High WFDC3 gene expression is associated with poor prognosis and reduced immune cells infiltration in pancreatic adenocarcinoma: A study using the TCGA database and bioinformatics analysis.

Whey-acidic-protein (WAP) four-disulfide core domain protein 3 (WFDC3) is one of the WAP family proteins. This protein family is associated with the development of solid tumors and affects the tumor immunological microenvironment. However, the prognostic value of WFDC3 in pancreatic adenocarcinoma (PAAD) and its effect on the tumor immune microenvironment is yet to be clarified. The Cancer Genome Atlas database and Genotype-Tissue Expression database were used to analyze the differential expression of WFDC3 between the tumor and adjacent tissues. The clinical significance of WFDC3 was analyzed in The Cancer Genome Atlas and International Cancer Genome Consortium database using WFDC3 transcripts and clinical information. In order to elucidate the underlying mechanisms, gene set enrichment analysis was conducted to determine potential activated pathways. Immune score evaluation and publicly available pharmacogenomics database [the Genomics of Drug Sensitivity in Cancer] were utilized to quantify immune cell infiltration and the effect on chemotherapeutic drug sensitivity. WFDC3 levels were higher in PAAD tissues than in normal pancreatic tissues. High levels of WFDC3 expression progressively increased as PAAD tumor stages progressed. Patients with elevated WFDC3 expression showed a poor prognosis. The gene set enrichment analysis analysis revealed that glutamate, arginine, and proline, and histidine metabolism levels were elevated in patients with a high WFDC3 expression phenotype. B, CD4+ T, and CD8+ T cell infiltration was diminished in PAAD tissues with elevated WFDC3 expression. According to pharmacogenomics, PAAD tissues with high WFDC3 expression are susceptible to gemcitabine. WFDC3 is highly expressed in PAAD, and patients with a high level of WFDC3 expression have a shorter overall survival time, indicating a poorer prognosis. High expression of WFDC3 may lead to the development of PAAD by affecting the amino acid metabolism and the tumor immunological microenvironment. WFDC3 may serve as a potential diagnostic and prognostic biomarker for PAAD patients.

Stemness analysis in hepatocellular carcinoma identifies an extracellular matrix gene-related signature associated with prognosis and therapy response.

Background: Tumor stemness is the stem-like phenotype of cancer cells, as a hallmark for multiple processes in the development of hepatocellular carcinoma (HCC). However, comprehensive functions of the regulators of tumor cell's stemness in HCC remain unclear. Methods: Gene expression data and clinical information of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) dataset as the training set, and three validation datasets were derived from Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC). Patients were dichotomized according to median mRNA expression-based stemness index (mRNAsi) scores, and differentially expressed genes were further screened out. Functional enrichment analysis of these DEGs was performed to identify candidate extracellular matrix (ECM)-related genes in key pathways. A prognostic signature was constructed by applying least absolute shrinkage and selection operator (LASSO) to the candidate ECM genes. The Kaplan-Meier curve and receiver operating characteristic (ROC) curve were used to evaluate the prognostic value of the signature. Correlations between signatures and genomic profiles, tumor immune microenvironment, and treatment response were also explored using multiple bioinformatic methods. Results: A prognostic prediction signature was established based on 10 ECM genes, including TRAPPC4, RSU1, ILK, LAMA1, LAMB1, FLNC, ITGAV, AGRN, ARHGEF6, and LIMS2, which could effectively distinguish patients with different outcomes in the training and validation sets, showing a good prognostic prediction ability. Across different clinicopathological parameter stratifications, the ECMs signature still retains its robust efficacy in discriminating patient with different outcomes. Based on the risk score, vascular invasion, α-fetoprotein (AFP), T stage, and N stage, we further constructed a nomogram (C-index = 0.70; AUCs at 1-, 3-, and 5-year survival = 0.71, 0.75, and 0.78), which is more practical for clinical prognostic risk stratification. The infiltration abundance of macrophages M0, mast cells, and Treg cells was significantly higher in the high-risk group, which also had upregulated levels of immune checkpoints PD-1 and CTLA-4. More importantly, the ECMs signature was able to distinguish patients with superior responses to immunotherapy, transarterial chemoembolization, and sorafenib. Conclusion: In this study, we constructed an ECM signature, which is an independent prognostic biomarker for HCC patients and has a potential guiding role in treatment selection.

Pan-Cancer Analyses Reveal Oncogenic and Immunological Role of PLOD2.

