Search

Objectives The aim of this study was to evaluate the prognostic value of high-sensitivity troponin T (hs-TnT) in addition to clinical risk factors and the CHA2DS2VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) risk score in patients with atrial fibrillation (AF). Background The level of troponin is a powerful predictor of cardiovascular events and mortality. Methods A total of 14,897 patients with AF were randomized to treatment with apixaban or warfarin in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial. The associations between baseline hs-TnT levels and outcomes were evaluated using adjusted Cox regression models. Results Levels of hs-TnT were measurable in 93.5% of patients; 75% had levels > 7.5 ng/l, 50% had levels > 11.0 ng/l, and 25% had levels > 16.7 ng/l. During a median 1.9-year period, the annual rates of stroke or systemic embolism ranged from 0.87% in the lowest hs-TnT quartile to 2.13% in the highest hs-TnT quartile (adjusted hazard ratio [HR]: 1.94; 95% confidence interval [CI]: 1.35 to 2.78; p ¼ 0.0010). The annual rates in the corresponding groups ranged from 0.46% to 4.24% (adjusted HR: 4.31; 95% CI: 2.91 to 6.37; p < 0.0001) for cardiac death and from 1.26% to 4.21% (adjusted HR: 1.91; 95% CI: 1.43 to 2.56; p ¼ 0.0001) for major bleeding. Adding hs-TnT levels to the CHA2DS2VASc score improved the C statistic from 0.620 to 0.635 for stroke or systemic embolism (p ¼ 0.0226), from 0.592 to 0.711 for cardiac death (p < 0.0001), and from 0.591 to 0.629 for major bleeding (p < 0.0001). Apixaban reduced rates of stroke, mortality, and bleeding regardless of the hs-TnT level. Conclusions Levels of hs-TnT are often elevated in patients with AF. The hs-TnT level is independently associated with an increased risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA2DS2VASc risk score. The benefits of apixaban as compared with warfarin are consistent regardless of the hs-TnT level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984) (J Am Coll Cardiol 2014;63:52–61) ª 2014 by the American College of Cardiology Foundation

We thank Gonzales et al for their valuable comments on the article on biomarkers from The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.1 The RE-LY trial included 18 113 patients with atrial fibrillation, cardiac biomarkers were analyzed from plasma samples obtained at randomization in 6189 of the participants. The results showed that both N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin I were strongly and independently related to thromboembolic outcomes regardless of clinical risk factors including heart failure. At randomization, all patients were classified as either having heart failure or not based on New York Heart Association class and on available information regarding previous measurements of left ventricular ejection fraction based on echocardiography, radionuclide, or angiogram assessments.2 NT-proBNP is a sensitive biomarker of left ventricular function, clinical heart failure, and a predictor of …

In the Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of apixaban was 5 mg twice daily; patients with at least 2 dose-reduction criteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL or higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban.To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria.Among 18 201 patients in the ARISTOTLE trial, 17 322 were included in this analysis. Annualized event rates of stroke or systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were evaluated. Interactions between the effects of apixaban vs warfarin and the presence of 1 or no dose-reduction criteria were assessed. The first patient was enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 2016.Analysis of major bleeding included events during study drug treatment. Analysis of stroke or systemic embolism was based on intention to treat.Of the patients with 1 or no dose-reduction criteria assigned to receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 dose-reduction criterion; these patients had higher rates of stroke or systemic embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with warfarin (n = 8657) on stroke or systemic embolism in patients with 1 dose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). Similarly, the benefit of 5 mg twice daily dose of apixaban compared with warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen for each dose-reduction criterion and across the spectrum of age, body weight, creatinine level, and creatinine clearance.Patients with atrial fibrillation and isolated advanced age, low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding but show consistent benefits with the 5 mg twice daily dose of apixaban vs warfarin compared with patients without these characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and appropriate for patients with only 1 dose-reduction criterion.clinicaltrials.gov Identifier: NCT00412984.

