O-GlcNAcylation of YY1 stimulates tumorigenesis in colorectal cancer cells by targeting SLC22A15 and AANAT.

Emerging studies have revealed that O-GlcNAcylation plays pivotal roles in the tumorigenesis of colorectal cancers (CRCs). However, the underlying mechanism still remains largely unknown. Here, we demonstrated that Yin Yang 1 (YY1) was O-GlcNAcylated by O-GlcNAc transferase (OGT) and O-GlcNAcylation of YY1 could increase the protein expression by enhancing its stability. O-GlcNAcylation facilitated transformative phenotypes of CRC cell in a YY1-dependent manner. Also, O-GlcNAcylation stimulates YY1-dependent transcriptional activity. Besides, we also identified the oncoproteins, SLC22A15 and AANAT, which were regulated by YY1 directly, are responsible for the YY1 stimulated tumorigenesis. Furthermore, we identified the main putative O-GlcNAc site of YY1 at Thr236, and mutating of this site decreased the pro-tumorigenic capacities of YY1. We concluded that O-GlcNAcylation of YY1 stimulates tumorigenesis in CRC cells by targeting SLC22A15 and AANAT, suggesting that YY1 O-GlcNAcylation might be a potential effective therapeutic target for treating CRC.

Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy: A case report and review of literature.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of death due to its complexity, heterogeneity, rapid metastasis and easy recurrence after surgical resection. We demonstrated that combination therapy with transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), Epclusa, Lenvatinib and Sintilimab is useful for patients with advanced HCC. CASE SUMMARY: A 69-year-old man who was infected with hepatitis C virus (HCV) 30 years previously was admitted to the hospital with abdominal pain. Enhanced computed tomography (CT) revealed a low-density mass in the right lobe of the liver, with a volume of 12.9 cm × 9.4 cm × 15 cm, and the mass exhibited a "fast-in/fast-out" pattern, with extensive filling defect areas in the right branch of the portal vein and an alpha-fetoprotein level as high as 657 ng/mL. Therefore, he was judged to have advanced HCC. During treatment, the patient received three months of Epclusa, three TACE treatments, two HAIC treatments, three courses of sintilimab, and twenty-one months of lenvatinib. In the third month of treatment, the patient developed severe side effects and had to stop immunotherapy, and the Lenvatinib dose had to be halved. Postoperative pathological diagnosis indicated a complete response. The patient recovered well after the operation, and no tumor recurrence was found. CONCLUSION: Multidisciplinary conversion therapy for advanced enormous HCC caused by HCV infection has a significant effect. Individualized drug adjustments should be made during any treatment according to the patient's tolerance to treatment.

Comparison of different methods for the isolation of mesenchymal stem cells from umbilical cord matrix: proliferation and multilineage differentiation as compared to mesenchymal stem cells from umbilical cord blood and bone marrow.

We have identified the most appropriate method of isolating human umbilical cord matrix-derived mesenchymal stem cells (UCM-MSCs) and compared morphological, phenotypic, proliferative, and differentiation characteristics of UCM-MSCs with bone marrow-derived MSCs (BM-MSCs) and umbilical cord blood-derived MSCs (UCB-MSCs). Three explant culture methods and 3 enzymatic methods were compared with regards to time for primary culture, cell number, cell morphology, immune phenotype, and differentiation potential. Morphological, phenotypic, proliferative, and differentiation characteristics of UCM-MSCs, BM-MSCs, and UCB-MSCs were also compared. UCM-MSCs isolated using the 10 mm size tissue explant method led to shorter primary culture time, higher numbers of isolated cells, and higher proliferation rates compared with other isolation methods. Immune phenotype and multilineage differentiation capacity did not differ significantly among 6 groups. UCM-MSCs had similar characteristics as BM-MSCs and UCB-MSCs, including fibroblastic morphology, typical immunophenotypic markers, and multilineage differentiation capacity. In comparison with UCB-MSCs and BM-MSCs, UCM-MSCs have higher proliferative capacity, higher rate of chondrogenic differentiation, and higher expression of CD 146. The results suggest that the 10 mm size tissue culture method is the optimal protocol for the isolation of UCM-MSCs. Given the distinct advantages of UC, such as accessibility, painless acquisition, and abundance of cells obtained, we propose that UC be considered an alternative to BM and UCB as a source of MSCs for cell therapy.

