Apelin-13 Pretreatment Promotes the Cardioprotective Effect of Mesenchymal Stem Cells against Myocardial Infarction by Improving Their Survival.

Although mesenchymal stem cell- (MSC-) based therapy has shown promising results for myocardial infarction (MI), low cell survival heavily limits its beneficial effects. Apelin plays an essential regulatory role in cell proliferation. This study was aimed at determining whether Apelin-13 pretreatment could improve the survival of MSCs in the ischemic heart and enhance their cardioprotective efficacy against MI. MSCs were pretreated with or without Apelin-13 for 24 hours and then exposed to serum deprivation and hypoxia (SD/H) for 48 hours. The mitochondrial morphology of MSCs was assessed by MitoTracker staining. The apoptosis of MSCs was determined by TUNEL staining. The level of mitochondrial reactive oxygen species (ROS) of MSCs was detected by Mito-Sox staining. MSCs and Apelin-13-pretreated MSCs were transplanted into the peri-infarct region in a mouse MI model. Apelin-13 pretreatment protected MSCs against SD/H-induced mitochondrial fragmentation and apoptosis. Apelin-13 pretreatment reduced ROS generation induced by SD/H in MSCs. Furthermore, Apelin-13 pretreatment enhanced the angiogenesis of MSCs under SD/H conditions. Mechanistically, Apelin-13 pretreatment inhibited SD/H-induced MSC apoptosis by downregulating mitochondrial fission via activation of the ERK pathway, and these effects were partially abrogated by ERK inhibitor U0126. Apelin-13 pretreatment promoted the survival of MSCs in the ischemic heart. Moreover, transplantation with Apelin-13-pretreated MSCs improved heart function and increased angiogenesis accompanied by decreased fibrosis compared with MSC transplantation at 28 days following MI. These findings reveal that pretreatment with Apelin-13 improves MSCs survival and enhances their therapeutic efficacy for MI. Our study provides a novel approach to improve MSC-based therapy for cardiovascular disease.

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence.

BACKGROUND: Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. METHODS: MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-ß-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence RESULTS: EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. CONCLUSION: Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction.

Screening and Identification of Potential Biomarkers for Hepatocellular Carcinoma: An Analysis of TCGA Database and Clinical Validation.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Up to now, many genes associated with HCC have not yet been identified. In this study, we screened the HCC-related genes through the integrated analysis of the TCGA database, of which the potential biomarkers were also further validated by clinical specimens. The discovery of potential biomarkers for HCC provides more opportunities for diagnostic indicators or gene-targeted therapies. METHODS: Cancer-related genes in The Cancer Genome Atlas (TCGA) HCC database were screened by a random forest (RF) classifier based on the RF algorithm. Proteins encoded by the candidate genes and other associated proteins obtained via protein-protein interaction (PPI) analysis were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The newly identified genes were further validated in the HCC cell lines and clinical tissue specimens by Western blotting, immunofluorescence, and immunohistochemistry (IHC). Survival analysis verified the clinical value of genes. RESULTS: Ten genes with the best feature importance in the RF classifier were screened as candidate genes. By comprehensive analysis of PPI, GO and KEGG, these genes were confirmed to be closely related to HCC tumors. Representative NOX4 and FLVCR1 were selected for further validation by biochemical analysis which showed upregulation in both cancer cell lines and clinical tumor tissues. High expression of NOX4 or FLVCR1 in cancer cells predicts low survival. CONCLUSION: Herein, we report that NOX4 and FLVCR1 are promising biomarkers for HCC that may be used as diagnostic indicators or therapeutic targets.

Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. COPD results from chronic inflammation of the lungs. Current treatments, including physical and chemical therapies, provide limited results. Stem cells, particularly mesenchymal stem cells (MSCs), are used to treat COPD. Here, we evaluated the safety and efficacy of umbilical cord-derived (UC)-MSCs for treating COPD. METHODS: Twenty patients were enrolled, 9 at stage C and 11 at stage D per the Global Initiative for Obstructive Lung Disease (GOLD) classification. Patients were infused with 106 cells/kg of expanded allogeneic UC-MSCs. All patients were followed for 6 months after the first infusion. The treatment end-point included a comprehensive safety evaluation, pulmonary function testing (PFT), and quality-of-life indicators including questionnaires, the 6-min walk test (6MWT), and systemic inflammation assessments. All patients completed the full infusion and 6-month follow-up. RESULTS: No infusion-related toxicities, deaths, or severe adverse events occurred that were deemed related to UC-MSC administration. The UC-MSC-transplanted patients showed a significantly reduced Modified Medical Research Council score, COPD assessment test, and number of exacerbations. However, the forced expiratory volume in 1 s, C-reactive protein, and 6MWT values were nonsignificantly reduced after treatment (1, 3, and 6 months) compared with those before the treatment. CONCLUSION: Systemic UC-MSC administration appears to be safe in patients with moderate-to-severe COPD, can significantly improve their quality of life, and provides a basis for subsequent cell therapy investigations. TRIAL REGISTRATION: ISRCTN, ISRCTN70443938. Registered 06 July 2019.

Reduced expression of Rap1GAP as a prognostic biomarker for primary gastric cancer patients.

BACKGROUND: Rap1GAP, a member of the family of GTPase-activating proteins, is reported to be involved in cancer development and progression. OBJECTIVE: The study aimed to investigate the expression and prognostic value of Rap1GAP in gastric cancer patients. METHODS: Real-time quantitative polymerase chain reaction and western blotting were performed to examine Rap1GAP expression in tumorous and matched adjacent non-tumorous gastric tissues. Immunohistochemical staining was used to analyze Rap1GAP expression in 456 gastric cancer tissues. The correlation between Rap1GAP expression level and clinicopathological features as well as gastric cancer prognosis was analyzed. RESULTS: Rap1GAP expression was remarkably decreased in tumor tissues at mRNA (p= 0.012) and protein (p= 0.034) level. Clinicopathological analysis revealed that low Rap1GAP expression was significantly correlated with tumor size (p= 0.033), histological grade (p= 0.034), T classification (p= 0.012), N classification (p= 0.006) and clinical stage (p= 0.005). Kaplan-Meier survival analysis revealed the association between low Rap1GAP expression and poor survival in gastric cancer patients. Furthermore, multivariate Cox regression analysis showed that Rap1GAP expression was an independent prognostic factor (p= 0.02). CONCLUSION: Rap1GAP may play a significant role in gastric cancer progression and act as a valuable prognostic marker for gastric cancer.

The Incidence, Risk Factors and Outcomes of Postoperative Acute Kidney Injury in Neurosurgical Critically Ill Patients.

We investigated the incidence, perioperative risk factors, and outcomes of postoperative acute kidney injury (AKI) in neurosurgical critically ill patients. A prospective multicenter cohort study was conducted, enrolling adult patients who underwent neurosurgical procedure and admitted to the neurosurgical intensive care units (ICU). Postoperative AKI was diagnosed within 7 days after surgery based on the Kidney Disease Improving Global Outcomes criteria. Of 624 enrolled patients, postoperative AKI occurred in 84 patients. AKI was associated with increased rates of ICU and in-hospital mortality, postoperative renal replacement therapy, postoperative tracheotomy, and postoperative tracheal reintubation. Patients who developed AKI had higher total ICU costs, prolonged length of hospital and ICU stay, and longer duration of postoperative mechanical ventilation. Multivariate analysis identified postoperative reoperation (adjusted odds ratio [OR] 5.70 [95% CI, 1.61-20.14]), postoperative concentration of serum cystatin C (adjusted OR 4.53 [95% CI, 1.98-10.39]), use of mannitol during operation (adjusted OR 1.97 [95% CI, 1.13-3.43]), postoperative APACHE II score (adjusted OR 1.11 [95% CI, 1.06-1.16]), and intraoperative estimated blood loss (adjusted OR 1.04 [95% CI, 1.00-1.08]) as independent risk factors for postoperative AKI. Postoperative AKI in neurosurgical critically ill cohort is prevalent and associated with adverse in-hospital outcomes.

Optimized construction of MUC1-VNTRn DNA vaccine and its anti-pancreatic cancer efficacy.

