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Find video protocols related to scientific articles indexed in Pubmed.
Mutational studies on resurrected ancestral proteins reveal conservation of site-specific amino acid preferences throughout evolutionary history.
Mol. Biol. Evol.
PUBLISHED: 11-14-2014
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Local protein interactions ("molecular context" effects) dictate amino acid replacements and can be described in terms of site-specific, energetic preferences for any different amino acid. It has been recently debated whether these preferences remain approximately constant during evolution or whether, due to co-evolution of sites, they change strongly. Such research highlights an unresolved and fundamental issue with far-reaching implications for phylogenetic analysis and molecular evolution modeling. Here, we take advantage of the recent availability of phenotypically supported laboratory resurrections of Precambrian thioredoxins and ?-lactamases to experimentally address the change of site-specific amino acid preferences over long geological timescales. Extensive mutational analyses support the notion that evolutionary adjustment to a new amino acid may occur, but to a large extent this is insufficient to erase the primitive preference for amino acid replacements. Generally, site-specific amino acid preferences appear to remain conserved throughout evolutionary history despite local sequence divergence. We show such preference conservation to be readily understandable in molecular terms and we provide crystallographic evidence for an intriguing structural-switch mechanism: energetic preference for an ancestral amino acid in a modern protein can be linked to re-organization upon mutation to the ancestral local structure around the mutated site. Lastly, we point out that site-specific preference conservation naturally leads to one plausible evolutionary explanation for the existence of intragenic global suppressor mutations.
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Investigating a potential biological treatment to prevent pathological fractures caused by unicameral bone cysts in children under 8 years.
Injury
PUBLISHED: 11-12-2014
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There is no consensus on when and how to treat unicameral bone cysts (UBCs), partly because of a lack of knowledge of the aetiology.
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Microtubule stabilization with paclitaxel does not protect against infarction in isolated rat hearts.
Exp. Physiol.
PUBLISHED: 11-09-2014
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Microtubules play a major role in transmitting mechanical forces within the myocardium, and in maintaining organelle function. However, this intracellular network is disrupted during myocardial ischemia/reperfusion. We assessed the effects of prevention of microtubule disruption with paclitaxel on ischemia/reperfusion injury in isolated rat cardiomyocytes and hearts. Isolated rat cardiomyocytes were submitted to normoxia (1h), or 45 min of simulated ischemia (SI) (pH 6.4, 0% O2, 37ºC) and reoxygenation, without or with treatment with the microtubule stabilizer paclitaxel (10(-5) M) or the inhibitor of microtubule polymerization colchicine (5·10(-6) M). SI leads to microtubule disruption before the onset of ischemic contracture. Paclitaxel attenuated both microtubule disruption and the incidence of hypercontracture, whereas treatment with colchicine mimicked the effects of SI/reoxygenation. In isolated normoxic rat hearts, treatment with paclitaxel induced concentration-dependent decreases in heart rate and left ventricular developed pressure, and increases in perfusion pressure. Despite protection against hypercontracture, paclitaxel pretreatment did not modify infarct size (60.37±2.27% in controls vs. 58.75±10.25, 55.44±10.32 and 50.06±10.14% after treatment with 10(-6), 3·10(-6) and 10(-5) M of paclitaxel) after 60 min of global ischemia and reperfusion in isolated rat hearts. Lack of protection correlates with a higher increase in cytosolic calcium levels during SI in cardiomyocytes treated with paclitaxel (2.32±0.15 vs. 1.13±0.16 a.u. in the presence or absence of paclitaxel 10(-6) M, p<0.05), but not with changes in aortic reactivity. In conclusion, microtubule stabilization with paclitaxel reduces hypercontracture in isolated rat cardiomyocytes but does not protect against infarction in isolated rat hearts. This article is protected by copyright. All rights reserved.
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Silencing of OPR3 in tomato reveals the role of OPDA in callose deposition during activation of defense responses against Botrytis cinerea.
Plant J.
PUBLISHED: 11-06-2014
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OPDA likely plays signaling roles in plant defense that do not depend on its further conversion to the phytohormone jasmonic acid. To elucidate the role of OPDA in tomato plant defense, we have silenced the 12-oxophytodienoate reductase 3 (OPR3) gene. Two independent transgenic tomato lines (SiOPR3-1 and SiOPR3-2) showed significantly reduced OPR3 expression upon infection with the necrotrophic pathogen Botrytis cinerea. Moreover, SiOPR3 plants are more susceptible to this pathogen, and this susceptibility is accompanied by a significant decrease in the OPDA levels and an almost abolished JA-Ile production. OPR3 silencing also leads to a major reduction in the expression of other genes of the jasmonic acid (JA) synthesis and signaling pathways after infection. These results confirm that in tomato plants, as in Arabidopsis, OPR3 determines OPDA availability for JA biosynthesis. In addition, we show that an intact JA biosynthetic pathway is required for proper callose deposition since its pathogen-induced accumulation is reduced in SiOPR3 plants. Interestingly, OPDA, but not JA, treatment restored basal resistance to B. cinerea and induced callose deposition in SiOPR3-1 and SiOPR3-2 transgenic plants. These results provide clear evidence that OPDA by itself plays a major role in basal defense of tomato plants against this necrotrophic pathogen. This article is protected by copyright. All rights reserved.
