Publications by authors named "Mingyang Xiao"

13 Publications

  • Page 1 of 1

Benzo[a]pyrene diol epoxide-induced transformed cells identify the significance of hsa_circ_0051488, a ERCC1-derived circular RNA in pulmonary squamous cell carcinoma.

Mol Carcinog 2021 10 28;60(10):684-701. Epub 2021 Jul 28.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China.

ERCC1 is a gene for repairing DNA damage whose function is related to carcinogenic-induced tumorigenesis and the effectiveness of platinum therapies. Circular RNAs (circRNAs) are products of posttranscriptional regulation with pleiotropic effects on the pathogenesis of lung cancer. We aim to identify that specific circRNAs derived from ERCC1 can regulate key biological processes involved in the development of lung cancer. We performed bioinformatics analysis, in vitro experiments, and analyzed clinical samples, to determine the biological features of a certain ERCC1-derived circRNA termed as hsa_circ_0051488 in benzo[a]pyrene diol epoxide-induced malignant transformed cell and lung cancer cell. The well-established model of transformed cells provided an ideal platform for analyzing the molecular characteristics of this circRNA in the malignant transformation of lung epithelial cell, which supports that hsa_circ_0051488 functions in the onset and growth of lung squamous cell carcinoma (LUSC). Further analysis indicates that the absence of hsa_circ_0051488 promoted the proliferation of cells with the malignant phenotype. Extensive experiments confirm that hsa_circ_0051488 is present in the cytoplasm and functioned as a competing endogenous RNA. In particular, hsa_circ_0051488 binds to mir-6717-5p, thereby modulating the expression of SATB2 gene, a lung cancer suppressor. Furthermore, our in silico experiments indicate that SATB2 can inhibit multiple tumor pathways and its expression positively correlated with the tumor suppressor gene CRMP1. These findings suggest a possible regulatory mechanism of hsa_circ_0051488 in LUSC, and that the newly discovered hsa_circ_0051488/miR-6717-5p/SATB2 axis may be a potential route for therapeutic intervention of LUSC.
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http://dx.doi.org/10.1002/mc.23335DOI Listing
October 2021

Co-exposure to BPA and DEHP enhances susceptibility of mammary tumors via up-regulating Esr1/HDAC6 pathway in female rats.

Ecotoxicol Environ Saf 2021 Sep 26;221:112453. Epub 2021 Jun 26.

Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New District, Shenyang 110122, Liaoning Province, PR China. Electronic address:

Breast cancer (BrCa) as one of the major malignancies threatening women's health worldwide occurs due to the genetic and environmental interactions. Epidemiological studies have suggested that exposure to endocrine disrupting chemicals (EDCs) can elevate the risk of breast cancer. Di-(2-ethylhexyl)-phthalate (DEHP) and bisphenol A (BPA) are known as two typical EDCs. Although several studies have implied that there appear to have adverse effects of exposure to BPA or DEHP alone on breast development, no study to date has demonstrated the exact toxic effect of combined exposure to DEHP and BPA on breast tumorigenesis. In the present study, we performed an in vivo experiment including 160 female Sprague-Dawley (SD) rats, in which 80 rats were randomly allocated to 4 groups including control group given to normal diet, DEHP (150 mg/kg body weight/day), BPA (20 mg/kg body weight/day), and DEHP (150 mg/kg body weight/day) combined with BPA (20 mg/kg body weight/day) by gavage for 30 weeks. Additionally, a DEN/MNU/DHPN (DMD)-induced carcinogenesis animal model was also established to assess their effect on tumor promotion. Namely, the other 80 SD rats were separated into another 4 groups: in addition to DMD initiation each group treated with vehicle, DEHP, BPA and the combination of BPA and DEHP respectively. Our data demonstrated that BPA alone or in combination with DEHP may induce hyperplasia of mammary glands, including the proliferation of ductal epithelial cells and an increase in the number of lobules and acinus after a 30-week exposure. Notably, co-exposure to DEHP and BPA increased the incidence and reduced the latency of mammary tumor, which seemed to enhance the susceptibility of carcinogens-induced tumor. Mechanistically, our results supported the hypothesis that exposure to BPA and DEHP might promote breast cancer dependent on Esr1 and HDAC6 as pivotal factors, and further lead to the activation of oncogene c-Myc. Our study suggested that BPA combined with DEHP facilitate the occurrence of mammary tumors, which contributed to advance our understanding in the complex effects of compound exposure to endocrine disrupting chemicals.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112453DOI Listing
September 2021

The m6A methyltransferase METTL14 inhibits the proliferation, migration, and invasion of gastric cancer by regulating the PI3K/AKT/mTOR signaling pathway.