Some previous studies have shown that PLOD2 has some value in tumorigenesis. However, the broad significance of PLOD2 has not been discussed in depth. This study was aimed at elaborated and summarized the value of PLOD2 in various tumors. First, we integrated GTEx, The Cancer Genome Atlas and Cancer Cell Line Encyclopedia databases to analyze the expression of PLOD2, and found that it was expressed differently in normal tissues and significantly highly expressed in most tumors compared with normal tissues. Second, our analysis revealed that PLOD2 expression was negatively correlated with the prognosis of several tumors. For gastric cancer, the median overall survival time was significantly higher in the PLOD2 low expression group [HR 0.616 (95%CI 0.442-0.858), p = 0.004]. Third, for tumor immunity, PLOD2 was significantly associated with tumor infiltration, including immune infiltrating cells; immune checkpoint expression; immune microenvironment scores (immune score, stromal score and estimate scores); immunotherapy-related scores (tumor mutational burden, microsatellite instability, tumor neoantigen burden); expression of DNA repair genes Mismatch Repairs and methyltransferase; and enrichment analyses identified PLOD2-associated terms and pathways. Lastly, twenty pairs of gastric cancer and adjacent immunohistochemistry showed that PLOD2 was significantly overexpressed in gastric cancer (p < 0.001). Collectively, PLOD2 played a significant role in tumorigenesis and maybe serve as a potential biomarker for diagnosis and prognosis in cancers.

A differential expression network method identifies ankylosing spondylitis-related genes.

BACKGROUND: The exact pathogenic mechanism of ankylosing spondylitis (AS) is still unclear. OBJECTIVE: we aimed to screen key genes associated with AS using differential expression network (DEN), and further to reveal the molecular mechanism of AS. MATERIALS AND METHODS: First, the gene expression data of AS were recruited and preprocessed. Meanwhile, differentially expressed genes (DEGs) were identified. Then, the DEN including the differential interactions and the nondifferential interactions were constructed, and the hub genes were determined according to degree centrality analysis of nodes. Finally, pathway enrichment analysis was conducted on these genes contained in the DEN to further to determine the importance of the hub genes. RESULTS: A total of 20,102 genes were obtained and 145 DEGs which including 99 upregulated genes and 46 downregulated genes were identified. Then, a DEN which contained 434 differential interactions and 2 nondifferential interactions were constructed. In the following, four hub genes which were USP7, hepatoma-derived growth factor, EP300, and split hand/foot malformation type 1 (SHFM1) were screened out. None of them was DEGs. Finally, the hub genes of EP300 and SHFM1 were enriched in the pathways of prostate cancer and adherens junction and proteasome pathway, respectively. CONCLUSIONS: Compared to the traditional differential genes methods, DEN is a more useful and comprehensive method to conduct on the AS. We predict that these genes (such as EP300 and SHFM1) could be chosen as novel predictive markers for AS.

A Novel Clinical-Simulated Suture Education for Basic Surgical Skill: Suture on the Biological Tissue Fixed on Standardized Patient Evaluated with Objective Structured Assessment of Technical Skill (OSATS) Tools.

BACKGROUND: Clinical-simulated training has shown benefit in the education of medical students. However, the role of clinical simulation for surgical basic skill training such as suturing techniques remains unclear. MATERIALS AND METHODS: Forty-two medical students were asked to perform specific suturing tasks at three stations with the different settings within four minutes (Station 1: Synthetic suture pad fixed on the bench, Station 2: Synthetic suture pad fixed on the standardized patient, Station 3: Pig skin fixed on the standardized patient); the OSATS (Objective Structured Assessment of Technical Skill) tool was used to evaluate the performance of students. A questionnaire was distributed to the students following the examination. RESULTS: Mean performance score of Station 3 was significant lower than that of Station 1 and 2 in the general performance including tissue handling, time, and motion. The suturing techniques of students at Station 2 and 3 were not as accurate as that at Station 1. Inappropriate tension was applied to the knot at Station 2 compared with Station 1 and 3. On the questionnaire, 93% of students considered clinical-simulated training of basic surgical skills was necessary and may increase their confidence in future clinical work as surgeons; 98% of students thought the assessment was more objective when OSATS tool was used for evaluation. CONCLUSION: Clinical simulation examination assessed with OSATS might throw a novel light on the education of basic surgical skills and may be worthy of wider adoption in the surgical education of medical students.

Elevated CXCL1 increases hepatocellular carcinoma aggressiveness and is inhibited by miRNA-200a.

