The selective cyclooxygenase-1 inhibitor SC-560 suppresses cell proliferation and induces apoptosis in human hepatocellular carcinoma cells

Two isoforms of cyclooxygenase (COX) are known, and to date most studies have implicated COX-2 in the development and progression of various human cancers. Increasing evidence suggests that COX-1 may also play a similar role. Indeed, we have recently observed that the dual COX-1/COX-2 inhibitor indomethacin induces apoptosis in human hepatocellular carcinoma (HCC) cell lines more effectively than the selective COX-2 inhibitors, possibly implicating COX-1 in HCC. In this study we investigated the expression of COX-1 in non-tumor and malignant human liver tissues, as well as the effects of the highly selective COX-1 inhibitor SC-560 on cell growth and apoptosis in human HCC cell lines. Expression of COX-1 was detected in nearly all the samples assayed, although with a high variability between non-tumoral (NT) and malignant tissues. The percentage of COX-1 positive cells was significantly higher in the NT tissues than in the tumors (p<0.0001). In well-differentiated HCC COX-1 expression was significantly higher than in the poorly-differentiated tissues (p<0.05). SC-560 showed a dose- and time-dependent inhibitory effect on HCC cell growth. The combination of the COX-1 inhibitor with nimesulide and CAY10404, two selective COX-2 inhibitors, resulted in additive effects on cell growth inhibition. SC-560 also inhibited colony formation in soft agar and induced apoptosis in HCC cells in a dose-dependent manner. Moreover, SC-560 decreased the levels of the anti-apoptotic proteins survivin and XIAP and activated caspase-3 and -7 in a dose- and time-dependent fashion. In conclusion, we report for the first time that the selective COX-1 inhibitor SC-560 exhibits anti-tumor and apoptotic effects in human HCC cells. Overall, our previous and present results suggest that both COX-1 and COX-2 inhibitors may have potential therapeutic implications in HCC patients.     

S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice

Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer's disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer's disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease.     

Divergent ecosystem responses within a benthic marine community to ocean acidification

Ocean acidification is predicted to impact all areas of the oceans and affect a diversity of marine organisms. However, the diversity of responses among species prevents clear predictions about the impact of acidification at the ecosystem level. Here, we used shallow water CO(2) vents in the Mediterranean Sea as a model system to examine emergent ecosystem responses to ocean acidification in rocky reef communities. We assessed in situ benthic invertebrate communities in three distinct pH zones (ambient, low, and extreme low), which differed in both the mean and variability of seawater pH along a continuous gradient. We found fewer taxa, reduced taxonomic evenness, and lower biomass in the extreme low pH zones. However, the number of individuals did not differ among pH zones, suggesting that there is density compensation through population blooms of small acidification-tolerant taxa. Furthermore, the trophic structure of the invertebrate community shifted to fewer trophic groups and dominance by generalists in extreme low pH, suggesting that there may be a simplification of food webs with ocean acidification. Despite high variation in individual species' responses, our findings indicate that ocean acidification decreases the diversity, biomass, and trophic complexity of benthic marine communities. These results suggest that a loss of biodiversity and ecosystem function is expected under extreme acidification scenarios.     

Treatment of fear memories: interactions between extinction and reconsolidation

Retrieval labilizes memory traces and these gates two protein synthesis-dependent processes in the brain: extinction, which inhibits further retrieval, and reconsolidation, which may enhance retrieval or change its content. Extinction may itself suffer reconsolidation. Interactions among these processes may be applied to treatments of fear memories, such as those underlying post-traumatic stress disorders.     

Custom dynamic stent for esophageal strictures in children

Background

Esophageal stenting represents a new strategy to avoid multiple dilations owing to stenosis relapse. Our custom stent improves esophageal motility unlike the widespread self-expandable plastic esophageal stents. The aim of the study was to confirm the efficacy of treatment with silicone custom stents in esophageal stenosis (ES) in pediatric patients.

Methods

A silicone stent of 7-, 9-, or 12.7-mm external diameter is built coaxially on a nasogastric tube that guarantees the correct position. The 2 ends are tailored to allow food passage between stent and esophageal wall. All patients received dexamethasone (2 mg/kg per day) for 3 days and ranitidine/proton-pump inhibitors. Study approval was obtained from our ethical board.

Results

From 1988 to 2010, 79 patients with ES, mean age 35.4 months (3-125 months), underwent esophageal hydrostatic/Savary dilations and custom-stent placement, left in place for at least 40 days. Stenting was effective in 70 (88.6%) of 79 patients. Fifty percent of the patients with effective treatment received only one dilation for stent placement. Fourteen patients received more stents successfully. There was one stent-related major complication.

Conclusion

Our custom stent improves treatment in ES. In caustic injuries, ES stenting represents the first option. In postsurgical ES, we stent after at least 5 dilations.     

Sensitivity to inhibition by β-chemokines correlates with biological phenotypes of primary HIV-1 isolates

Primary HIV-1 isolates were evaluated for their sensitivity to inhibition by β-chemokines RANTES (regulated upon activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1α (MIP-1α), and MIP-1β. Virus isolates of both nonsyncytium-inducing (NSI) and syncytium-inducing (SI) biological phenotypes recovered from patients at various stages of HIV-1 infection were assessed, and the results indicated that only the isolates with the NSI phenotype were substantially inhibited by the β-chemokines. More important to note, these data demonstrate that resistance to inhibition by β-chemokines RANTES, MIP-1α, and MIP-1β is not restricted to T cell line-adapted SI isolates but is also a consistent property among primary SI isolates. Analysis of isolates obtained sequentially from infected individuals in whom viruses shifted from NSI to SI phenotype during clinical progression exhibited a parallel loss of sensitivity to β-chemokines. Loss of virus sensitivity to inhibition by β-chemokines RANTES, MIP-1α, and MIP-1β was furthermore associated with changes in the third variable (V3) region amino acid residues previously described to correlate with a shift of virus phenotype from NSI to SI. Of interest, an intermediate V3 genotype correlated with a partial inhibition by the β-chemokines. In addition, we also identified viruses sensitive to RANTES, MIP-1α, and MIP-1β of NSI phenotype that were isolated from individuals with AIDS manifestations, indicating that loss of sensitivity to β-chemokine inhibition and shift in viral phenotype are not necessarily prerequisites for the pathogenesis of HIV-1 infection.     

