Publications by authors named "Mingjun Sun"

49 Publications

Potential Impact of ALKBH5 and YTHDF1 on Tumor Immunity in Colon Adenocarcinoma.

Front Oncol 2021 17;11:670490. Epub 2021 May 17.

Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, China.

Background: ALKBH5 and YTHDF1 are regarded as the eraser and reader, respectively, in N6-methyladenosine (m6A) modification. Recently, immune contexture has been drawing increasing attention in terms of the progression and treatment of cancers. This study aimed to determine the relationship between ALKBH5/YTHDF1 and immunological characteristics of colon adenocarcinoma (COAD).

Methods: Expression of ALKBH5 and YTHDF1 was investigated across TCGA and GEO validated in our study. Patients with COAD were divided into two clusters using consensus clustering based on the expression of ALKBH5 and YTHDF1. We then compared their clinical characteristics and performed gene set enrichment analysis (GSEA) to identify the functional differences. Immune infiltration analyses were conducted using ESTIMATE, CIBERSORT, and ssGSEA. In addition, we evaluated the expression of the targets of immune checkpoint inhibitors (ICIs) and calculated the tumor mutation burden (TMB) of the tumor samples. Weighted gene co-expression network analysis (WGCNA) was used to identify the genes related to both ALKBH5/YTHDF1 expression and immunity. GSE39582 was utilized for external validation of immunological features between the two clusters.

Results: Cluster 2 had high expression of ALKBH5 and lesser so of YTHDF1, whereas Cluster 1 had just the reverse. Cluster 1 had a higher N stage and pathological stage than Cluster 2. The latter had stronger immune infiltration, higher expression of targets of ICIs, more TMB, and a larger proportion of deficiency in mismatch repair-microsatellite instability-high (dMMR-MSI-H) status than Cluster 1. Moreover, WGCNA revealed 14 genes, including PD1 and LAG3, related to both the expression of ALKBH5/YTHDF1 and immune scores.

Conclusions: ALKBH5 and YTHDF1 influence immune contexture and can potentially transform cold tumors into hot tumors in patients with COAD.
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http://dx.doi.org/10.3389/fonc.2021.670490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165310PMC
May 2021

Comparative analysis of the main outer membrane proteins of Brucella in the diagnosis of brucellosis.

Biochem Biophys Res Commun 2021 Jun 11;560:126-131. Epub 2021 May 11.

Key Lab of Environment and Health, School of Public Health, Xuzhou Medical University, Xuzhou, 221004, China. Electronic address:

Brucellosis has placed a heavy economic burden on numerous countries and has consumed considerable medical resources worldwide. To improve the specificity and sensitivity of serological methods for diagnosing brucellosis, it is important to develop new diagnostic antigens. Brucella outer membrane proteins(omps) possess good immunogenicity, but there is a scarcity of comparative studies of these proteins in the clinical diagnosis of brucellosis. In this study, six recombinant Brucella outer membrane proteins, omp10, omp16, omp19, omp25, omp31 and BP26, were expressed in prokaryotic cells and utilized as diagnostic antigens. The clinical sera of humans, bovines and goats with brucellosis were analyzed by indirect ELISA using these proteins, lipopolysaccharide(LPS) and Rose Bengale Ag, served as positive-control antigens. In diagnosing human and goat serum, BP26 exhibited the highest diagnostic accuracy of 96.45% and 95.00%, respectively, while omp31 exhibited the strongest ability to detect Brucella in bovine serum with an accuracy of 84.03%. Cross-reaction experiments also confirmed that the diagnostic specificities of omp31 and BP26 were higher than those of the LPS and Rose Bengale Ag antigens. The results of this study indicate that omp31 and BP26 are candidate antigens with high potential application value in the clinical diagnosis of brucellosis.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.127DOI Listing
June 2021

Sputum cell-free DNA: Valued surrogate sample for the detection of EGFR exon 20 p.T790M mutation in patients with advanced lung adenocarcinoma and acquired resistance to EGFR-TKIs.

Cancer Med 2021 May 1;10(10):3323-3331. Epub 2021 May 1.

Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.

Background: Sputum cell-free DNA (cfDNA) is a valuable surrogate sample for assessing EGFR-sensitizing mutations in patients with advanced lung adenocarcinoma. Detecting EGFR exon 20 p.T790 M (p.T790 M) is much more challenging due to its limited availability in tumor tissues. Exploring sputum cfDNA as an alternative for liquid-based sample type in detecting p.T790 M requires potential improvement in clinical practice.

Methods: A total of 34 patients with EGFR-sensitive mutation-positive lung adenocarcinoma and acquired resistance to the first generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were enrolled. The sputum samples, and paired tumors and/or plasma samples were tested for p.T790 M mutation and concordance of p.T790 M status among the three sample types was analyzed.

Results: The overall concordance rate of p.T790 M mutation between sputum cfDNA and tumor tissue samples was 85.7%, with a sensitivity of 66.7% and a specificity of 100%. The sensitivity for detecting p.T790 M in sputum cfDNA was 100%, 66.7%, and 0% in the three sputum groups of malignant, satisfactory but no malignant cells, and unsatisfactory, respectively. The combined results of plasma cfDNA testing and sputum cfDNA testing further increased the sensitivity to 100% for p.T790 M detection in satisfactory but no malignant cells sputum group.

Conclusion: These findings revealed that cfDNA from malignant or satisfied but no malignant cells sputum is considered suitable for detecting p.T790 M mutation in patients with acquired resistance to first or second-generation EGFR-TKIs. The sputum cytological pathological evaluation-guided sputum cfDNA testing assists in significantly improving the sensitivity of p.T790 M detection, bringing significant value for the maximal application of third-generation EGFR-TKIs in second-line treatment.
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http://dx.doi.org/10.1002/cam4.3817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124129PMC
May 2021

Long non-coding RNA DICER1-AS1-low expression in arsenic-treated A549 cells inhibits cell proliferation by regulating the cell cycle pathway.

Environ Toxicol Pharmacol 2021 May 17;84:103617. Epub 2021 Feb 17.

