A short guide to hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer (HDGC) is the only known predisposition syndrome dominated by carcinoma of the stomach and with a recognised genetic cause. Germline mutations in the E-cadherin gene (CDH1) co-segregate with the disease in about half of the families with multiple diffuse gastric cancer. In these families, identification of the CDH1 mutation allows for clinical measures to be taken. Importantly, clinical intervention is likely to be therapeutic and associated with tolerable morbidity. This review is thus aimed at providing a current overview of the clinical management and the underlying biology of HDGC

Heterogeneous gene expression changes in colorectal cancer cells share the WNT pathway in response to growth suppression by APHS-mediated COX-2 inhibition

Cyclooxygenase-2 (COX-2), the prostaglandin (PG)-synthesizing enzyme overexpressed in colorectal cancer (CRC), has pleiotropic, cancer-promoting effects. COX-2 inhibitors (CIBs) interfere with many cancer-associated processes and show promising antineoplastic activity, however, a common mechanism of CIB action has not yet been established. We therefore investigated by microarray the global response towards the CIB APHS at a dose significantly inhibiting the growth of three COX-2-positive CRC but not of two COX-2-negative cell lines. None of the genes significantly (p = 0.005) affected by APHS were common to all three cell lines and 83% of the altered pathways were cell line-specific. Quantitative polymerase chain reaction (QPCR) on selected pathways confirmed cell line-specific expression alterations induced by APHS. A low stringency data analysis approach using BRB array tools coupled with QPCR, however, identified small expression changes shared by all COX-2-positive cell lines in genes related to the WNT pathway, the key driver of colonic carcinogenesis. Our data indicates a substantial cell line-specificity of APHS-induced expression alterations in CRC cells and helps to explain the divergent effects reported for CIBs. Further, the shared inhibition of the WNT pathway by APHS suggests one potential common mechanism behind the antineoplastic effects of COX-2 inhibition

Influence of the thermo-hydro-mechanical treatments of wood on the performance against wood degrading fungi

Hybrid poplar (Populus deltoides × Populus trichocarpa) and Douglas-fir (Pseudotsuga menziesii) wood specimens were densified with three variations of Thermo-Hydro-Mechanical (THM) treatment. The THM treatments differed in the steam environment, including transient steam (TS), saturated steam (SS), and saturated steam with 1 minute post-heat-treatment at 200°C (SS+PHT). The bending properties, FTIR spectra, and color of the THM wood specimens were studied before and after exposure to two different wood decay fungi; brown rot Gloeophyllum trabeum and white rot Trametes versicolor. The results showed that the performance of densified hybrid poplar wood was considerably poorer than performance of Douglas-fir heartwood. The FTIR spectra measurements did not show changes in the densified hybrid poplar wood, while some changes were evident in densified Douglas-fir specimens. After fungal degradation the most prominent changes were observed on the SS+PHT specimens. Color is one of the most important parameter predominantly influenced by the wood species and the intensity of the densification process for both wood species, while after the fungal exposure the color of all densified Douglas-fir specimens became more or less of the same appearance and densified hybrid poplar specimens resulted in lighter color tones, indicating that the patterns of degradation of the densified and nondensified specimens are similar. The 3-point bending test results determined that the THM treatment significantly increased the modulus of rupture (MOR) and modulus of elasticity (MOE) of the densified wood specimens, while the fungal exposure decreased the MOE and MOR in hybrid poplar and Douglas-fir specimens.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Springer and can be found at: http://link.springer.com/journal/226.Keywords: Color, Wood decay, FTIR, Densification, Wood, TH

Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis.

