Association between outdoor particulate air pollution and the risk of osteoporosis: a systematic review and meta-analysis.

Air pollution is a major threat to global health, which is associated with several adverse health outcomes and increased mortality. Few studies have investigated the association between air pollution and osteoporosis, and their findings were inconclusive. Our objective is to determine whether exposure to outdoor air pollution is causally associated with risk of osteoporosis. A systematic literature search of PubMed, Web of Science, Embase, and Cochrane Library for publications up to December 2020 was conducted for studies reporting the association between air pollution and osteoporosis. Meta-analysis was performed to estimate the pooled effect size of air pollution on osteoporosis using the relative risk (RR) and 95% confidence intervals (95% CI). Quality assessment was conducted, and all statistical analyses were performed by RevMan 5.3 software. Our search identified 9 eligible studies involving 9,371,212 patients. Meta-analysis revealed that there was an increased risk of osteoporosis (total body BMD and hip fracture) as a result of exposure to air pollution including PM2.5 and NO2. However, no significant excess risk of osteoporosis was found regardless of PM10, NO, and O3. In spite of a few number of epidemiological studies selected in the present literature review, this study indicated that the increased exposure to air pollutants was positively associated with high risk of osteoporosis. Further cohort studies with large sample sizes are needed to investigate different constituents and the duration of exposure of air pollutants.

Overexpression of EPS8L3 promotes cell proliferation by inhibiting the transactivity of FOXO1 in HCC.

The homology of epidermal growth factor receptor pathway substrate 8 (EPS8), EPS8L3, is elevated significantly in hepatocellular carcinoma (HCC) tissues and cell lines compared with the normal liver tissues and cell lines. The MTT and colony formation assays demonstrated that overexpressing EPS8L3 enhances, while silencing reduces the proliferation of HCC cells. Further experiments illustrated that overexpressing EPS8L3 promotes the expression of p-AKT, Cyclin D1, but inhibits the transcriptional activity of FOXO1. Besides, colony formation assay demonstrated that AKT inhibitor suppresses the effect of EPS8L3 on proliferation in EPS8L3-overexpressing cells, whereas AKT restores the proliferation of EPS8L3-silenced cells, suggesting that EPS8L3 might promote proliferation by hyperactivating the AKT signaling pathway and subsequently inhibiting the FOXO1 transcriptional activity. Our results provide new view between EPS8L3 and progression of human HCC, suggesting that EPS8L3 may be a novel therapeutic target for HCC.

Functional characterization of TRAP1-like protein involved in modulating fibrotic processes mediated by TGF-ß/Smad signaling in hypertrophic scar fibroblasts.

The transforming growth factor-ß1 (TGF-ß)-mediated signaling pathway is believed to be closely associated with wound healing and scar formation, in which TRAP1-like protein (TLP) plays a role in regulating the balance of Smad2 vs. Smad3 signaling. Our previous study revealed the relation between TLP and collagen synthesis in normal human skin fibroblasts. Here, we present a detailed analysis of the effects of TLP on the process of hypertrophic scar formation and contraction. To explore and verify a contribution of TLP to the pathological mechanism of hypertrophic scar fibroblasts (HSFb), we constructed lentiviral vectors that either overexpressed TLP or encoded small hairpin RNAs (shRNAs) targeting TLP, then we transfected them into HSFb. TLP knockdown in HSFb resulted in reduced levels of cell contraction, type I and type III collagen mRNA transcripts and protein expression, and higher levels of fibronectin (FN) compared to control groups. In addition, knockdown of TLP promoted the phosphorylation of Smad3 but repressed Smad2 and Erk-1/2 phosphorylation in human hypertrophic scar fibroblasts compared to control groups. The reduction of TLP did not interfere with HSF proliferative ability, but exogenous TLP cooperated with TGF-ß1 to increase cell viability. Together, our findings demonstrate evidence for a contribution of TLP expression in hypertrophic scar formation and contraction.

CXCL12 G801A polymorphism contributes to cancer susceptibility: a meta-analysis.