School of Public Health, Kunming Medical University, Kunming, 650500, China. Electronic address:

Arsenic, an environmental pollution with diverse toxicities, incurs public health problems. Arsenic trioxide could inhibit cell proliferation in vitro experiments, but the underlying mechanisms are not fully known. LncRNAs are also involved in the arsenic-induced toxicological responses. In our study, we found that the expression of lncRNA DICER1-AS1 was significantly inhibited by sodium arsenite in a dose-dependent manner. DICER1-AS1 silencing decreased the A549 cell proliferation and inhibited cell cycle progression. Importantly, DICER1-AS1 silencing induced upregulation of p21 and downregulation of Cyclin A2, Cyclin E2, CDK1 and PCNA. In conclusion, our study provided a new lncRNA-dictated regulatory mechanism participating in arsenic-induced inhibition of cell proliferation.
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http://dx.doi.org/10.1016/j.etap.2021.103617DOI Listing
May 2021

LncRNA-PCAT1 controls the growth, metastasis and drug resistance of human colon cancer cells.

J BUON 2020 Sep-Oct;25(5):2180-2185

Department of Gastroenterology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.

Purpose: The long non-coding (lnc) RNAs have been shown to exhibit profound regulatory roles in maintaining the growth and proliferation of human cancer cells. Taking this fact into consideration, the current research work was scheduled to explore the regulatory control of lncRNA-PCAT1 in maintaining the growth and progression of human colon cancer cell.

Methods: The expression of lncRNA-PCAT1 was assessed through qRT-PCR method. DAPI and acridine orange (AO)/ethidium bromide (EB) staining protocols along with the colony formation protocols were performed to evaluate the viability of cancer cells. The migratory and invasion properties of cancer cells were examined by the wound-healing and transwell assays, respectively. Western blotting was used to assess the expression of proteins of interest. MTT assay was used for the assessment of cell proliferation.

Results: lncRNA-PCAT1 was highly up-regulated in the colon cancer tissues and cancer cell lines. The repression of lncRNA-PCAT1 in colon cancer cells reduced their viability through induction of Bax/Bcl-2 mediated apoptosis. The inhibition of lncRNA-PCAT1 expression further declined the migration and invasion of colon cancer cells along with the decline of cell proliferation and enhanced the chemosensitivity of colon cancer cells.

Conclusion: lncRNA-PCAT1 expression may be utilized as a vital prognostic tool in colon cancer and highlighted its regulatory effects in maintaining the colon cancer growth and proliferation.
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December 2020

Inorganic arsenic-mediated upregulation of AS3MT promotes proliferation of nonsmall cell lung cancer cells by regulating cell cycle genes.

Environ Toxicol 2021 Feb 15;36(2):204-212. Epub 2020 Sep 15.

School of Public Health, Kunming Medical University, Kunming, China.

Long-term arsenic exposure can promote cancer through epigenetic mechanisms, and arsenite methyltransferase (AS3MT) plays an important role in this process. However, the expression patterns and mechanisms of AS3MT in arsenic carcinogenesis remain unclear. In this study, we found that the AS3MT was overexpressed in arsenic exposed population, non-small cell lung cancer (NSCLC) tissues, and A549 cells with sodium arsenite (NaAsO ) treatment for 48 hours. Besides, the level of AS3MT expression was positively correlated with the concentrations of urinary total arsenic (tAs), inorganic arsenic (iAs), methanearsonic acid (MMA), and dimethylarsinic acid (DMA) in all subjects. Functional experiments demonstrated that siRNA-mediated knockdown of AS3MT significantly inhibited proliferation of A549 cells. Mechanism investigation revealed that silencing of AS3MT inhibited proliferation by increasing mRNA expression levels of p21 and E2F1, and inhibiting CDK1, CDK2, CDK4, CDK6, Cyclin A2, Cyclin E1, Cyclin E2, and PCNA mRNA expression. Therefore, arsenic increased AS3MT expression in vivo and in vitro, which could directly act on the cell and affect the progression of NSCLC by regulating cell cycle genes.
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http://dx.doi.org/10.1002/tox.23026DOI Listing
February 2021

Arsenic exposure increased expression of HOTAIR and LincRNA-p21 in vivo and vitro.

Environ Sci Pollut Res Int 2021 Jan 20;28(1):587-596. Epub 2020 Aug 20.

School of Public Health, Kunming Medical University, No.1168 Chunrongxi Road Chenggong District, Kunming, Yunnan Province, China.

Arsenic is an environmental contaminant, its multiple effects on human tend to increase the rate of disease, cancer and other health problems. Some of long non-coding RNAs (lncRNAs) can be induced in major cellular processes such as necrosis, proliferation, and mutation. While the toxicity of arsenic is well established, the association between arsenic exposure and long non-coding RNAs has not been studied enough. This study investigated the association between arsenic and the expression of HOTAIR and LincRNA-p21 in vivo and vitro. In epidemiological studies, the expression of HOTAIR and LincRNA-p21 was increased after long-term arsenic exposure. HOTAIR and LincRNA-p21 expression were positively linked to monomethylarsenic acid (MMA), dimethylarsenic acid (DMA), inorganic arsenic (iAs), total arsenic (tAs), and MMA% and negatively linked to secondary methylation index (SMI). In A549 cells, arsenic exposure resulted in enhanced HOTAIR and LincRNA-p21 expression dose-dependently. The expression of HOTAIR was considerably high in the presence of NaAsO and MMA but showed no difference in DMA compared with control group. And LincRNA-p21 expression was increased in the presence of NaAsO, MMA, and DMA. The expression of HOTAIR and LincRNA-p21 induced by iAs was much higher than that induced by MMA and DMA. Compared with the control group, treatment of A549 cells with NaAsO/S-adenosylmethionine (SAM) and NaAsO/glutathione (GSH) combination increased HOTAIR and LincRNA-p21 expression. The expression of LincRNA-p21 in combination of NaAsO/GSH was significantly decreased compared with NaAsO alone. Besides, in the presence of arsenic, both of HOTAIR and LincRNA-p21 were upregulated significantly when P53 was knocked down. We revealed that inorganic arsenic, its methylated metabolites, and arsenic metabolism efficiency affect the expression of HOTAIR and LincRNA-p21.
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http://dx.doi.org/10.1007/s11356-020-10487-8DOI Listing
January 2021

H. pylori slyD, a novel virulence factor, is associated with Wnt pathway protein expression during gastric disease progression.

