Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma

AIMS: We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role. METHODS: HCC patients (113) who underwent hepatectomy were recruited to examine the clinical relevance of GPx3. The tumor suppressive role of GPx3 was studied by administration of recombinant GPx3 (rGPx3) or over-expression of GPx3 in HCC cells in vitro and in vivo. The therapeutic value of GPx3 for HCC was further investigated using human induced pluripotent stem cell derived mesenchymal stem cells (hiPSC-MSCs) as its delivery vehicle. RESULTS: Down-regulation of GPx3 significantly correlated with advanced tumor stage (P = 0.024), venous infiltration (P = 0.043) and poor overall survival (P = 0.007) after hepatectomy. Lower plasma GPx3 in HCC patients was significantly associated with larger tumor size (P = 0.011), more tumor nodules (P = 0.032) and higher recurrence (P = 0.016). Over-expression of GPx3 or administration of rGPx3 significantly inhibited proliferation and invasiveness of HCC cells in vitro and in vivo. Tumor suppressive activity of GPx3 was mediated through Erk-NFκB-SIP1 pathway. GPx3 could be delivered by hiPSC-MSCs into the tumor and exhibited tumor suppressive activity in vivo. CONCLUSIONS: GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients.published_or_final_versio

Optimizing the Dice Score and Jaccard Index for Medical Image Segmentation: Theory & Practice

The Dice score and Jaccard index are commonly used metrics for the evaluation of segmentation tasks in medical imaging. Convolutional neural networks trained for image segmentation tasks are usually optimized for (weighted) cross-entropy. This introduces an adverse discrepancy between the learning optimization objective (the loss) and the end target metric. Recent works in computer vision have proposed soft surrogates to alleviate this discrepancy and directly optimize the desired metric, either through relaxations (soft-Dice, soft-Jaccard) or submodular optimization (Lov\'asz-softmax). The aim of this study is two-fold. First, we investigate the theoretical differences in a risk minimization framework and question the existence of a weighted cross-entropy loss with weights theoretically optimized to surrogate Dice or Jaccard. Second, we empirically investigate the behavior of the aforementioned loss functions w.r.t. evaluation with Dice score and Jaccard index on five medical segmentation tasks. Through the application of relative approximation bounds, we show that all surrogates are equivalent up to a multiplicative factor, and that no optimal weighting of cross-entropy exists to approximate Dice or Jaccard measures. We validate these findings empirically and show that, while it is important to opt for one of the target metric surrogates rather than a cross-entropy-based loss, the choice of the surrogate does not make a statistical difference on a wide range of medical segmentation tasks.Comment: MICCAI 201

Data Imputation in EEG Signals for Brainprint Identification

Electroencephalograms (EEG) signals have very low signal-to-noise ratio, thus can be easily affected and changes over milliseconds. Normally, trials with excessive body movements or other types of artefacts with amplitude more than 100 µV should be discarded to reduce the noise stains. Scrapping the affected features is not advisable. Therefore, missing values imputation is essential to avoid incomplete data that may deteriorate the computational modelling performance. Hence, this paper proposes a similarity matching method to replace the missing values in the EEG trials. The main idea of the missing values imputation is based on the similarity measure between the trials. The trials with the highest similarity is taken to replace the missing values for the related EEG channels. Statistical evaluation and classification evaluation are used to evaluate the reliability of the proposed similarity matching method. The mean, variance and standard deviation are used for statistical evaluation. For the classification evaluation, the dataset is classified for brainprint identification by using the Incremental Fuzzy-Rough Nearest Neighbour (IncFRNN). The statistical evaluation proved that the proposed similarity matching imputation method is promising when the missing values are not come from the same channels. The classification results achieved the excellent performance with 98.19% in accuracy and 0.998 in AUC

A novel oxygen carrier sensitized Cisplatin based chemotherapy in hepatocellular carcinoma

Publication no. P-312BACKGROUND AND OBJECTIVE: Our previous study showed that acute phase liver graft injury not only promotes tumor recurrence, but also induces chemoresistance in recurrent HCC after liver transplantation [1]. Recently, we found that the oxygen carrier 'YQ23' significantly ameliorates hepatic IR injury and prevents tumor recurrence [2]. Here, we intended to explore the novel therapeutic strategy using oxygen carrier 'YQ23' to sensitize chemotherapy in ...postprin

