Role of NINJ1 in Gout Flare and Potential as a Drug Target.

Objective: To determine the role of nerve injury-induced protein 1 (NINJ1) introduced plasma membrane rupture (PMR) and damage-associated molecular patterns (DAMPs) release in the pathogenesis and progression of gout and to explore the potential of NINJ1 as a therapeutic target in gout. Methods: Both peripheral blood mononuclear cells (PBMCs) and serum sample from gout patients (n = 58) and healthy controls (n = 16) were collected and processed to NINJ1 expression, lactate dehydrogenase (LDH) detection, NINJ1 inhibition, and NINJ1 expression experiments, respectively. NINJ1 knockdown was carried out by lentivirus in a monosodium urate (MSU) induced rat model, and NINJ1 neutralizing antibody was applied in a MSU induced mouse model. Results: Our results found that NINJ1 was upregulated during a gout flare, and the resulting induction of PMR correlated with gout progression. NINJ1 knockdown significantly reduced the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and joint swelling in the rat model, and NINJ1 neutralizing antibody also significantly reduced gout flare in the mouse model and PBMCs. Moreover, NINJ1 expression is under NLRP3 inflammasome produced interleukin (IL)-1ß control. Conclusion: These results support the notion of a pathogenic role of NINJ1 introduced PMR in gout and provide a detailed mechanism for gout pathogenesis involving inflammatory cell death and DAMPs release introduced by IL-1ß. In addition, targeting NINJ1 might be a potential therapeutic approach for gout.

Microporous Formation Mechanism of Biaxial Stretching PA6/PP Membranes with High Porosity and Uniform Pore Size Distribution.

The low porosity and wide pore size distribution of biaxial stretching PP microporous membranes continue to be the primary impediments to their industrial application. To solve this problem, there is a critical and urgent need to study the micropore-forming mechanism of PP membranes. In this research, the interfacial micropore formation mechanism of PA6/PP membranes during biaxial stretching was investigated. PA6/PP membranes containing spherical PA6 and fibrillar PA6 were found to exhibit different interfacial micropore formation mechanisms. Numerous micropores were generated in the PA6/PP membranes, containing PA6 spherical particles via the interface separation between the PP matrix and PA6 spherical particles during longitudinal stretching. Subsequent transverse stretching further expanded the two-phase interface, promoting the breakdown and fibrosis of the PP matrix and forming a spider-web-like microporous structure centered on spherical PA6 particles. In PA6/PP membranes with PA6 fibers, fewer micropores were generated during longitudinal stretching, but the subsequent transverse stretching violently separated the PA6 fibers, resulting in a dense fiber network composed of PA6 fibers interwoven with PP fibers. Crucially, the PA6/PP biaxial stretching of microporous membranes presented an optimized pore structure, higher porosity, narrower pore size distribution, and better permeability than ß-PP membranes. Furthermore, this study explored a new approach to the fabrication of high-performance PA6/PP microporous membranes, with good prospects for potential industrial application.

The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese.

Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in MKK7 and lung cancer risk and prognosis. To decipher the precise mechanisms of MKK7 rare variants on lung cancer, a series of biological experiments was further performed. We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70-4.01). These rare variants strengthened patients' clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32-1.78). Functional experiments further verified that the MKK7 p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis in vivo and in vitro. Taken together, our findings proposed that the MKK7 p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.

Polymorphisms of NFκB1 and IκBα and Their Synergistic Effect on Nasopharyngeal Carcinoma Susceptibility.

Nasopharyngeal carcinoma (NPC) is a multifactoral and polygenic disease with high prevalence in Southeast Asia and Southern China. Environmental factors and genetic susceptibility play important roles in NPC pathogenesis. In the present study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in nuclear factor-kappa B (NFκB) and its inhibitor (IκBα) conferred consistent risks for NPC. Four putatively functional SNPs (NFκB1: rs28362491del>ins ATTG; NFκB2: rs12769316G>A; IκBα: rs2233406C>T and rs696G>A) were analyzed to evaluate their associations with NPC risk in total 1590 NPC cases and 1979 cancer-free controls. We found that the rs28362491 insATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of NPC (odds ratio [OR] = 1.30, 95% confidence interval [CI] = 1.09-1.55, and P = 2.80 × 10(-3)) compared with the del/del homozygous genotype. The rs696AA variant in IκBα had an increased risk of NPC (OR = 1.41, 95% CI = 1.20-1.66, and P = 2.28 × 10(-5)) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a. Furthermore, both adverse genotypes of NFκB/IκBα and their interaction also exerted an increased risk on NPC. Taken together, Our findings indicated that genetic variants in NFκB1 (rs28362491del>ins ATTG) and IκBα (rs696G>A) and their synergistic effect might contribute to NPC predisposition.