Protein kinases: The key contributors in pathogenesis and treatment of nonalcoholic fatty liver disease-derived hepatocellular carcinoma.

Protein kinases (PKs), one of the largest protein families, can be further divided into different groups based on their substrate or structure and function. PKs are important signaling messengers in numerous life activities, including cell metabolism, proliferation, division, differentiation, senescence, death, and disease. Among PK-related diseases, nonalcoholic fatty liver disease (NAFLD) has been recognized as a major contributor to hepatocellular carcinoma (HCC) and liver transplantation. Unfortunately, NAFLD-derived HCC (NAFLD-HCC) has poor prognosis because it is typically accompanied by older age, multiple metabolic syndromes, obstacles in early-stage diagnosis, and limited licensed drugs for treatment. Accumulating evidence suggests that PKs are implicated in the pathogenic process of NAFLD-HCC, via aberrant metabolism, hypoxia, autophagy, hypoxia, gut microbiota dysbiosis, and/or immune cell rearrangement. The present review aims to summarize the latest research advances and emphasize the feasibility and effectiveness of therapeutic strategies that regulate the expression and activities of PKs. This might yield clinically significant effects and lead to the design of novel PK-targeting therapies. Furthermore, we discuss emerging PK-based strategies for the treatment of other malignant diseases similar to NAFLD-HCC.

Has_circ_0000069 expression in breast cancer and its influences on prognosis and cellular activities.

Circular RNA (circRNA), as a newly discovered non-coding RNA with important regulatory potential, is closely related to the occurrence and progression of various tumors. This study aimed to investigate has_circ_0000069 expression in breast cancer and its influence on cellular activities. Using real-time quantitative polymerase chain reaction, has_circ_0000069 levels were measured in 137 pairs of tissue specimens, as well as cancer cell lines. The cellular activities of cell lines were determined by cell counting kit-8 (CCK-8) and Transwell assays. The potential targeting miRNAs were predicted and verified using an online database and dual-luciferase reporter assay. Has_circ_0000069 was highly expressed in breast cancer tissues and cells. The expression of has_circ_0000069 was associated with the five-year overall survival of patients. After silencing has_circ_0000069 in breast cancer cells, its expression reduced, and the ability of cell proliferation, migration, and invasion decreased. MiR-432 was verified as a targeting miRNA of has_circ_0000069. Has_circ_0000069 expression increased in breast cancer and was negatively related to patient's prognosis. Has_circ_0000069 may facilitate breast cancer tumor progression by sponging miR-432. These findings revealed that has_circ_0000069 may be a biomarker for predicting prognosis and a therapeutic target for treating patients with breast cancer.

Identification of circRNA-miRNA-mRNA network in luminal breast cancers by integrated analysis of microarray datasets.

Introduction: Circular RNAs (circRNAs) regulatory network is important in human cancer. We, therefore, mapped the regulatory networks driven by circRNA in luminal-subtype breast cancer. Methods: Breast cancer-related microarray datasets from GEO database were analyzed for the differentially expressed circRNAs, miRNAs, and mRNAs. The potential downstream RNAs were collected using Circular RNA Interactome or Targetscan database. Protein-protein interaction (PPI) analysis was performed for the filtered genes to identify hub genes. The functions were annotated by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. CircRNA-miRNA-mRNA networks were mapped using Cytoscape software. Hsa_circ_0086735-miR-1296-5p-STAT1 axis was used for verification. The expression levels of hsa_circ_0086735, miR-1296-5p, and STAT1 mRNA were confirmed by qRT-PCR in luminal-subtype tissues and cell lines. The interactions among them were verified by Luciferase reporter assay and RNA pull-down assay. Cell proliferation and apoptosis were assayed. Overall and distant metastasis-free survival was analyzed. Results: A total of 70 genes were finally targeted and enriched in multi-process and multi-pathway. Networks containing 96 circRNA-miRNA-mRNA axes were constructed. Hsa_circ_0086735 and STAT1 mRNA was upregulated in luminal breast cancer, while miR-1296-5p was downregulated. Hsa_circ_0086735-miR-1296-5p-STAT1 axis promotes breast cancer progression and contributes to tamoxifen resistance. High hsa_circ_0086735 was associated with poor overall and distant metastasis-free survival. Discussion: This study identified the hsa_circ_0086735-miR-1296-5p-STAT1 as an important regulatory axis in luminal-subtype breast cancer, aiding to determine potential therapeutic targets.