Considering mucin 1-variable number tandem repeat (MUC1-VNTRn) as a novel target for pancreatic cancer immunotherapy, the present study aimed to screen and identify the pVAX1-MUC1-VNTRn DNA vaccine with the strongest immunogenicity. Following construction of a pVAX1-MUC1-VNTRn plasmid, immature dendritic cells (DCs) were subjected to transfection, and mature DCs were then co-cultured with autologous T-cells. The numbers of cytotoxic T lymphocytes (CTLs) secreting interferon (IFN)-γ were determined using an enzyme-linked immunospot assay, and CytoTox® was also used to examine the MUC1-VNTRn-specific Lethal effect of CTLs on Capan2 cells. Additional in vivo experiments in mice were performed to confirm the antitumor effect of the DNA vaccine candidate. The present study successfully constructed the pVAX1-MUC1-VNTRn plasmid, which expresses the target protein in eukaryotic cells. Additionally, upon uptake of the pVAX1-MUC1-VNTRn plasmid, the immature DCs differentiated into mature DCs. The levels of the DC surface molecules cluster of differentiation (CD) 80, CD86, human leukocyte antigen-antigen D related, interleukin (IL)-12, IL-17 and IFN-γ were significantly higher, while the levels of IL-10 and IL-14 were lower, in mature DCs of the stimulated groups compared with the immature DCs of the non-stimulated groups (all P<0.01). In addition, the MUC1-VNTR6 and MUC1-VNTR9 groups, in which DCs were capable of activating autologous T-cells, showed increased IFN-γ-producing T-cells compared with the other groups (strong MUC1-VNTR1, weak VNTR1, VNTR3, VNTR4 and MUC1-cDNA groups; all P<0.001). In addition, the Lethal effect of CTLs on Capan2 cells in these two groups was stronger compared with the other groups (all P<0.001). Furthermore, the induced protective and therapeutic immune responses in mouse experiments showed that the pVAX1-MUC1-VNTR6DNA vaccine likely possessed the strongest immunogenicity, and its ability to inhibit panc02-MUC1 tumor growth was superior to other DNA vaccines (P<0.01). The present study provides compelling evidence that pVAX1-MUC1-VNTRn has the potential to express the target protein in eukaryotic cells, and thatpVAX1-MUC1-VNTR6 was characterized by the strongest Lethal effect in both in vivo and in vitro experiments.

Serum Insulin-Like Growth Factor Axis and the Risk of Pancreatic Cancer: Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the association between serum concentration of insulin-like growth factor (IGF) and the risk of pancreatic cancer (PaC). METHODS: We identified eligible studies in Medline and EMBASE databases (no reference trials from 2014 to 2016) in addition to the reference lists of original studies and review articles on this topic. A summary of relative risks with 95% confidence intervals (CI) was calculated using a random-effects model. The heterogeneity between studies was assessed using Cochran Q and I² statistics. RESULTS: Ten studies (seven nested case-control studies and three retrospective case-control studies) were selected as they met our inclusion criteria in this meta-analysis. All these studies were published between 1997 and 2013. The current data suggested that serum concentrations of IGF-I, IGF-II and insulin-like growth factor binding protein-3 (IGFBP-3)in addition to the IGF-I/IGFBP-3 ratio were not associated with an increased risk of PaC (Summary relative risks (SRRs) = 0.92, 95% CI: 0.67-1.16 for IGF-I; SRRs = 0.84, 95% CI: 0.54-1.15 for IGF-II; SRRs = 0.93, 95% CI: 0.69-1.17 for IGFBP-3; SRRs = 0.97, 95% CI: 0.71-1.23 for IGF-I/IGFBP-3 ratio). There was no publication bias in the present meta-analysis. CONCLUSION: Serum concentrations of IGF-I, IGF-II, IGFBP-1 and IGFBP-3 as well as the IGF-I/IGFBP-3 ratio were not associated with increased risk of PaC.

Effectiveness of ω-3 Polyunsaturated Fatty Acids Based Lipid Emulsions for Treatment of Patients after Hepatectomy: A Prospective Clinical Trial.