This study sought to assess the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels.Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases.In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors.Quartiles of NT-proBNP were: Q1, ≤363 ng/l; Q2, 364 to 713 ng/l; Q3, 714 to 1,250 ng/l; and Q4,1,250 ng/l. During 1.9 years, the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, an adjusted hazard ratio of 2.35 (95% confidence interval [CI]: 1.62 to 3.40; p 0.0001). Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, with an adjusted hazard ratio of 2.50 (95% CI: 1.81 to 3.45; p 0.0001). Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p = 0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p 0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level.NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984).

Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease.We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants.Among men, we found a positive association between height and glioma risk (≥ 190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (≥ 175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk.An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.

The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P(trend)

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Telomere biology is associated with cancer initiation and prognosis. Collected data suggest that blood cell telomere length (TL) can change over time, which may be related to development of common disorders, such as cardiovascular diseases and cancer. Recently, single nucleotide polymorphisms in the region of the human telomerase reverse transcriptase (hTERT) gene were associated with various malignancies, including glioma, lung and urinary bladder cancer, and telomerase RNA gene hTERC genotypes were recently linked to TL. In the present study a hypothetical association between identified genotypes in hTERT and hTERC genes and TL were investigated. We analyzed 21 polymorphisms, covering 90% of the genetic variance, in the hTERT gene, two genetic variants in hTERC, and relative TL(RTL) at average age 50 and 60 in 959 individuals with repeated blood samples. Mean RTL at age 60 was associated with four genetic variants of the hTERT gene (rs2736100, rs2853672, rs2853677, and rs2853676), two of which reported to be associated with cancer risk. Two alleles (rs12696304, rs16847897) near the hTERC gene were confirmed as also being associated with RTL at age 60. Our data suggest that hTERT and hTERC genotypes have an impact on TL of potential relevance and detectable first at higher ages, which gives us further insight to the complex regulation of TL.

Background— Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Methods and Results— Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS 2 and CHA 2 DS 2 -VASc risk scores. Patients were stratified based on troponin I concentrations: 1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17–3.39]; P =0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41–4.07]; P =0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05–6.29]; P P P Conclusions— Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Patient outcome from glioma may be influenced by germline variation. Considering the importance of DNA repair in cancer biology as well as in response to treatment, we studied the relationship between 1458 SNPs, which captured the majority of the common genetic variation in 136 DNA repair genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p < 0.05) associated with glioblastoma survival.

The leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family is comprised of three integral membrane proteins: LRIG1, LRIG2, and LRIG3. LRIG1 is a negative regulator of growth factor signaling. The expression and subcellular localization of LRIG proteins have prognostic implications in primary brain tumors, such as oligodendrogliomas and astrocytomas. The expression of LRIG proteins has not previously been studied in meningiomas. In this study, the expression of LRIG1, LRIG2, and LRIG3 was analyzed in 409 meningiomas by immunohistochemistry, and potential associations between LRIG protein expression and tumor grade, gender, progesterone receptor status, and estrogen receptor (ER) status were investigated. The LRIG proteins were most often expressed in the cytoplasm, though LRIG1 also showed prominent nuclear expression. Cytoplasmic expression of LRIG1 and LRIG2 correlated with histological subtypes of meningiomas (p = 0.038 and 0.013, respectively). Nuclear and cytoplasmic expression of LRIG1 was correlated with ER status (p = 0.003 and 0.004, respectively), as was cytoplasmic expression of LRIG2 (p = 0.006). This study is the first to examine the expression of LRIG proteins in meningiomas, and it shows a correlation between ER status and the expression of LRIG1 and LRIG2, which suggests a possible role for LRIG proteins in meningioma pathogenesis.

Today, the gut microbiota is considered a key organ in host nutritional metabolism and recent data have suggested that alterations in gut microbiota contribute to the development of type 2 diabetes and obesity. Accordingly, a whole range of beneficial effects relating to inflammation and gut health have been observed following administration of probiotics to both humans and different animal models. The objective of this study was to evaluate the metabolic effects of an oral probiotic supplement, Lactobacillus plantarum DSM 15313, to high-fat diet (HFD) fed C57BL/6J mice, a model of human obesity and early diabetes. The mice were fed the experimental diets for 20 weeks, after which the HFD had induced an insulin-resistant state in both groups compared to the start of the study. The increase in body weight during the HFD feeding was higher in the probiotic group than in the control group, however, there were no significant differences in body fat content. Fasting plasma glucose levels were lower in the group fed the probiotic supplement, whereas insulin and lipids were not different. Caecal levels of short-chain fatty acids were not significantly different between the groups. An oral glucose tolerance test showed that the group fed probiotics had a significantly lower insulin release compared to the control group, although the rate of glucose clearance was not different. Taken together, these data indicate that L. plantarum DSM 15313 has anti-diabetic properties when fed together with an HFD.

Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study.Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics.Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P = .0041), major bleedings (P = .0001), vascular death (P.0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P.0001). CRP was independently related to myocardial infarction (P = .0047), vascular death (P = .0004), and the composite thromboembolic outcome (P = .0001). When further adjusted for cardiac (troponin and N-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P.0001), major bleeding (P.0170) and the composite thromboembolic outcome (P.0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P = .0017) when adding IL-6 to the clinically used CHA2DS2-VASc risk score with net reclassification improvement of 28%.In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.

AIM: Clinical studies have suggested a role for dietary glycaemic index (GI) in body weight regulation and diabetes risk. Here, we investigated the long-term metabolic effects of low and high glycaemic diets using the C57BL/6J mouse model. METHODS: Female C57BL/6J mice were fed low or high glycaemic starch in either low-fat or medium-fat diets for 22 weeks. Oral and intravenous glucose tolerance tests were performed to investigate the effect of the experimental diets on glucose tolerance and insulin resistance. RESULTS: In this study, a high glycaemic diet resulted in impaired oral glucose tolerance compared to a low glycaemic diet. This effect was more pronounced in the group fed a medium-fat diet, suggesting that a lower dietary fat content ameliorates the negative effect of a high glycaemic diet. No effect on body weight or body fat content was observed in either a low-fat diet or a medium-fat diet. Static incubation of isolated islets did not show any differences in basal (3.3 mM glucose) or glucose-stimulated (8.6 and 16.7 mM glucose) insulin secretion between mice fed a low or high glycaemic diet. CONCLUSION: Together, our data suggest that the impaired glucose tolerance seen after a high glycaemic diet is not explained by altered β-cell function. (Less)

There is increasing recognition of familial propensity to glioma as a distinct clinical entity beyond a few rare syndromes; however its genetic basis is poorly understood. The role of p16(INK4A)/p14(ARF) and p53 mutations in sporadic glioma provides a strong rationale for investigating germline mutations in these genes as a cause of familial glioma. To survey the familial glioma phenotype and examine the contribution of germline mutation in p16(INK4A)/p14(ARF) and p53 to the disease we have analyzed a series of 101 index familial cases collected through the GLIOGENE Consortium (http://braintumor.epigenetic.org/). There was little evidence for within family correlations for tumour histology, suggesting generic susceptibility to glial tumors. We did not detect any functional mutations in p16(INK4A) or p14(ARF). One index case with glioblastoma multiforme (GBM) diagnosed at age 54 and had a family history comprised of a paternal aunt with GBM at age 55, carried the p53 R158H mutation, which is predicted to be functional and has previously been implicated as a cause of Li-Fraumeni syndrome. Our findings provide no evidence that p16(INK4A)/p14(ARF) and p53 mutations contribute significantly to familial glioma.

Sequencing of the human genome has recently been completed and mapping of the complete genomic variation is ongoing. During the last decade there has been a huge expansion of studies of genetic variants, both with respect to association studies of disease risk and for studies of genetic factors of prognosis and treatments response, i.e., pharmacogenomics. The use of genetics to predict a patient's risk of disease or treatment response is one step toward an improved personalised prevention and screening modality for the prevention of cancer and treatment selection. The technology and statistical methods for completing whole genome tagging of variants and genome wide association studies has developed rapidly over the last decade. After identifying the genetic loci with the strongest, statistical associations with disease risk, future studies will need to further characterise the genotype-phenotype relationship to provide a biological basis for prevention and treatment decisions according to genetic profile. This review discusses some of the general issues and problems of study design; we also discuss challenges in conducting valid association studies in rare cancers such as paediatric brain tumours, where there is support for genetic susceptibility but difficulties in assembling large sample sizes. The clinical interpretation and implementation of genetic association studies with respect to disease risk and treatment is not yet well defined and remains an important area of future research.

