PCAT1 promotes the proliferative and migratory potentials of ovarian cancer via targeting NEK2.

OBJECTIVE: The aim of this study was to clarify the potential role of PCAT1 in the occurrence and development of ovarian cancer (OC). PATIENTS AND METHODS: Expression levels of PCAT1 and NEK2 in OC tissues and cell lines were detected by quantitative Real-time polymerase chain reaction (qRT-PCR). Correlation between PCAT1 expression with tumor stage and prognosis of OC patients was analyzed. Knockdown or over-expression of PCAT1 and NEK2 were achieved by siRNA or lentivirus transfection, respectively. Subsequently, cell viability, apoptosis, cell cycle progression and migration were determined by cell counting kit-8 (CCK-8), flow cytometry and transwell assay, respectively. Furthermore, the protein levels of relative genes in Wnt pathway were detected by Western blot. RESULTS: PCAT1 was highly expressed in OC tissues and cell lines, especially in tumor tissues with stage III-IV compared with stage I-II. The prognosis of OC patients with higher expression of PCAT1 was significantly worse than those with lower expression. In vitro experiments confirmed that PCAT1 knockdown obviously inhibited proliferative and migratory potentials, whereas induced apoptosis of OC cells. No significant changes were observed in cell cycle progression of OC cells after knockdown or overexpression of PCAT1. Meanwhile, overexpression of PCAT1 remarkably upregulated the expression level of NEK2, which was the target gene of PCAT1. Interestingly, NEK2 knockdown could obviously suppress cell migration. Furthermore, Western blot results elucidated that PCAT1 knockdown could inhibit the protein levels of relative genes in Wnt pathway in OC cells. CONCLUSIONS: PCAT1 was highly expressed in OC tissues than adjacent normal tissues. PCAT1 overexpression significantly promoted proliferative and migratory potentials, whereas inhibited apoptosis of OC cells through upregulating NEK2 expression via Wnt pathway.

[Transjugular intrahepatic portosystemic shunt for esophagogastric variceal bleeding in liver cirrhosis: intended population and timing].

Esophagogastric variceal bleeding is a life-threatening complication of cirrhotic portal hypertension. Transjugular intrahepatic portosystemic shunt (TIPS) is an effective method for the treatment and prevention of esophagogastric variceal bleeding; however, right timing of TIPS and selection of appropriate candidates for TIPS are of vital importance in improving patients' survival rate and reducing mortality rate. This article reviews the intended population and right timing of TIPS for the treatment and prevention of esophagogastric variceal bleeding in liver cirrhosis.

Polymorphisms in interleukin-6 and interleukin-10 may be associated with risk of preeclampsia.

Preeclampsia is a common condition unique to pregnant women. Previous studies have suggested that several cytokines may contribute to defective placental invasion and endothelial damage in this condition. We investigated the influence of four single nucleotide polymorphisms (SNPs) in the promoters of IL-6 (-572G/C, -597G/A, and -174G/C) and IL-10 (-592A/C) on susceptibility to preeclampsia in a Chinese population. This study included 142 newly diagnosed preeclampsia patients and 260 controls recruited from Qingdao Women and Children's Hospital between January 2013 and May 2015. Genotyping of IL-6 and IL-10 SNPs was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Logistic regression analysis was then performed to determine the association between these variants and preeclampsia risk. Our findings indicated that compared to the AA genotype, the CC and AC+CC genotypes of IL-10 -592A/C correlate with elevated risk of developing preeclampsia, with adjusted odds ratios (and 95% confidence intervals) of 2.45 (1.26-4.72) and 1.71 (1.09-2.68), respectively. However, the IL-6 -572G/C, -597G/A, and -174G/C polymorphisms were not found to play a critical role in susceptibility to this disorder. In conclusion, the IL-10 -592A/C genetic variant was observed to be associated with preeclampsia risk in pregnant women.

[Holistic integrative medicine: the road to the future of the development of burn medicine].