Microb Pathog 2020 Nov 10;148:104428. Epub 2020 Aug 10.

Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, 110001, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China. Electronic address:

We have previously reported that the virulence factor HpslyD is related to the occurrence of gastric diseases. However, its mechanism of pathogenesis is still unclear. It is commonly believed that the Wnt/β-catenin pathway is indispensable for the development of gastric cancer, but it is unclear whether HpslyD and Wnt/β-catenin interact during the development of gastric diseases. Therefore, we measured the expression of E-cadherin, β-catenin, TCF4, and CDX2 proteins by IHC in gastric mucosa specimens from patients with different gastric diseases and compared the differences in protein expression to H. pylori-infection status. The results indicated that the expression of these proteins was associated with HpslyD infection. HpslyD subtype infection, rather than common H. pylori infection, may have a greater effect on the expression of Wnt proteins in atrophic gastritis and gastric cancer. Additionally, HpslyD strain infection promoted the expression of Wnt pathway-related proteins with the progression of gastric disease. This study provides insight into the pathogenesis of H. pylori-related gastric diseases and "type-based treatment" for H. pylori infection.
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http://dx.doi.org/10.1016/j.micpath.2020.104428DOI Listing
November 2020

First identification of a Brucella abortus biovar 4 strain from yak in Tibet, China.

Vet Microbiol 2020 Aug 10;247:108751. Epub 2020 Jun 10.

Laboratory of Zoonoses, National Animal Brucellosis Specialized Laboratory, China Animal Health and Epidemiology Center, Qingdao, 266032, China. Electronic address:

Brucellosis is one of the major zoonotic diseases in the world. In China, understanding on its causative agent Brucella is still limited. Recently, we isolated a Brucella strain XZ19-1 from yak in Lhasa, Tibet. Phenotypical characterization proved that it belongs to B. abortus biovar 4, a biotype that has never been reported in China. MLVA-16 genotyping revealed a novel profile (4-5-3-12-2-2-3-3-8-32-8-5-4-3-3-3) in this strain, while MLST sequence typing demonstrated that it belongs to ST 71. Furthermore, the whole genome of XZ19-1 strain was sequenced. Subsequent phylogenetic analysis demonstrated that XZ19-1was genetically more closely related to B. abortus strains originated from European countries rather than to those collected from China previously. Isolation and identification of XZ19-1 strain may thus indicate a unique Brucella lineage existing in Qing-Tibet plateau. These findings will help to improve the diagnosis and epidemiological studies of brucellosis in animals and human in this part of China.
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http://dx.doi.org/10.1016/j.vetmic.2020.108751DOI Listing
August 2020

Efficacy of transanal drainage tube and self-expanding metallic stent in acute left malignant colorectal obstruction.

Ann Palliat Med 2020 Jul 14;9(4):1614-1621. Epub 2020 Jul 14.

Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, China.

Background: The self-expanding metal stent (SEMS) or transanal drainage tube (TDT) methods can be used as a palliative treatment before tumor resection surgery. Studies systematically comparing the efficacy and characteristics between SEMS with TDT are limited, especially in a large-scale Chinese population. This retrospective study aimed to compare the outcomes of these treatment approaches.

Methods: This was a retrospective comparative study of patients with an acute malignant left colorectal obstruction who underwent a preoperative decompressive procedure with SEMS or TDT intervention between December 2014 and October 2017. The indicators after endoscopic treatment and tumor resection surgery between the SEMS and TDT groups were compared.

Results: 206 patients underwent endoscopic intervention to relieve obstruction, including 139 patients treated with SEMS and 67 patients treated with TDT. The technical success rates of the SEMS group and TDT group were 97.1% and 95.6%, respectively, and the rates of obstruction relief were 92.8% and 86.6%, respectively. TDT was more easily translocated than SEMS (P=0.02), and there was no significant difference in the incidence of other complications. However, SEMS had a lower complication rate than TDT (P=0.02), and could alleviate the obstruction faster (P<0.01). There were 72 patients and 44 patients who took resection surgery in the SEMS group and TDT group, respectively. The direct anastomosis rates were 73.6% and 63.6% (P=0.26), respectively, and only 1 case in the TDT group had anastomotic leakage. The surgery time of the SEMS group was significantly shorter than that of the TDT group (P=0.01). There was no significant difference between the 2 groups in terms of postoperative hospital stay (P=1.00) or total treatment costs for patients undergoing surgery (P=0.26).

Conclusions: Both TDT and SEMS could effectively relieve acute left malignant colorectal obstruction with safe and reliable results, and they could both reduce the stomas rate compared with traditional surgery. SEMS could alleviate obstruction faster than TDT and had fewer complications.
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http://dx.doi.org/10.21037/apm-19-458DOI Listing
July 2020

Rational Design of Oxygen Deficiency-Controlled Tungsten Oxide Electrochromic Films with an Exceptional Memory Effect.

ACS Appl Mater Interfaces 2020 Jul 13;12(29):32658-32665. Epub 2020 Jul 13.

Key Laboratory of Advanced Functional Materials and Devices of Anhui Province, Hefei 230009, China.

Owing to their nonemissive characteristics, electrochromic materials promise distinct advantages in developing next-generation eye-friendly information displays. Yet, it remains a challenge to manipulate the structure of the materials to achieve a strong memory effect with high optical contrast, which is of importance for displaying images with essentially zero energy consumption. Here, we design a mixed crystalline WO thin film implanted with massive oxygen deficiencies based on a conventional reactive magnetron sputtering process. The obtained WO film exhibits high dual-band optical modulation in both visible (VIS, 99.0% in 633 nm) and near-infrared (NIR, 94.2% in 1300 nm) regions as well as an exceptional memory effect (the colored transmittance increases only by 0.04% at 633 nm after 50 days). The enhanced electrochromic performance can be attributed to dense Li-ion binding sites as well as the trapping effect provided by the massive internal oxygen deficiencies. The strategy in this work bestows the WO thin film a promising candidate for developing electrochromic information displays and other energy-efficient devices as well.
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http://dx.doi.org/10.1021/acsami.0c06786DOI Listing
July 2020

Association between body mass index and survival outcomes for cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

J Transl Med 2020 06 12;18(1):235. Epub 2020 Jun 12.

