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Infectious Causes of Cancer
Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer
Article first published online: 22 FEB 2010
DOI: 10.1002/ijc.25274
Copyright © 2010 UICC
International Journal of Cancer
Volume 127, Issue 11, pages 2588–2597, 1 December 2010
Additional Information
How to Cite
Schneider, B. G., Peng, D.-F., Camargo, M. C., Piazuelo, M. B., Sicinschi, L. A., Mera, R., Romero-Gallo, J., Delgado, A. G., Bravo, L. E., Wilson, K. T., Peek, R. M., Correa, P. and El-Rifai, W. (2010), Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer. Int. J. Cancer, 127: 2588–2597. doi: 10.1002/ijc.25274
Publication History
- Issue published online: 22 FEB 2010
- Article first published online: 22 FEB 2010
- Manuscript Accepted: 8 FEB 2010
- Manuscript Received: 22 OCT 2009
Funded by
- NCRR/NIH (CTSA). Grant Number: 1 UL1 RR024975
- National Cancer Institute. Grant Numbers: P01 CA028842, R01 CA095103, R01 CA077955, R01 CA093999, P01 CA116087, P30DK058404, R01 DK053620, DK058587
- Abstract
- Article
- References
- Cited By
- Helicobacter;
- Colombia;
- Pyrosequencing;
- promoter;
- premalignant;
- intestinal metaplasia;
- epigenetics
Gene promoter CpG island hypermethylation is associated with Helicobacter pylori (H. pylori) infection and may be an important initiator of gastric carcinogenesis. To examine factors influencing methylation, we utilized bisulfite Pyrosequencing® technology for quantitative analysis of promoter DNA methylation in RPRM, APC, MGMT and TWIST1 genes using DNA from 86 gastric biopsies from Colombian residents of areas with high and low incidence of gastric cancer. H. pylori colonies were cultured from the same subjects, and gastric pathology was evaluated. Virulence factors cagA (including segments of the 3′ end, encoding EPIYA polymorphisms) and vacA s and m regions were characterized in the H. pylori strains. Using univariate analysis, we found significantly elevated levels of RPRM and TWIST1 promoter DNA methylation in biopsies from residents of the high-risk region compared to those from residents of the low-risk region. The presence of cagA and vacA s1m1 alleles were independently associated with elevated levels of promoter DNA methylation of RPRM and MGMT. Using multivariate analysis, DNA methylation of RPRM was associated with location of residence, cagA and vacA s1m1 status and methylation of TWIST1. We conclude that cagA and vacA virulence determinants are significantly associated with quantitative differences in promoter DNA methylation in these populations, but that other as yet undefined factors that differ between the populations may also contribute to variation in methylation status.
DNA methylation of promoter CpG islands is an important epigenetic regulatory mechanism for transcription. Methylated cytosines provide binding sites for various methyl-binding proteins, which interact with chromatin remodeling enzymes to stably repress transcription. In normal cells, repetitive elements are inactivated by DNA methylation, while the CpG islands of many housekeeping genes are protected from methylation. Conversely, in cancer cells, repetitive elements lose their methylation, and CpG islands in many promoters become aberrantly methylated. Inactivation of tumor suppressor genes by promoter hypermethylation is considered to be an important contributor to carcinogenesis.1
Gastric cancer is responsible for ∼800,000 deaths, annually worldwide,2 and the majority of these occur in the developing world. Infection with Helicobacter pylori (H. pylori) is the major environmental risk factor for gastric cancer.3 However, identification of H. pylori infection alone as a risk factor does not simplify the problem of gastric cancer prevention, because approximately half of the world's population is infected. Most of these persons will have only gastritis, and less than 1% will develop cancer. Global eradication of the infection by antibiotic use is impractical, due to cost and to the problem of generation of antibiotic-resistant strains of H. pylori and other pathogenic bacteria. Homo sapiens and H. pylori have coevolved over millennia, and the infection may produce some benefits for the host, such as reduced rates of asthma and lower risk of esophageal diseases.4–6 Therefore, identification of more accurate biomarkers for increased risk of gastric cancer could be beneficial in reducing the burden of mortality from this disease.
H. pylori strains vary in their ability to induce and promote gastric cancer. Among the well-established virulence factors is cagA, a marker for a pathogenicity island carried by some strains.7, 8 This gene encodes the CagA protein, which is injected into gastric epithelial cells by the type IV Cag secretion system of H. pylori. Once within the cell, CagA becomes tyrosine phosphorylated by Abl and Src family kinases, and then is able to bind to Src Homology 2-containing tyrosine phosphatase (SHP-2) and disrupt cell signaling.9 Numerous studies have found an association between the presence of CagA in infecting strains and gastric cancer risk.10 Among CagA positive strains, some variants are associated with an even greater risk for gastric cancer. CagA is polymorphic, containing 3 or more EPIYA (Glu-Pro-Ile-Tyr-Ala) motifs within its C-terminus. Among Western H. pylori strains, those with more than 3 EPIYA motifs have greater affinity for SHP-2 and disrupt epithelial cell morphology in vitro.11 Notably, persons infected with strains bearing CagA proteins with more than 3 EPIYA motifs are at a greater risk for gastric cancer than those harboring strains bearing only 3 motifs.12 We previously reported that in Colombian populations, persons infected with CagA positive strains with more than 3 EPIYA motifs have more severe gastric precancerous lesions.13
Another important H. pylori virulence factor is vacA, which encodes the vacuolating cytotoxin. This gene is also polymorphic: the sequence encoding the signal peptide is either s1 (with s1a, s1b and s1c subtypes), or s2; the middle portion of the gene is found as m1 or m2 alleles. Strains bearing vacA s1m1 alleles produce more toxin and are associated with more severe pathology than those bearing s2m2 alleles.14
Recent reports indicate that infection with H. pylori is associated with elevated levels of aberrant DNA methylation. Chan et al. found the presence of aberrant methylation of the CDH1 promoter to be associated with the presence of H. pylori in gastric mucosae of dyspeptic patients.15 Maekita et al. quantitatively examined methylation levels within promoters of LOX, HAND1, THBD, HRASLS, FLNC, ARC and CDKN2A (p16), and found increased methylation in DNAs from H. pylori-infected subjects compared to uninfected individuals.16 Additional affected gene promoters have been identified, including TWIST117–19 Leung et al. found a lower methylation density at the CDH1 promoter after H. pylori eradication,20 and an independent study examining H. pylori-associated promoter methylation in 5 genes (CDH1, p16, MLH1, APC and COX2) similarly reported that aberrant methylation was significantly reduced or completely eliminated 1 year after H. pylori eradication.21 Elevated methylation levels of the FLNC and CDKN2A (p16) genes in gastric mucosae of H. pylori-infected subjects have also been associated with elevated risk for gastric cancer.22, 23
We aimed to determine whether DNA methylation differences could be detected within the context of H. pylori infection in 2 populations in Colombia. Although situated only 143 miles apart, these 2 populations differ in gastric cancer incidence by approximately 25-fold (150 vs. 6 per 100,000).24 The high-risk region is in the rural Andes mountain villages, where the population is supported by agriculture. This population is of mixed Amerindian and Spanish extraction. The low-risk region is along the Pacific coast, where the economy is based on fishing. This population is of mixed African and Spanish ancestry. By 5 years of age, 80% of the children in both populations are infected with H. pylori, and infection is acquired at a rate that does not differ significantly between the 2 populations.25 The high-risk population has an elevated proportion of subjects infected with more virulent H. pylori strains (CagA positive, vacA s1m1), but this difference is estimated at 24% or less.26, 27 These populations provide a useful natural laboratory in which to examine risk factors and potential biomarkers for gastric cancer.
