15 research outputs found
Beyond the biosynthetic gene cluster paradigm: Genome-wide coexpression networks connect clustered and unclustered transcription factors to secondary metabolic pathways
Fungal secondary metabolites are widely used as therapeutics and are vital components of drug discovery programs. A major challenge hindering discovery of novel secondary metabolites is that the underlying pathways involved in their biosynthesis are transcriptionally silent under typical laboratory growth conditions, making it difficult to identify the transcriptional networks that they are embedded in. Furthermore, while the genes participating in secondary metabolic pathways are typically found in contiguous clusters on the genome, known as biosynthetic gene clusters (BGCs), this is not always the case, especially for global and pathway-specific regulators of pathways’ activities. To address these challenges, we used 283 genome-wide gene expression data sets of the ascomycete cell factory Aspergillus niger generated during growth under 155 different conditions to construct two gene coexpression networks based on Spearman’s correlation coefficients (SCCs) and on mutual rank-transformed Pearson’s correlation coefficients (MR-PCCs). By mining these networks, we predicted six transcription factors, named MjkA to MjkF, to regulate secondary metabolism in A. niger. Overexpression of each transcription factor using the Tet-On cassette modulated the production of multiple secondary metabolites. We found that the SCC and MR-PCC approaches complemented each other, enabling the delineation of putative global (SCC) and pathway-specific (MR-PCC) transcription factors. These results highlight the potential of coexpression network approaches to identify and activate fungal secondary metabolic pathways and their products. More broadly, we argue that drug discovery programs in fungi should move beyond the BGC paradigm and focus on understanding the global regulatory networks in which secondary metabolic pathways are embedded.DFG, 404295023, Etablierung eines innovativen Ko-Kultivierungssystems zur Hochdurchsatzidentifizierung von antimikrobiellen WirkstoffenEC/FP7/607332/EU/Quantitative Biology for Fungal Secondary Metabolite Producers/QUANTFUN
The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2
Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701
Infection with Hepatitis B and C Viruses and Risk of Lymphoid Malignancies in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Background: Case-control studies suggested a moderate, but consistent,
association of hepatitis C virus (HCV) infection with lymphoid tissue
malignancies, especially non-Hodgkin lymphoma (NHL). More limited data
suggested that hepatitis B virus (HBV) infection might also be
associated with NHL. However, prospective studies on the topic are few.
Methods: A nested case-control study was conducted in eight countries
participating in the EPIC prospective study. Seven hundred thirty-nine
incident cases of NHL, 238 multiple myeloma (MM), and 46 Hodgkin
lymphoma (HL) were matched with 2,028 controls. Seropositivity to
anti-HCV, anti-HBc, and HBsAg was evaluated and conditional logistic
regression was used to estimate odds ratios (OR) and corresponding 95%
confidence intervals (CI) for NHL, MM, or HL, and their combination.
Results: Anti-HCV seropositivity among controls in different countries
ranged from 0% to 5.3%; HBsAg from 0% to 2.7%; and anti-HBc from
1.9% to 45.9%. Similar nonsignificant associations were found with
seropositivity to HBsAg forNHL (OR = 1.78; 95% CI: 0.78-4.04), MM(OR =
4.00; 95% CI: 1.00-16.0), and HL(OR = 2.00; 95% CI: 0.13-32.0). The
association between HBsAg and the combination of NHL, MM, and HL(OR =
2.21; 95% CI: 1.124.33) was similar for cancer diagnosed less than 3
and 3 or more years after blood collection. No significant association
was found between anti-HCV and NHL, MM, or HL risk, but the
corresponding CIs were very broad.
Conclusions: Chronic HBV infection may increase the risk of lymphoid
malignancies among healthy European volunteers.
Impact: Treatment directed at control of HBV infection should be
evaluated in HBsAg-seropositive patients with lymphoid tissue
malignancies. Cancer Epidemiol Biomarkers Prev; 20(1); 208-14. (C) 2011
AACR
Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort
General obesity has been positively associated with risk of liver and probably with biliary tract cancer, but little is known about abdominal obesity or weight gain during adulthood. We used multivariable Cox proportional hazard models to investigate associations between weight, body mass index, waist and hip circumference, waist-to-hip and waist-to-height ratio (WHtR), weight change during adulthood and risk of hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic bile duct system cancer [EBDSC including gallbladder cancer (GBC)] among 359,525 men and women in the European Prospective Investigation into Cancer and Nutrition study. Hepatitis B and C virus status was measured in a nested casecontrol subset. During a mean follow-up of 8.6 years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC, including 76 cases of GBC, occurred. All anthropometric measures were positively associated with risk of HCC and GBC. WHtR showed the strongest association with HCC [relative risk (RR) comparing extreme tertiles 3.51, 95% confidence interval (95% CI): 2.095.87; ptrend < 0.0001] and with GBC (RR: 1.56, 95% CI: 1.122.16 for an increment of one unit in WHtR). Weight gain during adulthood was also positively associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI: 1.494.13; <0.001). No statistically significant association was observed between obesity and risk of IBDC and EBDSC. Our results provide evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC. Our findings support public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCC and GBC prevention in Western populations
Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST)
Epigenetic events have emerged as key mechanisms in the regulation of
critical biological processes and in the development of a wide variety
of human malignancies, including gastric cancer (GC), however precise
gene targets of aberrant DNA methylation in GC remain largely unknown.