J Clin Lab Anal 2021 Mar 12;35(3):e23655. Epub 2020 Dec 12.

Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Department of Surgical Oncology and General Surgery, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China.

Background: N6-methyladenosine (m6A) modification may participate in the regulation of occurrence and development of tumors. However, the m6A level and the potential regulatory mechanism of m6A in gastric cancer (GC) remain uncertain.

Methods: RNA m6A quantification assay was conducted to detect the m6A level in GC tissues and cell lines. Methyltransferase-like 14 (METTL14) expression in GC tissues was explored by bioinformatics and immunohistochemistry. Then, the function of METTL14 in GC cells was examined by CCK-8, colony formation assay, wound healing assay, and Transwell assay. Besides, Western blotting was conducted to probe the PI3K/AKT/mTOR pathway and the epithelial-mesenchymal transformation (EMT) pathway-related gene expression.

Results: The m6A modification level was decreased in GC and METTL14 was a key regulator resulting in m6A disorder in GC. METTL14 was downregulated in GC by analyzing both clinical samples and bioinformatics. METTL14 overexpression suppressed GC cell proliferation and aggression by deactivating the PI3K/AKT/mTOR pathway and the EMT pathway, respectively.

Conclusions: Our findings indicate that METTL14 partakes in the biological process of GC as a tumor suppressor and may be an emerging biomarker in GC.
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http://dx.doi.org/10.1002/jcla.23655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957981PMC
March 2021

Combined effects of di (2-ethylhexyl) phthalate and bisphenol A on thyroid hormone homeostasis in adolescent female rats.

Environ Sci Pollut Res Int 2020 Nov 17;27(32):40882-40892. Epub 2020 Jul 17.

Department of Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People's Republic of China.

Phthalates and bisphenols are two typical classes of endocrine-disrupting chemicals (EDCs) which cause endocrine disorder in humans and animals. Phthalates and bisphenols are suggested to be associated with thyroid dysfunction. However, the effects of combined exposure and the detailed mechanisms are yet poorly understood. We investigated the combined effects of di (2-ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) on thyroid function during puberty. Female Sprague Dawley rats were gavaged from postnatal 28 to 70 days with a single or combined exposure of DEHP (0, 150, and 750 mg/kg/day) and BPA (0, 20, and 100 mg/kg/day) according to a 3 × 3 factorial design. The thyroid weights reduced after combined exposure to the highest dose of DEHP and BPA, which noted their adverse effects on thyroid. Additionally, DEHP could increase the number of follicular epithelial cells in thyroid. Both DEHP and in combination with BPA could disturb the levels of thyroid hormones in serum, such as TT3 and TT4. Meanwhile, the possible mechanism was also discussed in the present study. DEHP treatment induced a significant increase of phosphorylation of cAMP-response element binding protein (Creb) via estrogen receptor α (Esr1), while the upregulation was nullified by the concomitant presence of BPA. In conclusion, the complex action of DEHP/BPA mixture may disturb the thyroid hormone homeostasis, which ultimately would affect the development of thyroid during puberty.
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http://dx.doi.org/10.1007/s11356-020-09949-wDOI Listing
November 2020

Renal denervation for treating congenital long QT syndrome: shortening the QT interval or modulating sympathetic tone?-Author's reply.

Europace 2019 11;21(11):1756-1757

Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Service Center, Chongqing, China.

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http://dx.doi.org/10.1093/europace/euz266DOI Listing
November 2019

AC138128.1 an Intronic lncRNA originating from ERCC1 Implies a Potential Application in Lung Cancer Treatment.

J Cancer 2019 9;10(16):3608-3617. Epub 2019 Jun 9.

Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, P.R. China.

Lung cancer is one of the most devastating tumors with a high incidence and mortality worldwide. Polymorphisms and expression of commonly predicted the occurrence and prognosis of lung cancer. However, few studies have focused on long non-coding RNAs related to though some studies reminded the importance of its post-transcriptional regulation. In the present study, an intronic lncRNA AC138128.1 originated from was firstly identified in microarray chip and database, and its possibility as a novel biomarker to predict lung cancer treatment was further discussed. Firstly, the qRT-PCR data showed that AC138128.1 expression was much lower in lung cancer comparing with its para-cancer tissues, which further analyzed by ROC curve. Similarly, the difference was also verified in 16HBE, A549 and LK cells. Then AC138128.1 expression was found to have an increasing trend in a dose or time-dependent manner after cisplatin treatment. Finally, the subcellular distribution of AC138128.1 reminded that AC138128.1 was mainly expressed in the nucleus. Interestingly a positive relationship between AC138128.1 and expression was only found in cancer tissues, which reminded AC138128.1 may be involved in the regulation of ERCC1. Therefore, as a preliminary exploration of the lncRNA originated from , the present study suggested AC138128.1 is of potential value in predicting platinum analogue benefit in lung cancer.
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http://dx.doi.org/10.7150/jca.31832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636308PMC
June 2019

Congenital long QT syndrome treated by renal sympathetic denervation.