Manganese-based Prussian blue nanoparticles inhibit tumor proliferation and migration via the MAPK pathway in pancreatic cancer.

Pancreatic cancer (PC) is one of the deadliest gastrointestinal malignancies. Advances in molecular biology and surgery have significantly improved survival rates for other tumors in recent decades, but clinical outcomes for PC remained relatively unchanged. Chemodynamic therapy (CDT) and Photothermal therapy (PTT) represent an efficient and relatively safe cancer treatment modality. Here, we synthesized Mn-doped Prussian blue nanoparticles (MnPB NPs) through a simple and mild method, which have a high loading capacity for drugs and excellent CDT/PTT effect. Cell line experiments in vitro and animal experiments in vivo proved the safety of MnPB NPs. We stimulated the PC cells with MnPB NPs and performed transwell migration assays. The migration of PC cells was reduced company with the decrease of two classical proteins: matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Moreover, MnPB NPs induced ferroptosis, which mediated the MAPK pathway and achieved tumor elimination in nude mice. This effective and safe strategy controlled by irradiation represents a promising strategy for pancreatic cancer.

N-Myristoylation by NMT1 Is POTEE-Dependent to Stimulate Liver Tumorigenesis via Differentially Regulating Ubiquitination of Targets.

BACKGROUND: A tremendous amount of studies have suggested that post-translational modifications (PTMs) play pivotal roles during tumorigenesis. Compared to other PTMs, lipid modification is less studied. Recently, N-myristoylation, one type of lipid modification, has been paid attention to the field of cancer. However, whether and how N-myristoylation exerts its roles in liver tumorigenesis still remains unclear. METHODS: Parallel reaction monitoring (PRM) was conducted to evaluate the expression of protein modification enzymes in paired tissues. Liver conditionally knocking NMT1 out mice model was used to assess the critical roles of N-myristoylation during liver tumorigenesis. Proteomics isobaric tags for relative and absolute quantification (iTraq) was performed to identify proteins that changed while NMT1 was knocked down. The click chemistry assay was used to evaluate the N-myristoylation levels of proteins. RESULTS: Here, N-myristolyation and its enzyme NMT1, but not NMT2, were found to be critical in liver cancer. Two categories of proteins, i.e., N-myristolyation down-regulated proteins (NDP, including LXN, RPL29, and FAU) and N-myristolyation up-regulated proteins (NUP, including AHSG, ALB, and TF), were revealed negatively and positively regulated by NMT1, respectively. Both NDP and NUP could be N-myristolyated by NMT1 indispensable of POTEE. However, N-myristolyation decreased and increased stability of NDP and NUP, respectively. Mechanistically, NDP-specific binding protein RPL7A facilitated HIST1H4H, which has ubiquitin E3 ligase function, to ubiquitinate NDP. By contrast, NUP-specific binding protein HBB prevented NUP from ubiquitination by HIST1H4H. Notably, function of RPL7A and HBB was all NMT1-dependent. Moreover, NDP suppressed while NUP stimulated transformative phenotypes. Clinically, higher levels of NMT1 and NUP with lower levels of NDP had worse prognostic outcome. CONCLUSION: Collectively, N-myristolyation by NMT1 suppresses anti-tumorigenic NDP, whereas it stimulates pro-tumorigenic NUP by interfering their ubiquitination to finally result in a pro-tumorigenic outcome in liver cancer. Targeting N-myristolyation and NMT1 might be helpful to treat liver cancer.