Holistic integrative medicine is the road to the future of the development of burn medicine. Not only burn medicine, but also human medicine gradually enters the era of holistic integrative medicine. Holistic integrative medicine is different from translational medicine, evidence-based medicine or precision medicine, which integrates the most advanced knowledge and theories in medicine fields with the most effective practices and experiences in clinical specialties to form a new medical system.

Successful Rescue of Late-onset Antibody-mediated Rejection 12 Years After Living-donor Intestinal Transplantation: A Case Report.

BACKGROUND: Antibody-mediated rejection (ABMR) has recently surfaced as a potential form of graft dysfunction after intestinal transplantation. METHODS: We present a case of an intestinal transplant recipient who developed late-onset ABMR 12 years after living-donor transplantation. An 18-year-old male recipient with a history of extensive intestinal resection secondary to acute bowel volvulus exhibited an excellent baseline immune profile for transplantation, including ABO-identical and HLA-haploidentical to the donor; a negative cross-match with a panel reactive antibody of 3.0%. RESULTS: Post-transplantation immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), and prednisone within the first year, followed by tacrolimus and MMF in the second year, and maintenance with tacrolimus monotherapy thereafter. The recipient experienced a single episode of indetermined acute cellular rejection 3 months after transplantation. Since then, he did not require any parenteral nutrition and had completely reintegrated with society. Twelve years later, the patient developed persistent diarrhea associated with transplant biopsy diffuse C4d deposition and circulating donor-specific antibodies. After the use of rituximab and intravenous immunoglobulin, the recipient stabilized 17 years after transplantation with complete recovery of intestinal mucosal damage. CONCLUSION: Late-onset ABMR can emerge after transplantation and must be considered a possible cause of graft dysfunction in long-term intestinal transplantation survivors.

[Current status of treatment of refractory ascites in patients with liver cirrhosis].

Ascites is a common clinical manifestation of cirrhotic portal hypertension, and about 60%-80% of cirrhotic patients develop the symptom of ascites within 10 years. Once ascites occurs, the 5-year survival rate is reduced from 80% to 50%. With the progression of liver diseases, approximately 5%-10% of patients with ascites develop refractory ascites, and the median survival time is only 6-12 months. This article reviews the definition and diagnosis of refractory ascites, evaluation of prognostic factors, and treatment regimens, including large-volume paracentesis combined with protein supplementation, transjugular intrahepatic portosystemic shunt, and liver transplantation.

Serum vitamin D level is associated with disease severity and response to ursodeoxycholic acid in primary biliary cirrhosis.

BACKGROUND: Serum vitamin D levels are associated with bone complications in patients with primary biliary cirrhosis (PBC). Increasing evidence suggests a nonskeletal role of vitamin D in various autoimmune and liver diseases. AIM: To investigate the clinical relevance of vitamin D levels in PBC, especially their association with the therapeutic effects of ursodeoxycholic acid (UDCA). METHODS: Consecutive PBC patients were retrospectively reviewed. 25-hydroxyvitamin D [25(OH)D] levels were determined in frozen serum samples collected before initiation of UDCA treatment. Response to UDCA was evaluated by Paris-I and Barcelona criteria. Logistic regressions were performed to identify the treatment response-associated parameters. RESULTS: Among 98 patients, the mean serum 25(OH)D concentration was 17.9 ± 7.6 ng/mL. 25(OH)D levels decreased with increasing histological stage (P = 0.029) and were negatively correlated with bilirubin and alkaline phosphatase levels. After 1 year of UDCA therapy, 31 patients failed to achieve complete response according to Paris-I criteria. The baseline 25(OH)D level was significantly lower in nonresponders (14.8 ± 6.4 vs. 19.3 ± 7.6 ng/mL, P = 0.005). Vitamin D deficiency at baseline was associated with an increased risk of incomplete response independent of advanced stages (OR = 3.93, 95% CI = 1.02-15.19, P = 0.047). Similar results were obtained when biochemical response was evaluated by Barcelona criteria. Furthermore, 25(OH)D levels were lower in patients who subsequently suffered death or liver transplantation (12.1 ± 4.6 vs. 18.4 ± 7.6 ng/mL, P = 0.023). CONCLUSIONS: 25(OH)D level is associated with biochemical and histological features in PBC. Pre-treatment vitamin D status is independently related to subsequent response to UDCA. Our results suggest that vitamin D status may have important clinical significance in PBC.