OBJECTIVE: The present study aimed to investigate the effectiveness of parenteral nutritional support with ω-3 PUFAs-based lipid emulsions in patients after liver resection. METHODS: A total of 119 patients were randomly assigned to the immunonutrition (IM) group (n = 59) and control group (n = 60). The IM group was continuously given Omegaven(®) 10% 100 mL/day rather than regular nutrition for five days postoperatively. Venous blood samples were obtained from all subjects before surgery and D1, D3 and D7 after surgery. RESULTS: No significant difference was found in baseline characteristics of the two groups. On D1 after surgery, no statistically significant differences were observed in the blood sample tests between the two groups. On D3 after surgery, the levels of white blood cell count (WBC), alanine aminotransferase (ALT), aspartate transaminase (AST) and total bilirubin (TBil) were dramatically decreased in the IM group (t = 3.065, p = 0.003; t = 2.149, p = 0.034; t = 5.313, p= 0.001; and t = 2.419, p = 0.017, respectively). Furthermore, on D7 after surgery, not only could a significant decrease be observed in the IM group concerning the levels of WBC, ALT and TBil (t = 3.025, p = 0.003; t = 2.094, p = 0.038; and t = 2.046, p = 0.043, respectively), but it was also seen in the level of Δprothrombintime (PT) (t = 2.450, p = 0.016). An increase in the level of prealbumin (Pre-Alb) in the IM group was observed on D7 after surgery (t = 2.237, p = 0.027). The frequency of total complications in the IM group were significantly lower than in the control group (χ² = 4.225, p = 0.040 and χ² = 3.174, p = 0.075). The trend favored the IM group in reducing the total infective complications rate (χ² = 3.174, p = 0.075). A significant decrease in the duration of the hospital stay after surgery was also observed in the IM group (t = 2.012, p = 0.047). CONCLUSION: ω-3 PUFAs-based lipid emulsions for treatment of patients after hepatectomy are safe and effective in controlling inflammation, protecting liver function, and consequently reducing the rate of total complications and the duration of the hospital stay.

XRCC1 Arg194Trp and Arg399Gln polymorphisms and risk of extrahepatic cholangiocarcinoma: a hospital-based case-control study in China.

BACKGROUND: Extrahepatic cholangiocarcinoma (ECCA) is a rare but devastating malignancy. Up to 90% of patients presenting with ECCA have no identifiable risk factors. The base excision repair (BER) pathway has a principal role in the repair of mutations caused by oxidized or reduced bases. The XRCC1 is one of the key proteins in the BER pathway. In this study, we investigated the influence of XRCC1 Arg194Trp and Arg399Gln polymorphisms on ECCA incidence. METHODS: The study included 189 ECCA patients and 216 controls. Genotypes were detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: For codon 194, the genotype frequencies of C/C, T/C and T/T were 51.3, 43.4 and 5.3%, respectively, in the ECCA cases compared with 54.2, 38.9 and 6.9%, respectively, in the controls. No statistically significant differences were observed in the genotype frequencies of codon 194 between the two groups compared to the control (TC, OR: 0.85, 95% CI: 0.57-1.28, TT, OR: 1.24, 95% CI: 0.54-2.89, TC+TT, OR: 0.89, 95% CI: 0.60-1.32). For codon 399, the genotype frequencies of G/G, G/A and A/A were 54.0, 37.0 and 9.0%, respectively, in the ECCA cases compared with 56.1, 39.8 and 4.1%, respectively, in the controls. No statistically significant differences were observed in the genotype frequencies codon 399 between the two groups compared to the control (GA, OR: 1.04, 95% CI: 0.69-1.56, AA, OR: 0.45, 95% CI: 0.19-1.04, GA+AA, OR: 0.92, 95% CI: 0.62-1.36). Meanwhile, no statistically significant differences were found in the haplotype and risk of developing ECCA compared to the control (CA, OR: 0.83, 95% CI: 0.49-1.39, TG, OR: 0.96, 95% CI: 0.58-1.60, TA, OR: 0.83, 95% CI: 0.38-1.82). CONCLUSION: The present study suggested that Arg194Trp and Arg399Gln polymorphism in the DNA repair gene XRCC1 was not statistically associated with risk of ECCA. It would be necessary to confirm these findings in a large sample size and multiethnic population study in future.

A measure to assess the ablative margin using 3D-CT image fusion after radiofrequency ablation of hepatocellular carcinoma.