MicroRNA-218-5p accelerates malignant behaviors of breast cancer through LRIG1

Abstract Objective: MicroRNAs play crucial roles in the pathogenesis of cancers. MiRNA-218-5p may act as either an oncogene or a tumor suppressor, but its role in the pathogenesis of Breast Cancer (BC) remains unclear. Methods: Infiltrative breast ductal carcinoma as well as corresponding adjacent normal samples were collected from 30 patients. Mimics and inhibitors of miRNA-218-5p or corresponding negative controls were transfected into BC cells. miRNA-218-5p expression was detected by quantitative PCR. The effects of miRNA-218-5p on the malignant behaviors of BC were assessed. Dual-luciferase reporter assay was employed to evaluate the binding of miRNA-218-5p to LRIG1. Results: BC tissues showed higher miRNA-218-5p expression as compared to the adjacent normal tissues. Ectopic miRNA-218-5p expression accelerated the cell cycle, cell growth and migration of BC, while repressed cell apoptosis. Interestingly, ectopic miRNA-218-5p expression down-regulated LRIG1 expression, and miRNA-218-5p could bind to LRIG1. Also, our study indicated that miRNA-218-5p up-regulated ErbB2 and EGFR expression by targeting LRIG1, suggesting that the LRIG1-mediated signaling pathway contributed to the pro-tumor effects of miRNA-218-5p on BC. Conclusion: MiRNA-218-5p up-regulates ErbB2 and EGFR expression by suppressing LRIG1 expression, thus promoting the malignant behaviors of BC. miRNA-218-5p may exert a pro-tumor effect on BC and serve as a therapeutic target for BC treatment.

Inhibition of RAB1A suppresses epithelial-mesenchymal transition and proliferation of triple-negative breast cancer cells.

RAB1A acts as an oncogene in various cancers, and emerging evidence has verified that RAB1A is an mTORC1 activator in hepatocellular and colorectal cancer, but the role of RAB1A in breast cancer remains unclear. In this investigation, RAB1A siRNA was successfully transfected in MDA-MB-231 and BT-549 human triple-negative breast cancer cells, and verified by real­time quantitative polymerase chain reaction and western blotting. Then, MTT cell proliferation, colony formation, cell invasion and wound healing assays were performed to characterize the function of RAB1A in the breast cancer cell lines. Downregulation of RAB1A inhibited cellular growth, cell migration, cell invasion and cell epithelial-mesenchymal transition. Furthermore, compared with NC siRNA transfected cells, RAB1A siRNA transfected breast cancer cells inhibited the phosphorylation of S6K1, the effector molecular of mTORC1. Collectively, our data suggested that RAB1A acts as an oncogene by regulating cellular proliferation, growth, invasion and metastasis via activation of mTORC1 pathway in triple-negative breast cancer.

Sirt1 suppresses Wnt/ßCatenin signaling in liver cancer cells by targeting ßCatenin in a PKAα-dependent manner.

Here, bioinformatics data from Sirt1 knock-out (KO) and knock-in (KI) mice suggest that Sirt1 inhibits Wnt/ßCatenin signaling in the liver. However, it is unclear how this relationship occurs and how it contributes to malignant phenotypes in liver cancer cells. We found that Sirt1 expression promotes phosphorylation of ßCatenin at Ser675, which may subsequently decrease expression of total-ßCatenin. Mechanistically, Sirt1 expression elevates phosphorylation of the alpha subunit of protein kinase A (PKAα), and this event is essential for Sirt1-induced phosphorylation of ßCatenin. The negative effects of Sirt1 on ßCatenin stability are also dependent on PKAα. Stimulating PKAα recruits ßTrCP, a well-known ubiquitin E3 ligase for ßCatenin, to ßCatenin. Interestingly, Sirt1 expression is able to up-regulate ßTrCP expression. Finally, we found that malignant phenotypes occur in hepatocytes when Sirt1 and ßCatenin are co-overexpressed, and such effects are enhanced by simultaneous knockdown of PKAα. In contrast, malignant phenotypes are abrogated upon knockdown of Sirt1, and this phenotype is magnified by knockdown of ßCatenin. Collectively, we conclude that suppression of both Sirt1 and Wnt/ßCatenin might be effective in treating liver cancer.