Material and Methods
Human subjects
The study population consisted of 86 men with dyspeptic symptoms, aged 31–60 years, who underwent upper endoscopy in gastroenterology clinics in 2 public hospitals between June and September, 2006. Ethics committees of the participating hospitals and of the Universidad del Valle in Cali, Columbia, approved the protocol for our study, and all patients provided informed consent. The subjects were residents of Tuquerres in the Andes Mountains and Tumaco on the Pacific Coast, both in the State of Nariño, Columbia. Exclusion criteria for the study were serious chronic diseases, previous gastrectomy or ingestion of proton pump inhibitors, H2-receptor antagonists or antimicrobials in the month prior to the endoscopy. Biopsy samples from the antrum (greater curvature, within 5 cm of the pylorus), incisura angularis (lesser curvature) and corpus (middle anterior wall) were obtained by a single experienced gastroenterologist. One biopsy from each site was fixed in buffered formalin and embedded in paraffin for histopathology. One biopsy from the gastric antrum was frozen in glycerol and thioglycolate for culture of H. pylori organisms. Another biopsy, from the antrum, was frozen without any added solution, for analysis of DNA methylation. Frozen biopsies were shipped on dry ice to Vanderbilt University in Nashville, TN, and were stored at −80°C until thawed for culture or methylation analysis.
Four-micron sections were stained with hematoxylin and eosin for the diagnosis performed independently by 2 experienced pathologists (MBP and PC). Discordant diagnoses were reviewed until a consensus was reached. Diagnosis was performed by established guidelines as normal, nonatrophic gastritis (NAG), multifocal atrophic gastritis without intestinal metaplasia (MAG), intestinal metaplasia (IM) or dysplasia (DYS).28, 29 Pathologists evaluated diagnoses blinded to residence of subjects.
H. pylori culture and genotyping
One antral and 1 corpus biopsy per person were homogenized under sterile conditions and cultured on selective Trypticase soy agar with 5% sheep blood and vancomycin (20 μg/ml), bacitracin (200 μg/ml), nalidixic acid (10 μg/ml) and amphotericin B (2 μg/ml), (all from Sigma, St Louis, MO), as previously described.13 Small gray translucent colonies characteristic of H. pylori appeared after 4 to 8 days. Identity of H. pylori was confirmed by morphology, Gram stains and assays for oxidase and urease. Pellets from 3 single colonies per biopsy were frozen for analysis. DNA was isolated with either a Puregene kit (Qiagen, Valencia, CA) or by proteinase K digestion overnight followed by phenol/chloroform extraction. In preliminary experiments, 2–5 colonies per person were analyzed from 28 subjects by DNA fingerprinting analysis to evaluate the frequency of mixed infections in the colonies harvested from the antral and corpus biopsies.30 In all 28 subjects, all colonies from the same person produced identical DNA amplification patterns, indicating that there were no mixed infections in the strains harvested from a single individual. Subsequently, all analyses for H. pylori virulence markers were performed on DNA from a single colony per subject, isolated from the antral biopsy.
DNA from 1 colony per participant was genotyped for cagA and vacA s and m regions. Analysis of cagA, including the polymorphic 3′ end, was previously described from H. pylori strains from our study population.13 The vacA s region of each strain was amplified by primers VA1F14 and Vac785 (R: AATACGCTCCCACGTATTGC), using an annealing temperature of 52°C. Polymerase chain reaction (PCR) products were treated with ExoSAP-IT (USB, Cleveland, OH) and sequenced using BigDye 3.1 terminator chemistry with an ABI 3130xl Genetic Analyzer. Two strains were genotyped for the vacA s region by PCR alone, using primers VA1F and VA1R14 followed by electrophoresis in a 1.5% agarose gel, discriminating a 259 bp fragment for s1 or a 286 bp fragment for s2. The vacA m region was defined by multiplex PCR using primers M1F2, M1R2, M2F1 and M2R1.31 Primer sequences and details of amplifications are described in Sicinschi et al.27
Methylation analysis
We used a Pyrosequencing® technique, which allows independent quantitative determination of methylation at selected CpG sites in the gene promoter. To obtain material for the analyses, gastric antral biopsies, 1 intact biopsy per person, were homogenized using disposable plastic pestles and digested overnight with proteinase K. DNA was isolated by phenol/chloroform extraction and quantitated with a Nanodrop instrument (Thermo Scientific, Wilmington, DE); 0.5–2 μg of DNA per biopsy was bisulfite modified, using a Zymo EZ Methylation Direct kit (Zymo Research Corp., Orange, CA). Modified DNA (20 ng per reaction) was amplified by PCR, using 0.2 μM of each primer, 2 units of hot start Taq DNA polymerase, and 0.2 mM of each deoxynucleotide triphosphate (dNTP) per reaction. Primer sequences and their location are listed in Table 1. Cycling programs were 95°C for 15 min., then 48 cycles of 95°C for 30 sec, 55°C for 30 sec, and 72°C for 30 sec, followed by a 5-min incubation at 72°C. PCR products were examined following gel electrophoresis in 1.5% agarose, to confirm that a single band was obtained. In preparation for Pyrosequencing, the biotinylated strand of each PCR product was isolated from 10 to 20 μl of each PCR product using a Vacuum Prep Tool (Qiagen), according to the manufacturer's protocol. Pyrosequencing reactions were performed in a PyroMark MD Pyrosequencing instrument (Qiagen), in the presence of 500 nM sequencing primer, following the manufacturer's recommendations. The positive control for methylation was methylated HeLa DNA (New England Biolabs, Ipswich, MA); the negative control was normal human blood DNA (Promega Corp., Madison, WI). Positive and negative controls were run with each experiment. Pyrosequencing assays contained a control for incomplete bisulfite modification. Methylation values used for analysis were the mean of the percent methylation measured for the first 3 potential methylation sites following the sequencing primer.
Statistical analysis
Age, histological diagnoses, levels of methylation at the 4 gene promoters, H. pylori virulence genes and number of EPIYA motifs were compared in a univariate fashion by risk area using χ2, Fisher's exact, Wilcoxon/Mann Whitney, Spearman and Student's t tests, as appropriate. Mathematical transformations of the 4 levels of methylation were evaluated to reduce data skewness. H. pylori status was analyzed several ways combining cagA and vacA genotyping. To assess the degree to which various factors explained levels of methylation, multivariate generalized linear models were used. For continuous and binary variables, the coefficients represent the average difference in percentage of methylation for a 1-unit change in the predictor (i.e., for every year of age or low- vs. high-risk area). In the case of H. pylori genotypes, the coefficient represents the average difference in percentage of methylation associated with being a part of the specified category (cagA and vacA s1m1 or other genotypes) as compared to the reference group (uninfected). Diagnosis was considered as an ordinal variable (0 = Normal/NAG, 1 = MAG and 2 = IM/DYS), for purposes of estimating the p-values in the test of linear trend (p-trend).
