from rats were isolated, cultured and purified by whole bone marrow adherence method. The rat BMSCs were induced to differentiate into adipocytes with dexamethasone, insulin and indomethacin. Blockage of the differentiation process was induced by 3-methylcholanthrene (3-MC). RESULTS: The differentiation experiment showed that at 30 days after the induction, oil red O staining-positive cells occurred with increased intracytolasmic lipid droplets, characteristic for adipocytes. The differentiation blockage experiment showed that at 30 days after induction, the deposits of oil red O staining-cytoplasmic lipid droplets was significantly reduced, indicating that the blocked cells were adipocytes, but not fully differentiated. Morphological identification showed that cell contact inhibition disappeared, abnormal cell nuclei, increased number of micronucleus aberration and karyotype abnormalities, indicating that malignant transformation of the stem cells occurred after the differentiation blockage. CONCLUSIONS: The results of this study show a blockage of the differentiation of that stem cells at the intermediate phase, and a tendency of malignant transformation of the stem cells. The results of our study provide new evidence that cancer stem cells may be originated by suppression of stem cell differentiation.

[The cooperation between p53 and Ras in tumorigenesis].

Inactivation of the tumor suppressor gene and activation of the oncogene cooperate to promote the multistep process of tumorigenesis. p53 is considered to be the most important tumor suppressor gene. p53 is usually found as a result of somatic missense mutation in approximately 50% of human cancers. Ras is found to be one of the most frequently mutated oncogenes in human tumors with the reported frequencies ranging from 30% to 90%. It has been found in many studies synergistic effect between tumor suppressor p53 and oncogene Ras occurs during the multistep process of tumorigenesis. According to the current reports, the cooperative effect between p53 and Ras can be divided into three types: the regulation of p53 for Ras function, , the regulation of Ras for p53, and the cooperation between p53 and Ras to control critical genes that are closely related to tumorigenesis. Understanding their synergistic effects will not only help us further disclose mechanism of tumorigenesis caused by p53 inactivation and Ras activation, but also facilitate personalized treatments and pharmacological target selection for cancer therapy. Therefore, we reviewed the recent progress of synergistic effect be-tween p53 and Ras and its role in tumorigenesis.

[The new function of p53 family and its pathway related proteins in female reproduction].

p53 is an important tumor suppressor gene and one of the key genes in sensing and regulating responses to the environmental stress. Recent study showed that cold winter temperature naturally selected p53 Arg72 in eastern Asian population, suggesting that p53 plays a role in reproduction. It has also been reported that some SNPs of p53, Mdm2(Murine double minute 2), MdmX and Hausp (Herpes virus-associated ubiquitin-specific protease) in p53 pathway are associated with the risk of the women's reproduction disorder. p53 regulates the LIF (leukaemia inhibitory factor) expression level by its DBD domain, and thus contributes to female reproduction by affecting the embryo implantation process. The MDM2, MDMX, and HAUSP proteins regulates the level and activity of p53 protein, which are critical for the appropriate p53 response in the embryo implantation process. The members of p53 family, p63 and p73, also play roles in female reproduction through other pathways. p63 has been implicated as a major regulator of oocyte death following treatment with irradiation and chemotherapeutic drugs, which prevents fetal malformation. p73 regulates the formation of spindle assembly complex(SAC). The dysfunction of SAC results in poor blastocyst quality and defects in kinetochore-microtubule associations, which leads to aneuploidy. This review summarized the function of p53 family and its pathway related proteins in female reproduction, pointed out a new method in improving the success rate in IVF-ET, and provided a new diagnosis idea for unexplained infertile women. It will facilitate personalized strategies in the infertility therapy.

Y-chromosome distributions among populations in Northwest China identify significant contribution from Central Asian pastoralists and lesser influence of western Eurasians.

Northwest China is closely adjacent to Central Asia, an intermediate region of the Eurasian continent. Moreover, the Silk Road through the northwest of China once had a vital role in the east-west intercommunications. Nevertheless, little has been known about the genetic makeup of populations in this region. We collected 503 male samples from 14 ethnic groups in the northwest of China, and surveyed 29 Y-chromosomal biallelic markers and 8 short tandem repeats (STRs) loci to reconstruct the paternal architecture. Our results illustrated obvious genetic difference among these ethnic groups, and in general their genetic background is more similar with Central Asians than with East Asians. The ancestors of present northwestern populations were the admixture of early East Asians peopling northwestward and later Central Asians immigrating eastward. This population mixture was dated to occur within the past 10 000 years. The J2-M172 lineages likely entered China during the eastward migration of Central Asians. The influence from West Eurasia through gene flows on the extant ethnic groups in Northwest China was relatively weak.