Book reviews

Amplified epidermal growth factor receptor (EGFR) signaling is supposed to contribute to clinical radiation resistance of glioblastoma multiforme (GBM). Therefore, inhibition of EGFR signaling pathways by the selective EGFR tyrosine kinase inhibitor, gefitinib (ZD1839, Iressa), may increase the therapeutic effects of radiotherapy. The effects of different schedules for administration of gefitinib on sensitivity to irradiation of the human glioma cell lines (251MG and SF-767), a rat glioma cell line (BT4C), and an immortalized rat brain endothelial cell line (RBE4) is reported. Differences in effects of the combined treatment on cell toxicity were determined by a fluorometric cytotoxicity assay, and nuclear DNA fragmentation was used for quantification of apoptosis. Pre-administration with gefitinib for 30 min prior to irradiation followed by continuous incubation with gefitinib significantly increased the cytotoxicity of SF-767, BT4C, and RBE4 cells. However, the human glioma cell line 251MG was protected against radiation-induced damage by this treatment schedule, at lower concentrations of gefitinib. Pre-administration with gefitinib for 24 h prior to irradiation without following incubation with gefitinib increased the cytotoxicity of SF-767 and BT4C cells. Post-irradiation treatment with gefitinib significantly increased the cytotoxicity in all cell lines except for 251MG. We demonstrated heterogeneity in the cytotoxic effects of gefitinib between cell lines. Response to gefitinib might be due to other mechanisms than through the EGF receptor as some of the cell lines showed sensitivity to gefitinib despite no or low expression of EGFR. This study also demonstrates the importance of timing of gefitinib administration when this agent is combined with irradiation.

BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

BACKGROUND: In the ARISTOTLE trial comparing apixaban with warfarin in pts with AF, apixaban 2.5mg was used in pts with 2 or more dose reduction (DR) criteria: age 80 years, creatinine 1.5mg/dL, weight 60kg. Pts assigned 2.5mg of apixaban vs. warfarin (n1⁄4831) had similar reductions in stroke/SE and major bleeding to pts assigned 5.0 mg of apixaban vs. warfarin (n1⁄417,370). METHODS: We compared pts assigned to apixaban 5.0mg or warfarin, with 1 of 3 DR criteria with pts with 0 of 3 criteria. Stroke/SE and major bleeding rates, hazard ratios and 95% CIs were evaluated, and interactions between treatment and the presence of 1 vs. 0 DR criteria were determined. RESULTS: Among pts assigned 5.0mg of apixaban or warfarin, 4046 (23%) had one DR criteria. These pts were older (77 vs. 68 years), of lighter weight (86 vs . 70 kg), and had worse renal function (creatinine 1.00 vs. 1.07 mL/min) than pts with no DR criteria. Pts with one DR criteria had more stroke/SE and major bleeding but had similar benefits of apixaban vs. warfarin on stroke/SE (p1⁄40.41) and major bleeding (p1⁄40.65). Similar patterns were seen for individual DR criteria. CONCLUSION: Pts with isolated advanced age ( 80 years), low body weight ( 60kg), or renal dysfunction (Cr 1.5mg/dL) had slightly more stroke/SE and significantly more major bleeding but similar benefits with apixaban 5.0mg BID compared with warfarin to pts with none of these characteristics. Apixaban 5.0mg BID is a safe and efficacious dose for these pts. BMS/Pfizer

Chromatographic sorbents used within the purification of peptide or protein based active pharmaceutical ingredients (APIs) are commonly subjected to caustic regeneration procedures, so-called CIP treatments. While polymeric materials remain unaffected by this treatment, silica-based sorbents are at an intrinsic risk of dissolution under high pH conditions, such as, e.g. 0.1M NaOH. It is common misconception that silica-based materials simply cannot be subjected to alkaline conditions above pH 9. Moreover, most studies covering the chemical stability of HPLC sorbents above pH 9 have been limited to the chromatographic conditions used for the separations themselves. Such studies have used buffered mobile phases up to pH 11 or 12. Very little focus has been put on the stability of the stationary phases when subjected to shorter but harsher pH conditions required for regeneration purposes, such as 0.1M NaOH (pH 13). Knowledge about the amount of so-called leachables, degradation products originating from the stationary phase, is of growing importance for the registration of pharmaceuticals for human use and is addressed in this work. This study compares the chemical stability of different commercially available reversed phase silica materials (C18) that are used in industrial scale preparative HPLC. The silica materials were subjected to NaOH regeneration conditions and it is shown that some materials are able to withstand 0.1M NaOH conditions without significant harm. It is demonstrated that contaminants present in the effluent in the range of 10-50 microg/mL can lead to significant contamination of API product fraction.

