B7-H3 protein is an important tumor antigen, but the expression of its isoforms, 4IgB7-H3 and 2IgB7-H3, in tumor tissues remains unknown due to the lack of specific monoclonal antibodies (mAbs). In the present study, a mAb (9C3) specifically recognizing 2IgB7-H3, but not 4IgB7-H3, was prepared. Using 9C3 and a previously prepared mAb (4H7) that recognizes 4IgB7-H3 and 2IgB7-H3, the differential expression of 2IgB7-H3 and 4IgB7-H3 was analyzed in a variety of tumor cell lines by flow cytometry. It was found that 4IgB7-H3 had a more broad spectrum of expression among the cell lines compared with 2IgB7-H3. The expression of the two isoforms was further examined in glioma tissues using reverse transcription-polymerase chain reaction and immunohistochemistry techniques. The data revealed that 2IgB7-H3, but not 4IgB7-H3, was specifically expressed in glioma. Taken together, these results demonstrated for the first time that 2IgB7-H3 is a valuable biomarker for the diagnosis of glioma.

Cystic change in metastatic lymph nodes of papillary thyroid carcinoma (PTC) is a diagnostic challenge for fine needle aspiration (FNA) because of the scant cellularity. The aim of this study was to evaluate the measurement of thyroglobulin in fine needle aspirate (Tg-FNA) for detecting metastatic PTC in patients with cystic neck lesions and to validate the optimal cutoff value of Tg-FNA. A total of 75 FNA specimens of cystic lesions were identified, including 40 of metastatic PTC. Predetermined threshold levels of 0.04 (minimum detection level), 0.9, 10.0, and 77.0 ng/mL (maximum normal serum-Tg level) were used to evaluate the diagnostic accuracy of Tg-FNA for metastatic PTC detection. The areas under the receiver operating characteristic curve for diagnosing metastatic PTC of Tg-FNA values of 0.04, 0.9, 10.0, and 77.0 ng/mL were 0.5 (95% confidence interval [CI], 0.382-0.618), 0.645 (95% CI, 0.526-0.752), 0.945 (95% CI, 0.866-0.984), and 0.973 (95% CI, 0.907-0.996), respectively. With a cutoff value of 77.0 ng/mL, the combination of Tg-FNA and FNA cytology showed superior diagnostic power (97.5% sensitivity and 100% specificity) compared to FNA cytology alone (80% sensitivity and 100% specificity). We recommend a Tg-FNA cutoff of 77.0 ng/mL, the maximum normal serum-Tg level, for cystic neck lesions.

Hydration with sodium bicarbonate is one of the strategies to prevent contrast-induced acute kidney injury (CI-AKI). The purpose of this study was to determine how strong is the evidence for sodium bicarbonate to prevent CI-AKI after coronary angiography (CAG) and/or percutaneous coronary intervention (PCI).We conducted PubMed, EMBASE, and CENTRAL databases to search for randomized controlled trials (RCTs) comparing the efficacy of sodium bicarbonate with sodium chloride to prevent CI-AKI after CAG and/or PCI. Relative risk (RR), standardized mean difference (SMD), or weighted mean difference (WMD) with 95% confidence intervals (CIs) was calculated. Heterogeneity, publication bias, and study quality were evaluated, sensitivity analyses, cumulative analyses, and subgroup analyses were performed. The risk of random errors was assessed by trial sequential analysis (TSA).Sixteen RCTs (3537 patients) met the eligibility criteria. Hydration with sodium bicarbonate showed significant beneficial effects in preventing CI-AKI (RR 0.67; 95% CI: 0.47-0.96, P = 0.029), decreasing the change in serum creatinine (SCr) (SMD -0.31 95% CI: -0.55 to -0.07, P = 0.011) and estimated glomerular filtration rate (eGFR) (SMD -0.17 95% CI: -0.30 to -0.04, P = 0.013). But no significant differences were observed in the requirement for dialysis (RR 1.11; 95% CI: 0.60-2.07, P = 0.729), mortality (RR 0.71; 95% CI: 0.41-1.21, P = 0.204) and reducing the length of hospital stay (LHS) (WMD -1.47; 95% CI: -4.14 to 1.20, P = 0.279). The result of TSA on incidence of CI-AKI showed the required information size (RIS = 6614) was not reached and cumulative z curve did not cross TSA boundary. The result of TSA on the requirement for dialysis and mortality demonstrated the required information sizes (RIS = 170,510 and 19,516, respectively) were not reached, and the cumulative z-curve did not cross any boundaries.The evidence that sodium bicarbonate reduces the incidence of CI-AKI is encouraging but more well-designed randomized controlled trails are required to allow definitive firm conclusion to be drawn.