In this study, we investigated the value of measurement of the chemokine CXCL1 in clinical management of hepatocellular carcinoma (HCC) and its possible role in the molecular pathogenesis of HCC. High CXCL1 expression predicted recurrence in HCC patients and promoted tumor progression in both in vivo and in vitro experimental systems. Overexpression of CXCL1 increased mitochondrial metabolism and activated the epithelial-to-mesenchymal transition (EMT). Using computational analysis we identified the microRNA miR-200a as a putative post-transcriptional regulator of CXCL1. We found that levels of miR-200a were inversely correlated with CXCL1 expression in HCC patient tissue samples by northern blot and qRT-PCR. Furthermore, CXCL1 was identified as a direct target which was bound and inhibited by miR- 200a. These findings provide new insights into the role of CXCL1 in HCC and its post-transcriptional regulation and suggest it may be a prognostic indicator for poor outcomes and a potential target for therapy.

Expression of G Protein-coupled Receptor 56 Is an Unfavorable Prognostic Factor in Osteosarcoma Patients.

G protein-coupled receptor 56 (GPR56) is an atypical G protein-coupled receptor, with the long extracellular N-terminus. GPR56 can trigger various downstream signaling responsible for cell survival, proliferation, adhesion, and migration. Expression of GPR56 is associated with cell malignant transformation and tumor cell metastasis in several carcinomas such as melanoma and glioma. Osteosarcoma is the most common malignant bone tumor in adolescents and young adults with high metastasis tendency. The overall survival of osteosarcoma is unsatisfied, partially due to the lacking of predictive markers for metastasis and overall prognosis. This study aimed at figuring out whether expression of the GPR56 was associated with clinicopathological features of osteosarcoma. Eighty-nine patients who received osteosarcoma operation between March 2004 and February 2011 in Linyi People's Hospital were recruited. Immunohistochemical staining (IHC) was carried out to identify the expression of GPR56 in those osteosarcoma tissues, and our cohort was divided into higher-expression group and lower-expression group according to the cut-off of IHC score. Expression of GPR56 in osteosarcoma tissues was correlated with the TNM stage and overall survival. Univariate and multivariate analysis showed that GPR56 could act as an independent prognosis factor for osteosarcoma. Western blot results demonstrated that GPR56-siRNA down-regulated the expression of GTP-RhoA and Ki67. GTP-RhoA participates in the cell migration process, while Ki67 plays important roles in cell proliferation, indicating GPR56 may function in tumor development. Correspondingly, we show that GPR56 regulates the proliferation and invasion capacity of osteosarcoma cells. Our study has revealed the prognostic value of GPR56 expression in osteosarcoma.

Overexpression of chaperonin containing TCP1, subunit 3 predicts poor prognosis in hepatocellular carcinoma.

AIM: To investigate the value of chaperonin containing TCP1, subunit 3 (CCT3) to predict the prognosis of patients with hepatocellular carcinoma (HCC) and determine its function in HCC progression. METHODS: CCT3 expression levels were examined in human non-cancerous liver tissues and a variety of HCC cell lines by quantitative real-time PCR and immunoblotting. CCT3 expression was suppressed by small interfering RNA. The effects of reducing CCT3 expression in HCC cells were tested. The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay, cell counting experiment, cell cycle assay, apoptosis assay and invasion assay were employed to evaluate cell functions in vitro. Immunohistochemistry was performed on HCC specimens. In addition, CCT3 expression in HCC specimens was also assessed at the protein and mRNA level. Associations between clinicopathological characteristics and prognosis were analyzed, along with the possible mechanisms involved in CCT3's function in HCC progression. RESULTS: The expression levels of CCT3 mRNA and protein were upregulated in HCC cell lines in contrast to adjacent non-cancerous tissues. Reducing CCT3 expression not only suppressed cell proliferation in cell counts, MTT assay, cell cycle assay and induced cell apoptosis (P < 0.05 vs negative control), but also inhibited the tumor cell invasion capacity in vitro (P < 0.01 vs negative control). Overexpression of CCT3 in the nuclei of cancer cells in HCC specimens (58 of 104 patients, 55.8%) was associated with poor prognosis in HCC patients (3-year survival rate, 55.5% vs 84.2%, P = 0.020) after hepatectomy. Mechanistic analyses showed that signal transducer and activator of transcription 3 (STAT3) activation was decreased even when stimulated by interleukin-6 after knocking down CCT3 in the HepG2 cell line. CONCLUSION: Overexpression of CCT3 in the nuclei of cancerous cells is associated with HCC progression. CCT3 may be a target that affects the activation of STAT3 in HCC.