[Whole genome amplification and its application in forensic individual identification].

Whole genome amplification (WGA) is a technique that could non-selectively amplify the genomic DNA. In recent years, intensive studies have been made on application of WGA in trace DNA amplification, which might be applied to amplify trace DNA collected from crime scenes and provide enough DNA templates for forensic individual identification. However, the problem of amplification bias happened in the complicated test materials from real crime scenes is still troublesome. Development of WGA method with low amplification bias and high yield is the main target of current forensic research. Here, we reviewed the advances and the application prospect of WGA in individual identification. This might provide a reference for solving the problem of the amplification bias.

Potential of RASSF1A promoter methylation as a biomarker for colorectal cancer: Meta-analysis and TCGA analysis.

The RAS association domain family protein 1A (RASSF1A) is a tumor suppressor in colorectal cancer (CRC), and is often inactived by hypermethylation. Therefore, we evaluated the association between RASSF1A hypermethylation and the risk and prognosis in CRC. We identified literature through searching PubMed and China National Knowledge Infrastructure databases, and then validated and supplemented the meta-analysis with TCGA analysis. Twenty-three studies involving 2886 subjects of CRC were examined. The meta-analysis showed that RASSF1A promoter methylation inferred high CRC risk (odds ratio, 6.53, 95% confidence interval 3.88-11.01, P < .001) and poor overall survival (hazard ratio 2.85, 95% CI 1.88-4.31, P < .001). The TCGA analysis suggested that effect of RASSF1A promotor methylation was affected by tumor localization (colon vs. rectum). RASSF1A promoter methylation was a predictor of high risk (OR 2.38, 95%CI 1.02-5.6, P = .046) and poor disease free survival(HR 2.25, 95%CI 1.27-3.99, P = .006)in colon adenocarcinoma, but the association was statistically insignificant in rectum adenocarcinoma(HR 1.58, 95% CI 0.69-3.59, P = .28). These results suggested RASSF1A hypermethylation is a risk and a potential prognostic biomarker in CRC.

[ALT--alternative lengthening of telomere].

The maintenance of the length and normal structure of telomeres is highly related to the development of senescence and tumorigenesis. The mechanisms of maintaining telomere are essential for cell growth and the reactivation of these mechanisms is an important step in tumor progression. The mechanism of telomere maintenance might be the reactivation of telomerase. In the case of telomerase deficiency, the mechanisms for maintaining the lengths of telomeres are referred to as alternative lengthening of telomere (ALT). The characteristics of the ALT cells include great heterogeneity of telomere size in individual cells, ALT-associated PML (promyelocytic leukemia) bodies, and evident homologous recombination. The ALT-related proteins and elevated homologous recombination found in ALT cells provide a possible mechanism for the alternative lengthening of telomere. The study of ALT provides a new view of crosstalk between senescence and tumorigenesis.

[Aging or tumor: the crosstalk between telomerase and p53].

Telomerase and p53 play critical roles in tumorigenesis and senescence. The mutation of p53 gene and the reactivation of telomerase have been found in most of the human tumors. Aiming telomerase and p53 genes have become important strategies in tumor therapy. We reviewed the aging and tumor phenotype in different status of telomerase and p53 (mTR/p53+/+; mTR/P53/), which indicated that telomere dysfunction could initiate or suppress the tumorigenesis depending on the status of p53. This helps further understanding of the crosstalk between p53 and telomerase in aging and tumorigenesis, and provides a new idea for treating tumor.

[Extraction and analysis of nuclear DNA from free margin of nail material].

To investigate the feasibility of DNA analysis from free margin of the nail, genomic DNA was extracted from the free margin of nail clipping of 10 volunteers using the proteinase K/SDS -based organic method, the Chelex-100 method, or a combined method. Target DNA was simultaneously amplified using a fluorescent multiplex AmpFlSTR Identifier kit. The PCR products were analyzed on the ABI PRISM 3130 Genetic Analyzer. The results showed that, compared with profiles achieved by genotyping of blood samples from each volunteer as reference, 100% concordance was achieved using the combined method. The STR genotype profiles obtained through the organic method were acceptable, despite preferential amplification at some loci. In contrast, no readable profiles could be determined when DNA was extracted by the Chelex-100 method, and there were a large number of alleles missing. Our data suggest that free margin of nail can be used for nuclear DNA analysis, but the type of DNA isolation method used is critical. The traditional organic extraction method works reasonably well for free margin nail DNA isolation, and combination of organic extraction and the Chelex-100 method works best.