Department of Gastroenterology, The First Hospital of China Medical University, 155 Nanjing bei Road, Shenyang, Liaoning, 110001, People's Republic of China.

Background: Immune checkpoint inhibitors (ICIs) have been increasingly applied in the treatment of several kinds of malignancies. Some clinical demographic characteristics were reported to be associated with the ICIs efficacy. The purpose of our current meta-analysis was to clearly evaluated the relationship between BMI and ICIs efficacy for cancer patients receiving immunotherapy.

Methods: A systematic search of Pubmed, EMBASE and conference proceedings was performed to investigate the influence of BMI on ICIs efficacy. Pooled analysis for overall survival (OS), progression-free survival (PFS) and immune-related adverse effects (IRAEs) were analyzed in current study.

Results: A total of 13 eligible studies comprising 5279 cancer patients treated with ICIs were included in the analysis. The pooled analysis showed there is positive association between high BMI and improved OS and PFS among patients with ICIs treatment (OS: HR = 0.62, 95% CI 0.55-0.71, P < 0.0001; I = 26.3%, P = 0.202); PFS: HR = 0.71, 95% CI 0.61-0.83, P < 0.0001; I = 0%, P = 0.591). There is no significant difference between the incidence of all grade IRAEs between obese, overweight patients and normal patients (Overweight vs Normal: pooled RR = 1.28, 95% CI 0.76- 2.18, P = 0.356; Obese vs Normal: pooled RR = 1.36, 95% CI 0.85- 2.17, P = 0.207).

Conclusion: An improved OS and PFS were observed in patients with high BMI after receiving ICIs treatment compared with patients of low BMI. No significant association between BMI and incidence of IRAEs was found in cancer patients after ICIs treatment.
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http://dx.doi.org/10.1186/s12967-020-02404-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291531PMC
June 2020

Sputum Cell-Free DNA: Valued Surrogate Sample for Detection of EGFR Mutation in Patients with Advanced Lung Adenocarcinoma.

J Mol Diagn 2020 07 11;22(7):934-942. Epub 2020 May 11.

Department of Pathology, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China. Electronic address:

Sputum is a common cytologic sample type, but its potential use in EGFR mutation detection in patients with lung cancer is not fully evaluated. This study established an improved sputum cell-free DNA (cfDNA) extraction method study and applied a super-amplification refractory mutation system to detect the EGFR mutation status in sputum cfDNA. The sputum sediments were used for cytology evaluation. The study included 102 lung adenocarcinoma patients; 65 patients (63.7%) were positive for EGFR mutations in tumor samples. EGFR mutation status was positive in 30 patients (29.4%) by sputum cfDNA testing, achieving an overall sensitivity and specificity of 46.2% and 100%, respectively. Comparison of EGFR mutation status in tumor samples revealed that the sensitivity of testing sputum cfDNA in 40 patients with stage I to IIIA versus 62 patients with stage IIIB to IV was 24% (6/25) versus 65.0% (26/40). Through cytology evaluation, the sputum specimens from 62 advanced patients were classified into three categories: 10 were unsatisfactory; 34 were satisfactory but had no malignant cells; and 18 had malignant cells. The sensitivities of these three categories were 0% (0/8), 71.4% (15/21), and 100% (11/11), respectively. These findings revealed that with the improved cfDNA extraction method and sputum cytology evaluation, sputum cfDNA is a valuable surrogate sample type for detecting clinical EGFR mutations in advanced lung adenocarcinoma patients.
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http://dx.doi.org/10.1016/j.jmoldx.2020.04.208DOI Listing
July 2020

Melatonin Enhances the Development of Porcine Cloned Embryos by Improving DNA Methylation Reprogramming.

Cell Reprogram 2020 06 24;22(3):156-166. Epub 2020 Mar 24.

College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China.

Incomplete DNA methylation reprogramming in cloned embryos leads to poor cloning efficiency. Melatonin has been proven to improve the development of cloned embryos, however, the role of melatonin during somatic cell nuclear transfer remains unclear. This work demonstrated that 10 M melatonin significantly enhanced the developmental progress, reduced the arrested rate before zygotic genome activation, and upregulated the blastocyst rate of cloned embryos. Melatonin also promoted the pseudo-pronucleus formation, increased blastocyst cell number, and reduced embryo apoptosis through upregulating the expression of antiapoptosis factors while downregulating the transcription of proapoptosis genes. Further study displayed that DNA methylation reprogramming related genes were greatly improved in cloned embryos when treated with melatonin; then, melatonin effectively promoted genomic DNA demethylation and DNA remethylation, DNA demethylation of pluripotency related gene , DNA methylation maintenance of imprinted gene , and DNA remethylation of tissue-specific gene in cloned embryos. Thus, zygotic genome activation related gene , pluripotency related genes , , and , imprinted genes and , and blastocyst quality related genes and were remarkably upregulated, and tissue-specific genes and were considerably silenced. In conclusion, melatonin enhanced the development of cloned embryos by ameliorating DNA methylation reprogramming. This work reveals that melatonin can regulate DNA methylation reprogramming and provides a novel insight to improve cloning efficiency.
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http://dx.doi.org/10.1089/cell.2019.0103DOI Listing
June 2020

Prognostic significance of PD-L1 expression on cell-surface vimentin-positive circulating tumor cells in gastric cancer patients.

Mol Oncol 2020 04 28;14(4):865-881. Epub 2020 Feb 28.

Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China.