Polymorphism in mature microRNA-608 sequence is associated with an increased risk of nasopharyngeal carcinoma.

Accumulative evidences indicated that microRNAs (miRNAs) can function as tumor suppressors and oncogenes, in which genetic variations are implicated in various cancer susceptibilities. However, it remains unclear whether single nucleotide polymorphisms (SNPs) in mature miRNA sequence alter nasopharyngeal carcinoma (NPC) susceptibility. In this study, we analyzed associations between eight SNPs in miRNA mature sequences (i.e., rs3746444T>C in hsa-mir-499, rs4919510C>G in hsa-mir-608, rs13299349G>A in hsa-mir-3152, rs12220909G>C in hsa-mir-4293, rs2168518G>A in hsa-mir-4513, rs8078913T>C in hsa-mir-4520a, rs11237828T>C in hsa-mir-5579, and rs9295535T>C in hsa-mir-5689) and NPC susceptibility in southern China with 906 NPC cases and 1072 cancer-free controls, and validated the significant findings in eastern China with 684 cases and 907 healthy controls. Functional assays were further performed to identify the biological effects of these polymorphisms. We found that rs4919510C>G polymorphism showed a consistent association with NPC risk in southern China (GC+GG versus CC genotype, odds ratio [OR]=1.36, 95% confidence interval [CI]=1.10-1.70) and eastern China (GC+GG versus CC: OR=1.37, 95% CI=1.08-1.74). After the two populations were merged, the ORs and 95% CI were 1.38 and 1.18 to 1.62, respectively. Moreover, the rs4919510C>G adverse genotypes significantly interacted with Epstein-Barr virus (EBV) infection on increasing NPC risk (P=0.001). The functional assay further showed that the CNE-2 cell lines that transfected with miR-608-rs4919510G allele expression vector exerted more colony number formations than cell lines that transfected with miR-608-rs4919510C allele expression vector (P=0.001). These data suggested that rs4919510C>G of miR-608 may be a susceptible biomarker of NPC in China.

Sequence Variation in Mature MicroRNA-499 Confers Unfavorable Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

PURPOSE: This study was implemented to investigate the associations between SNP in mature microRNA (miRNA) sequence and lung cancer prognosis and to verify the function of those SNP. EXPERIMENTAL DESIGN: Eight SNPs (rs3746444T>C in hsa-mir-499, rs4919510C>G in hsa-mir-608, rs13299349G>A in hsa-mir-3152, rs12220909G>C in hsa-mir-4293, rs2168518G>A in hsa-mir-4513, rs8078913T>C in hsa-mir-4520a, rs11237828T>C in hsa-mir-5579, and rs9295535T>C in hsa-mir-5689) were analyzed in a southern Chinese population with 576 patients with lung cancer, and the significant results were validated in two additional cohorts of 346 and 368 patients, respectively. A series of experiments were performed to evaluate the relevancies of those potentially functional SNPs. RESULTS: We found that the microRNA-499 rs3746444T>C polymorphism exhibited a consistently poor prognosis for patients with lung cancer in the discovery set [HR, 1.24; 95% confidence interval (CI), 1.02-1.49; P = 0.028], in the validation set I (HR, 1.31; 95% CI, 1.01-1.71; P = 0.048) and in the validation set II (HR, 1.45; 95% CI, 1.12-1.86; P = 0.004). The adverse effect of CT/CC variants was more remarkable in patients receiving platinum-based chemotherapy. Further functional assays demonstrated that the rs3746444C variant allele influences the expression of several cancer-related genes and affects lung cancer cells' proliferation and tumor growth in vivo and in vitro via the cisplatinum resistance. CONCLUSION: Our findings suggested that the rs3746444T>C polymorphism in mature miR-499 sequence could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy, which may be a useful biomarker to predict lung cancer patients' prognosis.

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer.

Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case-control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR=1.44, 95% CI=1.23-1.68) and caused poor lung function, and it similarly augmented risk (OR=1.49, 95% CI=1.29-1.73) and worsened prognosis (hazard ratio (HR)=1.25, 95% CI=1.07-1.45) of lung cancer. The ≥4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.

The Functional Copy Number Variation-67048 in WWOX Contributes to Increased Risk of COPD in Southern and Eastern Chinese.

Recent studies have recognized the genetic variants in the WW domain-containing oxidoreductase (WWOX) gene as genetic determinants of lung function, reflecting that the WWOX gene may be a susceptible factor of chronic obstructive pulmonary disease (COPD), which characters as poor lung function. We have previously showed that the copy number variation-67048 (CNV-67048) of WWOX was associated with lung cancer risk. Here, we hypothesized that the CNV-67048 affects COPD susceptibility. Based on a two-stage case-control study with a total of 1791 COPD patients and 1940 controls of southern and eastern Chinese, we found that the loss genotypes (0-copy and 1-copy) of CNV-67048 harbored a significantly increased risk of COPD, with an odds ratio (OR) as 1.29 (1.11-1.49) when compared with the common 2-copy genotype. The pre-forced expiratory volume in one second (pre-FEV1) to pre-forced vital capacity (pre-FVC) of carriers with loss genotypes (0.729 ± 0.130) was significantly lower than carriers with 2-copy genotype (0.747 ± 0.124; p = 7.93 × 10(-5)). However, no significant difference was observed on pre-FEV1, pre-FVC and the annual decline of pre-FEV1 between the loss genotypes and 2-copy genotype carriers. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to COPD, which might be a genetic biomarker to predict risk of COPD in Chinese.

Risk factors shared by COPD and lung cancer and mediation effect of COPD: two center case-control studies.

PURPOSE: To reveal the shared risk factors for chronic obstructive pulmonary disease (COPD) and lung cancer, and to analyze the mediation effect of COPD during lung carcinogenesis. METHODS: We conducted four independent case-control studies included 1,511 COPD patients and 1,677 normal lung function controls and 1,559 lung cancer cases and 1,679 cancer-free controls during 2002-2011 in southern and eastern Chinese. RESULTS: Eight factors were observed to be consistently associated with both diseases risk, including pre-existing tuberculosis, smoking, passive smoking, occupational exposure to metallic toxicant, poor housing ventilation, biomass burning, cured meat consumption, and seldom vegetables/fruits consumption. Furthermore, smoking and biomass burning conferred significantly higher risk effects on lung cancer in individuals with pre-existing COPD than those without. COPD also had significant mediation effects during lung carcinogenesis caused by smoking, passive smoking, and biomass burning, which explained about 12.0 % of effect, 3.8 % of effect, and 6.1 % of effect of these factors on lung tumorigenesis in turn. CONCLUSION: Our study mapped a shared spectrum of etiological factors for both COPD and lung cancer in Chinese, and COPD acts as a mediator during lung cancer development. These observations should be in consideration for the prevention of both diseases.

A functional polymorphism in the 3'-UTR of PXR interacts with smoking to increase lung cancer risk in southern and eastern Chinese smoker.

Pregnane X receptor (PXR) is an important member of the nuclear receptor superfamily that copes with various endobiotic and xenobiotic stimuli, such as carcinogens by regulating an array of environmental response genes. Low PXR expression has been shown to promote tumor initiation and metastasis. The aim of the current study was to investigate whether the single nucleotide polymorphisms (SNPs) of PXR could alter lung cancer susceptibility in Chinese by affecting the function or expression of PXR. We genotyped three putatively functional SNPs of PXR (i.e., rs3814055C>T, rs3732360C>T, and rs3814058C>T) and analyzed their associations with lung cancer risk in a two-stage case-control study with a total of 1559 lung cancer cases and 1679 controls in the southern and eastern Chinese population. We found that in comparison to the rs3814058CC common genotype, the rs3814058T variants (TC/TT) which is located in the 3'-untranslated region (3'-UTR) of PXR conferred a consistently increased risk of lung cancer in both the southern Chinese (odd ratios (OR)=1.24, 95% confidence interval (CI)=1.03-1.49) and the eastern Chinese (OR=1.33, 95% CI=1.02-1.75). The variants also significantly interacted with smoking on increasing cancer risk (p=0.023). Moreover, lung cancer tissues with the rs3814058T variants showed significantly lower PXR expression than those with rs3814058CC genotype in the smokers (p=0.041). These results suggested that the rs3814058C>T polymorphism of PXR interacts with smoking on increasing lung cancer risk in Chinese smokers, which might be a functional genetic biomarker for lung cancer.