Here, we have combined pyrosequencing-based quantitative analysis of DNA
methylation in 98 GC cases and 64 controls nested within the European
Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in
cancer tissue and non-tumorigenic adjacent tissue of an independent
series of GC samples. A panel of 10 cancer-associated genes (CHRNA3,
DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and
LINE-1 repetitive elements were included in the analysis and their
association with clinicopathological characteristics (sex, age at
diagnosis, anatomical sub-site, histological sub-type) was examined.
Three out of the 10 genes analyzed exhibited a marked hypermethylation,
whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation,
in gastric tumors. Among differentially methylated genes, we identified
new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in
GC, suggesting that epigenetic deregulation of these genes and their
corresponding cellular pathways may promote the development and
progression of GC. We also found that global demethylation of tumor cell
genomes occurs in GC, consistent with the notion that abnormal
hypermethylation of specific genes occurs concomitantly with genome-wide
hypomethylation. Age and gender had no significant influence on
methylation states, but an association was observed between LINE-1 and
MLH1 methylation levels with histological subtype and anatomical
sub-site. This study identifies aberrant methylation patters in specific
genes in GC thus providing information that could be exploited as novel
biomarkers in clinics and molecular epidemiology of GC. (C) 2011
Elsevier Ireland Ltd. All rights reserved
Hepatocellular Carcinoma Risk Factors and Disease Burden in a European Cohort: A Nested Case-Control Study
Background To date, no attempt has been made to systematically determine
the apportionment of the hepatocellular carcinoma burden in Europe or
North America among established risk factors.
Methods Using data collected from 1992 to 2006, which included 4 409 809
person-years in the European Prospective Investigation into Cancer and
nutrition (EPIC), we identified 125 case patients with hepatocellular
carcinoma, of whom 115 were matched to 229 control subjects. We
calculated odds ratios (ORs) for the association of documented risk
factors for hepatocellular carcinoma with incidence of this disease and
estimated their importance in this European cohort.
Results Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection (OR = 9.10, 95% confidence interval [CI] = 2.10 to 39.50
and OR = 13.36, 95% CI = 4.11 to 43.45, respectively), obesity (OR =
2.13, 95% CI = 1.06 to 4.29), former or current smoking (OR = 1.98,
95% CI = 0.90 to 4.39 and OR = 4.55, 95% CI = 1.90 to 10.91,
respectively), and heavy alcohol intake (OR = 1.77, 95% CI = 0.73 to
4.27) were associated with hepatocellular carcinoma. Smoking contributed
to almost half of all hepatocellular carcinomas (47.6%), whereas 13.2%
and 20.9% were attributable to chronic HBV and HCV infection,
respectively. Obesity and heavy alcohol intake contributed 16.1% and
10.2%, respectively. Almost two-thirds (65.7%, 95% CI = 50.6% to
79.3%) of hepatocellular carcinomas can be accounted for by exposure to
at least one of these documented risk factors.
Conclusions Smoking contributed to more hepatocellular carcinomas in
this Europe-wide cohort than chronic HBV and HCV infections. Heavy
alcohol consumption and obesity also contributed to sizeable fractions
of this disease burden. These contributions may be underestimates
because EPIC volunteers are likely to be more health conscious than the
general population
Plasma phospholipid fatty acid concentrations and risk of gastric adenocarcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST)
Background: Epidemiologic data suggest that diet is a risk factor in the
etiology of gastric cancer. However, the role of dietary fatty acids, a
modifiable risk factor, remains relatively unexplored.
Objective: The objective of this study was to determine the association
of plasma phospholipid fatty acid concentrations, as biomarkers of
exogenous and endogenously derived fatty acids, with the risk of gastric
adenocarcinoma in a case-control study nested within the European
Prospective Investigation into Cancer and Nutrition-Europe Gastric
Cancer (EPIC-EURGAST).
Design: Fatty acids were measured by gas chromatography in
pre-diagnostic plasma phospholipids from 238 cases matched to 626
controls by age, sex, study center, and date of blood donation.
Conditional logistic regression models adjusted for Helicobacter pylori
infection status, BMI, smoking, physical activity, education, and energy
intake were used to estimate relative cancer risks.
Results: Positive risk associations for gastric cancer were observed in
the highest compared with the lowest quartiles of plasma oleic acid (OR:
1.72; 95% CI: 1.01, 2.94), di-homo-gamma-linolenic acid (OR: 1.92; 95%
CI: 1.10, 3.35), alpha-linolenic acid (OR: 3.20; 95% CI: 1.70, 6.06),
and the ratio of MUFAs to saturated fatty acids, as an indicator of
stearoyl-CoA desaturase-1 enzyme activity (OR: 1.40; 95% CI: 0.81,
2.43). An inverse risk association was observed with the ratio of
linoleic to alpha-linolenic acid (OR: 0.37; 95% CI: 0.20, 0.66).