[The polymorphism of Y chromosome and mtDNA distribution among two Bai populations].

In the same ethnic group, people residing at different places may have genetic difference. The difference can be the results of migration and admixture events happened in history. To clarify the genetic relationship and micro-evolution of two Bai ethnic populations residing in Yunnan and Hunan province respectively,we investigated their genetic difference from paternal and maternal genealogy with six other ethnic groups as outgroups. Fourteen loci from mtDNA and thirteen loci from Y chromosome were selected for genotyping using PCR-RFLP methods. Result showed that H6 and H8 are the same dominant Y chromosome haplotypes in two Bai groups. However,the distribution of mtDNA haplogroups showed difference between two Bai populations. D, B, M8 are the predominant haplogroups in Hunan Bai ethnic population, whereas M, G, F are dominant in Yunnan Bai ethnic population. Principal Component (PC) analysis based on the Y chromosome haplotypes showed that two Bai ethic populations cluster together. It shows a close paternal genetic relationship between two Bai ethnic populations. From the mtDNA PC plot, it is clear that Hunan Bai is close to Hunan Han and Tujia, whereas Yunnan Bai is close to ethnic groups living in Yunnan province. The difference of mtDNA haplogroup distribution in two Bai people may reflect the maternal gene flow between ethnic groups living in Hunan province after the ancestors of Hunan Bai migrated from Yunnan province to Hunan province 800 years ago.

[Advances in research on oncolytic adenoviruses in tumor therapy].

Oncolytic adenoviruses (Ads), which are live, replication-competent viruses that can selectively replicate in tumor cells and lead to cell lysis, have been used in tumor therapy. But due to the complexity and high mutability of human tumors, it becomes a major strategy to improve the selectivity, efficacy, and safety of oncolytic Ads. The oncolytic Ads that can express short hairpin RNA, cytokines, suicide gene, and matrix-modulating proteins have higher antitumor activity than the wild type. Tumor-specific promoters, especially hTERT and HRE promoters, increase the selectivity of oncolytic Ads for tumor cells. Moreover, oncolytic Ads surface-modified by polyethylene glycol (PEG), liposomes, biodegradable nanoparticles, and polypeptides have reduced immunogenicity and hepatotoxicity and improved antitumor activity when systemically administered, and the selectivity of oncolytic Ads can be significantly increased when linking PEG to antibodies, small peptides, cytokines, and ligands. Therefore, engineered oncolytic Ads combining the advantages of viral and non-viral vectors, as well as immunotherapy, are a promising strategy for improving the efficacy of targeted virotherapy.

Association of DR4 (TRAIL-R1) polymorphisms with cancer risk in Caucasians: an updated meta-analysis.

Death receptor 4 (TRAIL-R1 or DR4) polymorphisms have been associated with cancer risk, but findings have been inconsistent. To estimate the relationship in detail, a meta-analysis was here performed. A search of PubMed was conducted to investigate the association between DR4 C626G, A683C and A1322G polymorphisms and cancer risk, using odds ratios (ORs) with 95% confidence intervals. The results suggested that DR4 C626G and A683C polymorphisms were indeed associated with cancer risk (for C626G, dominant model, OR 0.991, 95%CI 0.866-1.133, p=0.015; for A683C, additive model, OR=1.140, 95%CI: 0.948-1.370, p=0.028; dominant model, OR=1.156, 95%CI: 0.950-1.406, p=0.080) in the Caucasian subgroup. However, the association was not significant between DR4 polymorphism A1322G with cancer risk in Caucasians (For A1322G, additive model: OR 1.085, 95%CI 0.931-1.289, p=0.217; dominant model: OR 1.379, 95%CI 0.934-2.035, p=0.311; recessive model: OR 1.026, 95%CI 0.831-1.268 p=0.429.). In summary, our finding suggests that DR4 polymorphism C626G and A683 rather than A1322G are associated with cancer risk in Caucasians.