Role of the oxidative metabolic burst in the antibody-dependent cellular cytotoxicity mediated by neutrophil polymorphonuclears

The purpose of the present study was to investigate the mechanisms by which neutrophil polymorphonuclears (PMN) mediate antibody-dependent cellular cytotoxicity (ADCC). Under experimental conditions which allow target cell phagocytosis, PMN were found to efficiently kill IgG-sensitized ox erythrocytes, as determined by the 51Cr release assay. Inhibition of the target cell ingestion by colchicine did not affect the PMN cytotoxic activity, suggesting that target cell phagocytosis does not represent an essential step in the PMN-mediated ADCC against erythrocytes. PMN from patients with Chronic Granulomatous Disease, who have defective oxidative metabolic burst, displayed an impaired ADCC activity, which was unaffected by changes in the phagocytic capacities induced by colchicine. The results indicate that, under the experimental conditions employed, both the intracellular and the extracellular target cell destruction by PMN involve oxygen-dependent mechanisms.     

Status and Prospects of Cubic Silicon Carbide Power Electronics Device Technology

Wide bandgap (WBG) semiconductors are becoming more widely accepted for use in power electronics due to their superior electrical energy efficiencies and improved power densities. Although WBG cubic silicon carbide (3C-SiC) displays a modest bandgap compared to its commercial counterparts (4H-silicon carbide and gallium nitride), this material has excellent attributes as the WBG semiconductor of choice for low-resistance, reliable diode and MOS devices. At present the material remains firmly in the research domain due to numerous technological impediments that hamper its widespread adoption. The most obvious obstacle is defect-free 3C-SiC; presently, 3C-SiC bulk and heteroepitaxial (on-silicon) display high defect densities such as stacking faults and antiphase boundaries. Moreover, heteroepitaxy 3C-SiC-on-silicon means low temperature processing budgets are imposed upon the system (max. temperature limited to ~1400 °C) limiting selective doping realisation. This paper will give a brief overview of some of the scientific aspects associated with 3C-SiC processing technology in addition to focussing on the latest state of the art results. A particular focus will be placed upon key process steps such as Schottky and ohmic contacts, ion implantation and MOS processing including reliability. Finally, the paper will discuss some device prototypes (diodes and MOSFET) and draw conclusions around the prospects for 3C-SiC devices based upon the processing technology presented.     

Assessment of toxic potential of mycotoxin contaminated bread during in vitro human digestion on human B lymphoid cell line

Ingestion of food is considered a major route of exposure to many contaminants including mycotoxins. The amount of mycotoxin resisting to the digestion process and potentially absorbable by the systemic circulation is only a smaller part of that ingested. In vitro digestion models turn useful for evaluating mycotoxins bioaccessibility during the intestinal transit and can be intended as a valuable tool for the assessment of mycotoxin bioavailability in food. In this paper we describe a study aimed at investigating toxicity of in vitro gastro-duodenal digests of mycotoxin contaminated bread collected along the digestion time-course. Toxicity tests were carried out on a sensitive RPMI lymphoid B cell line chosen as the most suitable lineage to assess toxicity retained by gastro-duodenal digests. In parallel, a chemical quantification of T-2 and HT-2 toxins contaminating the bread digests was accomplished during the gastric and duodenal transit. The digestive fluids undergoing chemical and toxicological analysis were collected at the beginning and end of gastric phase, and after completion of the duodenal phase. Results proved that a correlation between HT-2 content and toxicity did exist although a more persistent toxic activity was displayed in the later stage of the duodenal phase. This persistent toxicity might be explained by the co-occurrence of unknown HT-2-related conjugates or metabolites formed during digestion.     

Lymphoid enhancer binding factor-1 (LEF1) expression as a prognostic factor in adult acute promyelocytic leukemia

Lymphoid enhancer-binding factor 1 (LEF1) is a downstream effector of the Wnt/ β-catenin signaling pathway. High LEF1 expression has been reported as a prognostic marker in hematologic malignancies. We evaluated the prognostic significance of LEF1 expression in 78 adult acute promyelocytic leukemia (APL) patients. APL samples were dichotomized at the median value and divided into: LEF1^low and LEF1^high. LEF1^high patients had lower WBC counts at baseline and were less likely to carry a FLT3 -ITD than LEF1^low patients. Early death occurred only in the LEF1^low group. Moreover, LEF1^low expression was associated with a high Sanz score. Survival analysis of 61 APL patients < 60 years revealed that the LEF1^high group had a significantly longer overall survival (OS). Cox analysis for OS confirmed only LEF1 expression as an independent prognostic factor. Of the 17 patients over the age of 60, those in the LEF1^high group showed a higher median survival. In silico analysis identified 9 differentially expressed, up-modulated genes associated with a high expression of LEF1; the majority of these genes is involved in the regulation of apoptosis. Our study provides evidence that LEF1 expression is an independent prognostic factor in APL, and could be used in patients risk stratification.