Regression analyses were individually applied to original and mathematically transformed variables. As the results were similar, only those results based on the original variables are presented. Data were analyzed using the software package Stata 10.0 (Stata Corporation, College Station, TX). Prism 5.0b (GraphPad Software, La Jolla, CA) was used to generate Figure 1.
A kappa coefficient of reliability was run on 64 replicates to assess reproducibility of the Pyrosequencing results. This analysis produced a kappa statistic of 0.29 (95% CI = 0.27–0.37, bias corrected), with complete agreement of 31% of samples, a standard error of 0.023 and a correlation coefficient of 0.983 (p < 0.0001).
Subjects and their infecting H. pylori strains
Table 2 shows the description of the subjects from the high- and low-risk populations and their infecting H. pylori strains. Age distributions and prevalence of H. pylori infection were similar in the 2 groups, but the high-risk population had more advanced gastric precancerous lesions (p = 0.021). Among the 64 strains that were analyzed for vacA s region by sequencing, all were s1b. Among the cagA positive strains, most had EPIYA patterns of ABC (66% of the cagA positive strains from the low-risk region, and 57% of those from the high-risk region). This difference was not significant. Of the remaining cagA positive strains, most were ABCC, but some variants were found: an AC strain in the low-risk region, and 1 each of ABCCC, ABBCC, ABBC, ABCBC and BCC in the high-risk region.13
Unadjusted analysis
In univariate analysis, levels of methylation (either medians or means) in the RPRM and TWIST1 promoters were significantly associated with the area of residence of the subject, with more methylation being found in the DNA from subjects in the high-risk area. No significant difference was detected for the APC or MGMT promoters.
Considering results from the entire set of DNA samples, generalized unadjusted linear regression models showed that levels of methylation in the RPRM and MGMT promoters were positively and significantly associated with histological diagnoses (coefficient: 2.1; p-trend = 0.018 for RPRM; coefficient: 3.0; p-trend = 0.003 for MGMT). Coefficients indicate that as lesions progressed, higher levels of methylation were observed. In the small number of uninfected patients, median percent methylation was 8% for RPRM (n = 4), 38% for APC (n = 3), 39% for MGMT (n = 4) and 6.5% for TWIST1 (n = 4). Regarding H. pylori infection, the presence of cagA and vacA s1m1 alleles was associated with elevated levels of methylation of RPRM and MGMT. Interestingly, the association with APC was inverse, such that more virulent H. pylori strains were associated with less methylation of this gene. Age was not associated with levels of methylation.
Multivariate analysis
Multivariate regression models incorporated effects of geographic area, diagnosis, age and genotypes of the infecting H. pylori strain (classified as uninfected, cagA positive, vacA s1m1 and all other genotypes; Table 3). Because alternative grouping of variables of H. pylori status, including numbers of EPIYA motifs, or analysis by the presence of cagA alone, did not improve the explanatory capacity of the models and led to similar results, parsimonious models with the highest adjusted R2 (coefficient of determination) are presented. In these models, the observed mean differences between area and RPRM or TWIST1 remained statistically significant, as did the differences between H. pylori virulence genes and RPRM, MGMT or APC. Adjustment for covariates significantly attenuated the differences between histological diagnoses and levels of methylation of RPRM and MGMT. Age did not have any significant effect on the levels of methylation.
Because significant correlations exist between TWIST1 (correlation coefficient ρ = 0.58; p < 0.001) and MGMT (ρ = 0.39; p = 0.001) with RPRM, the combined effect of methylation in these genes was simultaneously evaluated in a regression model using methylation of RPRM as outcome and including the covariates from the multivariate model. When TWIST1 and MGMT were included as covariates, TWIST1 was significantly associated with RPRM (coefficient, 1.04; p < 0.0001) and MGMT showed a trend toward significance (Coefficient, 0.14; p = 0.078). All effects were independent, as there was no significant interaction or effect modification between any of the covariates in the multivariate model.
An interesting outlier
One biopsy from a resident of the high-risk region was a notable outlier. DNA from this biopsy showed elevated methylation at all the 4 regions examined, for RPRM (55% methylation, compared to a median of 21%, 95% CI: 19–23%), for TWIST1 (38% methylation, compared to a median of 10%, 95% CI: 8–11%), for APC (37%, compared to a median of 23%, 95% CI: 22–27%) and MGMT (73%, compared to a median of 58%, 95% CI: 55–61%; Fig. 1). Histopathological analysis of paraffin-embedded biopsies of the same subject showed extensive intestinal metaplasia in all 3 sites examined (antrum, corpus and incisura angularis) and focal areas of indefinite dysplasia in antrum and corpus.
In an attempt to understand mechanisms that regulate progression toward gastric cancer, we compared 2 populations that differ greatly in the incidence of this disease, although they have equally high prevalence of H. pylori infection.26, 27 As expected, the 2 populations differed in diagnosis, with more severe lesions occurring more frequently in the high-risk region. We detected a trend for the presence of the more virulent cagA positive, vacA s1m1 strains more often in the high-risk region, consistent with our findings in prior studies with different subjects from these populations.26, 27 The quantitative method used to measure DNA methylation allowed us to detect differences in levels of methylation previously missed by earlier methods, such as methylation-specific PCR, which reveals only that methylation is present, without quantitating it. In our study, low levels of methylation present in uninfected patients could be measured; this methylation may occur due to environmental stressors not examined in our analysis. Univariate analysis comparing methylation levels of tissues representing the 2 populations showed differences in methylation of 2 genes: RPRM and TWIST1. When we examined several possible covariates of methylation, using multivariate analysis, geographic area remained as an independent effect, with more methylation in RPRM and TWIST1 in the high-risk region.
Because many epidemiological studies have shown an association of cagA and vacA s1m1 with gastric cancer risk, we sought to determine if these virulence factors were associated with promoter methylation in the 4 genes examined. For RPRM and MGMT, an independent effect of cagA and vacA s1m1 on methylation levels was detected. In contrast, for APC, decreased levels of promoter methylation were associated with more virulent H. pylori genotypes. Unadjusted analyses showed that levels of methylation in the RPRM and MGMT promoters were significantly associated with the histological diagnoses, but adjustment for genotypes of the infecting H. pylori strains significantly attenuated the associations. This attenuation is likely due to the association between H. pylori infection and diagnosis of more severe lesions. Our study also demonstrated differential methylation of RPRM and TWIST1 promoters by geographic area, even after adjustment for histological diagnosis and virulence determinants. These results indicate that other virulence determinants of the infecting strains are likely to be responsible for those differences, and/or that additional features distinguishing the 2 populations, such as diet or genetic features of the host, are important in differentiating risk.