Esophagogastric devascularization without splenectomy in portal hypertension: safe and effective?

BACKGROUND: Esophagogastric variceal hemorrhage is a life-threatening complication of portal hypertension. In this study, we compared the therapeutic effect of a novel surgical procedure, esophagogastric devascularization without splenectomy (EDWS), with the widely used modified esophagogastric devascularization (MED) with splenectomy for the treatment of portal hypertension. METHODS: Fifty-five patients with portal hypertension were included in this retrospective study. Among them, 27 patients underwent EDWS, and the other 28 patients underwent MED. Patients' characteristics, perioperative parameters and long-term follow-up were analyzed. RESULTS: The portal venous pressure was decreased by 20% postoperatively in both groups. The morbidity rate of portal venous system thrombosis in the EDWS group was significantly lower than that in the MED group (P=0.032). The 1- and 3-year recurrence rates of esophagogastric variceal hemorrhage were 0% and 4.5% in the EDWS group, and 0% and 8.7% in the MED group, respectively (P=0.631). CONCLUSIONS: EDWS is a safe and effective treatment for esophagogastric varices secondary to portal hypertension in selected patients. Patients treated with EDWS had a lower complication rate of portal venous system thrombosis compared with those treated with conventional MED.

Prognostic value of glypican-3 in patients with HBV-associated hepatocellular carcinoma after liver transplantation.

BACKGROUND: Glypican-3 (GPC-3) is frequently overexpressed in hepatocellular carcinoma (HCC). Recent studies have shown that GPC-3 is a highly efficient diagnostic biomarker of HCC and an indicator of poor prognosis in HCC patients who have undergone hepatectomy. However, its prognostic value in patients with HBV-associated HCC after liver transplantation (LT) is not clear. The present study is to evaluate the prognostic value of GPC-3 in patients with HBV-associated HCC after LT. METHODS: A cohort of 104 HCC patients with HBV-associated cirrhosis who had undergone LT at our hospital between 2002 and 2011 were enrolled in this study. Samples of HCC were taken from these patients. GPC-3 protein expression was detected in paraffin-embedded specimens using immunohistochemistry. All related clinical data were obtained from the China Liver Transplant Registry. The relationship between GPC-3 expression and clinicopathological parameters was analyzed. Univariate and multivariate Cox-regression analyses were used to identify risk factors for poor prognosis. RESULTS: GPC-3 was expressed in samples from 74 (71.2%) of the 104 patients. GPC-3 was expressed only in HCC cells. Positive staining was correlated with tumor size (P=0.004), encapsulation (P=0.018), pathological stage (P=0.027), portal vein invasion (P=0.043), tumor differentiation (P=0.002) and the Milan criteria (P=0.016). The 5-year survival rate and disease-free survival rate of patients with GPC-3-positive were lower than those (38.2% vs 75.4%, P<0.001; 30.8% vs 69.7%, P=0.001) of patients with GPC-3-negative. Multivariate Cox-regression analysis revealed that GPC-3 was an independent risk factor for 5-year survival rate (P=0.031) and disease-free survival rate (P=0.047), together with tumor differentiation, Milan criteria and pre-operative alpha-fetoprotein. CONCLUSION: GPC-3 is a potential biomarker for poor prognosis after LT in HCC patients with HBV-associated cirrhosis.

Hepatocellular carcinoma recurrence is an independent risk factor for HB recurrence after liver transplantation.

BACKGROUND/AIMS: To confirm the relationship between hepatitis B recurrence and Hepatocellular carcinoma recurrence. METHODOLOGY: Data from 340 patients undergoing liver transplantation for HBV-related liver disease were retrospectively evaluated. Clinically relevant variables were analyzed using univariate models. Significant variables were subjected to multivariate logistic regression analysis to identify the independent predictors for HBV recurrence. Fifteen samples removed from HCC recurrence patients were stained for HBsAg and HBcAg. RESULTS: The analyzed population included 283 male and 57 female patients. The mean age was 48.5±9.33 years and median follow-up was 47 months. Hepatitis B relapsed in 16 patients (4.7%). Univariate analysis indicated that HCC (P=0.022) and HCC recurrence (P=0.000) were associated to post transplantation HB. Multivariate analysis identified HCC recurrence as an independent risk factor for HB recurrence (hazard ratio: 23.262 (95% CI: 3.752, 144.216); P <0.001). Three of 15 metastatic lesions were positive for HBsAg and 1 lesion was positive for HBcAg. Conclusion: HCC recurrence is an independent risk factor for post transplantation recurrence of hepatitis.