Although circulating tumor cells (CTCs) have shown promise as potential biomarkers for diagnostic and prognostic assessment in gastric cancer (GC), determining the predictive and prognostic value of programmed death-ligand 1 (PD-L1)-positive CTCs in patients with GC is a challenge. Here, we identified that the expression of total vimentin (VIM) protein was positively correlated with PD-L1 and inhibited CD8 T-cell activation in patients with GC according to bioinformatics analysis. Notably, coexpression of PD-L1 and cell-surface VIM (CSV) was detected by immunofluorescence and immunohistochemistry assay in locally advanced GC tumor specimens and metastatic lymph nodes. Likewise, CSV expression level was significantly decreased after transiently knocking down PD-L1 in GC cell lines. Based on our established CTC detection platform, CTCs were isolated from peripheral blood samples collected from 70 patients (38 resectable and 32 unresectable) with GC using magnetic positive selection and a CSV-specific monoclonal antibody, 84-1. CSV PD-L1 CTCs were observed in 50 of 70 (71%) GC patient samples, ranging from 0 to 261 mL . A higher number of CSV PD-L1 CTCs were significantly associated with a short survival duration and poor therapeutic response. This study demonstrated that detection of PD-L1 CTCs using a CSV-enrichment method has promising value as a clinically relevant prognostic marker for GC.
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http://dx.doi.org/10.1002/1878-0261.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138401PMC
April 2020

CircRNAs and its relationship with gastric cancer.

J Cancer 2019 15;10(24):6105-6113. Epub 2019 Oct 15.

Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, China.

Circular RNAs (circRNAs), as a type of tissue specific RNA with more stable structure than linear RNAs, was poorly understood on its correlation with gastric cancer (GC). In this review, we outline the synthesis and characteristics of circRNAs and generalize their categories and functions. Through comprehensive analysis of the reported results, we find that circRNAs not only participate in the regulation of gastric cancer (GC) cell biological behaviors, such as proliferation, invasion, migration and epithelial mesenchymal transition (EMT), but also are related to the clinicopathological features of GC such as tumor differentiation, TNM stage and metastasis, etc. According to the present screening and verification results, circRNAs are suggested to be used as biomarkers for the early diagnosis and prognosis prediction of GC, and those circRNAs involved in the genesis and development of GC have the potential as novel targets for the individualized treatment of GC.
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http://dx.doi.org/10.7150/jca.32927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856571PMC
October 2019

Circulating tumor DNA methylation for predicting cancer risk: a diagnostic meta-analysis.

Future Oncol 2019 Oct 3;15(30):3513-3525. Epub 2019 Oct 3.

Tumor Etiology & Screening Department of Cancer Institute & General Surgery, the First Hospital of China Medical University, Shenyang 110001, PR China.

We conducted a meta-analysis to assess diagnostic accuracy of circulating tumor DNA methylation in cancer. Studies were searched from PubMed, Embase, Web of Science and China National Knowledge Infrastructure databases for articles published until December 2018. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and summary receiver operating characteristic were used to assess the diagnostic value, and MethHC database was used for verification. 13 studies with 1237 subjects and 676 cancer patients were enrolled. The area under curve was 0.80 (95% CI: 0.76-0.83), the pooled sensitivity was 0.35 (95% CI: 0.31-0.39) and the specificity was 0.97 (95% CI: 0.95-0.98). Verification by MethHC database was almost consistent with the result of meta-analysis. Circulating tumor DNA methylation is a potential biomarker for predicting cancer.
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http://dx.doi.org/10.2217/fon-2019-0219DOI Listing
October 2019

Water Clusters in Lignite and Desorption Energy Calculation by Density Functional Theory.

ACS Omega 2019 Sep 20;4(10):14219-14225. Epub 2019 Aug 20.

National Engineering Research Center of Coal Preparation and Purification, and School of Chemical Engineering and Technology, China University of Mining and Technology, Xuzhou 221008, Jiangsu, China.

The interaction of water and hydrophilic sites with hydroxyl, carboxyl, and multiple oxygen-containing functional groups (OFGs) in lignite molecules was studied by density functional theory. The adsorption of water molecules on the lignite surface initially resulted in the formation of hydrogen bond-driven stable rings by three to four water molecules, followed by the formation of three-dimensional water clusters like a ″patchwork″. Aqueous layer thickness obtained from the water cluster size was 0.4-0.6 nm, which was consistent with the experimental data. Thus, pore-filling water beyond this range was less affected by the OFGs on the surface. Calculation of the adsorption energy predicts that the water clusters were primarily formed in the hydrophilic sites with three OFGs (site 1, including a carbonyl group, an alcoholic hydroxyl group and an etheroxy group in tetrahydropyran), then in COOH, and in O-H. For isolated hydroxyl groups, the interaction between the hydroxyl group and water molecules was weaker than that between the water molecules. When the water cluster was located at the hydrophilic sites with two or more OFGs, the adsorption energy of lignite-water interaction was higher than that of water-water interaction. Investigating the thermodynamics of the adsorption process at a molecular scale will help in understanding both drying and resorption process of dried lignite during industrial production.
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http://dx.doi.org/10.1021/acsomega.9b01417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733174PMC
September 2019

Assessment on reticuloendotheliosis virus infection in specific-pathogen-free chickens based on detection of yolk antibody.

PLoS One 2019 22;14(4):e0213978. Epub 2019 Apr 22.

College of Veterinary Medicine, Shandong Agricultural University, Taian, China.

Reticuloendotheliosis virus (REV) is the most frequent exogenous virus that contaminates attenuated vaccines. Therefore, it is extremely important to select REV-free specific-pathogen-free (SPF) chicken embryos. Generally, REV infection is assessed by detecting REV antibodies in SPF chickens. This present study seeks to evaluate REV infection by replacing serum antibody detection with yolk antibody detection. A cohort of 40 nineteen-week-old SPF chickens were artificially inoculated with REV, with 32 SPF chickens raised in another isolation environment served as a blank control. Eggs and serum from 23-week-old chickens were sampled, and yolks were diluted separately to ratios of 1:150, 1:200, 1:300 and 1:400, which were detected together with serum. We found that the yolk antibody detection findings at a dilution of 1:300 had the highest coincidence rate compared with that based on serum antibody measurements. At a dilution ratio of 1:300 for yolk antibody, 72 chickens were continuously observed for 10 weeks from 25- to 34-weeks-old. Our findings were based on serum antibody or yolk antibody detection, and the evaluation results were completely consistent. Therefore, all serum antibody-positive chickens were yolk antibody-positive, and vice versa. Accordingly, vaccine producers can estimate REV cleanliness in a poultry farm by sampling yolk antibody titers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476468PMC
December 2019

Cathelicidin Suppresses Colon Cancer Metastasis via a P2RX7-Dependent Mechanism.