In a prior examination of promoter methylation status and H. pylori virulence determinants, Watanabe et al. examined methylation of MINT25, RORA, GDNF, ADAM23, PRDM5 and MLF1 in gastric washings from Korean subjects with and without gastric cancer.32 These investigators tested for the presence of cagA in infecting strains and found no association with methylation. A difference from our study, besides the ethnicity of the subjects, is that Watanabe et al. assayed cagA by PCR on DNA from gastric washings, in contrast to our method of PCR using DNA from cultured bacteria. Culture is likely to be a more sensitive method for detection of H. pylori and its virulence determinants. In addition, as gastric lesions become more advanced, H. pylori infection is often lost, so that evaluation of H. pylori and its virulence determinants in gastric cancers may under-represent the infection originally present.33 Thus, our study on premalignant lesions may have been more likely to detect infections originally present.
Park et al. examined methylation levels in a set of genes by quantitative methods, comparing premalignant gastric tissues and gastric cancers, with and without H. pylori infection,34 and found significant differences between infected and uninfected subjects, in the DNA samples from gastritis, but not from intestinal metaplasia, adenomas or gastric cancers. While some studies have found H. pylori-related methylation to be associated with age,19, 35 others,15, 36 including the current study, have found no significant associations. However, the age range of our subjects was 29 years, and it is possible that with a broader age range, a significant association might be detected.
The genes we chose to study have been previously noted to be associated with development of gastric cancer. One such gene was RPRM, a p53-dependent mediator of the G2/M cell cycle checkpoint.37RPRM is a tumor suppressor, which is inactivated by promoter methylation in a variety of human tumors, including gastric adenocarcinoma.38 Notably, RPRM promoter methylation has been reported in premalignant conditions such as Barrett's esophagus39 and nonmalignant gastric epithelia.38 Aberrant methylation of RPRM may be detected by methylation-specific PCR (MSP) in plasma of gastric cancer patients, in contrast to plasma of control subjects, suggesting the potential of RPRM as a biomarker for early gastric cancer.40 Our results also support the identification of this gene as one that may be altered early in the progression toward gastric cancer.
Another gene we examined was the APC (adenomatous polyposis coli) gene, which encodes a component of a multiprotein complex that inactivates β-catenin in the Wnt signaling pathway. A critical tumor suppressor in the gastrointestinal tract, APC is expressed in the stomach as 2 isoforms originating from promoters 1A and 1B.41 Methylation in gastric tissue occurs predominantly in promoter 1A, and for this reason, this promoter is frequently examined in studies of hypermethylation in gastric cancer.42, 43 However, in contrast to the colon, methylation at promoter 1A in gastric mucosae is not predominantly tumor related, but is frequently found in non-malignant gastric mucosae,44 as we also observed. Promoter 1B is not methylated, and gene expression studies have shown that transcription of APC in the stomach is regulated primarily from this promoter.44, 45 Consequently methylation at promoter 1A in gastric mucosae is likely to be a passenger, rather than a driver of carcinogenesis. Among the 4 genes we examined, after adjustment for diagnosis, it is notable that only the APC promoter showed a decrease in methylation in DNAs from subjects from the high-risk region.
MGMT encodes O-6-methylguanine-DNA methyltransferase (also called O-6-alkylguanine-DNA alkyltransferase), a DNA repair enzyme that removes alkylation adducts from guanine. MGMT must be constantly renewed, as part of defense against mutagens. MGMT promoter hypermethylation is associated with a wide variety of tumors, including gastric cancers.46 Our assays detected a relatively high level of MGMT promoter methylation in most of the gastric biopsies. Additional studies will be necessary to determine how these elevated levels are related to MGMT gene expression.
TWIST1 encodes a basic-helix–loop-helix transcription factor called Twist1 that regulates metastasis47 and epithelial-to-mesenchymal transition.48 Twist1 represses transcription of E-cadherin and TIMP1 (an inhibitor of matrix metalloproteinases)49 and promotes migration in neoplastic cells.50, 51 Although the Twist1 protein may have tumor- or metastasis-promoting effects, paradoxically, hypermethylated TWIST1 is reported in cancers of the stomach and other tumor types.48, 52 All of our Colombian subjects, with the exception of 1 outlier, had relatively low levels of TWIST1 hypermethylation.
Limitations of our study include the fact that we examined DNA from biopsies containing premalignant lesions, instead of DNA from gastric cancers. Our goal was to investigate early events in gastric carcinogenesis, and not all these events may lead to cancer. Another limitation is the use of entire biopsies for our DNA preparation, so that mixed cell types are included. Although most of the cells contributing DNA were gastric epithelial cells, other cells including stromal and inflammatory cells may have contributed to the differences in methylation levels that we measured. Additional studies employing microdissection will be useful to confirm identity of the cell type demonstrating alterations in methylation levels.
A topic of intense investigation is the mechanism(s) by which promoter methylation becomes dysregulated during the development of cancer, and how inflammation may promote this process. In our study, we found that 2 of the 4 genes we examined (RPRM and TWIST1) increased together in levels of methylation, and a third (MGMT) trended toward such an increase, consistent with a common or related mechanism affecting most of the genes we studied. Results from an outlier subject, whose biopsy showed high or remarkably elevated promoter methylation in all 4 genes examined, are consistent with the existence of a global methylation defect that can occur early in the stages of carcinogenesis. Although this widespread hypermethylation was observed in only 1 subject, we expect progression of H. pylori-related disease to occur in only a small minority of infected persons, and therefore events occurring within the gastric mucosae of these rare individuals provoke great interest. Analysis of DNA methylation of additional genes and the effect of that methylation on gene transcription will be necessary to clarify early events in H. pylori-related gastric cancer development.
The mechanisms by which virulent H. pylori infection may influence promoter hypermethylation remain obscure, but several hypotheses which involve enhancement of DNA methyltransferase activity have been proposed. H. pylori infection promotes gastric epithelial cell proliferation and increased production of epidermal growth factor (EGF) and its receptor53; the EGF receptor has greater activity with the more virulent cagA positive strains.54 EGF administered to gastric epithelial cells in culture increases DNA methyltransferase activity.55
Another possible mechanism by which H. pylori can promote hypermethylation involves the effect of nitric oxide on DNA methyltransferase. Katayama et al. noted that the RUNX3 gene promoter in the human gastric cancer cell line MKN45 can become methylated by coculture with H. pylori and macrophages, and this effect can be replicated by substituting nitric oxide (NO) for the bacteria and macrophages.56 Inhibition of NO synthesis in the coculture reversed the methylation. Hmadcha et al. reported that treatment of an insulinoma cell line by IL-1β or NO could inactivate the FMR1 and HPRT genes by hypermethylation.57 This effect was apparently mediated by enhancement of DNA methyltransferase activity, without an increase in transcription of the methyltransferase gene.
In conclusion, RPRM and TWIST1 promoter DNA methylation were found to be elevated in gastric biopsies from residents of the high-risk region compared to those from residents of the low-risk region in Colombia. Virulence genes cagA and vacA s1m1 in the infecting H. pylori strains were independently associated with elevated levels of methylation of RPRM and MGMT. Alterations in DNA methylation are early changes in the progression of premalignant lesions and have the potential to serve as biomarkers for gastric cancer risk.
The authors wish to acknowledge Ms. Jacki Huckins (Qiagen) for assistance in assay design for the RPRM Pyrosequencing assay. The content presented here is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
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- 25Age at acquisition of Helicobacter pylori infection: Comparison of two areas with contrasting risk of gastric cancer. Helicobacter 2004; 9: 262–270., , , , , , .