Europace 2019 Nov;21(11):1741

Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Cardiac Arrhythmia Service Center, Chongqing, China.

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http://dx.doi.org/10.1093/europace/euz191DOI Listing
November 2019

An Antagonism Joint Action of Lead and Di-2-Ethylhexyl Phthalate Explains an Improved Ability of Learning and Memory after Combined Exposure in Weaning Rats.

Biol Trace Elem Res 2019 Sep 6;191(1):126-134. Epub 2018 Dec 6.

Department of Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People's Republic of China.

Lead and di-2-ethylhexyl phthalate (DEHP) are widely distributed in the environment, and their neurotoxicity has caused a widespread concern. The complexity of environmental exposure provides the possibility of their combined exposure. The present study aims to describe a joint neurotoxicity and clarify the potential mechanism after combined exposure to lead and DEHP. A 2 × 3 factorial design was used to analyze either single effects or their interaction by a subchronic lead and DEHP exposure model of the male weaning rats. Similar to the previous study, lead or DEHP single exposure showed an increased neurotoxicity. Interestingly, our neurobehavioral test showed the rats in the combined exposure groups had a better ability of learning and memory compared with the single-exposure ones. It seemed to reflect an antagonism joint action in neurotoxicity after combined exposure. The content of dehydroepiandrosterone (DHEA) in serum and the mRNA level of brain-derived neurotrophic factor (Bdnf) in the hippocampus showed a similar trend to the ability of learning and memory. However, there was insufficient evidence to support the joint action on some indexes of oxidative stress such as malondialdehyde (MDA), the ratio of reduced glutathione(GSH) to oxidized glutathione(GSSG), γglutamylcysteine synthetase (γ-GCS), glutathione-s transferase (GST), and nuclear factor E2-related factor 2 (Nrf2) mRNA expression in the hippocampus. In a word, our current study reminded a unique antagonism joint action of neurotoxicity after combined exposure to lead and DEHP, which may contribute to understanding some shallow mechanism of the joint toxicity due to the complexity of environmental pollutant exposure.
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http://dx.doi.org/10.1007/s12011-018-1586-5DOI Listing
September 2019

Rs3212986 polymorphism, a possible biomarker to predict smoking-related lung cancer, alters DNA repair capacity via regulating ERCC1 expression.

Cancer Med 2018 12 19;7(12):6317-6330. Epub 2018 Nov 19.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, China.

Single nucleotide polymorphisms (SNPs) in 3'UTR of key DNA repair enzyme genes are associated with inter-individual differences of DNA repair capacity (DRC) and susceptibility to a variety of human malignancies such as lung cancer. In this study, seven candidate SNPs in 3'UTR of DRC-related genes including ERCC1 (rs3212986, rs2336219, and rs735482), OGG1 (rs1052133), MLH3 (rs108621), CD3EAP (rs1007616), and PPP1R13L (rs6966) were analyzed in 300 lung cancer patients and controls from the northeast of China. Furthermore, we introduced ERCC1 (CDS+3'UTR) or CD3EAP (CDS) cDNA clone to transfect HEK293T and 16HBE cells. Cell viability between different genotypes of transfected cells exposed to BPDE was detected by CCK-8 assay, while DNA damage was visualized using γH2AX immunofluorescence and the modified comet assay. We found that minor A-allele of rs3212986 could reflect a linkage with increasing risk of NSCLC. Compared with CC genotype, AA genotype of ERCC1 rs3212986 was a high-risk factor for NSCLC (OR = 3.246; 95%CI: 1.375-7.663). Particularly stratified by smoking status in cases and controls, A allele of ERCC1 rs3212986 also exhibited an enhanced risk to develop lung cancer in smokers only (P < 0.05). Interestingly, reduced repair efficiency of DNA damage was observed in 293T ERCC1(AA) and 16HBE ERCC1(AA), while no significant difference was appeared in two genotypes of CD3EAP (3' adjacent gene of ERCC1) overexpressed cells. Our findings suggest that rs3212986 polymorphism in 3'UTR of ERCC1 overlapped with CD3EAP may affect the repair of the damage induced by BPDE mainly via regulating ERCC1 expression and become a potential biomarker to predict smoking-related lung cancer.
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http://dx.doi.org/10.1002/cam4.1842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308093PMC
December 2018

Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment.