Mol Ther Oncolytics 2019 Mar 29;12:195-203. Epub 2019 Jan 29.

Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

The antimicrobial peptide cathelicidin inhibits development of colitis-associated colon cancer. However, the role of cathelicidin in colon cancer metastasis remains unknown. We hypothesized that cathelicidin is effective in inhibiting colon cancer metastasis. Human colon cancer HT-29 cells were injected intravenously into nude mice. Control HA-tagged adeno-associated virus (HA-AAV) or cathelicidin-overexpressing AAV (-HA-AAV) were injected intravenously into nude mice on the same day. Four weeks later, the nude mice were assessed for lung and liver metastases. Human colon cancer SW620 cells were used to study the effect of cathelicidin on cell migration and cytoskeleton. Incubation of SW620 cells with cathelicidin dose-dependently reduced cell migration, disrupted cytoskeletal structure, and reduced βIII-tubulin (TUBB3) mRNA expression. The addition of the P2RX7 antagonist KN62, but not the FPRL1 antagonist WRW4, prevented the LL-37-mediated inhibition of cell migration and TUBB3 mRNA expression. The -HA-AAV-overexpressing group showed significantly reduced human CK20 protein (by 60%) and TUBB3 mRNA expression (by 40%) in the lungs and liver of the HT-29-loaded nude mice, compared to the HA-AAV control group. Intraperitoneal injection of KN62 reversed the -HA-AAV-mediated inhibition of human CK20 and TUBB3 expression in the lungs and liver of HT-29-loaded nude mice. In conclusion, cathelicidin inhibits colon cancer metastasis via a P2RX7-dependent pathway.
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http://dx.doi.org/10.1016/j.omto.2019.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389776PMC
March 2019

SIX1 is upregulated in gastric cancer and regulates proliferation and invasion by targeting the ERK pathway and promoting epithelial-mesenchymal transition.

Cell Biochem Funct 2018 Dec 31;36(8):413-419. Epub 2018 Oct 31.

Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.

Sine oculis homeobox homologue 1 (SIX1) is a Six class homeobox gene conserved throughout many species. It has been reported to act as an oncogene and is overexpressed in many cancers. However, the function and regulatory mechanism of SIX1 in gastric cancer (GC) remains unclear. In our study, we detected protein levels of SIX1 via immunohistochemistry (IHC) and its proliferation and invasion effects via CCK8 and transwell assays. Additionally, expression of cyclin D1, MMP2, p-ERK, and EMT-related proteins was measured by western blotting. We found that SIX1 had significantly higher expression in GC tissues and that it could promote GC cell proliferation and invasion. Also, overexpression of SIX1 increased the expression of cyclin D1, MMP2, p-ERK, and EMT-related proteins, which could all be inhibited by knocking down SIX1. In conclusion, SIX1 is upregulated in GC tissues. It can promote GC cell proliferation by targeting cyclin D1, invasion via ERK signalling, and EMT pathways by targeting MMP2 and E-cadherin. SIGNIFICANCE OF THE STUDY: Our study showed that SIX1 was upregulated in GC tissues, and promoted GC cell proliferation by targeting cyclin D1, invasion via ERK signalling, and EMT pathways by targeting MMP2 and E-cadherin. These results suggested the potential regulatory mechanism of SIX1 in proliferation and invasion of gastric cancer.
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http://dx.doi.org/10.1002/cbf.3361DOI Listing
December 2018

Submucosal Tunneling Endoscopic Resection for Large and Irregular Submucosal Tumors Originating from Muscularis Propria Layer in Upper Gastrointestinal Tract.

J Laparoendosc Adv Surg Tech A 2018 Nov 25;28(11):1364-1370. Epub 2018 Sep 25.

Department of Gastroenterology, The First Hospital of China Medical University , Shenyang, China .

Background: The majority of submucosal tumors (SMTs) are benign. However, large SMTs with irregular outer shapes are proved to harbor a higher risk for malignancy. Submucosal tunneling endoscopic resection (STER) has emerged as a feasible technique for resecting SMTs.

Objective: To evaluate the safety and efficacy of STER for large and irregular SMTs with a diameter no <35 mm originating from the muscularis propria layer, and to share the technical skills of STER for complete and en bloc resection.

Patients And Methods: We retrospectively reported 10 cases in which the new technique of STER was performed to remove large and irregular SMTs with a diameter no <35 mm of upper gastrointestinal tract in our hospital between April 2014 and April 2017.

Results: All 10 (100%) patients underwent STER successfully, with a mean operation time of 156 minutes. Among the 10 SMTs, 3 (30%) were located in the esophagus, 7 (70%) were in the cardia. All the SMTs had a maximum diameter no <35 mm, ranging from 35 to 100 mm. The mean size was 57.2 mm. En bloc resection was achieved in 8 (80%) of the tumors. Only two (20%) of the SMTs were resected into more than one piece. Complication occurred in 1 (10%) of the patients as a representation of pneumothorax. No recurrence was noted during a median follow-up of 15 months.

Conclusion: In this retrospective study, STER may be an effective and safe technique resecting large and irregular SMTs with a diameter no >40 mm in transverse diameter and no >100 mm in longitudinal diameter.
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http://dx.doi.org/10.1089/lap.2017.0607DOI Listing
November 2018

Chemically initiated liquid-like behavior and fabrication of periodic wavy Cu/CuAu nanocables with enhanced catalytic properties.

Nanoscale 2018 May;10(19):9012-9020

State Key Laboratory of Physical Chemistry of Solid Surface, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.