Caveolae, plasma membrane invaginations particularly abundant in adipocytes, have been suggested to be important in organizing insulin signalling. Insulin-induced activation of the membrane bound cAMP degrading enzyme, phosphodiesterase 3B (PDE3B) is a key step in insulin-mediated inhibition of lipolysis and is also involved in the regulation of insulin-mediated glucose uptake and lipogenesis in adipocytes. The aim of this work was to evaluate whether PDE3B is associated with caveolae. Subcellular fractionation of primary rat and mouse adipocytes demonstrated the presence of PDE3B in endoplasmic reticulum and plasma membrane fractions. The plasma membrane PDE3B was further analyzed by detergent treatment at 4 degrees C, which did not solubilize PDE3B, indicating an association of PDE3B with lipid rafts. Detergent-treated plasma membranes were studied using Superose-6 chromatography which demonstrated co-elution of PDE3B with caveolae and lipid raft markers (caveolin-1, flotillin-1 and cholesterol) at a Mw of > 4000 kDa. On sucrose density gradient centrifugation of sonicated plasma membranes, a method known to enrich caveolae, PDE3B co-migrated with the caveolae markers. Immunoprecipitation of caveolin-1 using anti caveolin-1 antibodies co-immunoprecipitated PDE3B and immunoprecipitation of flag-PDE3B from adipocytes infected with a flag-PDE3B adenovirus resulted in co-immunoprecipitation of caveolin-1. Studies on adipocytes with disrupted caveolae, using either caveolin-1 deficient mice or treatment of adipocytes with methyl-beta-cyclodextrin, reduced the membrane associated PDE3B activity. Furthermore, inhibition of PDE3 in primary rat adipocytes resulted in reduced insulin stimulated glucose transporter-4 translocation to caveolae, isolated by immunoprecipitation using caveolin-1 antibodies. Thus, PDE3B, a key enzyme in insulin signalling, appears to be associated with caveolae in adipocytes and this localization seems to be functionally important. (c) 2006 Elsevier Inc. All rights reserved.

Recent studies have demonstrated that AMP-activated protein kinase (AMPK) in the hypothalamus is involved in the regulation of food intake. Because exercise is known to influence appetite and cause substrate depletion, it may also influence AMPK in the hypothalamus. Male rats that either rested or ran for 30 or 60 min on a treadmill (22 m/min, 10% slope) were sacrificed immediately after exercise or after 60 min recovery either in the fasted state or after oral gavage with glucose (3g/kg body weight). Exercise decreased muscle and liver glycogen substantially. Hypothalamic total or alpha2-associated AMPK activity and phosphorylation state of the AMPK substrate acetyl-CoA carboxylase were not changed significantly immediately following treadmill running or during fed or fasted recovery. Plasma ghrelin increased (P0.05) by 40% during exercise whereas the concentration of PYY was unchanged. In recovery, glucose feeding increased plasma glucose and insulin concentrations whereas ghrelin and PYY decreased to (ghrelin) or below (PPY) resting levels. It is concluded that 1h of strenuous exercise in rats does not elicit significant changes in hypothalamic AMPK activity despite an increase in plasma ghrelin. Thus, changes in energy metabolism during or after exercise are likely not coordinated by changes in hypothalamic AMPK activity.