Successful ABO-incompatible living-related intestinal transplantation: a 2-year follow-up.

ABO-incompatible intestinal transplantation has rarely been performed due to poor patient outcomes. Herein we present a case of successful ABO-incompatible intestinal transplantation with a 2-year follow-up. A 16-year-old female with a history of extensive bowel resection received an ABO-incompatible living donor bowel graft from her father (blood type AB graft into a type A recipient). Posttransplant immunosuppression consisted of an initial anti-CD20, plasmapheresis/intravenous immunoglobulin before transplantation, followed by an anti-thymocyte globulin (ATG) induction and splenectomy, and maintenance with tacrolimus and prednisone. Her postoperative course was remarkable for a single episode of rejection on day 14 which responded promptly to treatment with methyprednisolone and ATG. Three months after transplantation, the patient developed an abdominal abscess requiring open surgical drainage. No viral infections were encountered. Posttransplant anti-B antibody titers and anti-B7 donor-specific antibody levels remained low. At a 2-year follow-up, the patient showed a progressive weight gain of 5.0 kg. This case illustrates that ABO-incompatible living-related bowel transplantation is immunologically feasible and is associated with good outcomes for the recipient. The management of blood type antibodies and the use of adequate immunosuppression in the early period of the procedure may be the keys to the success of future cases.

Inhibitory effects of indirubin derivative PHII-7 on invasion and migration in metastatic cancer.

UNLABELLED: PHII-7, a derivative of indirubin, showed significant anti-cancer activities in vivo and in vitro. We asked whether treating human metastatic cancers and multidrug resistant cancer with PHII-7 would inhibit their invasion and migration. Cell growth was tested by MTT assay and colony formation assay. Apoptosis was examined by flow cytometry. Transwell-based assay and wound healing assay were used to examine cell invasion and migration. Real-time PCR assay and western blot assay were performed to test gene expression on mRNA and protein level, respectively. Firstly, we confirmed that MCF-7/ADR cells showed more invasive and migratory properties compared with MCF-7 cells which were associated with several EMT markers, such as E-cadherin, Slug and vimentin. Secondly, we found that slightly toxic doses of PHII-7 decreased the number of cells that invaded a model epithelial basement membrane and that migrated by switching the molecular signature of the cells from mesenchymal to epithelial. And PHII-7 significantly regulated expression of several epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin, Slug, ß-catenin and vimentin. Thirdly, compared with control, PHII-7 inhibited cell proliferation in a time- and dose-dependent manner. Higher doses of PHII-7 also induced apoptosis through activating PARP, caspase-9 and caspase-3. PHII-7 significantly inhibited invasion and migration in both metastatic cancers and multidrug resistant cancer. Our results may provide several data for future application of PHII-7 on drug design and patients treatment. KEYWORDS: PHII-7, invasion, migration, multidrug resistance, epithelial-mesenchymal transition.

MicroRNA-296-5p increases proliferation in gastric cancer through repression of Caudal-related homeobox 1.

Caudal-related homeobox 1 (CDX1), an intestinal-specific transcription factor, has been reported to have vital roles in gastric intestinal metaplasia (IM). Although IM is a high-risk factor for gastric cancer (GC), the specific role of CDX1 in GC is largely unknown. In this study, we investigated the expression of CDX1 and its functional roles in GC, and its upstream regulatory mechanisms at the microRNA (miRNA) level were further explored. We found that CDX1 is lost in GC when compared with adjacent IM tissues. Gain-of-function studies showed that CDX1 significantly inhibited GC cell growth by inducing cell cycle arrest and apoptosis. Interestingly, we identified and verified an onco-mir, miR-296-5p, as a direct upstream regulator of CDX1. miR-296-5p overexpression significantly promoted GC cell growth and attenuated the CDX1-induced anti-growth effects by recurring cell cycle distribution and apoptotic status, whereas knockdown of miR-296-5p decreased GC cell growth. Furthermore, we found that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the subsequent downstream changes in protein levels related to cell cycle and apoptosis partly account for the miR-296-5p-CDX1-induced GC growth promotion. In addition, the detection of miR-296-5p and expression of CDX1 in primary GC tissues and adjacent IM tissues revealed that miR-296-5p is inversely correlated with CDX1, further supporting our in vitro results. Our results showed an anti-growth effect of CDX1 and identified its miRNA regulatory mechanism in GC. The identification of this novel miR-296-5p-CDX1-ERK1/2 axis sheds new light on the understanding of the process from IM to GC and may provide therapeutic targets for the treatment of GC.