Conclusion: These data suggest that a specific prediagnostic plasma
phospholipid fatty acid profile, characterized mainly by high
concentrations of oleic acid, alpha-linolenic acid, and
di-homo-gamma-linolenic acid, which presumably reflect both a complex
dietary pattern and altered fatty acid metabolism, may be related to
increased gastric cancer risk. Am J Clin Nutr 2011;94:1304-13
Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study
Background: The Mediterranean dietary pattern is believed to protect
against cancer, although evidence from cohort studies that have examined
particular cancer sites is limited.
Objective: We aimed to explore the association between adherence to a
relative Mediterranean diet (rMED) and incident gastric adenocarcinoma
(GC) within the European Prospective Investigation into Cancer and
Nutrition study.
Design: The study included 485,044 subjects (144,577 men) aged 35-70 y
from 10 European countries. At recruitment, dietary and lifestyle
information was collected. An 18-unit rMED score, incorporating 9 key
components of the Mediterranean diet, was used to estimate rMED
adherence. The association between rMED and GC with respect to anatomic
location (cardia and noncardia) and histologic types (diffuse and
intestinal) was investigated. A calibration study in a subsample was
used to control for dietary measurement error.
Results: After a mean follow-up of 8.9 y, 449 validated incident GC
cases were identified and used in the analysis. After stratification by
center and age and adjustment for recognized cancer risk factors, high
compared with low rMED adherence was associated with a significant
reduction in GC risk (hazard ratio: 0.67; 95% CI: 0.47, 0.94). A 1-unit
increase in the rMED score was associated with a decreased risk of GC of
5% (95% CI: 0.91, 0.99). There was no evidence of heterogeneity
between different anatomic locations or histologic types. The calibrated
results showed similar trends (overall hazard ratio for GC: 0.93; 95%
CI: 0.89, 0.99).
Conclusion: Greater adherence to an rMED is associated with a
significant reduction in the risk of incident GC. Am J Clin Nutr
2010:91:381-90
Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort
General obesity has been positively associated with risk of liver and
probably with biliary tract cancer, but little is known about abdominal
obesity or weight gain during adulthood. We used multivariable Cox
proportional hazard models to investigate associations between weight,
body mass index, waist and hip circumference, waist-to-hip and
waist-to-height ratio (WHtR), weight change during adulthood and risk of
hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic
bile duct system cancer [EBDSC including gallbladder cancer (GBC)]
among 359,525 men and women in the European Prospective Investigation
into Cancer and Nutrition study. Hepatitis B and C virus status was
measured in a nested casecontrol subset. During a mean follow-up of 8.6
years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC,
including 76 cases of GBC, occurred. All anthropometric measures were
positively associated with risk of HCC and GBC. WHtR showed the
strongest association with HCC [relative risk (RR) comparing extreme
tertiles 3.51, 95% confidence interval (95% CI): 2.095.87; ptrend <
0.0001] and with GBC (RR: 1.56, 95% CI: 1.122.16 for an increment of
one unit in WHtR). Weight gain during adulthood was also positively
associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI:
1.494.13; <0.001). No statistically significant association was observed
between obesity and risk of IBDC and EBDSC. Our results provide evidence
of an association between obesity, particularly abdominal obesity, and
risk of HCC and GBC. Our findings support public health recommendations
to reduce the prevalence of obesity and weight gain in adulthood for HCC
and GBC prevention in Western populations
Alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
Background: Gastric cancer (GC) is the second leading cause of cancer
death worldwide. The association between alcohol consumption and GC has
been investigated in numerous epidemiologic studies with inconsistent
results.
Objective: We evaluated the association between alcohol consumption and
GC risk.
Design: We conducted a prospective analysis in the European Prospective
Investigation into Cancer and Nutrition (EPIC) cohort, which included
444 cases of first primary gastric adenocarcinoma. HRs and 95% CIs for
GC were estimated by using multivariable Cox proportional hazards
regression for consumption of pure ethanol in grams per day, with
stratification by smoking status, anatomic subsite (cardia, noncardia),
and histologic subtype (diffuse, intestinal). In a subset of
participants, results were further adjusted for baseline Helicobacter
pylori serostatus.
Results: Heavy (compared with very light) alcohol consumption (>= 60
compared with 0.1-4.9 g/d) at baseline was positively associated with GC
risk (HR: 1.65; 95% CI: 1.06, 2.58), whereas lower consumption amounts
(<60 g/d) were not. When we analyzed GC risk by type of alcoholic
beverage, there was a positive association for beer (>= 30 g/d; HR:
1.75; 95% CI: 1.13, 2.73) but not for wine or liquor. Associations were
primarily observed at the highest amounts of drinking in men and limited
to noncardia subsite and intestinal histology; no statistically
significant linear dose-response trends with GC risk were observed.
Conclusion: Heavy (but not light or moderate) consumption of alcohol at
baseline (mainly from beer) is associated with intestinal-type noncardia
GC risk in men from the EPIC cohort. Am J Clin Nutr 2011;94:1266-75