The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development-contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC

A novel diffuse gastric cancer susceptibility variant in E-cadherin (CDH1) intron 2: A case control study in an Italian population

<p>Abstract</p> <p>Background</p> <p>Inherited genetic factors such as E-cadherin (<it>CDH1</it>) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for <it>CDH1 </it>transcription has been identified in <it>CDH1 </it>intron 2.</p> <p>Methods</p> <p>We genotyped all known polymorphisms located within conserved sequences of <it>CDH1 </it>intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using χ²-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis.</p> <p>Results</p> <p>We observed a significant (p < 0.0004) association of the <it>CDH1 </it>163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09–9.93) and 1.38 (95%CI = 0.75–2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and <it>H. pylori </it>infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied.</p> <p>Conclusion</p> <p>The <it>CDH1 </it>163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.</p

Modeling the material resistance of wood - part 2: validation and optimization of the Meyer-Veltrup model

Service life planning with timber requires reliable models for quantifying the effects of exposure-related parameters and the material-inherent resistance of wood against biotic agents. The Meyer-Veltrup model was the first attempt to account for inherent protective properties and the wetting ability of wood to quantify resistance of wood in a quantitative manner. Based on test data on brown, white, and soft rot as well as moisture dynamics, the decay rates of different untreated wood species were predicted relative to the reference species of Norway spruce (Picea abies). The present study aimed to validate and optimize the resistance model for a wider range of wood species including very durable species, thermally and chemically modified wood, and preservative treated wood. The general model structure was shown to also be suitable for highly durable materials, but previously defined maximum thresholds had to be adjusted (i.e., maximum values of factors accounting for wetting ability and inherent protective properties) to 18 instead of 5 compared to Norway spruce. As expected, both the enlarged span in durability and the use of numerous and partly very divergent data sources (i.e., test methods, test locations, and types of data presentation) led to a decrease in the predictive power of the model compared to the original. In addition to the need to enlarge the database quantity and improve its quality, in particular for treated wood, it might be advantageous to use separate models for untreated and treated wood as long as the effect of additional impact variables (e.g., treatment quality) can be accounted for. Nevertheless, the adapted Meyer-Veltrup model will serve as an instrument to quantify material resistance for a wide range of wood-based materials as an input for comprehensive service life prediction software

Modelling the material resistance of wood - Part 3: relative resistance in above- and in-ground situations - results of a global survey

Durability-based designs with timber require reliable information about the wood properties and how they affect its performance under variable exposure conditions. This study aimed at utilizing a material resistance model (Part 2 of this publication) based on a dose–response approach for predicting the relative decay rates in above-ground situations. Laboratory and field test data were, for the first time, surveyed globally and used to determine material-specific resistance dose values, which were correlated to decay rates. In addition, laboratory indicators were used to adapt the material resistance model to in-ground exposure. The relationship between decay rates in- and above-ground, the predictive power of laboratory indicators to predict such decay rates, and a method for implementing both in a service life prediction tool, were established based on 195 hardwoods, 29 softwoods, 19 modified timbers, and 41 preservative-treated timbers

Exercise Improves Outcomes of Surgery on Fatty Liver in Mice: A Novel Effect Mediated by the AMPK Pathway.

OBJECTIVE To investigate whether exercise improves outcomes of surgery on fatty liver, and whether pharmacological approaches can substitute exercising programs. SUMMARY OF BACKGROUND DATA Steatosis is the hepatic manifestation of the metabolic syndrome, and decreases the liver's ability to handle inflammatory stress or to regenerate after tissue loss. Exercise activates adenosine monophosphate-activated kinase (AMPK) and mitigates steatosis; however, its impact on ischemia-reperfusion injury and regeneration is unknown. METHODS We used a mouse model of simple, diet-induced steatosis and assessed the impact of exercise on metabolic parameters, ischemia-reperfusion injury and regeneration after hepatectomy. The same parameters were evaluated after treatment of mice with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Mice on a control diet served as age-matched controls. RESULTS A 4-week-exercising program reversed steatosis, lowered insulin levels, and improved glucose tolerance. Exercise markedly enhanced the ischemic tolerance and the regenerative capacity of fatty liver. Replacing exercise with AICAR was sufficient to replicate the above benefits. Both exercise and AICAR improved survival after extended hepatectomy in mice challenged with a Western diet, indicating protection from resection-induced liver failure. CONCLUSIONS Exercise efficiently counteracts the metabolic, ischemic, and regenerative deficits of fatty liver. AICAR acts as an exercise mimetic in settings of fatty liver disease, an important finding given the compliance issues associated with exercise. Exercising, or its substitution through AICAR, may provide a feasible strategy to negate the hepatic consequences of energy-rich diet, and has the potential to extend the application of liver surgery if confirmed in humans