- 26Virulence-associated genotypes of Helicobacter pylori: do they explain the African enigma? Am J Gastroenterol 2002; 97: 2839–2842., , , .Direct Link:
- 27Helicobacter pylori genotyping and sequencing using paraffin-embedded biopsies from residents of. Colombian areas with contrasting gastric cancer risks. Helicobacter 2008; 13: 135–145., , , , , , , , .
- 28Classification and grading of gastritis. The updated Sydney System International Workshop on the Histopathology of Gastritis Houston 1994. Am J Surg Pathol 1996; 20: 1161–81., , , .
- 29Gastric dysplasia - the Padova international classification. Am J Surg Pathol 2000; 24: 167–176., , , , , , , , .
- 30Construction of a Helicobacter pylori genome map and demonstration of diversity at the genome level. J Bacteriol 1992; 174: 6800–6806., , , .
- 31Helicobacter pylori genotyping in gastric adenocarcinoma and MALT lymphoma by multiplex PCR analyses of paraffin wax embedded tissues. Mol Pathol 2003; 56: 36–42., , , , , .
- 32Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes. Gastroenterology 2009; 136: 2149–58., , , , , , , , , , , , et al.
- 33Helicobacter pylori infection, serum pepsinogen level and gastric cancer: a case-control study in Japan. Jpn J Cancer Res 1995; 86: 64–71., , , , , , , , , , et al.
- 34Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer, stratified for Helicobacter pylori infection. J Pathol 2009; 19: 410–16., , , , .
- 35Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation. Am J Pathol 2003; 163: 1551–6., , , , , .
- 36CpG island hypermethylation of tumor-suppressor genes in H. pylori-infected non-neoplastic gastric mucosa is linked with gastric cancer risk. Helicobacter 2008; 13: 35–41., , , , , .
- 37Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase. J Biol Chem 2000; 275: 22627–30., , , , , , .
- 38Aberrant methylation of Reprimo in human malignancies. Int J Cancer 2005; 115: 503–10., , , , , , , , , , , .
- 39Reprimo methylation is a potential biomarker of Barrett's-Associated esophageal neoplastic progression. Clin Cancer Res 2006; 12: 6637–42., , , , , , , , , , , , et al.
- 40Reprimo as a potential biomarker for early detection in gastric cancer. Clin Cancer Res 2008; 14: 6264–9., , , , , , , , , , .
- 41Multiple forms of the APC gene transcripts and their tissue-specific expression. Hum Mol Genet 1993; 2: 283–7., , , , .
- 42Profile of aberrant CpG island methylation along multistep gastric carcinogenesis. Lab Invest 2003; 83: 519–26., , , .
- 43Analysis of Adenomatous Polyposis Coli promoter hypermethylation in human cancer. Cancer Res 2000; 60: 4366–71., , , , , , , , , , , .
- 44Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia. Oncogene 2000; 19: 3642–6., , , , , , , , , , , , et al.
- 45Adenomatous polyposis coli 1A is likely to be methylated as a passenger in human gastric carcinogenesis. Cancer Lett 2009; 285: 182–9., , , , , .
- 46Epigenetic silencing of the MGMT gene in cancer. Biochem Cell Biol 2005; 83: 429–37., , .
- 47Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117: 927–39., , , , , , , , , .
- 48A twist for survival and cancer progression. Br J Cancer 2006; 94: 13–7., , .
- 49Negative regulation of TIMP1 is mediated by transcription factor TWIST1. Int J Oncol 2009; 35: 181–6., , .
- 50Twist expression promotes migration and invasion in hepatocellular carcinoma. BMC Cancer 2009; 9: 240., , , , , , , , , , , , et al.
- 51TWIST-1 is overexpressed in neoplastic choroid plexus epithelial cells and promotes proliferation and invasion. Cancer Res 2009; 69: 2219–23., , , , , , , , , , , .
- 52Differential expression of the epithelial-mesenchymal transition regulators snail. SIP1, and twist in gastric cancer. Am J Pathol 2002; 161: 1881–91., , , , , , , .
- 53Helicobacter pylori -stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EBG. Biochem Biophys Res Comm 2002; 295: 695–701., , , , , .
- 54cag+ Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol Chem 2001; 276: 48127–48134., , , , , .
- 55E-cadherin gene promoter hypermethylation in H. pylori-induced enlarged fold gastritis. Helicobacter 2007; 12: 523–31., , , , , , , , .
- 56Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem Biophys Res Commun 2009; 388: 496–500., , .
- 57Methylation-dependent gene silencing induced by interleukin 1beta via nitric oxide production. J Exp Med 1999; 190: 1595–604., , , .


text:
|ESPN.com: Big Ten
|[Print without images]
"Everything inside of me said, 'I don't want the media to stop me from going,'" Brown told the Journal Star. "Then I realized it was going to be a circus, and everybody already knows how I think. My views stand the same. As I prayed about it, I thought it was not in the Lord's will for me to testify."

subset: commoncrawl


text:
Apache OpenWebBeans-1.2.0 has been released
The Apache OpenWebBeans Team is proud to announce the release of
Apache OpenWebBeans-1.2.0
Apache OpenWebBeans is an Apache License v2 licensed implementation of the JSR-299 "Context and Dependency Injection for Java EE" and JSR-330 "atinject" specifications. OpenWebBeans has a modular structure and provides Dependency Injection scaling from Java SE environments up to EE6 server clusters with complicated ClassLoader hierarchies or OSGi environments.
openwebbeans-1.2.0 implements the CDI-1.0 API, passes the JSR-330 TCK and the JSR-299 standalone TCK.
Distribution packages can be downloaded from
The release is also available in maven.central
More info can be found at
The Apache OpenWebBeans Team
Posted at 06:31AM Jun 12, 2013 by struberg in General | Comments[5] |
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text:
Thu, 10/07/2014 - 12:02
KKR has acquired a majority interest in OEG Offshore Group, a provider of specialist equipment to the offshore oil and gas industry.
OEG's executive management retain a significant holding in the company.
OEG is headquartered in Aberdeen, UK with regional hubs in the main offshore oil and gas regions including Singapore, Australia, and the US and 20 further diversified stocking locations worldwide.
OEG manufactures and leases specialist Cargo Carrying Units which are essential items used by oil and gas operators and their service providers to transport equipment and supplies to and from rigs and platforms as part of their day-to-day offshore operations. In addition, OEG has a fleet of modular workspaces which serve as temporary offices or laboratories by engineers or other personnel undertaking work on offshore platforms or rigs.
John Heiton, CEO of OEG, says: "We have achieved significant growth in OEG to date but our teams have the appetite to accelerate our further development through both organic and acquisitive means. We believe that KKR will be an excellent partner to achieve those aims, given their global network and experience as a leading investor in the energy services sector. We are delighted to co-invest with KKR to develop OEG into a leading global provider of field support equipment to the offshore energy industry."
Dominic Murphy, member and head of KKR operations in the UK, says: "OEG has built an impressive track record of growth and has an exciting development path ahead, expanding its fleet, geographic coverage, and suite of products and services. We are enthusiastic about partnering with John Heiton and his team who combine deep industry expertise with strong commercial acumen and relationships in the offshore oil and gas industry and logistics sector."