OBJECTIVES: To examine the feasibility of three-dimensional computed tomography (3D-CT) image fusion in facilitating assessment of the ablative margin (AM) after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: This study involved 75 patients with solitary HCC who underwent RFA. The AM was evaluated using 3D-CT image fusion. All cases were categorized into two groups based on the extent of the AM: in Group A, sufficient AM was obtained, which was greater than or equal to 5 mm; in Group B, the lesion was also ablated successfully, but a 5 mm AM was not obtained. RESULTS: 3D-CT Image Fusion was performed on 36 and 39 patients in Group A and Group B, respectively. The 1, 3, 5 year RFS was 87.6%, 63.2%, 50.6% for Group A, and 77.2%, 51.5%, 35.6% for Group B, respectively (P = 0.042); the corresponding OS was 94.3%, 73.8%, 64.6%, and 86.2%, 60.5%, 47.6%, respectively (P = 0.046). Multivariate analysis showed that the AM (P = 0.048, HR = 2.15, 95% CI 1.01-4.60) and Pre-NLR were independent prognostic factors for PFS. CONCLUSIONS: 3D-CT image fusion is a feasible and useful method to evaluate the AM after RFA of HCC.

Cholelithiasis and risk of pancreatic cancer: systematic review and meta-analysis of 21 observational studies.

PURPOSE: To investigate the association between cholelithiasis and risk of pancreatic cancer (PaC). METHODS: We identified eligible studies in MEDLINE and EMBASE up to August 1, 2013 and the reference lists of original studies and review articles on this topic. Summary relative risks (SRRs) with their 95 % confidence intervals (CIs) were calculated with a random-effects model. RESULTS: Twenty-one studies (15 case-control studies, 6 cohort studies) met eligibility criteria. The current data suggest that cholelithiasis is associated with a 25 % excess risk of PaC (SRRs = 1.25, 95 % CI 1.10-1.41; test for heterogeneity p = 0.006, I (2) = 47.6 %). In subgroup analysis of timing of exposure, seven of eight studies in patients whose diagnosis of cholelithiasis made more than specified year (5, 3, 2, or 1 year) prior to cancer diagnosis showed no association for PaC, while all three studies in patients diagnosed less than specified year before cancer diagnosis showed a positive association. There was no publication bias in the present meta-analysis. CONCLUSION: This meta-analysis supports the hypothesis that a history of cholelithiasis may significantly increase PaC risk, particularly in Asian countries. However, the positive association disappeared over time, suggesting that cholelithiasis may be the early symptoms of PaC.

Aberrant expression of nuclear KPNA2 is correlated with early recurrence and poor prognosis in patients with small hepatocellular carcinoma after hepatectomy.

Karyopherin α2 (KPNA2) functions as an adaptor that transports several proteins to the nucleus. Emerging evidence suggests that KPNA2 plays a crucial role in oncogenesis and early recurrence. In the present study, we evaluated the expression pattern of KPNA2 in 221 hepatocellular carcinoma (HCC) specimens and matching adjacent, non-tumorous tissues (NT) by immunohistochemical assays. We found that nuclear KPNA2 expression was significantly upregulated (30.3 %, 67/221) in HCC tissues; however, no nuclear expression of KPNA2 in NT tissues was observed. A correlation analysis demonstrated that nuclear KPNA2 expression was positively associated with serum AFP level, tumor differentiation, vascular invasion, BCLC stage and early recurrence (all p < 0.05). Nuclear KPNA2 expression was associated with a poor prognosis in HCC patients. Univariate and multivariate analyses demonstrated that KPNA2 was an independent prognostic factor for both overall survival (p < 0.001) and time to recurrence (p < 0.001) in HCC patients. Furthermore, in a validation cohort, nuclear expression of KPNA2 was observed in 16 of 47 (34.0 %) small hepatocellular carcinoma patients. Importantly, the risk of recurrence associated with nuclear KPNA2 expression (9/16, 56.2 %) was significantly higher than the risk associated with an absence of nuclear KPNA2 expression (6/31, 19.3 %; p = 0.01). Our results demonstrate that nuclear KPNA2 expression is a poor prognostic biomarker for HCC, especially for early-stage HCC.

Decreased ITIH5 expression is associated with poor prognosis in primary gastric cancer.