Eukaryotic cells have complex membranes that consist of a number of lipid and protein species. The majority of the lipids present are phospholipids, with glycosphingolipids being present at much lower levels, representing only a few percent of total cellular lipid content. Glycosphingolipids are not required for membrane integrity (Ichikawa, Nakajo et al. 1994) but function in conjunction with cholesterol in the formation of membrane microdomains or rafts that facilitate certain signalling events in cells (Kobayashi and Hirabayashi 2000; Galbiati, Razani et al. 2001; Munro 2003). They have been implicated to play a role in a number of biological processes (Bektas and Spiegel 2004; Zhang and Kiechle 2004) and are required for embryogenesis (Yamashita, Wada et al. 1999). In this review we will focus on the sub-family of glycosphingolipids that have glucosylceramide (Ichikawa and Hirabayashi 1998) as their core structure, the glucosphingolipids (GSLs).

Global regulatory circuits together with more specific local regulators play a notable role when cells are adapting to environmental changes. Lactococcus lactis is a lactic acid bacterium abundant in nature fermenting most mono- and disaccharides. Comparative genomics analysis of the operons encoding the proteins and enzymes crucial for catabolism of lactose, maltose and threhalose revealed an obvious unity in operon organisation. The local regulator of each operon was located in a divergent transcriptional direction to the rest of the operon including the transport protein-encoding genes. Furthermore, in all three operons a catabolite responsive element (CRE) site was detected inbetween the gene encoding the local regulator and one of the genes encoding ! sugar transport protein. It is evident that regardless of type of transport system and catabolic enzymes acting upon lactose, maltose and trehalose, respectively, Lc. lactis shows unity in both operon organisation and regulation of these catabolic operons. This knowledge was further extended to other catabolic operons in Lc. lactis and the two related bacteria Lactobacillus plantarum and Listeria monocytogenes. Thirty-nine catabolic operons responsible for degradation of sugars and sugar alcohols in Lc. lactis, Lb. plantarum and L. monocytogenes were investigated and the majority of those possessed the same organisation as the lactose, maltose and trehalose operons of Lc. lactis. Though, the frequency of CRE sites and their location varied among the bacteria. Both Lc. lactis and Lb. plantarum showed CRE sites in direct proximity to genes coding for proteins responsible for sugar uptake. However, in, L. monocytogenes CRE sites were not frequently found and not in the vicinity of genes encoding transport proteins, suggesting a more local mode of regulation of the catabolic operons found and/or the use of inducer control in this bacterium. &COPY; 2004 Elsevier GrnbH. All rights reserved.

Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.

A three-fold increased risk for glioma among first degree relatives (FDR) to glioma patients has previously been shown. This study compared familial cases with sporadic controls of glioma to see if phenotypic differences could be detected. Different pathways to tumour growth and progression were investigated including cell cycle regulating genes (p53) and growth factors (epidermal growth factor receptor, EGFR), angiogenesis (vascular endothelial growth factor, VEGF and microvessel density, MVD), pathways of detoxification (glutathione-S-transferase, GST pi) and multidrug resistance (P-glycoprotein, Pgp).Thirty-seven cases of familial gliomas, identified in a population-based study, were compared to 58 sporadic glioma controls chosen with a negative family history of glioma. The immunohistochemistry was performed with standard procedures using the LABSA kit (Zymed lab).Familial cases had significantly more frequent p53- and Pgp-negative tumours, also when correcting for age, sex and histopathology. However, Pgp was no longer significant after correcting for p53 status indicating a correlation between Pgp and p53. A significant difference between VEGF-negative to VEGF-positive tumours (low- or high-grade) was shown, but it was no longer significant when correcting for p53 status.Our study investigated phenotypic differences of familial glioma compared to sporadic control. Our finding of a distinct pattern of increased p53- and Pgp-negativity among cases warrants further investigation.