Financial details of the transaction have not been disclosed.
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Sat, 28 Mar 2015 00:00:00 GMTFront Office Equity Derivatives Quant | NYC
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Sat, 28 Mar 2015 00:00:00 GMT


text:
Size zero? They're living ZOMBIES!
*ahem* Anyway
What's wrong with them? Maybe it's because they're too afraid to eat food, some kind of phobia I suppose.
See, it's easy to just dismiss all of it if you're not obese or anything. I can more or less identify with the people who want to be thin because I used to want to be thin... no, scrap that, I still want to be thin. Except that I don't want to be a size zero, I just want to be a UK size 6 and hopefully stop there (I'm currently a size 8, which is... a US 4??? The size differences are confusing). And I'm bulimic, yes I am. I still throw up, though less frequently than I used to.
Basically what I'm driving at is... well, you can't just stand around and make a great noble speech about inner beauty because it's not going to help. Getting a person back on the path to being healthy is something that's MUCH easier said than done. When you're overweight, and everyone else around you isn't, and celebrities all seem to be shedding the excess weight so effortlessly, things get really upsetting. And you start doing crazy things to lose weight.
I don't know about you, but I feel that nothing in extremity is good, thin is definitely much better than obese.
Size zero? They're living ZOMBIES!
*ahem* Anyway
What's wrong with them? Maybe it's because they're too afraid to eat food, some kind of phobia I suppose.
I guess some people who are a size zero has that fear that they still look fat. And yet they still dieting and getting even more skinnier.
Usually a little meat on them means your fat. I think its great to be skinny as long as your not starving yourself or are purging. Nothing wrong with being fit. It fine to have a little meat on you if your in your recommended body weight. Nicole Richie looks like she use to be hot, but pushed it to far as of late. Which she didnt need to do because she was perfect b4.*ahem* Anyone going to down to that size is just... ridiculous.
I'm not sure how anyone sees that as beautiful, I mean, there are those who constantly think they're ugly just cuz they have some meat on them, but come on!!!
Well even though we try to tell these ppl that size zero is unhealthy... that's not what they see everyday on the mass media..... When I was 8th grader I starve myself almost to literal death because "I was tooo fat because I was size 10...." My mom practically saved my life.... she saw my changes and everything and she helped me through.... but tell you what I cried a lot cos I thought because I was "fat" I was ugly......
Now... one has to start to believe in oneself and start to be self-confident.... skinny it s not equals to beauty.... being healthy it is. It will be awesome if you don't pay attention to the mass media that tells you: "be skinny doesn't matter if you are not healthy.... you have to be able to wear this or that"
Also I know of many guys that just lookfor "pretty skinny girls" those guys aren't worthy.... they wouldn't see the real beauty that you have. Start by yourself thinking that you are beautiful the way you are. YOU ARE BEAUTIFUL. You don't need a size zero to tell you that.... now get up and eat a double cheese burger and a salad and then go for a walk to the park... enjoy your life... you just have one life to live.
Nothing less from Pyro ^_^ Great Sig ^_^ THANK YOU!!!!"show me.... THE BEAST!!!" The Beauty and the Beast movie
You know its the inside that is more beautiful than the outside. That's what I believe. No matter if your ugly/fat/skinny etc. the inside is always the most precious. And I wish more people would believe that now-a-days.
Nothing less from Pyro ^_^ Great Sig ^_^ THANK YOU!!!!"show me.... THE BEAST!!!" The Beauty and the Beast movie


text:
Meet the new MK: The Zionist Union's Eitan Broshi
Congress delegation shares concerns about Iran's nuclear capability
Ambassador Dermer says US-Israel relationship strong
Kulanu expands coalition demands
Emergency room visits fewer with urgent-care clinics in the community
Health Ministry: Avoid dangerous infections from cleaning pond fish
Israel has second-lowest abortion rate in Europe, continues to drop
Passover health warning: Avoid dangerous infections from cleaning pond fish
Study: Israeli patents in US jump 21%
It's Passover cleanup time in Israel and e-waste recycling is on the rise
American-Israeli team secures US gov't grant to build Burundi's first solar field
Eco Wave Power to establish its first Chinese power station
Art Garfunkel to perform at Bloomfield Stadium
Entranced by Infected Mushroom
Damian Marley to serenade Rishon
Cinematic reality
Maccabi Tel Aviv meets Gala in crunch clash
Sinai Says: Another bizarre decision by BSL in changing playoff format again
Israel frustrated by Belgium at Teddy
Enormous Belgium showdown for Israel
Israel: PA is in cahoots with Hamas, has no right to threaten us in name of int'l law
NGOs petition to reopen case of Palestinian killed by an IDF tear gas canister
Watch: David's Sling shoots down mock missile in successful trial
ICC welcomes 'State of Palestine' as 123rd member
Khaled Mashaal says Israeli election results will boost extremism
ADL, B'nai B'rith urge 'Daily Show' pick Trevor Noah to avoid distasteful jokes about Jews
Edinburgh University students accused of anti-Semitism over Passover BDS vote
Diaspora discord: Indiana Jews and the US state's new 'religious freedom' law
Rabbi reverses himself: Iran, not Obama, is Haman
Jewish charities strive to prepare for Passover amid war-torn Ukraine
Analysis: Saudis would develop own nuclear program in reaction to nuclear Iran
Content and form prove elusive in marathon nuclear talks with Iran
Partial salaries to be paid to Palestinians as Israel withholds funds
Twitter buzzes with 'Arab April Fools'
ISIS takes over large parts of Palestinian refugee camp in southern Damascus
JPost Editorial: Going green
Candidly speaking: Uniting to resist Obama's unprecedented hostility
Letters to the editor
Who was the pharaoh of the Exodus?
Encountering peace: The world is not against us
The blood libel Haggada
The turning point
Travel tech start-ups
On wings of carbon
Veterans: On target
Fusing modern and traditional in the kitchen
Book Review: Perceptive Haggada
Hot off the Arab press
Let's cooperate
Shabbat screenings
Passover perspective
On the field and in court
Happily Eva After: Times, they are a-interestin'
Music and the mamaloshen
What's the catch?
Kayaking for gold on the Kinneret
Why Tunisia?
Palestine – words matter but their meaning matters more
A nuclear deal with Iran – would it stick?
When words matter and when they don't
מִצְעַד הָאָבִיב
שִירִים מֵהַבַּיִת
מִי לָקַח אֶת הַגְבִינָה שֶלִי?