There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

The phytohormone auxin is essential for plant growth and development, and YUCCA (YUC) proteins catalyze a rate-limiting step for endogenous auxin biosynthesis. Despite YUC family genes have been isolated from several species, systematic expression analyses of YUCs in response to abiotic stress are lacking, and little is known about the function of YUC homologs in agricultural crops. Cucumber (Cucumis sativus L.) is a world cultivated vegetable crop with great economical and nutritional value. In this study, we isolated 10 YUC family genes (CsYUCs) from cucumber and explored their expression pattern under four types of stress treatments. Our data showed that CsYUC8 and CsYUC9 were specifically upregulated to elevate the auxin level under high temperature. CsYUC10b was dramatically increased but CsYUC4 was repressed in response to low temperature. CsYUC10a and CsYUC11 act against the upregulation of CsYUC10b under salinity stress, suggesting that distinct YUC members participate in different stress response, and may even antagonize each other to maintain the proper auxin levels in cucumber. Further, CsYUC11 was specifically expressed in the male flower in cucumber, and enhanced tolerance to salinity stress and regulated pedicel and stamen development through auxin biosynthesis in Arabidopsis.

Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells.

In order to decrease the incidence of flap necrosis after reconstructive surgeries, new approaches are required. In the present study, a model of venous congested flaps in rats was established to test the heat shock protein (HSP) 90α, 'F-5', protein as an intervention therapy to alleviate ischemia-reperfusion injury. A recombinant plasmid pET15b-F-5 carrying the HSP90α gene was constructed and the induced protein was purified from bacterial cell cultures. The rats in the study were divided into three different intervention groups: group A rats were treated with normal saline prior to flap establishment, group B rats were treated with HSP90α, 'F-5', protein prior to flap establishment, and group C rats were treated with the same 'F-5' protein after the surgical procedure. Additionally, the reperfusion time-points, ischemia for 6 or 8 h (5 rats each), were established in each group. After set periods of time, the flaps were observed for skin appearance, blood flow, survival rate and histological changes including neovascularization and re-epithelialization. The results showed that the flaps in the rats pre-treated with 'F-5' protein performed better than the flaps of rats in the other two groups: the blood flow was higher, flap survival rate was increased, inflammatory cell infiltration was decreased and angiogenesis increased, and new skin structure was better completed by the end of the experiment. The parameters examind were improved for all the groups when the ischemia time was 6 h instead of 8 h. In conclusion, HSP90α intervention prior to flap establishment was shown to be beneficial in the model of ischemia-reperfusion injury in venous-congested flaps.

Goose can develop severe hepatic steatosis without overt injury, thus it may serve as a unique model for uncovering how steatosis-related injury is prevented. To identify the markedly prosteatotic and protective mechanisms, we performed an integrated analysis of liver transcriptomes and gut microbial metagenomes using samples collected from overfed and normally-fed geese at different time points. The results indicated that the fatty liver transcriptome, initially featuring a 'metabolism' pathway, was later joined by 'cell growth and death' and 'immune diseases' pathways. Gut microbiota played a synergistic role in the liver response as microbial and hepatic genes affected by overfeeding shared multiple pathways. Remarkably, the complement system, an inflammatory component, was comprehensively suppressed in fatty liver, which was partially due to increased blood lactic acid from enriched Lactobacillus. Data from in vitro studies suggested that lactic acid suppressed TNFα via the HNF1α/C5 pathway. In conclusion, gut microbes and their hosts respond to excess energy influx as an organic whole, severe steatosis and related tolerance of goose liver may be partially attributable to gut microbiotic products and suppressed complement system, and lactic acid from gut microbiota participates in the suppression of hepatic TNFα/inflammation through the HNF1α/C5 pathway.