CXCL12 is an important alpha-chemokine that regulates many essential biological processes including tumor development and metastasis. The CXCL12 G801A polymorphism is associated with multiple kinds of malignant cancer, but the associations are inconsistent. To derive a more precise estimation of the relationship, we conducted a meta-analysis of 16 publications with 2,888 cases and 3,611 controls. We used the odds ratio (OR) corresponding to 95% confidence interval (CI) to estimate the strength of association. The increased risk of overall cancer was found in the homozygote comparison (AA vs. GG, OR=1.43, 95℅CI=1.07-1.91), the recessive model (AA vs. GG+GA, OR=1.26, 95℅CI=1.03-1.54), and the dominant model (GA+AA vs. GG, OR=1.35, 95℅CI=1.15-1.58). In the stratified analyses, the associations were significant in breast cancer, Asians and hospital-based controls. In conclusion, this meta-analysis suggests that the CXCL12 G801A polymorphism may be a risk factor of cancer, especially in the subgroups of breast cancer, Asians and hospital-based controls.

USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation.

Lys63-linked polyubiquitination of transforming growth factor-ß-activated kinase 1 (TAK1) has an important role in tumor necrosis factor-α (TNFα)-induced NF-κB activation. Using a functional genomic approach, we have identified ubiquitin-specific peptidase 4 (USP4) as a deubiquitinase for TAK1. USP4 deubiquitinates TAK1 in vitro and in vivo. TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation. Overexpression of USP4 wild type, but not deuibiquitinase-deficient C311A mutant, inhibits both TNFα- and TAK1/TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-κB activation. Notably, knockdown of USP4 in HeLa cells enhances TNFα-induced TAK1 polyubiquitination, IκB kinase phosphorylation, IκBα phosphorylation and ubiquitination, as well as NF-κB-dependent gene expression. Moreover, USP4 negatively regulates IL-1ß-, LPS- and TGFß-induced NF-κB activation. Together, our results demonstrate that USP4 serves as a critical control to downregulate TNFα-induced NF-κB activation through deubiquitinating TAK1.

Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion.

BACKGROUND: Focal adhesion kinase (FAK) is overexpressed in a variety of cancers, such as breast, colon, prostate, ovary, and lung cancers. However, the mechanism by which extracellular matrix fibronectin stimulates lung cancer cell migration and invasion through FAK remains to be investigated. METHODS: The signalling pathways in fibronectin-mediated lung cancer cell migration and invasion were examined using western blotting. The metastasis function was detected by wound healing, migration and invasion assays. Further, RNA interference and kinase inhibitors were also used to study the downstream signals. RESULTS: In this study, we examined the FAK signalling pathways in relation to calpain-2 and RhoA in fibronectin-mediated lung cancer cell migration and invasion. We found that A549 lung epithelial cells stimulated by fibronectin showed increased phosphorylation of FAK and its downstream targets, Src, ERK1/2, phosphatidylinositol 3'-kinase (PI3K), and Akt. Consistent with this observation, depletion of FAK by siRNA resulted in the inhibition of Src, ERK1/2, PI3K, and Akt activity. In addition, the Src inhibitor, PP2, blocked the phosphorylation of FAK, ERK1/2, PI3K, and Akt. Conversely, inhibition of MEK1/2 using PD98059 reduced the expression of matrix metalloproteinase-9 (MMP9) and calpain-2. The PI3K inhibitor, LY294002, further blocked the expression of MMP9 and RhoA. Inhibition of both MEK1/2 and PI3K caused reduced cell migration and invasion. CONCLUSION: Our data suggest that fibronectin-mediated activation of FAK that leads to lung cancer metastasis could occur through ERK or PI3K/Akt regulation of MMP9/calpain-2 or MMP9/RhoA activity, respectively.

PTPN22 allele polymorphisms in 15 Chinese populations.

Protein tyrosine phosphatase non-receptor 22 (PTPN22) is involved in the negative regulation of T-cell responsiveness. Recently, it has been reported that a single nucleotide polymorphism (SNP), C1858T, in the gene PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), is associated with an increased risk of a number of autoimmune diseases. To study the mutant frequency and polymorphism of PTPN22 in Chinese populations, 1085 individuals from 15 Chinese populations distributing widely from north to south were collected. The genotypes of PTPN22-C1858T were determined by polymerase chain reaction-restriction fragment length polymorphism with the digestion of restriction endonuclease RsaI. Of the 1085 individuals, 31 of whom were heterozygote (PTPN22-1858C/T), the frequency of PTPN22-1858T allele in those tested individuals was 1.43%. Moreover, the frequencies of PTPN22-1858T had significant variance in 15 populations of China (chi(2) = 74.1650, P < 0.01).

Human gastric adenocarcinoma allelotype on chromosomes 17 and 18.