Association between cigarette smoking and RASSF1A gene promoter hypermethylation in lung cancer patients: a meta- analysis.

OBJECTIVES: Epidemiological studies have shown that molecular mechanisms underlying the development of lung cancers differ between smokers and unsmokers. Aberrant promoter methylation in some tumor suppressor genes is frequent in lung tumors from smokers but rare in those from non-smokers. Recently, many studies have investigated the association between cigarette smoking and RASSF1A gene promoter hypermethylation in lung cancer patients, but a unanimous conclusion could not be reached. We therefore performed this meta-analysis to derive a more precise estimation of any association. STUDY DESIGN: An electronic search of PubMed and Chinese Biomedicine databases was conducted to select studies. A total of 19 case-control studies were chosen, and odds ratios (ORs) with confidence intervals (CIs) were used to assess the strength of associations. RESULTS: The case-control studies covered 2, 287 lung cancer patients: 63.4%(1449) of the patients were smokers, 36.6% (838) were unsmokers. The overall results suggested that smokers with lung cancer had a 1.297-fold (95% CI: 1.066~1.580, p=0.010, p=0.087) higher risk for RASSF1A gene hypermethylation than the non-smokers. In the stratified analysis, an increased risk of RASSF1A gene hypermethylation in smokers than in non-smokers was found in Asian (OR=1.481, 95%CI: 1.179~1.861, p=0.001, p=0.186). CONCLUSIONS: This meta-analysis supports the idea that RASSF1A gene hypermethylation is associated with cigarette smoking-induced lung cancer.

Association of RASSF1A promoter methylation with lung cancer risk: a meta-analysis.

RASSF1A, regarded as a candidate tumor suppressor, is frequently silenced and inactivated by methylation of its promoter region in many human tumors. However, the association between RASSF1A promoter methylation and lung cancer risk remains unclear. To provide a more reliable estimate we conducted a meta-analysis of cohort studies to evaluate the potential role of RASSF1A promoter methylation in lung carcinogenesis. Relevant studies were identified by searches of PubMed, Web of Science, ProQest and Medline databasesusing the following key words: 'lung cancer or lung neoplasm or lung carcinoma', 'RASSF1A methylation' or 'RASSF1A hypermethylation'. According to the selection standard, 15 articles were identified and analysised by STATA 12.0 software. Combined odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the association between RASSF1A promoter methylation and lung cancer risk. A chi-square-based Q test and sensitivity analyses were performed to test between-study heterogeneity and the contributions of single studies to the final results, respectively. Funnel plots were carried out to evaluate publication bias. Overall, a significant relationship between RASSF1A promoter methylation and lung cancer risk (OR, 16.12; 95%CI, 11.40-22.81; p<0.001) with no between-study heterogeneity. In subgroup analyses, increased risk of RASSF1A methylation in cases than controls was found for the NSCLC group (OR, 13.66, 95%CI, 9.529- 19.57) and in the SCLC group (OR, 314.85, 95%CI, 48.93-2026.2).

Updated meta-analysis on HER2 polymorphisms and risk of breast cancer: evidence from 32 studies.

BACKGROUND: Several studies have been performed to investigate the association of the HER2 Ile655Val polymorphism and breast cancer risk. However, the results were inconsistent. To understand the precise relationship, a meta-analysis was here conducted. MATERIALS AND METHODS: A search of PubMed conducted to investigate links between the HER2 Ile655Val polymorphism and breast cancer, identified a total of 32 studies, of which 29, including 14,926 cases and 15,768 controls, with odds ratios (ORs) with 95% confidence intervals were used to assess any association. RESULTS: In the overall analysis, the HER2 Ile655Val polymorphism was associated with breast cancer in an additive genetic model (OR=1.136, 95% CI 1.043-1.239, p=0.004) and in a dominant genetic (OR=1.118, 95% CI 1.020-1.227, p=0.018), while no association was found in a recessive genetic model. On subgroup analysis, an association with breast cancer was noted in the additive genetic model (OR=1.111, 95% CI: 1.004-1.230, p=0.042) for the Caucasian subgroup. No significant associations were observed in Asians and Africans in any of the genetic models. CONCLUSIONS: In summary, our meta-analysis findings suggest that the HER2 Ile655Val polymorphism is marginally associated with breast cancer susceptibility in worldwide populations with additive and dominant models, but not a recessive model.