No abstract available

Emerging studies suggest that dominant peripheral tolerance is a major mechanism of immune escape in disseminated leukemia. Using an established murine acute myeloid leukemia (AML) model, we here show that systemic administration of recombinant IL-33 dramatically inhibits the leukemia growth and prolongs the survival of leukemia-bearing mice in a CD8+ T cell dependent manner. Exogenous IL-33 treatment enhanced anti-leukemia activity by increasing the expansion and IFN-γ production of leukemia-reactive CD8+ T cells. Moreover, IL-33 promoted dendritic cell (DC) maturation and activation in favor of its cross presentation ability to evoke a vigorous anti-leukemia immune response. Finally, we found that the combination of PD-1 blockade with IL-33 further prolonged the survival, with half of the mice achieving complete regression. Our data establish a role of exogenous IL-33 in reversing T cell tolerance, and suggest its potential clinical implication into leukemia immunotherapy.

Integral membrane proteins (IMPs) control the flow of information and nutrients across cell membranes, yet IMP mechanistic studies are hindered by difficulties in expression. We investigate this issue by addressing the connection between IMP sequence and observed expression levels. For homologs of the IMP TatC, observed expression levels vary widely and are affected by small changes in protein sequence. The effect of sequence changes on experimentally observed expression levels strongly correlates with the simulated integration efficiency obtained from coarse-grained modeling, which is directly confirmed using an in vivo assay. Furthermore, mutations that improve the simulated integration efficiency likewise increase the experimentally observed expression levels. Demonstration of these trends in both Escherichia coli and Mycobacterium smegmatis suggests that the results are general to other expression systems. This work suggests that IMP integration is a determinant for successful expression, raising the possibility of controlling IMP expression via rational design.

PSG9 is a member of the pregnancy-specific glycoprotein (PSG) family and has been shown to contribute to the progression of colorectal cancer (CRC) and cancer-related angiogenesis. Here, we aim to investigate abnormal PSG9 levels in patients with CRC and to emphasize the role of PSG9 in driving tumorigenesis. Serum from 140 patients with CRC and 125 healthy controls as well as 74 paired tumors and adjacent normal tissue were used to determine PSG9 levels. We discovered that PSG9 was significantly increased in serum (P<0.001) and in tumor tissues (P<0.001) from patients with CRC. Interestingly, the increased PSG9 levels correlated with poor survival (P=0.009) and microvessel density (MVD) (P=0.034). The overexpression of PSG9 strongly promoted the proliferation and migration of HCT-116 and HT-29 cells. However, PSG9 depletion inhibited the proliferation of SW-480 cells. Using a human umbilical vein endothelial cell tube-forming assay, we found that PSG9 promoted angiogenesis. The overexpression of PSG9 also increased the growth of tumor xenografts in nude mice. Co-immunoprecipitation experiments revealed that PSG9 was bound to SMAD4. The PSG9/SMAD4 complex recruited cytoplasmic SMAD2/3 to form a complex, which enhanced SMAD4 nuclear retention. The PSG9 and SMAD4 complex activated the expression of multiple angiogenesis-related genes (included IGFBP-3, PDGF-AA, GM-CSF, and VEGFA). Together, our findings illustrate the innovative mechanism by which PSG9 drives the progression of CRC and tumor angiogenesis. This occurs via nuclear translocation of PSG9/SMAD4, which activates angiogenic cytokines. Therefore, our study may provide evidence for novel treatment strategies by targeting PSG9 in antiangiogenic cancer therapy.

Growing evidence has revealed that microRNAs could regulate the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells and predict the prognosis of PDAC. Here the comparative microRNA expression profiles of the good and poor prognosis groups were performed by microRNA microarray. MicroRNA-891b (miR-891b) was screened and validated to be a prognostic predictor of PDAC in the initial group and further evaluated to be an independent predictor for the overall survival of resectable PDACs in an independent cohort. By a series of cellular and animal experiments, as well as clinical specimen analyses, miR-891b was confirmed to target the Cbl-b gene, promot the expression of tumor suppressor p21 protein and inhibit the proliferation of PDAC cells. The results provide a theoretical basis for the study of miR-891b as an independent prognostic predictor of PDAC and the role of miR-891b/Cbl-b pathway in this prediction, as well as the identification of new targets for PDAC.