The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

Rare inherited syndromes that to some extent explain familial glioma include Turcot's syndrome, Li-Fraumeni syndrome and neurofibromatosis types I and II. The majority of families with glioma do not meet the clinical criteria for any of these syndromes. In order to study the genetic origin of familial glioma, tumour DNA (n = 35) or blood samples (n = 8) were collected from 25 families. The glioma tumours were tested for microsatellite instability (MSI) with two markers, BAT25 and BAT26, since glioma is associated with hereditary non-polyposis colon cancer (HNPCC) in Turcot's syndrome. Furthermore, p53 was screened from blood DNA (exons 2-11) with temporal temperature gradient electrophoresis (TTGE) since germline mutations in p53 are seen in Li-Fraumeni syndrome. In gliomas, there is a wide variety of somatic mutations, such as, for instance, in p53, the epidermal growth factor receptor (EGFR) and p16. The tumour suppressor gene PTEN is also often somatically mutated in glioma, therefore it is attractive as a candidate gene for germline mutations in familial glioma. Blood DNA was directly sequenced for mutations in PTEN exons 1-9. The analysis showed that no mutations were found in either of the studied tumour suppressor genes, and no MSI-positive tumours were found. A common polymorphism in p53 at codon 72 (arginine/proline) was found in 6/8 of the patients. Apparently, mutation in the tested tumour suppressor genes or DNA mismatch repair genes does not explain the familial glioma observed in these families.

The glycosphingolipid (GSL) lysosomal storage diseases are caused by mutations in the genes encoding the glycohydrolases that catabolize GSLs within lysosomes. In these diseases the substrate for the defective enzyme accumulates in the lysosome and the stored GSL leads to cellular dysfunction and disease. The diseases frequently have a progressive neurodegenerative course. The therapeutic options for treating these diseases are relatively limited, and for the majority there are no effective therapies. The problem is further compounded by difficulties in delivering therapeutic agents to the brain. Most research effort to date has focused on strategies for augmenting enzyme levels to compensate for the underlying defect. These include bone marrow transplantation (BMT), enzyme replacement and gene therapy. An alternative strategy that we have been exploring is substrate deprivation. This approach aims to balance the rate of GSL synthesis with the impaired rate of GSL breakdown. The imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits the first step in GSL biosynthesis and has been used to evaluate this approach. Studies in an asymptomatic mouse model of Tay-Sachs disease have shown that substrate deprivation prevents GSL storage in the CNS. In a severe neurodegenerative mouse model of Sandhoff disease, substrate deprivation delayed the onset of symptoms and disease progression and significantly increased life expectancy. Combining NB-DNJ and BMT was found to be synergistic in the Sandhoff mouse model. A clinical trial in type I Gaucher disease has been undertaken and has shown beneficial effects. Efficacy was demonstrated on the basis of significant decreases in liver and spleen volumes, gradual but significant improvement in haematological parameters and disease activity markers, together with diminished GSL biosynthesis and storage as determined by independent biochemical assays. Further trials in type I Gaucher disease are in progress; studies are planned in patients with GSL storage in the CNS.

Strips of rat soleus muscle were incubated in media containing a superoxide generating system and/or the nitric oxide donor sodium nitroprusside (SNP) before the maximal catalytic activities of aconitase, citrate synthase, and oxoglutarate dehydrogenase were measured. The maximal activities of aconitase and oxoglutarate dehydrogenase were both decreased by 25-30% by superoxide anions; however, only the maximal activity of aconitase was decreased, by approximately 50%, by incubation of muscles with SNP. Furthermore, when both superoxide and NO were present in the medium, aconitase activity was decreased by 70%. The maximal activity of citrate synthase was not affected by any of the treatments. This is the first time that superoxide anions or NO has been shown to inactivate aconitase and oxoglutarate dehydrogenase in skeletal muscle. It is suggested that these effects may be responsible for some alterations in skeletal muscle metabolism, and these possibilities are discussed.

ADMA and SDMA predict outcomes in patients with chronic atrial fibrillation : an ARISTOTLE substudy