Association between Helicobacter pylori infection and the risk of colorectal neoplasia: a systematic review and meta-analysis.

AIM: The existing evidence on the relationship between Helicobacter pylori infection and the risk of colorectal neoplasia is inconsistent. We conducted a systematic review with a meta-analysis to explore this relationship and to determine whether the relationship varies according to the study characteristics. METHOD: We searched the PubMed database and the reference lists of pertinent articles published up to July 2012. Summary odds ratios (ORs) with their 95% confidence intervals (CIs) were estimated using a random-effects model. RESULTS: Twenty-seven studies including 3792 cases of colorectal adenoma (CRA) and 3488 cases of colorectal cancer (CRC) were identified. Overall, H. pylori infection was associated with an increased risk of CRA (OR = 1.66, 95% CI 1.39-1.97, I(2)  = 54.3%) and CRC (OR = 1.39, 95% CI 1.18-1.64, I(2)  = 35.8%), although there was significant heterogeneity among the studies. Subgroup analysis revealed that the positive correlation did not differ by sex, geographic variation or subsite of neoplasia, but might vary by the method of detection of H. pylori. The study was underpowered to determine the risk of colorectal neoplasia associated with cytotoxin-associated gene A-positive H. pylori. CONCLUSION: This meta-analysis demonstrates a positive association between H. pylori infection and the risk of colorectal neoplasia.

Sorafenib combined with transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma: a large-scale multicenter study of 222 patients.

BACKGROUND: Data on the efficacy and safety of sorafenib in combination with transarterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma (HCC) are lacking. PATIENTS AND METHODS: In this multicenter retrospective study, 222 consecutive HCC patients receiving combination therapy were enrolled between June 2008 and July 2011. RESULTS: Chronic hepatitis B was the predominant cause of HCC (86%). Eighty percent patients were at Barcelona Clinic Liver Cancer (BCLC) stage C, and 86% patients were in Child-Pugh (CP) A class. The overall median survival was 12 months (95% CI 10.1-13.9). The overall incidence of adverse events (AEs) was 87%. In 177 BCLC-C patients, performance status, the number of HCC nodules, Child-Pugh score and macrovascular invasion were significantly associated with overall survival (OS) and were included in the final risk scores (R), where R = 5 × (vascular invasion: 0 if no, 1 yes) + 6 × (CP: 0 if A, 1 if B) + 7 × (no. of lesions: 0 if 1-2, 1 ≥3) + 8 × ( Eastern Cooperative Oncology Group, ECOG: 0 if 0, 1 ≥1). CONCLUSIONS: Sorafenib in combination with TACE should be considered a safe and effective therapy for advanced HCC. Further validation of the new subgroup of BCLC-C stage is warranted in an independent patient cohort.

In vivo molecular imaging of gastric cancer by targeting MG7 antigen with confocal laser endomicroscopy.