אֵיתָן פוֹנְד
Getting a young start
A culinary festival starring the women next door
Global girl power
Apartheid South Africa: Israel edition
Sa'ar says national unity government is 'still on the table'
Israeli parties prepare legislative demands for Netanyahu's new coalition
With full term possible, Netanyahu may outlast Ben-Gurion (and Obama)
Arab sector turnout for recent elections reached 63.5%, polling data shows
Joubran: Polls have to include parties that don't pass threshold
West Bank hopes to make ancient church popular tourist destination
'The Resistance' against Pope Francis
Israeli doctors save life of Iraqi Christian toddler who fled ISIS
Christian Friends of Magen David Adom donate ambulance in Jerusalem
Christians celebrate Palm Sunday in the Holy Land
Sar-el Volunteers Tour the Negev Desert with KKL-JNF
Green Leadership Conference in Hamalachim-Shahariya Forest
Scenic Lookout in Memory of Lt-Gen. Amnon Lipkin Shahak
Following in the Footsteps of Meir Har-Zion
President of Lombardy Tours Israel Prior to Milan Expo
French Students Get to Know the Real Israel
Serbian PM Plants a Tree in the Grove of Nations
Sharing and Learning - German Forestry Students Intern with KKL-JNF
New Bio-filters Purify Surface Runoff Water for Reuse
Future Tour Guides Discover the Negev with KKL-JNF
The Shamir Drilling Project
Graduation Ceremony for Rosh HaAyin's Volunteer Firefighters
From Sunny Israel to Cold Canada
Walking for Water with KKL France in the Mountains of Eilat
JNF Ontario Community Mission Tours the Western Negev
Celebrating 50 Years of German-Israeli Diplomatic Relations
The Negev Conference on Agricultural Research and Development
Arava Open Day: Food Security for Israel and the Entire World
Living Green in Israel: the Contest and the Winners
Addressing Climate Change Conference
From Think Tank to Environmental Consultant
Award Winning Designer Launches Career as Wedding Dressmaker
Outdoor Fitness Israel: An Innovative Fitness Program Developed By UK Olim
The Burstein Brothers: 3 Oleh Siblings in the IDF
5 Tips to Land a Job in Israel
Starting Your Own Business in Israel: Real Life Examples
5 Strategies for Finding Your Professional Place in Israel
PetBNB:An Olah's Unusual Canine Startup
36 Hours in Southern Israel
Food Shopping In Israel
How Women Can Have it All in Israel
The Eisenberg's Long Journey Home
Why Retirees are Thriving in Israel
Thanks to Aliyah video
6 Frequently Asked Questions about Israeli Healthcare
Starting Over in Israel
VIDEO: Are you ready for the South?
Sovev Tel Aviv, Israel's Largest Biking Event
Running Through Color
Formula 1 Racecars Zip Through Jerusalem
Make yourself at home… in Israel
NBN Announces Bonei Zion Prize Recipients for 2015
NefeshB'Nefesh Provides Services to Bnot Sherut
How Doctors Are Impacting Israel's South
Over 1,000 IDF 'lone soldiers' attend personal errand day in Tel Aviv
04.02.2015 | 13 Nisan, 5775
JPost Editorial: Going green
Candidly speaking: Uniting to resist Obama's unprecedented hostility
Letters to the editor
Who was the pharaoh of the Exodus?
Encountering peace: The world is not against us
Media comment: Passover cleaning
Terror of the Islamic State
Passover: Liberating God, Jews and Judaism
Washington watch: The French connection
Trevor Noah – a little too soon to panic
Editorial: Passover wage hike
The making of a great leader
05/06/2012 22:26
US voters at a polling station in the US 370.
(photo credit:Reuters)
When my Labor Zionist cousins made aliya from New York City in the 1950s to an
agricultural moshav outside Ra'anana they cast off comfort, kin, and familiarity
for the yoke of pioneering Zionism. It was inevitable that they'd lose touch
with the Brooklyn Dodgers, Joe DiMaggio's love life, and the fate of the Third
Avenue El. Just getting hold of a delayed copy of the Herald Tribune
would have been a coup. And the thought of casting an absentee ballot in the
presidential contest between Republican Dwight D. Eisenhower and Democrat Adlai
Stevenson did not even cross their minds.Nowadays, Americans living in
Israel will find voting in the 2012 presidential elections no trickier than
keeping up with Season Five of Mad Men. As an ex-New Yorker, I am able to apply
to vote via a Federal website or through my local board of elections. It
seems I am eligible to vote in municipal contests and, for all I know, in school
board races. Having downloaded and filled out an application, all I need do is
affix my signature and airmail the forms to the Board of Elections on Ninth
Avenue. Anticipating approval of my submission, the board has already emailed to
wish me "a great voting experience this year!" Filing overseas tax returns is a
legal obligation, holding a second passport may be prudent, and feeling devotion
to America is only natural. But as someone who has no expectations of returning
to live in the United States I see voting as an exploitation rather than an
exercise of my rights, and as a betrayal of my Zionist bona fides. Did Herzl and
Jabotinsky go to their early graves so that I could exercise my right to vote in
America? THAT'S NOT the way Kory Bardash of Republicans Abroad sees it. A strong
America, he argues, helps secure a strong and independent Israel. "By helping to
elect officials that understand and support Israel's struggle against an ever
increasing hostile world that looks to delegitimize it, those that vote in the
US election can help support [the Zionist] dream."Advocates of absentee
balloting also argue that with taxation comes representation. Expats living in
London have no compunction about voting in US elections so why should those
living in Tel Aviv feel differently? According to Bardash, Israel's 300,000
Americans make it the fifth-largest expat community. Many maintain deep
connections through family, friends and frequent visits. Moreover, 115 countries
allow absentee voting and they can't all be wrong.All true, but Israel
doesn't allow absentee balloting. And there is no groundswell of
sentiment to give 500,000 expat Israelis (about 10 percent of the population)
whose lives are permanently centered in America, Russia, or Germany the right to
vote. On the other hand, Cabinet Secretary Zvi Hauser did lately direct a
quasi-public think tank to explore whether – and to what extent – to enfranchise
Israelis abroad.He is weighing one option in particular that, if
endorsed by the cabinet and passed by the Knesset, would extend limited voting
rights to some 42,000 Israelis on a one-off basis who have been abroad for no
more than four years –among them university students, post-army trekkers,
visiting academics, business people, tourists and airline crews.Given
Israel's size that could be enough, cumulatively, to influence the outcome of
two Knesset seats. Historically, however, any reforms have been opposed by
strange bedfellows: the ultra-Orthodox Shas party, some national-religious
factions, the Arab bloc, and the leftist Haaretz newspaper.While
sensible reforms extending the vote to those temporarily out of the country
could make it through the Knesset, no one expects the franchise to be handed
broadly to ex-Israelis permanently living overseas. The consensus seems to be
that those who have permanently made their lives elsewhere have ceded their say
in life-and-death decisions affecting the Jewish state.Plainly, for
expat US citizens the circumstances are quite different. Some Israeli-Americans
will vote out of a sense of patriotism; of those many will weigh the moral
dilemma of exercising power without personally having to pay the consequences.
Some, naturally, will not cast absentee ballots because of lethargy. And still
others will consciously refrain from voting because for them answering the
Zionist call for the ingathering of the Jewish people in the land of Israel
necessitates, perforce, abdication of involvement in the political affairs of
one's former homeland.This article first appeared in Jewish Ideas Daily
and is re-published with permission.