A Newfound association between MDC1 functional polymorphism and lung cancer risk in Chinese.

Mediator of DNA damage checkpoint protein 1 (MDC1) plays an early and core role in Double-Strand Break Repair (DDR) and ataxia telangiectasia-mutated (ATM) mediated response to DNA double-strand breaks (DSBs), and thus involves the pathogenesis of several DNA damage-related diseases such as cancer. We hypothesized that the single nucleotide polymorphisms (SNPs) of MDC1 which have potencies on affecting MDC1 expression or function were associated with risk of lung cancer. In a two-stage case-control study, we tested the association between 5 putatively functional SNPs of MDC1 and lung cancer risk in a southern Chinese population, and validated the promising association in an eastern Chinese population. We found the SNP rs4713354A>C that is located in the 5'-untranslated region of MDC1 was significantly associated with lung cancer risk in both populations (P = 0.001), with an odds ratio as 1.33(95% confidence interval = 1.14­1.55) for the rs4713354C (CA+CC) genotypes compared to the rs4713354AA genotype. The correct sixth sentence is: The gene-based analysis rested with these SNPs suggested the MDC1 as a susceptible gene for lung cancer (P = 0.057) [corrected]. Moreover, by querying the gene expression database, we further found that the rs4713354C genotypes confer a significantly lower mRNA expression of MDC1 than the rs4713354AA genotype in 260 cases of lymphoblastoid cells (P = 0.002). Our data suggested that the SNP rs4713354A>C of MDC1 may be a functional genetic biomarker for susceptibility to lung cancer in Chinese.

Genetic variant in the 3'-untranslated region of VEGFR1 gene influences chronic obstructive pulmonary disease and lung cancer development in Chinese population.

Lung inflammation and epithelial to mesenchymal transition (EMT) are two pathogenic features for the two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. VEGFR1 (or FLT1) plays a certain role in promoting tumour growth, inflammation and EMT. To simultaneously test the association between the single nucleotide polymorphisms (SNPs) in VEGFR1 and risk of COPD and lung cancer would reveal genetic mechanisms shared by these two diseases and joint aetiology. We conducted a two-population hospital-based case-control study. Three potential functional SNPs (rs664393, rs7326277 and rs9554314) were genotyped in southern Chinese and validated in eastern Chinese to explore their associations with COPD risk in 1511 COPD patients and 1677 normal lung function controls, and with lung cancer risk in 1559 lung cancer cases and 1679 cancer-free controls. We also detected the function of the promising SNP. Individuals carrying the rs7326277C (CT+CC) variant genotypes of VEGFR1 had a significant decrease in risk of both COPD (OR = 0.78; 95% CI = 0.68-0.90) and lung cancer (OR = 0.79; 95% CI = 0.64-0.98), compared with those carrying the rs7326277TT genotype. Functional assays further showed that the rs7326277C genotypes had lower transcriptional activity and caused decreased VEGFR expression, compared with the rs7326277TT genotype. However, no significant association was observed for the other two SNPs (rs664393 and rs9554314) and either COPD or lung cancer risk. Our data suggested that the rs7326277C variant of VEGFR1 could reduce both COPD and lung cancer risk by lowering VEGFR1 mRNA expression; the SNP might be a common susceptible locus for both COPD and lung cancer.

Effects of a functional variant c.353T>C in snai1 on risk of two contextual diseases. Chronic obstructive pulmonary disease and lung cancer.