BACKGROUND AND STUDY AIMS: In vivo molecular imaging represents a powerful tool for the immediate diagnosis of gastric cancer. In this study, the monoclonal antibody MG7, which is a specific molecular marker against gastric cancer, was labeled with fluorescent agents to enable in vivo real-time imaging by confocal laser endomicroscopy (CLE). PATIENTS AND METHODS: In vivo molecular imaging was performed in tumor-bearing mice from two kinds of human gastric cancer cell lines. Xenograft tumors were visualized in vivo first with a whole-body fluorescent imaging device and then by CLE using fluorescently labeled MG7 antibody. Gastric cancerous tissue and noncancerous mucosa from human biopsies or surgical specimens were also examined ex vivo by CLE. RESULTS: Intravital imaging of xenograft tumors revealed a specific cellular signal, whereas no specific signal was observed in control tissue or in mice injected with irrelevant antibodies. An ex vivo experiment on human specimens using a rigid confocal probe showed positive fluorescent staining in 22/23 samples diagnosed as gastric cancer and weak signals in 5/23 noncancerous tissue samples. CLE evaluation correlated well with immunohistochemical findings. CONCLUSIONS: Screening tumors in vivo by CLE may help to detect MG7-Ag-positive tissues, decrease the sampling error by screening the large tumor surface not routinely screened by biopsy or conventional immunohistochemistry, and facilitate early detection of gastric carcinoma.

Screening and identification of peritoneal metastasis-related genes of gastric adenocarcinoma using a cDNA microarray.

With the aim of identifying peritoneal metastasis-related genes in gastric cancer, we performed a broad analysis of differential gene expression between the parental cell line GC9811 and its highly metastatic peritoneal counterpart, cell line GC9811-P. Two fluorescent cDNA probes, labeled with Cy3 and Cy5 dyes, were prepared from GC9811 and GC9811-P mRNA samples by the reverse transcription method. The two color probes were then mixed and hybridized to a cDNA chip constructed with double-dots from 11,901 human genes; this was scanned at two wavelengths. The experiment was repeated twice. In GC9811-P cells, 218 genes were upregulated and 30 genes were downregulated compared with the parental cell lines. Some selected genes were confirmed by RT-PCR and Western blot; we found that S100A4 and CTNNB1 were upregulated and PTEN was downregulated in GC9811-P cells. Identification of these differentially expressed genes could contribute to disclose the molecular mechanisms involved and provide new targets for therapeutic intervention to avoid peritoneal dissemination of gastric adenocarcinoma.

Altitudinal variations in flower and bulbil production of an alpine perennial, Polygonum viviparum L. (Polygonaceae).

Two opposite views exist regarding sexual versus asexual reproductive performance of Polygonum viviparum. One suggests that increasing altitude favors flower production, while the other suggests that increasing altitude increases bulbil production. In this study, we present an investigation of the reproductive performance of 13 populations of P. viviparum on the Qinghai-Tibet Plateau (QTP). Our results show that, with increasing altitude, the height of inflorescence and total number of flowers and bulbils decrease significantly, but there is no significant effect on bulbil and flower number. In addition, there is a weak correlation between the proportion of flowers per population and altitude in our study sites due to the exception population 12, which is in a disturbed habitat. We conclude that more resources might be allocated to flowers in populations at higher altitudes, indicating the importance of sexual reproduction over asexual reproduction in alpine plants of QTP.

Transgenic cyclooxygenase-2 expression and high salt enhanced susceptibility to chemical-induced gastric cancer development in mice.

Cyclooxoygenase (COX)-2 overexpression is involved in gastric carcinogenesis. While high-salt intake is a known risk factor for gastric cancer development, we determined the effects of high salt on gastric chemical carcinogenesis in COX-2 transgenic (TG) mice. COX-2 TG mice were developed in C57/BL6 strain using the full-length human cox-2 complementary DNA construct. Six-week-old COX-2 TG and wild-type (WT) littermates were randomly allocated to receive alternate week of N-methyl-N-nitrosourea (MNU, 240 p.p.m.) in drinking water or control for 10 weeks. Two groups of mice were further treated with 10% NaCl during the initial 10 weeks. All mice were killed at the end of week 50. Both forced COX-2 overexpression and high-salt intake significantly increased the frequency of gastric cancer development in mice as compared with WT littermates treated with MNU alone. However, no additive effect was observed on the combination of high salt and COX-2 expression. We further showed that MNU and high-salt treatment increased chronic inflammatory infiltrates and induced prostaglandin E(2) (PGE(2)) production in the non-cancerous stomach. Whereas high-salt treatment markedly increased the expression of inflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 beta and IL-6) in the gastric mucosa, COX-2 overexpression significantly altered the cell kinetics in the MNU-induced gastric cancer model. In conclusion, both high salt and COX-2 overexpression promote chemical-induced gastric carcinogenesis, possibly related to chronic inflammation, induction of PGE(2), disruption of cell kinetics and induction of inflammatory cytokines.