JAK2 inhibitor combined with DC-activated AFP-specific T-cells enhances antitumor function in a Fas/FasL signal-independent pathway.

OBJECTIVE: Combination therapy for cancer is more effective than using only standard chemo- or radiotherapy. Our previous results showed that dendritic cell-activated α-fetoprotein (AFP)-specific T-cells inhibit tumor in vitro and in vivo. In this study, we focused on antitumor function of CD8(+) T-cells combined with or without JAK2 inhibitor. METHODS: Proliferation and cell cycle were analyzed by CCK-8 and flow cytometry. Western blot was used to analyze the expression level of related protein and signaling pathway. RESULTS: We demonstrated reduced viability and induction of apoptosis of tumor cells with combination treatment. Intriguingly, cell cycle was blocked at the G1 phase by using AFP-specific CD8(+) T-cells combined with JAK2 inhibitor (AG490). Furthermore, an enhanced expression of BAX but no influence on Fas/FasL was detected from the tumor cells. CONCLUSION: These results indicate a Fas/FasL-independent pathway for cellular apoptosis in cancer therapies with the treatment of AFP-specific CD8(+) T-cells combined with JAK2 inhibitor.

Braun enteroenterostomy during pancreaticoduodenectomy decreases postoperative delayed gastric emptying.

BACKGROUND: Modified digestive reconstruction during pancreaticoduodenectomy (PD) may affect the postoperative incidence of delayed gastric emptying (DGE). The purpose of this study is to investigate whether Braun enteroenterostomy following PD can reduce the incidence of DGE. METHODS: Four hundred seven patients who received PD with child reconstruction from June 2000 to March 2013 were divided into 2 groups: 206 patients with Braun enteroenterostomy (Child-Braun group) and 201 patients without Braun enteroenterostomy (Child-non-Braun group). Clinical data were retrospectively extracted; univariate and multivariate analyses were performed to investigate the association between Braun enteroenterostomy and DGE. RESULTS: DGE was less frequent in the Child-Braun group than in the Child-non-Braun group (6.7% vs. 26.87%, P < .001). The multivariate logistic regression analysis showed that Braun enteroenterostomy was the only significant independent factor associated with the reduced DGE after PD with Child reconstruction, with an odds ratio of 4.485 (95% confidence interval: 2.372 to 8.482, P < .001). CONCLUSION: Braun enteroenterostomy reduces the incidence of postoperative DGE associated with PD.

Braun Enteroenterostomy Following Pancreaticoduodenectomy: A Systematic Review and Meta-Analysis.