Int J Oncol 2018 Jun 29;52(6):2155-2165. Epub 2018 Mar 29.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, P.R. China.

Numerous genes are arranged in complex overlapping and interlaced patterns, and such arrangements potentially contribute to the regulation of gene expression. Previous studies have demonstrated that a region in chromosome 19q13.2-3 encompassing the overlapping genes excision repair cross-complementation group 1 (ERCC1), CD3e molecule associated protein (CD3EAP) and protein phosphatase 1 regulatory subunit 13 like (PPP1R13L) was found to be associated with the risk and prognosis of non-small cell lung cancer (NSCLC). The present study confirmed the hypothesis that there are co-expression patterns among these overlapping genes. The suggestive bioinformatic evidence of The Cancer Genome Atlas was verified by quantitative polymerase chain reaction (qPCR) analysis of NSCLC tissue samples. In addition, a cisplatin-induced DNA damage cell model was assessed by microarray analysis, qPCR and 3' rapid amplification of cDNA ends (3'RACE) to verify and quantify the expression levels of co-expressed alternative splicing isoforms in the NSCLC tissues, as well as in cancer A549 and normal 16HBE cells. The expression of CD3EAP exon 1 was demonstrated to be significantly associated with PPP1R13L exon 1, while CD3EAP exon 3 was significantly associated with ERCC1 exon 11 in normal and NSCLC tissues. It was observed that short transcripts of ERCC1, CD3EAP and PPP1R13L are co-expressed in A549 cells and full-length transcripts are co-expressed in 16HBE cells. Furthermore, a novel transcriptional regulation pattern was described based on the positional associations of overlapping genes. The region encompassing the overlapping genes ERCC1, CD3EAP and PPP1R13L may be involved in linking the upstream and downstream genes, while the different splicing isoforms of ERCC1 affect the expression of its overlapping genes, suggesting potential application in cisplatin resistance in NSCLC treatment.
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http://dx.doi.org/10.3892/ijo.2018.4347DOI Listing
June 2018

The polymorphisms of miRNA-binding site in MLH3 and ERCC1 were linked to the risk of colorectal cancer in a case-control study.

Cancer Med 2018 04 8;7(4):1264-1274. Epub 2018 Mar 8.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, China.

Colorectal cancer (CRC), as a malignant tumor of lower digestive tract, has been found to have an increasing morbidity and mortality in China. It was particularly important to find some earlier biomarkers to predict the risk and prognosis. In this study, several polymorphisms on 3'UTR of three DNA repair genes including MLH3 rs10862, ERCC1 rs3212986, ERCC1 rs735482, ERCC1 rs2336219, and OGG1 rs1052133 were chosen by bioinformatics exploration, and then, a case-control study of 200 CRC cases and controls was performed. Furthermore, a dual-luciferase assay was also carried out to certify whether the candidate miRNA can regulate its target gene and the selected SNPs have a valid effect on the target miRNA. Finally, both of ERCC1 rs3212986 and MLH3 rs108621 were shown to be associated with the risk of CRC. Comparing with rs3212986 CC genotype, AA was at a higher risk (OR = 3.079, 95% CI: 1.192-7.952). For MLH3 rs108621, comparing with TT genotype, CC and TC were at a higher risk of CRC in male (OR = 5.171, 95% CI: 1.009-26.494; OR = 1.904, 95% CI: 1.049-3.455). Interestingly, an analysis combining both ERCC1 rs3212986 and MLH3 rs108621 also showed an increased risk of CRC. In addition, a dual-luciferase assay showed that miR-193a-3p could regulate MLH3, and the polymorphism rs108621 could alter the miR-193a-3p binding to MLH3. Therefore, MLH3 rs108621 may be associated with the risk of CRC due to the effect of miR-193a-3p on MLH3, which reminded the possibility as potential susceptibility biomarkers to predict the risk of CRC.
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http://dx.doi.org/10.1002/cam4.1319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911615PMC
April 2018

Genetic polymorphisms in 19q13.3 genes associated with alteration of repair capacity to BPDE-DNA adducts in primary cultured lymphocytes.

Mutat Res Genet Toxicol Environ Mutagen 2016 Dec 29;812:39-47. Epub 2016 Oct 29.

Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China. Electronic address:

Benzo[a]pyrene(B[a]P), and its ultimate metabolite Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), are classic DNA damaging carcinogens. DNA damage in cells caused by BPDE is normally repaired by Nucleotide Excision Repair (NER) and Base Excision Repair (BER). Genetic variations in NER and BER can change individual DNA repair capacity to DNA damage induced by BPDE. In the present study we determined the number of in vitro induced BPDE-DNA adducts in lymphocytes, to reflect individual susceptibility to Polycyclic aromatic hydrocarbons (PAHs)-induced carcinogenesis. The BPDE-DNA adduct level in lymphocytes were assessed by high performance liquid chromatography (HPLC) in 281 randomly selected participants. We genotyped for 9 single nucleotide polymorphisms (SNPs) in genes involved in NER (XPB rs4150441, XPC rs2228001, rs2279017 and XPF rs4781560), BER (XRCC1 rs25487, rs25489 and rs1799782) and genes located on chromosome 19q13.2-3 (PPP1R13L rs1005165 and CAST rs967591). We found that 3 polymorphisms in chromosome 19q13.2-3 were associated with lower levels of BPDE-DNA adducts (MinorT allele in XRCC1 rs1799782, minor T allele in PPP1R13L rs1005165 and minor A allele in CAST rs967571). In addition, a modified comet assay was performed to further confirm the above conclusions. We found both minor T allele in PPP1R13L rs1005165 and minor A allele in CAST rs967571 were associated with the lower levels of BPDE-adducts. Our data suggested that the variant genotypes of genes in chromosome 19q13.2-3 are associated with the alteration of repair efficiency to DNA damage caused by Benzo[a]pyrene, and may contribute to enhance predictive value for individual's DNA repair capacity in response to environmental carcinogens.
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http://dx.doi.org/10.1016/j.mrgentox.2016.10.004DOI Listing
December 2016

Genetic Polymorphisms in XRCC1, CD3EAP, PPP1R13L, XPB, XPC, and XPF and the Risk of Chronic Benzene Poisoning in a Chinese Occupational Population.

PLoS One 2015 17;10(12):e0144458. Epub 2015 Dec 17.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, P.R. China.

Objectives: Individual variations in the capacity of DNA repair machinery to relieve benzene-induced DNA damage may be the key to developing chronic benzene poisoning (CBP), an increasingly prevalent occupational disease in China. ERCC1 (Excision repair cross complementation group 1) is located on chromosome 19q13.2-3 and participates in the crucial steps of Nucleotide Excision Repair (NER); moreover, we determined that one of its polymorphisms, ERCC1 rs11615, is a biomarker for CBP susceptibility in our previous report. Our aim is to further explore the deeper association between some genetic variations related to ERCC1 polymorphisms and CBP risk.

Methods: Nine single nucleotide polymorphisms (SNPs) of XRCC1 (X-ray repair cross-complementing 1), CD3EAP (CD3e molecule, epsilon associated protein), PPP1R13L (protein phosphatase 1, regulatory subunit 13 like), XPB (Xeroderma pigmentosum group B), XPC (Xeroderma pigmentosum group C) and XPF (Xeroderma pigmentosum group F) were genotyped by the Snapshot and TaqMan-MGB® probe techniques, in a study involving 102 CBP patients and 204 controls. The potential interactions between these SNPs and lifestyle factors, such as smoking and drinking, were assessed using a stratified analysis.

Results: An XRCC1 allele, rs25487, was related to a higher risk of CBP (P<0.001) even after stratifying for potential confounders. Carriers of the TT genotype of XRCC1 rs1799782 who were alcohol drinkers (OR = 8.000; 95% CI: 1.316-48.645; P = 0.022), male (OR = 9.333; 95% CI: 1.593-54.672; P = 0.019), and had an exposure of ≤12 years (OR = 2.612; 95% CI: 1.048-6.510; P = 0.035) had an increased risk of CBP. However, the T allele in PPP1R13L rs1005165 (P<0.05) and the GA allele in CD3EAP rs967591 (OR = 0.162; 95% CI: 0039~0.666; P = 0.037) decreased the risk of CBP in men. The haplotype analysis of XRCC1 indicated that XRCC1 rs25487A, rs25489G and rs1799782T (OR = 15.469; 95% CI: 5.536-43.225; P<0.001) were associated with a high risk of CBP.

Conclusions: The findings showed that the rs25487 and rs1799782 polymorphisms of XRCC1 may contribute to an individual's susceptibility to CBP and may be used as valid biomarkers. Overall, the genes on chromosome 19q13.2-3 may have a special significance in the development of CBP in occupationally exposed Chinese populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144458PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683048PMC
June 2016
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