ZNRD1 might mediate UV irradiation related DNA damage and repair in human esophageal cancer cells by regulation of ERCC1.

The downregulation of zinc ribbon domain-containing 1 (ZNRD1) protein was recently found to partially reverse the resistance of human leukemia cells toward chemical therapeutic drugs. Therefore, the ZNRD1 protein might be involved in the process of DNA damage and repair. To explore the possible protective effects of ZNRD1 on DNA damage induced by ultraviolet (UV)-C irradiation in human esophageal squamous cancer cell line EC109, we designed and transfected a expression vector into EC109 cells, and established an overexpression cell line. The single-cell gel electrophoresis (comet assay) was used to investigate the DNA damage and repair in UV-C-irradiated control and transfected cells. It was found that the ZNRD1-expressing cells exhibited a significant enhanced DNA repair capacity. Moreover, the overexpression of ZNRD1 could upregulate the expression of excision repair cross-complementing 1 (ERCC1) gene. Collectively, these findings suggested that ZNRD1 might play an important role in the process of DNA damage and repair by regulating the expression of ERCC1.

Overexpression of PrPC and its antiapoptosis function in gastric cancer.

Cellular prion protein (PrP(C)), a glycosylphosphatidylinositol-anchored membrane protein, was found in our lab to be widely expressed in gastric cancer cell lines. In order to evaluate its biological significance in human gastric cancer, we investigated its expression in a large series of gastric tissue samples (n = 124) by immuno histochemical staining with the monoclonal antibody 3F4. Compared with normal tissues, gastric adenocarcinoma showed increased PrP(C) expression, correlated with the histopathological differentiation (according to the WHO and Lauren classifications) and tumor progression (as documented by pTNM staging). To better understand the underlying mechanism, we introduced the PrP(C) and two pairs of RNAi into the poorly differentiated gastric cancer cell line AGS and found that PrP(C) suppressed ROS and slowed down apoptosis in transfected cells. Further study proved that the apoptosis-related protein Bcl-2 was upregulated whereas p53 and Bax were downregulated in the PrP(C)-transfected cells. A reverse effect was observed in PrP(C) siRNA-transfected cells. These results strongly suggested that PrP(C) might play a role as an effective antiapoptotic protein through Bcl-2-dependent apoptotic pathways in gastric cancer cells. Further study into the mechanism of these relationships might enrich the knowledge of PrP, better our understanding of the nature of gastric carcinoma, and further develop possible strategies to block or reverse the development of gastric carcinoma.

Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2.

Apoptosis-inducing factor (AIF) represents a caspase-independent apoptotic pathway in the cell, and a mitochondrial localization sequence-truncated AIF (AIFDelta1-120) can be relocated from the cytoplasm to the nucleus and exhibit a constitutive proapoptotic activity. Here, we generated a chimeric immuno-AIF protein, which comprised an HER2 antibody, a Pseudomonas exotoxin translocation domain and AIFDelta1-120. Human Jurkat cells transfected with the immuno-AIF gene could express and secrete the chimeric protein, which selectively recognized HER2-overexpressing tumor cells and was endocytosed. Subsequent cleavage of truncated AIF from immuno-AIF and its release from the internalized vesicles resulted in apoptosis of tumor cells. Intramuscular injection of the immuno-AIF gene caused significant suppression of tumors and substantially prolonged mice survival in an HER2-overexpressing xenograft tumor model. Our study demonstrates the feasibility of the immuno-AIF gene as a novel approach to treating cancers that overexpress HER2.