Inter-α-trypsin inhibitors (ITIs) are a family of serine protease inhibitors that comprise one light chain and a variable set of heavy chains (ITI heavy chains, ITIHs). ITIH5 is a new member of the ITIH family that contains two domains conserved in all known ITIHs: vault protein IT and von Willebrand type A. Recent studies suggest that ITIH5 expression may be altered in certain types of cancer. This study aimed to investigate ITIH5 expression in clinical tumor specimens from gastric cancer patients and its prognostic value for gastric cancer. ITIH5 expression was detected in fresh gastric cancer tissues (T) and the matched adjacent non-tumor tissues (ANT) using real-time quantitative reverse transcription-PCR and Western blotting. ITIH5 expression was retrospectively detected in 331 paraffin-embedded, banked samples using immunohistochemical staining. ITIH5 mRNA and protein expression was significantly downregulated in gastric cancer tissues compared to the ANT. There was a significant association between ITIH5 expression and histological grade (P = 0.020), N classification (P = 0.047), and clinical stage (P = 0.011). Patients with low ITIH5 expression had shorter survival compared to those with high ITIH5 expression. Multivariate analysis showed that ITIH5 expression was an independent prognostic factor for overall survival of gastric cancer patients (P = 0.034). Our data suggest that ITIH5 could play an important role in gastric cancer and may serve as a valuable prognostic biomarker and potential molecular therapy target for gastric cancer.

[Comparison of long-term outcomes between Billroth-I and Roux-en-Y reconstruction after distal gastrectomy].

OBJECTIVE: To compare the long-term outcomes of Billroth-I and Roux-en-Y reconstruction after distal gastrectomy. METHODS: Clinical data of 151 patients with gastric cancer undergoing distal gastrectomy in the Affiliated Oncologic Hospital of Guangzhou Medical University between June 2000 and June 2010 were analyzed retrospectively. Reconstruction was performed with Billroth-I in 87 patients (B-I group) and Roux-en-Y in 64 (R-Y group). All the patients were followed up for at least 3 years. Three years after operation, clinical symptoms, endoscopic findings, nutritional status, gallstone formation, and late gastrointestinal complications were compared between the two groups. RESULTS: Three years after operation, gastroesophageal reflux symptoms were found in 10 patients (11.5%) in B-I group and in 3 (4.7%) in R-Y group, and dumping syndrome was diagnosed in 8 patients (9.2%) in B-I group and in 3 (4.7%) in R-Y group, but the differences between the two groups were not statistically significant (both P>0.05). Endoscopic examination showed that the amount of residue in the gastric stump, remnant gastritis-reflux esophagitis, and bile reflux in R-Y group were better as compared to B-I group (all P<0.05). Body weight, serum albumin level, and total cholesterol level were similar in the two groups (all P>0.05). The incidences of gallstone formation and late gastrointestinal complications did not differ between B-I group and R-Y group (13.2% vs. 15.8%, and 8.0% vs. 4.7% respectively, both P>0.05). CONCLUSION: As compared with Billroth-I, Roux-en-Y is associated with better long-term outcomes in terms of less remnant gastritis-reflux esophagitis and less bile reflux into the gastric remnant.

Reduced expression of uroplakin 1A is associated with the poor prognosis of gastric adenocarcinoma patients.

BACKGROUND: The aim of this study was to investigate the expression and prognostic significance of Uroplakin1A (UPK1A) in gastric adenocarcinoma patients. Functional studies were also analyzed in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Real-time quantitative PCR (RT-qPCR), western blotting, and immunohistochemical (IHC) staining methods were used to analyze the expression of UPK1A in primary gastric adenocarcinoma tissue samples. Compared with matched adjacent non-tumor, the expression of UPK1A in fresh surgical specimens was reduced, which was confirmed by RT-qPCR (P<0.01) and western blotting analysis (P<0.01). The paraffin specimens from a consecutive series of 445 gastric adenocarcinoma patients who underwent surgery between 2003 and 2006 were analyzed by IHC staining. The relationship between UPK1A expression, clinicopathological factors, and survival were evaluated. IHC staining analysis revealed that the reduced expression of UPK1A was observed in 224 cases (50.3%). Additionally, the correlation analysis of clinicopathological factors demonstrated that reduced expression of UPK1A was significantly associated with histological grade (P = 0.022), node metastasis (P<0.001) and tumor node metastasis (TNM) stage (P = 0.008) (7th edition of the International Union Against Cancer (UICC)). Furthermore, Kaplan-Meier survival analysis revealed that the reduced expression of UPK1A was significantly associated with poor prognosis (P = 0.043). Cox hazards model analysis indicated that UPK1A expression was an independent risk factor at the 0.1 level (P = 0.094). The function of UPK1A in cell cycle, migration, and invasion was investigated by overexpressing UPK1A in the MKN45 gastric cancer cell line. The elevated expression of UPK1A cells induced G1 phase arrest and significantly inhibited migration and invasion. CONCLUSIONS/SIGNIFICANCE: The reduced expression of UPK1A might play a role in the progression of gastric cancer. Thus, UPK1A could be a potential favorable biomarker associated with gastric cancer prognosis.