A Dedicated Promoter Drives Constitutive Expression of the Cell-Autonomous Immune Resistance GTPase, Irga6 (IIGP1) in Mouse Liver

Background: In general, immune effector molecules are induced by infection. Methodology and Principal Findings: However, strong constitutive expression of the cell-autonomous resistance GTPase, Irga6 (IIGP1), was found in mouse liver, contrasting with previous evidence that expression of this protein is exclusively dependent on induction by IFNc. Constitutive and IFNc-inducible expression of Irga6 in the liver were shown to be dependent on transcription initiated from two independent untranslated 59 exons, which splice alternatively into the long exon encoding the full-length protein sequence. Irga6 is expressed constitutively in freshly isolated hepatocytes and is competent in these cells to accumulate on the parasitophorous vacuole membrane of infecting Toxoplasma gondii tachyzoites. Conclusions and Significance: The role of constitutive hepatocyte expression of Irga6 in resistance to parasites invading from the gut via the hepatic portal system is discussed

Glutathione Peroxidase 3 Delivered by hiPSC-MSCs Ameliorated Hepatic IR Injury via Inhibition of Hepatic Senescence

Background and Aims: Down-regulation of GPx3 accelerated hepatic senescence, which further caused overwhelming inflammation and severe liver graft injury. MSCs derived from human induced pluripotent stem cells (hiPSC-MSCs) have been developed as more efficient delivery vehicle with the property of injury tropism. Here, we aimed to explore the suppressive role of GPx3 in hepatic IR injury using novel delivery system of hiPSC-MSCs. Methods: The mice IR injury model with partial hepatectomy was established. The engineered hiPSC-MSCs delivering GPx3 was constructed. All the mice were segregated into three groups. hiPSC-MSC-GPx3, hiPSC-MSC-pCDH (vector control) or PBS were injected via portal vein after reperfusion. Liver injury was evaluated by histological and serological test. Hepatic apoptosis was detected by Tunel staining and remnant liver regeneration was assessed by Ki67 staining. The role of hepatic senescence in liver graft injury was evaluated in rat orthotopic liver transplantation model. The suppressive effect of GPx3 on hepatic senescence was examined in mice IR injury model and confirmed in vitro. Hepatic senescence was detected by SA-β-Gal and P16/ink4a staining. Results: GPx3 can be successfully delivered by hiPSC-MSCs into liver tissues. Histological examination showed that hiPSC-MSC-GPx3 treatment significantly ameliorated hepatic IR injury post-operation. Significantly lower LDH (891.43±98.45 mU/mL, P<0.05) and AST (305.77±36.22 IU/L, P<0.01) were observed in hiPSC-MSC-GPx3 group compared with control groups. Less apoptotic hepatocytes were observed and the remnant liver regeneration was more active in hiPSC-MSC-GPx3 group. In rat orthotopic liver transplantation model, more senescent hepatocytes were observed in small-for-size liver graft, in which GPx3 expression was significantly compromised. In mice IR injury model, hiPSC-MSC-GPx3 significantly suppressed hepatic senescence. In addition, rGPx3 inhibited cellular senescence of liver cells in a dose dependent manner. Four candidate genes (CD44, Nox4, IFNG, SERPERINB2) were identified to be responsible for suppressive effect of GPx3 on hepatic senescence. Conclusion: Engineered hiPSC-MSCs delivering GPx3 ameliorated hepatic IR injury via inhibition of hepatic senescence.published_or_final_versio

Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice

<p>Abstract</p> <p>Background</p> <p>Ginsenoside Rg3, a saponin extracted from ginseng, inhibits angiogenesis. The combination of low-dose chemotherapy and anti-angiogenic inhibitors suppresses growth of experimental tumors more effectively than conventional therapy or anti-angiogenic agent alone. The present study was designed to evaluate the efficacy of low-dose gemcitabine combined with ginsenoside Rg3 on angiogenesis and growth of established Lewis lung carcinoma in mice.</p> <p>Methods</p> <p>C57L/6 mice implanted with Lewis lung carcinoma were randomized into the control, ginsenoside Rg3, gemcitabine and combination group. The quality of life and survival of mice were recorded. Tumor volume, inhibitive rate and necrosis rate were estimated. Necrosis of tumor and signals of blood flow as well as dynamic parameters of arterial blood flow in tumors such as peak systolic velocity (PSV) and resistive index (RI) were detected by color Doppler ultrasound. In addition, expression of vascular endothelial cell growth factor (VEGF) and CD31 were observed by immunohistochemstry, and microvessel density (MVD) of the tumor tissues was assessed by CD31 immunohistochemical analysis.</p> <p>Results</p> <p>Quality of life of mice in the ginsenoside Rg3 and combination group were better than in the control and gemcitabine group. Combined therapy with ginsenoside Rg3 and gemcitabine not only enhanced efficacy on suppression of tumor growth and prolongation of the survival, but also increased necrosis rate of tumor significantly. In addition, the combination treatment could obviously decrease VEGF expression and MVD as well as signals of blood flow and PSV in tumors.</p> <p>Conclusion</p> <p>Ginsenoside Rg3 combined with gemcitabine may significantly inhibit angiogenesis and growth of lung cancer and improve survival and quality of life of tumor-bearing mice. The combination of chemotherapy and anti-angiogenic drugs may be an innovative and promising therapeutic strategy in the experimental treatment of human lung cancer.</p

Fine mapping of qSTV11KAS, a major QTL for rice stripe disease resistance

Rice stripe disease, caused by rice stripe virus (RSV), is one of the most serious diseases in temperate rice-growing areas. In the present study, we performed quantitative trait locus (QTL) analysis for RSV resistance using 98 backcross inbred lines derived from the cross between the highly resistant variety, Kasalath, and the highly susceptible variety, Nipponbare. Under artificial inoculation in the greenhouse, two QTLs for RSV resistance, designated qSTV7 and qSTV11KAS, were detected on chromosomes 7 and 11 respectively, whereas only one QTL was detected in the same location of chromosome 11 under natural inoculation in the field. The stability of qSTV11KAS was validated using 39 established chromosome segment substitution lines. Fine mapping of qSTV11KAS was carried out using 372 BC3F2:3 recombinants and 399 BC3F3:4 lines selected from 7,018 BC3F2 plants of the cross SL-234/Koshihikari. The qSTV11KAS was localized to a 39.2 kb region containing seven annotated genes. The most likely candidate gene, LOC_Os11g30910, is predicted to encode a sulfotransferase domain-containing protein. The predicted protein encoded by the Kasalath allele differs from Nipponbare by a single amino acid substitution and the deletion of two amino acids within the sulfotransferase domain. Marker-resistance association analysis revealed that the markers L104-155 bp and R48-194 bp were highly correlated with RSV resistance in the 148 landrace varieties. These results provide a basis for the cloning of qSTV11KAS, and the markers may be used for molecular breeding of RSV resistant rice varieties

Hepatotoxicity or Hepatoprotection? Pattern Recognition for the Paradoxical Effect of the Chinese Herb Rheum palmatum L. in Treating Rat Liver Injury

The hepatotoxicity of some Chinese herbs has been a cause for concern in recent years. However, some herbs, such as rhubarb, have been documented as having both therapeutic and toxic effects on the liver, leading to the complex problem of distinguishing the benefits from the risks of using this herb. To comparatively analyze the dose-response relationship between rhubarb and hepatic health, we administrated total rhubarb extract(RE) to normal and carbon tetrachloride(CCl4)-treated rats for 12 weeks at 4 dosage levels(2.00, 5.40, 14.69 and 40.00 g·kg−1, measured as the quantity of crude material), followed by biochemical and histopathological tests of the rats' livers. A composite pattern was extracted by factor analysis, using all the biochemical indices as variables, into a visual representation of two mathematically obtained factors, which could be interpreted as the fibrosis factor and the cellular injury factor, according to the values of the variable loadings. The curative effect of administering the two lowest dosages of RE to CCl4-treated rats was mainly expressed as a decrease in the extent of cellular injury. The hepatoprotective mechanism of RE might be related to its antioxidant effect, the antagonism of the free radical damage to hepatocytes caused by CCl4. By contrast, the RE-induced liver damage was mainly expressed as a significant increase in the amount of fibrosis in both normal rats at all dosage levels and CCl4-treated rats at the two highest dosage levels. Therefore, the hepatotoxic potential of RE could be attributable to the liver cell fibrosis induced by high doses of the herb. This study illustrates the bidirectional potential of rhubarb and demonstrates the feasibility of using factor analysis to study the dose-response relationships between herbal medicines and hepatotoxicity or the healing effects of these herbs by extracting the underlying interrelationships among a number of functional bio-indices in a holistic manner