Pancreaticoduodenectomy (PD) holds high postoperative morbidity. How to resolve this issue is challenged. An additional anastomosis (Braun enteroenterostomy) following PD may decrease the postoperative morbidity, but holds conflicting results. The objective of this study is to investigate the advantages and disadvantages of Braun enteroenterostomy in PD.Clinical studies compared perioperative outcomes between the Braun group and the non-Braun group following PD before December 21, 2014 were retrieved and filtered from PubMed, EMBASE, Web of Science, the Cochrane Library, and Chinese electronic databases (VIP database, WanFang database, and CNKI database). Relevant data were extracted according to predesigned sheets. Blood loss, operating time, and postoperative mortality and morbidity were evaluated using odds ratio (OR), weighted mean difference, or standard mean difference (SMD).Ten studies concerning 1614 patients were included. No significant differences between the Braun and the non-Braun group were identified in mortality (OR: 0.65, 95% confidence interval [CI]: 0.26-1.60), intraoperative blood loss (SMD: -0.035, 95% CI: -0.253 to 0.183), postoperative pancreatic fistula (POPF) (OR: 0.67, 95% CI: 0.35-1.67), bile leakage (OR: 0.537, 95% CI: 0.287-1.004), postoperative gastrointestinal hemorrhage (OR: 1.17, 95% CI: 0.578-2.385), intraabdominal abscesses (OR: 0.793, 95% CI: 0.444-1.419), wound complications (OR: 0.806, 95% CI: 0.490-1.325), and hospital stay (SMD: -0.098, 95% CI: -0.23 to 0.033). Braun enteroenterostomy extended operating time (SMD: 0.39, 95% CI: 0.02-0.78), but it was associated with lower reoperation rate (OR: 0.380, 95% CI: 0.149-0.968), lower morbidity rate (OR: 0.66, 95% CI: 0.49-0.91), lower clinically relevant delayed gastric emptying (Grades B and C) (OR: 0.375, 95% CI: 0.164-0.858), lower nasogastric tube reinsertion (OR: 0.436, 95% CI: 0.232-0.818), and less postoperative vomiting (OR: 0.444, 95% CI: 0.262-0.755).Braun enteroenterostomy can be safely performed during PD. It is beneficial for patients and could be recommended in PD from the current published data.PROSPERO registration number: CRD42015016198.

The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis.

Stromal cell-derived factor-1 (SDF-1) and its receptor, CXC chemokine receptor-4 (CXCR4), are important regulators in the migration of bone marrow mesenchymal stem cells (BMSCs). However, the mechanisms underlying this effect in acute pancreatitis (AP) have not been investigated. In this study, BMSCs were identified by specific cell surface markers and differentiation potentials, and labeled with chloromethylbenzamido-1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (CM-Dil) for in vivo cell tracking. AP was induced by retrograde infusion of sodium taurocholate into the common bile duct in rats. The expression of SDF-1 in the injured pancreas was determined by immunohistochemistry and western blot analysis. BMSCs were incubated with or without anti-CXCR4 antibody and the contribution of SDF-1 to the migration of BMSCs was investigated. Our results demonstrated that the expression of SDF-1 was significantly increased in the injured pancreas, and that these levels peaked on days 5-7 and began to decrease on day 10. SDF-1 induced a dose-dependent migration of BMSCs in an in vitro transwell migration assay, which was almost completely blocked by AMD3100 (CXCR4-specific antagonist) or anti-CXCR4 antibody. In addition, by encouraging the migration of CM-Dil-labeled BMSCs, the SDF-1/CXCR4 axis facilitated the repair of the injured pancreas. This effect was inhibited by the anti-CXCR4 antibody. Taken together, these results indicate that the interaction of locally produced SDF-1 with CXCR4 on BMSCs, has an important regulatory role in the migration of BMSCs towards the injured pancreas in AP.

Effect of interferon-γ on NF-κB and cytokine IL-18 and IL-27 in acute pancreatitis.

The objective of our work was to evaluate the effect of interferon-γ (IFN-γ) on cytokine expression in rat acute pancreatitis (AP). AP was introduced to rats which were divided into Control, AP and IFN-γ group. Rats in the AP and IFN-γ group were sacrificed as 6, 12 and 24 h after IFN-γ treatment. The serum amylase (AMA), endotoxin and cytokines were detected. The pathological examination and immunofluorescence staining of pancreas for TNF-α, NF-κB and IL-18 were performed. The serum AMA increased significantly at 6 h and reduced at 48 h after AP. The increase in IFN-γ was higher than that in AMA. IL-18 increased in the AP and IFN group, and IFN increased markedly at 48 h after AP. IL-27 reduced at 24 h after AP compared with AP group. In the AP group, the immunostaining of cytokines increased. In the IFN group, the edema in the pancreas was more severe, and NF-κB and IL-18 expression was higher than that in the other two groups. IFN-γ can increase serum IL-18 and reduce IL-27 in AP. IFN-γ can increase serum IL-18 and reduce serum IL-27 in AP. The increase in NF-κB and IL-18 may exert influence on pro-inflammatory cytokines to deteriorate inflammation in the pancreas. Thus, to control the IFN-γ might has promise to attenuate pancreatitis.