Solid crystalline materials have long range order in their atomic arrangement while liquids have short range order, and the transition between them is usually caused by heat and/or pressure. Herein, we report the finding that chemical processes may play a similar role as heat and initiate liquid-like behavior of crystalline nanomaterials at a temperature far below their melting points. When the straight Cu/CuAu crystalline nanocables are dispersed in organic amine at 80 °C under ambient conditions, the continuous oxidation of Cu atoms on the surface and diffusion of Cu atoms from the core to the surface would break up the long-range ordered arrangement of atoms and lead to the transformation of an anisotropic crystal into an isotropic liquid-like state, which resulted in the evolution of the straight morphology of the nanocables into periodic wavy structures following the Rayleigh instability. It was also demonstrated that periodic wavy [email protected] nanocables exhibit much better catalytic activity than straight [email protected] nanocables towards the reduction of p-nitrophenol into p-aminophenol by NaBH4. Our results not only provide new insights into the transition between a solid crystal and a liquid-like state at the nanoscale, but also facilitate the development of new strategies for the synthesis of functional nanomaterials.
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http://dx.doi.org/10.1039/c8nr01174eDOI Listing
May 2018

Association of miRNA biosynthesis genes and polymorphisms with cancer susceptibility: a systematic review and meta-analysis.

Biosci Rep 2018 06 27;38(3). Epub 2018 Jun 27.

Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China

Single nucleotide polymorphisms (SNPs) in miRNA biosynthesis genes and were indicated to be correlated with cancer risk. We comprehensively reviewed and analyzed the effect of and polymorphisms on cancer risk. Eligible articles were selected according to a series of inclusion and exclusion criteria. Consequently, ten case-control studies (from nine citations) with 4265 cancer cases and 4349 controls were involved in a meta-analysis of seven most prevalent SNPs (rs10719 T/C, rs6877842 G/C, rs2291109 A/T, rs642321 C/T, rs3757 G/A, rs417309 G/A, rs1640299 T/G). Our findings demonstrated that the rs417309 SNP in was significantly associated with an elevated risk of overall cancer in every genetic model. In stratified analysis, correlations of rs10719 and rs6877842 SNPs were observed in Asian and laryngeal cancer subgroups, respectively. Moreover, associations of the rs417309 SNP could also be found in numerous subgroups including: Asian and Caucasian population subgroups; laryngeal and breast cancer subgroups; population-based (PB) and hospital-based (HB) subgroups. In conclusion, the rs10719, rs6877842 SNPs, and rs417309 SNP play pivotal roles in cancerogenesis and may be potential biomarkers for cancer-forewarning.
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http://dx.doi.org/10.1042/BSR20180072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019356PMC
June 2018

Association between polymorphisms and cancer risk: a systematic review and meta-analysis.

Biosci Rep 2018 06 12;38(3). Epub 2018 Jun 12.

Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China

Current studies have explored the correlation between the single nucleotide polymorphisms (SNPs) of pregnane X receptor () and cancer risk. However, the findings were conflicting. Hence, we performed a comprehensive review and meta-analysis for these researches to determine the effect of polymorphisms on the risk of cancer. Eligible publications were collected based on a series of rigorous inclusion and exclusion criteria. In consequence, a total of eight case-control studies (from seven citations) covering 11143 cases and 12170 controls were involved in a meta-analysis of ten prevalent SNPs (rs10504191 G/A, rs3814058 C/T, rs6785049 A/G, rs1464603 A/G, rs1523127 A/C, rs2276706 G/A, rs2276707 C/T, rs3732360 C/T, rs3814055 C/T, rs3814057 A/C). The correlations between SNPs and cancer risk were estimated by odds ratios (ORs) with their 95% confidence intervals (95%CIs). The findings demonstrated that rs3814058 polymorphism (CT compared with CC: pooled OR = 1.280, =6.36E-05; TT compared with CC: pooled OR = 1.663, =2.40E-04; dominant model: pooled OR = 1.382, =2.58E-08; recessive model: pooled OR = 1.422, =0.002; T compared with C: pooled OR = 1.292, =6.35E-05) and rs3814057 polymorphism (AC compared with AA: pooled OR = 1.170, =0.036; dominant model: pooled OR = 1.162, =0.037) were associated with the risk of overall cancer. In stratified analyses, rs3814058 polymorphism was revealed to increase the cancer risk in lung cancer subgroup. In summary, this meta-analysis indicates that the rs3814057 and rs3814058 polymorphisms of gene play crucial roles in the pathogenesis of cancer and may be novel biomarkers for cancer-forewarning in overall population or in some particular subgroups.
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http://dx.doi.org/10.1042/BSR20171614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997801PMC
June 2018

Downregulation of the long non-coding RNA XLOC_010588 inhibits the invasion and migration of colorectal cancer.

Oncol Rep 2018 Apr 12;39(4):1619-1630. Epub 2018 Feb 12.

Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Long non-coding RNAs (lncRNAs) have emer-ged as major players in many biological and pathological processes; however, investigation into the function of lncRNAs in the development and progression of cancer is in its infancy. Therefore, clarification of the mechanism by which cancer‑related lncRNAs function is of critical importance in research on tumorigenesis. It has been demonstrated that the lncRNA XLOC_010588 is expressed at a low level in cervical cancer, and that this has significant impact on the proliferation of cervical cancer cells. However, the expression pattern and functional roles of XLOC_010588 in colorectal cancer (CRC) remain unclear. In the present study, it was demonstrated that the expression of XLOC_010588 was significantly higher in CRC tissues when compared with that in adjacent normal tissues, and that XLOC_010588 was closely associated with metastasis and poor prognosis, thus indicating that XLOC_010588 may function as an oncogene. Additionally, downregulation of XLOC_010588 expression markedly inhibited the invasion and migration of CRC cells. Furthermore, it was demonstrated that XLOC_010588 may regulate the progression of CRC via the epithelial-mesenchymal transition (EMT) pathway. Notably, downregulation of XLOC_010588 inhibited the invasion and migration of CRC cells by regulating genes associated with EMT. Our findings revealed that XLOC_010588 may be considered as a novel potential diagnostic biomarker in CRC.
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http://dx.doi.org/10.3892/or.2018.6260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868398PMC
April 2018

Multiple Locus Variable-Number Tandem-Repeat and Single-Nucleotide Polymorphism-Based Typing Reveals Multiple Lineages in Currently Endemic in China.