Remote ischemic preconditioning (RIPC) has been proven to reduce the ischemia-reperfusion injury. However, its effect on children receiving congenital cardiac surgery (CCS) was inconsistent. We therefore performed the current meta-analysis of randomized controlled trials (RCTs) to comprehensively evaluate the effect of RIPC in pediatric patients undergoing CCS.PubMed, Embase, and Cochrane library were searched to identify RCTs assessing the effect of RIPC in pediatric patients undergoing CCS. The outcomes included the duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, postoperative cardiac troponin (cTnI) level, hospital length of stay (HLOS), postoperative inotropic score, and mortality. Subgroup and sensitivity analysis were also performed as predesigned. The meta-analysis was performed with random-effects model despite of heterogeneity. Sensitivity and subgroup analysis were predesigned to identify the robustness of the pooled estimate.Nine RCTs with 697 pediatric patients were included in the meta-analysis. Overall, RIPC failed to alter clinical outcomes of duration of MV (standard mean difference [SMD] -0.03, 95% confidence interval [CI] -0.23-0.17), ICU length of stay (SMD -0.22, 95% CI -0.47-0.04), or HLOS (SMD -0.14, 95% CI -0.55-0.26). Additionally, RIPC could not reduce postoperative cTnI (at 4-6 hours: SMD -0.25, 95% CI -0.73-0.23; P = 0.311; at 20-24 hours: SMD 0.09, 95% CI -0.51-0.68; P = 0.778) or postoperative inotropic score (at 4-6 hours: SMD -0.19, 95% CI -0.51-0.14; P = 0.264; at 24 hours: SMD -0.15, 95% CI -0.49-0.18; P = 0.365).RIPC may have no beneficial effects in children undergoing CCS. However, this finding should be interpreted with caution because of heterogeneity and large-scale RCTs are still needed.

Immunologic checkpoint marker B7 homolog 1 (B7-H1) plays a fundamental role in the initiation and progression of gastric cancer (GC); however, the clinicopathologic significance and prognostic value of B7-H1 in GC remains controversial. In this study, we aimed to assess their relationship through a meta-analysis.Medline/PubMed, EMBASE, the Cochrane Library databases, and Grey literature were searched up to August 10, 2015, for eligible studies of the association between B7-H1 expression and overall survival in GC. The hazard ratio and its 95% confidence interval (CI) were calculated from the included studies. Moreover, the odds ratio (OR) was also extracted to evaluate the association between the clinicopathologic parameters of participants and B7-H1 expression.Five studies involving 481 patients were included in the meta-analysis. The pooled results showed that positive B7-H1 expression was a negative predictor for overall survival with hazard ratio of 1.74 (95% CI: 1.40-2.17; Pheterogeneity = 0.146) in GC. Additionally, increased B7-H1 was found to be significantly associated with positive lymph node metastasis (OR = 2.61, 95% CI: 1.78-3.84; Pheterogeneity = 0.004) and poorer tumor stage (OR = 2.28, 95% CI: 1.39-3.74; Pheterogeneity = 0.006); however, higher B7-H1 expression was not significantly correlated with poorer tumor differentiation (OR = 1.29, 95% CI: 0.90-1.86; Pheterogeneity = 0.013) and bigger tumor size (OR = 1.18, 95% CI: 0.81-1.73; Pheterogeneity = 0.104).The meta-analysis suggested that B7-H1 could act as a significant biomarker in the poor prognosis of gastric carcinoma.