Ileo-colonic intussusception secondary to small-bowel lipomatosis: a case report.

Intestinal lipomatosis is a rare disease with an incidence at autopsy ranging from 0.04% to 4.5%. Because the lipomas are diffusely distributed in the intestine, most patients are symptom-free, and invasive intervention is not advised by most doctors. Here, we describe a case with intussusception due to small-bowel lipomatosis. Partial small bowel resection and anastomosis were performed because the intestinal wall was on the verge of perforation. This case indicates that regular follow-up is necessary and endoscopic treatment should be considered to avoid surgical procedures if the lipoma is large enough to cause intestinal obstruction.

Graft versus host disease after liver transplantation: a case report.

In documenting clinical experience in the diagnosis and treatment of graft versus host disease (GVHD), we retrospectively analyzed data of one case that has developed GVHD after liver transplantation. This patient exhibited fever, skin rash, and diarrhea on day 9 after liver transplantation. His liver function was normal. Skin biopsy showed scattered keratinocytes accompanied by satellite-like lymphocyte infiltration and basal cell liquefaction degeneration. After carefully analyzing the complications, we took the strategy of decreasing the dose of tacrolimus. Thereafter, the patient's temperature decreased to normal, his skin rashes subsided, and his diarrhea was relieved. This case suggests that reducing the dosage of immunosuppressive agents can be an effective strategy for GVHD after liver transplantation.

[Management of hepatic artery related complications and its outcome during liver transplantation].

OBJECTIVE: To explore the experience of hepatic arterial reconstruction and management of its complications. METHODS: The clinical data of 570 consecutive orthotopic liver transplantation patients performed from May 2001 to May 2009 in Peking University People's Hospital were analyzed retrospectively in order to summarize the key factors of hepatic arterial reconstruction and the experience of management of its complications. RESULTS: Arterial complications developed in 18 (3.1%) of the 570 patients including 11 cases of hepatic artery thrombosis, 5 cases of hepatic artery stenosis and 2 cases of hepatic artery rupture. Of the 11 cases with early complication (within 4 weeks), 7 patients died, including 2 due to the rupture of hepatic artery and 5 due to acute liver failure and sepsis of hepatic artery thrombosis. Of the 7 cases with late complication, 4 patients died, including 1 due to graft failure and 3 due to ischemic-type biliary complications. CONCLUSION: Good quality of donor artery and proper choice of microsurgical anastomosis technique in hepatic artery reconstruction could significantly reduce the incidence of its complication. Early detection and diagnosis with active early interventional therapy can improve prognosis of the patients.

[Analysis of 565 cases of liver transplantation at a single transplantation center].

OBJECTIVE: To determine the preventative and curative strategies after liver transplantation by investigating the risk factors on prognosis. METHODS: The data of 565 consecutive patients who underwent orthotopic liver transplantation were retrospectively analyzed with the survival rate and complication morbidity. RESULTS: The follow-up time ranges from 3 to 104 months of all the 565 patients after liver transplantation. From January 2004 to January 2009, the patient survival rates were 91.2% after 1 month, 84.9% after 1 year, 69.2% after 3 years, and 66.1% after 5 years, while they were 87.8%, 73.2%, 60.2%, and 57.7% from May 2000 to December 2003. The patient survival rates were 83.3% after 1 year, 79.8% after 3 years, and 78.5% after 5 years in non-hepatocellular carcimoma (non-HCC) group, while they were 78.4%, 49.1%, and 45.1% in HCC group. In early stage after surgery, the morbidities of re-operation due to intra-abdominal hemorrage, vascular complication, severe infection, acute renal failure and primary graft dysfunction were 1.1%, 1.6%, 13.6%, 7.4%, and 1.2%, while in late stage, the morbidities of HCC recurrence, biliary complications, HBV recurrence, de novo malignancy, chronic graft dysfunction were 40.3%, 6.7%, 2.1%, 0.9%, 0.9%, and 1.1%, respectively. The HCC recurrent rates were 8.1% versus 62.5% in matching Milan criteria group or exceeding Milan criteria group and the median survival time was 19.6 months of all recurrent patients. CONCLUSION: Liver transplantation has been the effective treatment for end stage liver disease. Due to the shortage of graft,we prefer to do operations for the patients without HCC or the patients with HCC but matching Milan Criteria.