Functional polymorphisms in the CYP2C19 gene contribute to digestive system cancer risk: evidence from 11,042 subjects.

BACKGROUND: CYP2C19 belongs to the cytochrome P450 superfamily of enzymes involved in activating and detoxifying many carcinogens and endogenous compounds, which has attracted considerable attention as a candidate gene for digestive system cancer. CYP2C19 has two main point mutation sites (CYP2C19*2, CYP2C19*3) leading to poor metabolizer (PM) phenotype. In the past decade, the relationship between CYP2C19 polymorphism and digestive system cancer has been reported in various ethnic groups; however, these studies have yielded contradictory results. METHODS: To clarify this inconsistency, we performed this meta-analysis. Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. RESULTS: In total, 18 studies with 4,414 cases and 6,628 controls were included. Overall, significantly elevated digestive system cancer risk was associated CYP2C19 PM with OR of 1.66 (95%CI: 1.31-2.10, P<10(-5)) when all studies were pooled into the meta-analysis. There was strong evidence of heterogeneity (P = 0.006), which largely disappeared after stratification by cancer type. In the stratified analyses according to cancer type, ethnicity, control source and sample size, significantly increased risks were found. CONCLUSIONS: In summary, our meta-analysis suggested that the PM phenotype caused by the variation on CYP2C19 gene is associated with increased risk of digestive system cancer, especially in East Asians.

Expression of NOD2 in a rat model of acute pancreatitis.

OBJECTIVES: To observe the expression of nucleotide-binding oligomerization domain 2 (NOD2) in rats with acute pancreatitis (AP). METHODS: Sprague-Dawley rats were randomly divided into sham operation (SO) groups and AP groups. Acute pancreatitis was induced with retrograde infusion of sodium taurocholate into the biliopancreatic duct. They were then killed at 3, 6, 12, 24, and 48 hours after induction of AP. Blood biochemical indicators were detected with automatic biochemistry analyzer. Nuclear factor-κB (NF-κB) was measured by immunohistochemistry. The NOD2 was detected by real-time quantitative polymerase chain reaction and Western blot. Tumor necrosis factor-α (TNF-α) was determined by enzyme-linked immunosorbent assay. RESULTS: Compared with the SO group, the level of messenger RNA and protein of NOD2 in pancreatic tissue and peritoneal white blood cells (PWBCs) in the AP groups significantly declined (P < 0.05). The messenger RNA level of NOD2 in the AP groups was correlated positively with amylase (P < 0.05) and negatively with TNF-α (P < 0.05); TNF-α significantly decreased in the AP groups, whereas NF-κB significantly increased (P < 0.05). CONCLUSIONS: The NOD2 may play an important role in the up-regulation and activation of NF-κB during inflammation reactions in AP.

Last intron of the chemokine-like factor gene contains a putative promoter for the downstream CKLF super family member 1 gene.

The genes for chemokine-like factor (CKLF) and four chemokine-like factor super family members (CKLFSF1-4) are tightly linked on chromosome 16, with only 325 bp separating CKLF and CKLFSF1. We used Northern blotting and RT-PCR to show that these two genes are expressed independently of one another. We then used a novel computational promoter prediction method based on the interaction among transcription factor binding sites (TFBSs) to identify a putative promoter region for the CKLFSF1 gene. Our method predicted a promoter region in the last intron of the upstream gene, CKLF. We PCR amplified the predicted promoter region and used a luciferase assay to show that the region was able to drive the luciferase gene. DNA decoy experiments indicated that 214 bp fragment neighboring the TATA box markedly inhibited CKLFSF1 gene expression. Sequence analysis of the region revealed a typical TATA box (TATATAA) and multiple potential transcription factor binding sites, providing further evidence for this being a functional promoter for CKLFSF1. This work provides the first evidence of a promoter from one gene located in an intron of another.