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Federal Law Enforcement to Announce Significant Activity Regarding the Aryan Brotherhood of Texas
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Principal Deputy Assistant Attorney General Marshall L. Miller of the Department of Justice's Criminal Division and U.S. Attorney Kenneth Magidson of the Southern District of Texas, along with several leaders from various federal, state and local law enforcement agencies, will participate in a press conference to announce significant activity regarding the Aryan Brotherhood of Texas TODAY, AUGUST 13, AT 1:30 P.M. CDT
Marshall L. Miller, Principal Deputy Assistant Attorney General, Justice Department's Criminal Division
Kenneth Magidson, United States Attorne y, Southern District of Texas
Robert W. Elder Special Agent in Charg e, ATF-Houston Field Division
Carlos J. Barron, Assistant Special Agent in Charge , FBI-Houston Field Division
David M. Marwell, Special Agent in Charge
, Homeland Security Investigations-Dallas Field Division
WHAT: Press conference
United States Attorney's Office
1000 Louisiana, Suite 2300
Houston, Texas 77002
NOTE: Media planning to attend the press conference are asked to notify Angela Dodge, Public Affairs Officer, Southern District of Texas, at 713-567-9388 or via email at firstname.lastname@example.com . Those attending are urged to arrive at least 30 minutes in advance of the scheduled conference time to allow for security checks and set-up. All media representatives must present a valid government-issued photo identification upon arriving at the U.S. Attorney's Office.
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Baby Love eBook from Red Heart Yarns
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28 Baby Hats and Baby Booties
By: Melissa Conner, Editor of FaveCrafts.com
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Welcome a new little one into your life with this collection of 28 Baby Hats and baby Booties. With knit and crochet patterns to suit everyone's style, taste, and skill level, this collection is great to have on hand if you or someone you love is expecting a new little bundle of joy this year!
No matter what your knit or crochet skill level, baby booties are a quick and easy project that babies of all ages will appreciate. Knit and crochet baby booties are great for using up leftover yarn and you can make a whole assortment of them over the course of a lazy weekend. Expecting moms will love getting these little handmade gifts and these sweet handmade booties are sure to be treasured and cherished for years to come.
Once you have your assortment of booties all ready to go, don't forget to whip up a few knit and crocheted hats as well. New baby hats are always a welcome gift for new moms and, like the booties, these hats can be made as you catch up on your favorite TV show.
From head to toe, these 28 baby hats and booties are sure to please babies and toddlers of all ages.
28 Baby Hats and Baby Booties
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Knit Baby Hats
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Chips must fall
By Don Carroll
Published: 2015-02-28
he axe of a woodcutter must land true on a log to quickly slice through its hardened grain. To do that the woodcutter must stay focused on the wedge hes opening and ignore the chips that scatter about. The same can hold true of a murder trial. The truth is buried in a maze of conflicting evidence and lawyers for the prosecution and defense seek to guide the court away from the scattering to show clear proof of guilt or innocence.
The trial of Amanda Knox and Raffaele Sollecito is expected to reach a late March climax March 25 is the assigned date in the crucible of the Court of Cassation (Italy's highest appellate court) where five justices will hear the appeal against their conviction for the 2007 murder of Meredith Kercher in Perugia. All three were students at the time.
The notorious case has given all levels of Italy's court system trial, appellate and Court of Cassation a mother lode of conflicting evidence. In play is the veracity of DNA evidence on a kitchen knife, whether a second knife was used, police procedure in gathering and handling evidence, police interrogation tactics, Knox's behavior following her arrest, and Rudy Guede's confession to committing the murder he is serving a 16-year sentence. Allegations of sex games, crime scene investigation practices, and the role of broken glass have also been analyzed.
I recently discussed the case with Knoxs defense attorney Carlo Dalla Vedova. He was adamant about the proof the state needs to convict his client. In Italian legal terms, the evidence must meet three fundamental criteria. It must be "precise, " "certain" and "in accordance" precisi, certo e concordante.
"Precise" in that there can be only one explanation for what happened. "Certain" in that there can be no doubt about the quality of the evidence. Finally, these two elements must jibe they must be "in accordance," or perfectly linked. Any doubt about any of these factors, said Dalla Vedova, and the court must rule in favor of the defendants, based on reasonable doubt.
To convict Knox and then-boyfriend Sollecito, the prosecution must prove both were at the scene of the crime; that the knife cited as the murder weapon is just that; that no scientific doubt exists regarding the DNA evidence on that knife and no alternative explanation exists than it having been used to murder Kercher.
The prosecution's use of circumstantial evidence to theoretically explain the crime as well as the motives and intent of the defendants has long been under fire. Again, it will be precision and certainty that matter.
The case has a complex history. In December 2009 a trial court in Perugia convicted the defendants, with Knox and Sollecito each sentenced to long jail terms. But two years later a Court of Appeals in Florence overturned the ruling. On March 26, 2013, following an appeal by the prosecution, the Court of Cassation ordered a new trial, and on Jan. 30, 2014 the Court of Appeals in Florence reinstated the original guilty verdict. The defendants appealed that decision claiming the evidence did not support it. Now the case returns to the Court of Cassation.
The hearing is likely to be held in a small courtroom in Rome's Palazzo della Giustizia near the banks of the Tiber River. The press but no cameras will be allowed into the courtroom. There will be a limited public gallery.
The reporting judge (relatore) will summarize the previous court decisions, after which the state prosecutor (procuratore generale) will present the state's charges against the defendants. Finally, Dalla Vedova and co-counsel Luciano Ghirga will present Knox's defense, with Giulia Buongiorno and Luca Maori doing the same for Sollecito.
The hearing will emphasize brevity. Attorneys will be limited to 20-minute presentations while the state prosecutor will have somewhat more time. The court is expected to announce its decision on the day of the hearing or the next day at the latest. It may find for the defendants, in which case the state can appeal; it may annul the appeal court decision and remand for a new trial; or it may confirm the guilty verdict.
The final scenario would end the third stage of the Italian criminal trial system, exhausting the defendants' ability to appeal. Sollecito, who is in Italy, would begin his jail sentence. Italy would then be confronted with the matter of whether to seek extradition for the 27-year-old Knox, who returned to the United States in 2011.
Over the years, the case has been rife with changing verdicts, differing shades of evidentiary interpretation, accusations, grandstanding, media mania and politics. That makes it easy enough to imagine this appeal will come down to which side blinks first, the prosecution or the defense.
But after more than seven years, the Italian criminal justice system owes Knox, Sollecito and Kercher's family a final, well-considered and sure-footed ruling on whether the prosecution has proved its case. Only when the justices decide beyond any reasonable doubt that the evidence presented in Florence was precise, certain and in accordance can they rule. After which the chips will fall where they may.
Editor's note: The author practiced with the Dalla Vedova Studio Legale firm from 1984 to 1991.
Don Carroll
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Sin Kiske is a new Guilty Gear Xrd character birthed by the union of Ky Kiske and Dizzy
Guilty Gear Xrd will have another Kiske in town when it launches -- Sin -- the son of Ky and Dizzy. He has a special modifier called "Full Stomach," that lowers a bar with every special move -- you have to eat food to recover it.
For reference, Ky is representative of holy elements in the Guilty Gear franchise and devotes himself to God, and Dizzy is a demon-like entity (though she is kind, seeing as that she's roughly eight years old in human years) that is half-human with a fast-aging body. Sin was part of the lore and found previously in Guilty Gear 2, but this will mark his 2D competitive fighting debut (Xrd is technically 3D, but plays like a 2D game nonetheless).
It's possible that Dizzy could have aged a bit more by the events of Xrd, but it's just...weird, even for Guilty Gear standards. He sounds really fun to play though.
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