RATIONALE: Epithelial-mesenchymal transition (EMT) plays a key role in the development of chronic obstructive pulmonary disease (COPD) and lung cancer. OBJECTIVES: There are five major EMT regulatory genes (Snai1, Slug, Zeb1, Zeb2, and Twist1) involved in EMT. We hypothesized that germline variants in these genes may influence the development of both diseases. METHODS: Seven genetic variants were genotyped in two two-stage case-control studies with 2,072 lung cancer cases and 2,077 control subjects, and 1,791 patients with COPD and 1,940 control subjects to show their associations with development of both diseases. MEASUREMENTS AND MAIN RESULTS: An exon variant c.353T>C(p.Val118Ala) of Snai1 harbored decreased risks of lung cancer (CT/CC vs. TT: odds ratio [OR], 0.76; 95% confidence interval [CI], 0.65-0.90) and COPD (CC vs. CT vs. TT: OR, 0.75; 95% CI, 0.63-0.89), and c.353T>C affected lung cancer risk indirectly through COPD (COPD accounted for 6.78% of effect that the variant had on lung cancer). Moreover, c.353T>C was correlated with lung cancer stages in smoking patients (P = 0.013), and those with the c.353C genotypes were less likely to have metastasis at diagnosis than those with the c.353TT genotype (OR, 0.60; 95% CI, 0.41-0.88). The c.353C allele encoding p.118Ala attenuated Snai1's ability to up-regulate mesenchymal biomarkers (i.e., fibronectin and vimentin) expression, and to promote EMT-like changes, including morphologic changes, cell migration, and invasion. However, these effects were not observed for the other variants. CONCLUSIONS: The functional germline variant c.353T>C (p.Val118Ala) of Snai1 confers consistently decreased risks of lung cancer and COPD, and this variant affects lung cancer risk through a mediation effect of COPD.

The functional polymorphism of NBS1 p.Glu185Gln is associated with an increased risk of lung cancer in Chinese populations: case-control and a meta-analysis.

NBS1 plays pivotal roles in maintaining genomic stability and cancer development. The exon variant rs1805794G>C (p.Glu185Gln) of NBS1 has been frequently studied in several association studies. However, the results were conflicting. Also, the function of this variant has never been well studied. In the current study, we performed a two centers case-control study and function assays to investigate the effect of the variant rs1805794G>C on lung cancer risk in Chinese, and a meta-analysis to summarize the data on the association between rs1805794G>C and cancer risk. We found that compared with the rs1805794GG genotype, the C genotypes (CG/CC) conferred a significantly increased risk of lung cancer in Chinese (OR=1.40, 95% CI=1.21-1.62) and interacted with medical ionizing radiation exposure on increasing cancer risk (Pinteraction=0.015). The lymphocyte cells from the C genotype individuals developed more chromatid breaks than those from the GG genotype carriers after the X-ray radiation (P=0.036). Moreover, the rs1805794C allele encoding p.185Gln attenuated NBS1's ability to repair DNA damage as the cell lines transfected with NBS1 cDNA expression vector carrying rs1805794C allele had significantly higher DNA breaks than those transfected with NBS1 cDNA expression vector carrying rs1805794G allele (P<0.05). The meta-analysis further confirmed the association between the variant rs1805794G>C and lung cancer risk, that compared with the GG genotype, the carriers of C genotypes had a 1.30-fold risk of cancer (95% CI=1.14-1.49, P=8.49×10(-5)). These findings suggest that the rs1805794G>C of NBS1 may be a functional genetic biomarker for lung cancer.

Synthesis and pH-responsive "schizophrenic" aggregation of a linear-dendron-like polyampholyte based on oppositely charged polypeptides.

A novel linear-dendron-like polyampholyte, poly(L-lysine)-b-D2-poly(L-glutamic acid) [PLL-b-D2-(PLGA)4], where D2 is the second generation of poly(amido amine), was prepared by hydrolyzing poly(ε-benzyloxycarbonyl-L-lysine)-b-D2-poly(γ-benzyl-L-glutamate) copolymer which was synthesized via a combination of ring-opening polymerization and click chemistry. The pH-responsive self-assembly behaviors of PLL-b-D2-(PLGA)4 were investigated in detail. It is found that PLL-b-D2-(PLGA)4 can self-assemble into PLGA-core aggregates at acidic pH and PLL-core aggregates at alkaline pH, which was accompanied with the coil-to-helix conformational transition of PLGA and PLL segments, respectively. The self-assembled aggregates with various morphologies, such as large compound micelles, worm-like micelles, large compound vesicles, simple vesicles, and rigid tubular structures have been obtained in "schizophrenic" aggregation process with simply increasing the solution pH. The hierarchical assembled fractal structures of PLL-b-D2-(PLGA)4 were observed during the solvent evaporation at high pH value.

Functional genetic polymorphisms in PP2A subunit genes confer increased risks of lung cancer in southern and eastern Chinese.

Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and functions as a tumor suppressor that negatively regulates the activity of some oncogenic kinases. Recent studies have reported that PP2A expression was suppressed during lung carcinogenesis, we there hypothesized that the single nucleotide polymorphisms (SNPs) in PP2A subunit genes may affect PP2A function and thus contribute to lung cancer susceptibility. In a two-stage case-control study with a total of 1559 lung cancer patients and 1679 controls, we genotyped eight putative functional SNPs and one identified functional SNP (i.e., rs11453459) in seven major PP2A subunits (i.e., PPP2R1A, PPP2R1B, PPP2CA, PPP2R2A, PPP2R2B, PPP2R5C, PPP2R5E) in southern and eastern Chinese. We found that rs11453459G (-G/GG) variant genotypes of PPP2R1A and the rs1255722AA variant genotype of PPP2R5E conferred increased risks of lung cancer (rs11453459, -G/GG vs. -: OR = 1.31, 95% CI = 1.13-1.51; rs1255722, AA vs. AG/GG: OR = 1.27, 95% CI = 1.07-1.51). After combined the two variants, the number of the adverse genotypes was positively associated with lung cancer risk in a dose-response manner (P trend = 5.63 × 10(-6)). Further functional assay showed that lung cancer tissues carrying rs1255722AA variant genotype had a significantly lower mRNA level of PPP2R5E compared with tissues carrying GG/GA genotypes. However, such effect was not observed for the other SNPs and other combinations. Our findings suggested that the two functional variants in PPP2R1A and PPP2R5E and their combination are associated with lung cancer risk in Chinese, which may be valuable biomarkers to predict risk of lung cancer.

[Human umbilical cord blood mononuclear cell transplantation promotes long-term neurobehavioral functional development of newborn SD rats with hypoxic ischemic brain injury].

OBJECTIVE: To explore the effect of human umbilical cord blood mononuclear cells (UCBMC) promoting nerve behavior function and brain tissue recovery of neonatal SD rat with hypoxic ischemic brain injury (HIBI). METHOD: A modified newborn rat model that had a combined hypoxic and ischemic brain injury as described by Rice-Vannucci was used, early nervous reflex, the Morris water maze and walking track analysis were used to evaluate nervous behavioral function, and brain MRI, HE staining to evaluate brain damage recovery. RESULT: Newborn rat Rice-Vannucci model showed significant brain atrophy, obvious hemiplegia of contralateral limbs,e.g right step length [(7.67 ± 0.46) cm vs. (8.22 ± 0.50) cm, F = 1.494] and toe distance [(0.93 ± 0.06) cm vs. (1.12 ± 0.55) cm, F = 0.186] were significantly reduced compared with left side, learning and memory ability was significantly impaired compared with normal control group (P < 0.01); Cliff aversion [(8.44 ± 2.38) s vs.(14.22 ± 5.07) s, t = 4.618] and negative geotaxis reflex time [(7.26 ± 2.00) s vs. (11.76 ± 3.73) s, t = 4.755] on postnatal 14 days of HIBI+ transplantation group were significantly reduced compared with HIBI+NaCl group (P < 0.01) ; the Morris water maze experiment showed escape latency [ (23.11 ± 6.64) s vs. (34.04 ± 12.95) s, t = 3.356] and swimming distance [ (9.12 ± 1.21) cm vs.(12.70 ± 1.53) cm, t = 17.095] of HIBI+transplantation group were significantly reduced compared with those of HIBI+NaCl group (P < 0.01) ; the residual brain volume on postnatal 10 d [ (75.37 ± 4.53)% vs. (67.17 ± 4.08)%, t = -6.017] and 67 d [ (69.05 ± 3.58)% vs.(60.83 ± 3.69)%, t = -7.148]of HIBI+ transplantation group were significantly larger than those of HIBI+NaCl group (P < 0.01); After human UCBMC transplantation, left cortical edema significantly reduced and nerve cell necrosis of HIBI+ transplantation group is not obvious compared with HIBI+NaCl group. CONCLUSION: Human UCBMC intraperitoneal transplantation significantly promoted recovery of injured brain cells and neurobehavioral function development.

A functional polymorphism in the promoter of ERK5 gene interacts with tobacco smoking to increase the risk of lung cancer in Chinese populations.