Allelic losses of multiple chromosome loci in gastric adenocarcinoma suggest that inactivation of tumour suppressor genes in these regions may be important for tumourigenesis. To define deletion intervals and find candidate tumour suppressor genes involved in gastric adenocarcinoma pathogenesis, a genome-wide search for loss of heterozygosity (LOH) was conducted in 45 patients with primary gastric adenocarcinoma. Investigations using 29 microsatellite markers spanning chromosomes 17 and 18 showed allelic deletion in 29 (64%) specimens at one or more loci. Five LOH overlap regions, three newly identified as deletion regions, were defined: RI, D17S831 - D17S921 at 17p12-13.3; RII, D17S1868 - D17S787 at 17q21.3-22; RIII, D17S785 - D17S928 at 17q25.3; RIV, D18S61 - D18S1161 at 18q22; and RV, D18S462 - D18S70 at 18q22-q23. Eleven (24%) patients with chromosome 17 allelic loss also showed LOH on 18q, with at least one region of overlapping. LOH mapping showed allelic losses were widespread on both chromosomes and suggests the possibility that multiple tumour suppressor genes, including one or more that are unknown, might be inactivated in the aetiology of gastric adenocarcinoma.

CCR2 allele polymorphisms in 15 Chinese ethnic populations.

Chemokine receptor-2 (CCR2) is a co-receptor for the entry of human immunodeficiency virus-1 (HIV-1) into the target cells. A mutation in CCR2 (CCR2-64I) exhibited a protective effect to delay the progression of acquired immunodeficiency syndrome (AIDS). To study the mutant frequency and polymorphism of CCR2 in Chinese populations, 1082 individuals from 15 Chinese populations distributing widely from north to south were collected. The genotypes of CCR2-64I were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with the digestion of restriction endonuclease FokI. Of the 1082 individuals, 352 (32.53%) were carriers of CCR2-64I allele, 257 of whom (23.75%) were heterozygotes (CCR2-64V/I), whereas 95 (8.78%) were homozygotes (CCR2-64V/V). The frequency of the CCR2-64I allele in those tested individuals was 20.66%. This prevalence of CCR2-64I was higher than what was known for American and European populations. Moreover, the frequencies of CCR2-64I were generally higher in northern China than they were in southern China, and the frequencies had significant variance in 15 populations of China (chi2 = 27.135, P = 0.018).

Effects of silencing of mutant p53 gene in human lung adenocarcinoma cell line Anip973.

The mutational spectrum of p53 gene and the biological effects of mutant p53 protein vary greatly from one type of tumor to another. To investigate the biological effects of mutant p53 gene in human lung adenocarcinoma, mutant p53 was silenced by RNA interference (RNAi) in cell line Anip973. Then, the effects of mutant p53 silencing on cell cycle distribution and regulators, and on the TGFbeta/BMP signaling pathway were then investigated by flow cytometry, RT-PCR, and cDNA array screening. This study showed that mutant p53 silencing in Anip973 resulted in G1 arrest and G2/M arrest, for which the increased expression of p27 gene might be an important contribution factor. It was also found that the absence of mutant p53 affected the signal transduction of TGFbeta/BMP pathway mainly by up-regulating the expression of BMP superfamily cytokine growth differentiation factor 9 (GDF9), activin superfamily cytokine inhibin beta B (INHBB), smads target genes insulin-like growth factor binding protein 3 (IGFBP3) and involucrin (IVL). These results indicated the basic mechanism and the significant effects of mutant p53 on specific biological processes such as cell cycle and signal transduction in lung adenocarcinoma. These activities of mutant p53 may contribute to its 'gain of function' effects, which accelerate the oncogenesis and promotion of the tumor.

[Genescan analysis of the loss of heterozygosity on the long arm of chromosome 6 in non-small cell lung cancer].

To investigate if there are microsatellite loci in the long arm of chromosome 6 that have close relationship with non-small cell lung cancer, Multiple PCR approach was used to analyze the 36 loci in the long arm of chromosome 6. The PCR products were analyzed in PAGE and then the electrophoresis maps were analyzed with Genescan and Genotyper. There is different LOH frequency in different loci. The total frequency of LOH in 41 lung cancers was 78%(32/41), with the highest frequency of LOH was detected on the locus D6S302(75%). There are 14 loci which have LOH frequency more than 20% and the loci are mainly located in 2 regions: 6q16.3-q21 [6 loci D6S458 (21.43%), D6S1694 (26.92%), D6S1717 (35.71%), D6S1565 (40%), D6S302 (75%), D6S1706 (36.36%) and 6q26-q27 (5 loci D6S1550 (38.46%), D6S264 (20%), D6S1585 (25%), D6S446 (33.33%), D6S281 (30.77%)], There may be tumor suppressor genes located in the two regions, which have a close relationship with non-small cell lung cancer.