Background Rye products have previously been shown to induce comparatively low post-prandial insulin responses; irrespectively of their glycaemic indices (GI). However, the mechanism behind this lowered insulin demand remains unknown. An improved insulin economy might contribute to the benefits seen in epidemiological studies with whole grain diets on metabolic risk factors and weight regulation. The objective of this study was to explore the mechanism for a reduced post-prandial insulin demand with rye products. Methods 12 healthy subjects were given flour based rye products made from endosperm, whole grain or bran, produced with different methods (baking, simulated sour-dough baking and boiling) as breakfasts in random order in a cross-over design. White wheat bread (WWB) was used as a reference. Blood glucose, serum insulin, plasma ghrelin and subjective satiety were measured during 180 minutes. To evaluate the course of post-meal glycaemia, a measure of the glycaemic profile (GP) was introduced defined as the duration for the incremental post-prandial blood glucose response divided with the blood glucose incremental peak (min/mM). Results The study shows that whole grain rye breads and endosperm rye products induced significantly (p < 0.05) lower insulinaemic indices (II's) than WWB. Rye bran bread (RBB) produced significantly higher II compared with all the other rye products. Furthermore, the acute insulin response showed better correlations with the GP than with the GI of the products. The endosperm rye bread and the whole grain rye bread with lactic acid induced a significantly higher GP than RBB, WWB, white wheat- and whole grain rye porridge, respectively. A low insulin incremental peak was associated with less severe late post-prandial hypoglycaemia (r = 0.38, p < 0.001), and hypoglycaemia was negatively correlated to subjective satiety at 180 min (r = -0.28, p < 0.05). A low insulin incremental peak was also associated with a milder recovery of plasma ghrelin in the late post-prandial phase (180 min, r = 0.34, p < 0.01). Conclusion Our study shows that endosperm and wholegrain rye products induce low acute insulinaemic responses and improved glycaemic profiles. The results also suggest that the rye products possess beneficial appetite regulating properties. Further studies are needed to identify the unknown property or bioactive component(s) responsible for these beneficial metabolic features of rye.

Background Maltose metabolism is initiated by an ATP-dependent permease system in Lactococcus lactis. The subsequent degradation of intracellular maltose is performed by the concerted action of Pi-dependent maltose phosphorylase and β-phosphoglucomutase. In some Gram-positive bacteria, maltose metabolism is regulated by a maltose operon regulator (MalR), belonging to the LacI-GalR family of transcriptional regulators. A gene presumed to encode MalR has been found directly downstream the maltose phosphorylase-encoding gene, malP in L. lactis. The purpose of this study was to investigate the physiological role of the MalR protein in maltose metabolism in L. lactis.

Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13–2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09–2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00–1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2. Electronic supplementary material The online version of this article (doi:10.1007/s13277-015-4742-y) contains supplementary material, which is available to authorized users.

This book investigates the contemporary processes involved in the telling and hearing of narratives of sexual violence and rape in a number of public arenas: mass media, social media, the courts and the legislative apparatus.

One obstacle to developing new treatments for glioma is the generally poor understanding of glioma aetiology. The only generally accepted environmental risk factor or glioma is ionizing radiation. Glioma aetiology has also been shown to contain a genetic component, in part through observations that individuals in families with a history of glioma have an elevated risk of developing glioma themselves. The genetic component in glioma aetiology has been further substantiated through genome wide association studies (GWAS). These studies have identified associations between a number of common genetic variants and an increased glioma risk. However, the studies have all been of case-control design (i.e. including cases at diagnosis), and as such they presumably suffer from a degree of survival bias. Survival bias risks being introduced in a study when rapidly fatal cases are not included. This is an inherent risk of case-control designs, which is particularly pronounced when studying a disease with very poor prognosis, such as glioma. Ultimately, survival bias may result in erroneous conclusions, as it is impossible to separate associations with prognosis from associations with risk of disease. To accurately confirm previously identified glioma risk variants, and ascertain whether they are associated with risk or with prolonged survival, we investigated these variants in a set of pre-diagnostic serum samples (594 cases and 591 matched controls). Analyses of population based, pre-diagnostic samples eliminates the risk of survival bias, and enables distinction between genetic variants associated with glioma risk (i.e. aetiology) and genetic variants associated with prognosis. The serum samples were acquired through The Janus Serum Bank, a Norwegian population based biobank reserved for cancer research. Variant detection was achieved by means of cycling temperature capillary electrophoresis. Our investigation confirmed the association with glioma risk for the investigated variants within five genomic regions; 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). This is indicative of these variants being truly associated with glioma risk, and thus may impact gliomagenesis. However, previously identified risk variants within the 5p15.33 (TERT) and 7p11.2 (EGFR) could not be positively confirmed by this study. The lack of positive confirmation raises the question whether EGFR and TERT genetic variants are linked with prolonged survival, rather than with glioma aetiology.