Mitogen/extracellular signal-regulated kinase-5 (MEK5)/extracellular signal-regulated protein kinase-5 (ERK5) pathway plays a pro-oncogenic role in tumourigenesis by anticell apoptosis, promoting cell proliferation and differentiation in response to extracellular stimuli. As overexpressed MEK5/ERK5 is involved in the development of lung cancer, we hypothesised that the single nucleotide polymorphisms (SNPs) in MEK5 and ERK5 genes may influence gene expression and thus be associated with lung cancer risk. Five putative functional polymorphisms (rs3743353T>C, rs7172582C>T and rs2278076A>G of MEK5 and rs3866958G>T and rs2233083C>T of ERK5) were genotyped in two independent case-control studies with a total of 1559 lung cancer patients and 1679 controls in southern and eastern Chinese population. We found the rs3866958G>T of ERK5 was significantly associated with lung cancer risk, while other SNPs were not. Compared with the rs3866958TG/TT genotypes, the GG genotype conferred an increased risk of lung cancer (odds ratio = 1.30, 95% confidence interval = 1.12-1.51, P = 5.0×10(-4)), and this effect was more pronounced in smokers, accompanying with a significant interaction with smoking (P interaction = 0.013). The GG genotype also had significant higher mRNA levels of ERK5 in lung cancer tissues than TG/TT genotypes (P = 1.0×10(-4)); the luciferase reporter with the G allele showed significant higher transcription activities than the T allele, especially after the treatment with tobacco extract in vitro. Our data indicated that the functional polymorphism rs3866958G>T in ERK5 was associated with an increased lung cancer risk in smokers by virtue of the positive interaction with smoking on promoting the ERK5 expression, which might be a valuable indicator for predicting lung cancer risk in smokers.

Sipa1 promoter polymorphism predicts risk and metastasis of lung cancer in Chinese.

Signal-induced proliferation associated gene 1 (Sipa1) is a signal transducer to activate the Ras-related proteins and modulate cell progression, differentiation, adhesion and cancer metastasis. In this study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in Sipa1 are associated with lung cancer risk and metastasis. Three common SNPs (rs931127A > G, rs2448490G > A, and rs3741379G > T) were genotyped in a discovery set of southern Chinese population and then validated the promising SNPs in a validation set of an eastern Chinese population in a total of 1559 lung cancer patients and 1679 cancer-free controls. The results from the two sets were consistent, the rs931127GG variant genotype had an increased risk of lung cancer compared to the rs931127AA/GA genotypes (OR = 1.27; 95% CI = 1.09-1.49) after combination of the two populations, and the rs931127GG interacted with pack-year smoked on increasing lung cancer risk (P = 0.037); this SNP also had an effect on patients' clinical stages (P = 0.012) that those patients with the rs931127GG genotype had a significant higher metastasis rate and been advanced N, M stages at diagnosis. However, these associations were not observed for rs2448490G > A and rs3741379G > T in the discovery set. Our data suggest that the SNP rs931127A > G in the promoter of Sipa1 was significantly associated with lung cancer risk and metastasis, which may be a biomarker to predict the risk and metastasis of lung cancer.

Effect of EME1 exon variant Ile350Thr on risk and early onset of breast cancer in southern Chinese women.

Essential meiotic endonuclease 1 homolog 1 (EME1) is a key DNA repair protein that participates in the recognition and repair of DNA double-strand breaks. Deficiency of the EME1 gene can lead to spontaneous genomic instability and thus contribute to tumorgenesis. We hypothesized that the exon variants of EME1 confer genetic susceptibility to breast cancer. In a case-control study of 748 breast cancer patients and 778 normal controls, we analyzed the association between two exon variants of EME1 (i.e.,Ile350Thr: rs12450550T > C and Glu69Asp: rs3760413T > G) and breast cancer risk. We found that compared to the common Ile/Ile genotype, the Thr variant genotypes (Thr/Ile + Thr/Thr) conferred a 1.47-fold increased risk of breast cancer (OR=1.47, 95% CI=1.13-1.92). The variant Ile350Thr was also associated with early onset of breast cancer (r = -0.116, P = 0.002). The mean age of onset was 44.4 years for Thr/Thr genotype carriers and 46.5 years for Thr/Ile genotype carriers, which was significantly lower than that (49.4 years) for Ile/Ile genotype carriers (P = 0.006). Moreover, no significant association was observed between the Glu69Asp variant and breast cancer risk. Our findings suggest that the EME1 variant Ile350Thr contributes to an increased risk and early onset of breast cancer.