Heparanase (HPSE) and vascular endothelial growth factor C (VEGF-C) are important cytokines that promote metastasis and angiogenesis in numerous malignant neoplasms, however, their association remains unclear in pancreatic ductal cell adenocarcinoma (PDAC). The present study aimed to investigate whether HPSE has a positive correlation with VEGF-C expression and to uncover the role it plays in the in vitro invasion of BxPC-3 cells (a pancreatic carcinoma cell line), and to analyze the value of joint detection of HPSE and VEGF-C for PDAC patients. A recombinant plasmid, GV230/HPSE was constructed and BxPC-3 cells were transiently transfected with GV230/HPSE or siRNA against HPSE. The expression levels of HPSE and VEGF-C were compared using reverse transcription quantitative PCR (RT-qPCR) and immunoblotting. The metastatic potential of treated BxPC-3 cells was evaluated using a Transwell® invasion assay. The relative mRNA levels of HPSE and VEGF-C in 34 PDAC specimens were assessed by RT-qPCR. The results of the RT-qPCR demonstrated a 10.7- and 3.24-fold elevation (P<0.01) of HPSE mRNA and VEGF-C mRNA, respectively, in GV230/HPSE group, whereas the HPSE siRNA group were downregulated for these mRNAs (-2.45-fold, P<0.01; -1.84-fold, P<0.01). The same pattern for protein expression was detected using immunoblot assays. In Transwell® invasion assays 138±5 cells in GV230/HPSE group and 53±4 cells in siRNA group migrated through the Matrigel®. A negative correlation between the mRNA levels of HPSE and VEGF-C in PDAC specimens and the prognosis factors of the postoperative patients was identified. Spearman rank correlation analysis indicated a positive correlation between HPSE and VEGF-C in PDAC (r=0.812, P<0.01). HPSE regulates the expression of VEGF-C and facilitates invasion of BxPC-3 in vitro. Joint detection of HPSE and VEGF-C may therefore be clinically useful in determining the prognosis of pancreatic cancer patients.

Automatic brain image labeling is highly demanded in the field of medical image analysis. Multiatlas-based approaches are widely used due to their simplicity and robustness in applications. Also, random forest technique is recognized as an efficient method for labeling, although there are several existing limitations. In this paper, the authors intend to address those limitations by proposing a novel framework based on the hierarchical learning of atlas forests.

Bioartificial liver (BAL) system has emerged as an alternative treatment to bridge acute liver failure to either liver transplantation or liver regeneration. One of the main reasons that the efficacy of the current BAL systems was not convincing in clinical trials is attributed to the lack of friendly interface between the membrane and the hepatocytes in liver bioreactor, the core unit of BAL system. Here, we systematically compared the biological responses of hepatosarcoma HepG2 cells seeded on eight, commercially available biocompatible membranes made of acetyl cellulose-nitrocellulose mixed cellulose (CA-NC), acetyl cellulose (CA), nylon (JN), polypropylene (PP), nitrocellulose (NC), polyvinylidene fluoride (PVDF), polycarbonate (PC) and polytetrafluoroethylene (PTFE). Physicochemical analysis and mechanical tests indicated that CA, JN and PP membranes yield high adhesivity and reasonable compressive and/or tensile features with friendly surface topography for cell seeding. Cells prefer to adhere on CA, JN, PP or PTFE membranes with high proliferation rate in spheriod-like shape. Actin, albumin and cytokeratin 18 expressions are favorable for cells on CA or PP membrane, whereas protein filtration is consistent among all the eight membranes. These results further the understandings of cell growth, morphology and spreading, as well as protein filtration on distinct membranes in designing a liver bioreactor.

Podocyte apoptosis is a major mechanism that leads to proteinuria in many kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. RhoA is one of Rho GTPases that has been well studied and plays a key role in regulating cytoskeletal architecture. Previous study showed that insufficient RhoA could result in rat aortic smooth muscle cell apoptosis. However, whether RhoA is involved in podocyte apoptosis remains unknown.

Myelodysplastic syndrome (MDS) is a group of heterogeneous hematopoietic stem cell malignancies with a high risk of transformation into acute myeloid leukemia (AML). Clonal evolutions are significantly associated with transformation to AML. According to a gene expression microarray, atg3 is downregulated in MDS patients progressing to leukemia, but less is known about the function of Atg3 in the survival and death of MSD/AML cells. Moreover, the role of autophagy as a result of bortezomib treatment is controversial. The current study was designed to investigate the function of Atg3 in SKM-1 cells and to study the effect of Atg3 on cell viability and cell death following bortezomib treatment.