Decreased expression of the mitochondrial metabolic enzyme aconitase (ACO2) is associated with poor prognosis in gastric cancer.

Alterations in energy metabolism play a major role in cancer development. Aconitase (ACO2) is an essential enzyme located in the mitochondria and catalyzes the interconversion of citrate and isocitrate in the tricarboxylic acid cycle. Recent studies suggest that the expression of ACO2 may be altered in certain types of cancer. The purpose of this study was to examine ACO2 expression in clinical tumor specimens from patients with gastric cancer and to evaluate the clinical relevance of ACO2 expression in gastric cancer. A total of 456 paraffin-embedded gastric cancer tissues and 30 pairs of freshly frozen tissues were used in this study. Real-time quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemical staining were performed to measure ACO2 expression in tumor tissues and matched adjacent non-tumorous tissues. The results showed that the expression of ACO2 was significantly down-regulated in gastric cancer tissues compared with matched adjacent nontumorous tissues and was associated with clinical stage (p = 0.001), T classification (p = 0.027), N classification (p = 0.012), M classification (p = 0.002), and pathological differentiation states (p = 0.036). Patients with lower ACO2 expression had a shorter survival time than those with higher ACO2 expression. Univariate and multivariate analyses indicated that ACO2 expression functions as an independent prognostic factor (p < 0.001). Our data suggested that ACO2 could play an important role in gastric cancer and may potentially serve as a prognostic biomarker.

[Predicting value of serum CEA and CA19-9 in neoadjuvant chemotherapy for advanced gastric carcinoma].

OBJECTIVE: To investigate the predictive value of CEA and CA19-9 in tumor progression, prognosis and neoadjuvant chemotherapy of advanced gastric cancer. METHODS: Clinical data of 322 patients with advanced gastric cancer(54 cases undergoing neoadjuvant chemotherapy) from the Affiliated Oncologic Hospital of Guangzhou Medical College were reviewed. Serum CEA and CA19-9 levels were detected by electrochemiluminescence immunoassay, while the expression of CEA and CA19-9 protein in 54 pairs of tumor tissues and matched biopsies neoadjuvant chemotherapy were determined by immunohistochemistry. RESULTS: The expression levels of serum CEA and CA19-9 were closely related to tumor invasion, lymph node metastasis and TNM stage(all P<0.05). The 5-year cumulative survival rates of patients with serum CEA-positive and CA19-9-positive were 17.0% and 11.9%, compared with 34.6% and 34.8% of the patients with serum CEA-negative and CA19-9-negative respectively (both P<0.05). Neoadjuvant chemotherapy could down-regulate CEA and CA19-9 expressions in tumor tissues(P<0.05), while there was no significantly difference in serum level(P>0.05). CONCLUSIONS: The expressions of serum CEA and CA19-9 are closely associated with tumor progression and prognosis in advanced gastric cancer. However, further study should be done to evaluate their value in selecting patients to receive neoadjuvant chemotherapy.

[Preoperative intra-arterial chemotherapy for progressive lower rectal cancer].

OBJECTIVE: To evaluate the therapeutic effect of preoperative regional intra-arterial chemotherapy (PRAC) on progressive lower rectal cancer. METHODS: Forty-five patients with progressive lower rectal cancer were divided into groups A (23 cases) and B (22 cases) for treatment with PRAC 1 to 2 weeks prior to surgical tumor resection or with surgical resection only, respectively. RESULTS: PRAC caused obvious tissue degeneration and necrosis of rectal cancer with a total effective rate of 95.65%. The rates of radical resection in groups A and B were 91.3% and 72.27%, respectively. The 1-year postoperative survival rates of the two groups were 95.65% and 86.36%, with 3-year survival of 89.96% and 68.18%, and 3-year postoperative recurrence rates of 8.69% and 27.27%, respectively. The anal preservation rates of the two groups were 78.26% and 59.09%. CONCLUSION: PRAC can increase radical resection rates, promote the postoperative survival and anal preservation rate, and lower the recurrence rate in patients with lower rectal cancer.