G1 arrest and relative protein expressions in mouse thymocytes induced by whole body X-ray irradiation.

OBJECTIVE: To investigate the molecular regulation of G1 arrest of mouse thymocytes induced by ionizing radiation. METHODS: Cell cycle was analyzed by flow cytometry (FCM) following staining of cells with propidium iodide. Fluorescent staining and flow cytometry analysis were employed for measurement of protein expression. RESULTS: It was demonstrated that G1 phase of mouse thymocytes increased significantly at 12 h after whole body irradiation (WBI) with the doses of 0.5, 1.0 and 2.0 Gy, and at 24 h following 2.0 Gy exposure, measured by FCM. In the time course experiment, it was found that G1 phase of thymocytes increased significantly at 4 h, reached a peak level at 24 h and came down toward 48 h after WBI with 2.0 Gy X-rays. The results also showed that after 2.0 Gy exposure, the expression of proteins in mouse thymocytes increased significantly from 1 h to 8 h for p53, for p21 from 4 h to 48 h, and for MDM2 at 4 h and 8 h, measured by FCM. But no change was found for GADD45 protein expression. CONCLUSION: These results suggest that G1 arrest could be induced by a single dose of 0.5 Gy, 1.0 Gy or 2.0 Gy, and its molecular control might be established through the p53-p21 pathway.

Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization.

Comparative genomic hybridization (CGH) has been applied to detect recurrent chromosome alterations in 62 primary gastric carcinomas. Several nonrandom chromosomal changes, including gains of 8q (31 cases, 50%), 20q (29 cases, 47%) with a minimum gain region at 20q11. 2-q12, 13q (21 cases, 34%) with a minimum gain region at 13q22, and 3q (19 cases, 31%) were commonly observed. The regions most frequently lost included: 19p (23 cases, 37%), 17p (21 cases, 33%), and 1p (14 cases, 23%). High copy number gain (DNA sequence amplification) was detected in 6 cases. Amplification of 8q23-q24.2 and 20q11.2-q12 were observed in 3 cases. Gain of 20q and loss of 19p were confirmed by fluorescence in situ hybridization using corresponding bacterial artificial chromosomes (BAC) clones from those regions. The gain and loss of chromosomal regions identified in this study provide candidate regions involved in gastric tumorigenesis.

Cytogenetic study of twenty-three primary squamous cell carcinomas of the lung.

Fifty-seven primary squamous cell carcinomas of the lung were analyzed cytogenetically. Karyotyping was possible in seven cases, and chromosome counting without detailed analysis was possible in 16 other cases. The results suggested that structural chromosome rearrangements related to the short arms of chromosomes 1(5/7), 9(3/7), and 11(6/7), and the long arms of chromosomes 6(4/7) and 7(6/7) may be the primary and non-random chromosome defects which are closely associated with human lung squamous cell carcinoma. These primary and non-random chromosome defects are believed to confer a proliferative advantage to cells carrying them, and to be involved in the pathogenesis of human lung squamous cell carcinoma.

The origin of isochromosomes and their significance in tumorigenesis of human lung cancer.

Isochromosomes related to chromosomes 1, 5, 6, 8, and 9 were frequently observed in 23 cases of lung cancer. Their existence in tumor cells might be nonrandom. Premature centromere separation (PCS) was found in the PGT-131 cell line of a lung cancer. It is suggested that PCS may play a role in the formation of isochromosomes in lung cancer.

Direct chromosome analysis of 50 primary breast carcinomas.

Direct chromosome analyses were performed in 50 cases of primary breast carcinoma. Thirty-six cases had modal chromosome counts in the diploid range; the other 14 cases were polyploid. Of the 22 cases with detailed G-banding analyses, the most frequent structural changes involved chromosome 1 (15 of 22), 3 (13 of 22), and 6 (13 of 22). Deletion of chromosome 1p was noted in nine cases, and both 3p- and 6q- were noted in 10 cases.