Front Vet Sci 2017 14;4:215. Epub 2017 Dec 14.

Laboratory of Zoonoses, Chinese Animal Health and Epidemiology Center, Qingdao, China.

Brucellosis is a worldwide zoonotic disease caused by spp. In China, brucellosis is recognized as a reemerging disease mainly caused by specie. To better understand the currently endemic strains in China, three genotyping methods were applied to 110 strains obtained in past several years. By MLVA genotyping, five MLVA-8 genotypes were identified, among which genotypes 42 (1-5-3-13-2-2-3-2) was recognized as the predominant genotype, while genotype 63 (1-5-3-13-2-3-3-2) and a novel genotype of 1-5-3-13-2-4-3-2 were second frequently observed. MLVA-16 discerned a total of 57 MLVA-16 genotypes among these strains, with 41 genotypes being firstly detected and the other 16 genotypes being previously reported. By BruMLSA21 typing, six sequence types (STs) were identified, among them ST8 is the most frequently seen in China while the other five STs were firstly detected and designated as ST137, ST138, ST139, ST140, and ST141 by international multilocus sequence typing database. Whole-genome sequence (WGS)-single-nucleotide polymorphism (SNP)-based typing and phylogenetic analysis resolved Chinese strains into five clusters, reflecting the existence of multiple lineages among these Chinese strains. In phylogeny, Chinese lineages are more closely related to strains collected from East Mediterranean and Middle East countries, such as Turkey, Kuwait, and Iraq. In the next few years, MLVA typing will certainly remain an important epidemiological tool for infection analysis, as it displays a high discriminatory ability and achieves result largely in agreement with WGS-SNP-based typing. However, WGS-SNP-based typing is found to be the most powerful and reliable method in discerning strains and will be popular used in the future.
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http://dx.doi.org/10.3389/fvets.2017.00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735110PMC
December 2017

DNMT1 overexpression predicting gastric carcinogenesis, subsequent progression and prognosis: a meta and bioinformatic analysis.

Oncotarget 2017 Nov 4;8(56):96396-96408. Epub 2017 Oct 4.

Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Shenyang, Liaoning, China.

DNMT1 is important in maintaining DNA methylation, and participates in the oncogenesis via up- or down-regulation leading to hyper-methylation or hypo-methylation. In the meta and bioinformatic analysis, we found that DNMT1 expression was higher in gastric cancer, compared with normal ( < 0.00001), para-cancerous ( = 0.0004) and dysplasia ( < 0.00001) tissues. DNMT1 up-regulation was associated with gender (OR = 2.27, = 0.006), differentiation (OR = 0.21, = 0.01) and TNM stage (OR = 0.31, = 0.0005). Through TCGA database, DNMT1 overexpression increased gastric cancer risk, but unrelated with clinicopathological parameters and prognosis. Kaplan-Meier plotter showed, an increasing expression of DNMT1 was positive for overall survival rates of patients with stage III and IV ( = 0.044; = 0.047), N2 and N1-3 phases of lymph node metastasis ( = 0.023; = 0.032), as well as those with or without distant metastasis ( = 0.0052; = 0.021). For DNMT1 negative patients, the progression-free survival rates was better in patients with Her2+ or Her2- than positive ones ( = 0.00015; = 0.031). Besides, surgery alone was effective for the overall survival rates in patients with DNMT1 high expression ( = 0.035), while 5-Fu was useful for those with low expression ( < 0.05). In conclusion, these findings provided evidence that DNMT1 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.
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http://dx.doi.org/10.18632/oncotarget.21480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707109PMC
November 2017

Adalimumab for Uveitis in Juvenile Idiopathic Arthritis.

N Engl J Med 2017 08;377(8):789

First Affiliated Hospital of China Medical University, Shenyang, China

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http://dx.doi.org/10.1056/NEJMc1708646DOI Listing
August 2017

WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response.

Cell Death Dis 2017 07 27;8(7):e2955. Epub 2017 Jul 27.

Department of Surgery and Cancer, Molecular Therapeutics Unit and Ovarian Cancer Action Research Centre, Imperial College London, Hammersmith Hospital, London, UK.

There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel also activates endoplasmic reticulum (ER) stress. Here, we examine the role of WWOX (WW domain containing oxidoreductase), a gene frequently lost in several cancers, in mediating paclitaxel response. We examine the ER stress-mediated apoptotic response to paclitaxel in WWOX-transfected epithelial ovarian cancer (EOC) cells and following siRNA knockdown of WWOX. We show that WWOX-induced apoptosis following exposure of EOC cells to paclitaxel is related to ER stress and independent of the antimitotic action of taxanes. The apoptotic response to ER stress induced by WWOX re-expression could be reversed by WWOX siRNA in EOC cells. We report that paclitaxel treatment activates both the IRE-1 and PERK kinases and that the increase in paclitaxel-mediated cell death through WWOX is dependent on active ER stress pathway. Log-rank analysis of overall survival (OS) and progression-free survival (PFS) in two prominent EOC microarray data sets (Tothill and The Cancer Genome Atlas), encompassing ~800 patients in total, confirmed clinical relevance to our findings. High WWOX mRNA expression predicted longer OS and PFS in patients treated with paclitaxel, but not in patients who were treated with only cisplatin. The association of WWOX and survival was dependent on the expression level of glucose-related protein 78 (GRP78), a key ER stress marker in paclitaxel-treated patients. We conclude that WWOX sensitises EOC to paclitaxel via ER stress-induced apoptosis, and predicts clinical outcome in patients. Thus, ER stress response mechanisms could be targeted to overcome chemoresistance in cancer.
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http://dx.doi.org/10.1038/cddis.2017.346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550887PMC
July 2017