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Evolution of Conformational Dynamics Determines the Conversion of a Promiscuous Generalist into a Specialist Enzyme.
Mol. Biol. Evol.
PUBLISHED: 10-13-2014
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?-lactamases are produced by many modern bacteria as a mechanism of resistance toward ?-lactam antibiotics, the most common antibiotics in use. ?-lactamases, however, are ancient enzymes that originated billions of years ago. Recently, proteins corresponding to 2- to 3-Gy-old Precambrian nodes in the evolution of Class A ?-lactamases have been prepared and shown to be moderately efficient promiscuous catalysts, able to degrade a variety of antibiotics with catalytic efficiency levels similar to those of an average modern enzyme. Remarkably, there are few structural differences (in particular at the active-site regions) between the resurrected enzymes and a penicillin-specialist modern ?-lactamase. Here, we propose that the ancestral promiscuity originates from conformational dynamics. We investigate the differences in conformational dynamics of the ancient and extant ?-lactamases through MD simulations and quantify the contribution of each position to functionally related dynamics through Dynamic Flexibility Index. The modern TEM-1 lactamase shows a comparatively rigid active-site region, likely reflecting adaptation for efficient degradation of a specific substrate (penicillin), whereas enhanced deformability at the active-site neighborhood in the ancestral resurrected proteins likely accounts for the binding and subsequent degradation of antibiotic molecules of different size and shape. Clustering of the conformational dynamics on the basis of Principal Component Analysis is in agreement with the functional divergence, as the ancient ?-lactamases cluster together, separated from their modern descendant. Finally, our analysis leads to testable predictions, as sites of potential relevance for the evolution of dynamics are identified and mutations at those sites are expected to alter substrate-specificity.
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Dietary intake of acrylamide and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 10-11-2014
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Acrylamide, classified in 1994 by IARC as 'probably carcinogenic' to humans, was discovered in 2002 in some heat-treated, carbohydrate-rich foods. The association between dietary acrylamide intake and epithelial ovarian cancer risk (EOC) has been previously studied in one case-control and three prospective cohort studies which obtained inconsistent results, and could not further examine histological subtypes other than serous EOC. The present study was carried out in the European Prospective Investigation into Cancer and Nutrition (EPIC) sub-cohort of women (n=325,006). Multivariate Cox proportional hazards models were used to assess the association between questionnaire-based acrylamide intake and EOC risk. Acrylamide was energy-adjusted using the residual method, and was evaluated both as a continuous variable (per 10µg/day) and in quintiles; when subgroups by histological EOC subtypes were analyzed, acrylamide intake was evaluated in quartiles. During a mean follow-up of 11 years, 1,191 incident EOC cases were diagnosed. At baseline, the median acrylamide intake in EPIC was 21.3 ?g/day. No associations, and no evidence for a dose-response were observed between energy-adjusted acrylamide intake and EOC risk (HR10µg/day:1.02, 95%CI:0.96-1.09; HRQ5vsQ1:0.97, 95%CI:0.76-1.23). No differences were seen when invasive EOC subtypes (582 serous, 118 endometrioid, and 79 mucinous tumors) were analyzed separately. This study did not provide evidence that acrylamide intake, based on food intake questionnaires, was associated with risk for EOC in EPIC. Additional studies with more reliable estimates of exposure based on biomarkers may be needed.
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Prediagnostic immunoglobulin E levels and risk of chronic lymphocytic leukemia, other lymphomas and multiple myeloma-results of the European Prospective Investigation into Cancer and Nutrition.
Carcinogenesis
PUBLISHED: 09-30-2014
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Previous epidemiological studies suggest an inverse association between allergies, marked by elevated immunoglobulin (Ig) E levels, and non-Hodgkin lymphoma (NHL) risk. The evidence, however, is inconsistent and prospective data are sparse. We examined the association between prediagnostic total (low: <20; intermediate: 20-100; high >100 kU/l) and specific IgE (negative: <0.35; positive ?0.35 kU/I) concentrations against inhalant antigens and lymphoma risk in a study nested within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 1021 incident cases and matched controls of NHL, multiple myeloma (MM) and Hodgkin lymphoma with a mean follow-up time of 7 years were investigated. Multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CI) were calculated by conditional logistic regression. Specific IgE was not associated with the risk of MM, B-cell NHL and B-cell NHL subtypes. In contrast, total IgE levels were inversely associated with the risk of MM [high level: OR = 0.40 (95% CI = 0.21-0.79)] and B-cell NHL [intermediate level: OR = 0.68 (95% CI = 0.53-0.88); high level: OR = 0.62 (95% CI = 0.44-0.86)], largely on the basis of a strong inverse association with chronic lymphocytic leukemia [CLL; intermediate level: OR = 0.49 (95% CI = 0.30-0.80); high level: OR = 0.13 (95% CI = 0.05-0.35)] risk. The inverse relationship for CLL remained significant for those diagnosed 5 years after baseline. The findings of this large prospective study demonstrated significantly lower prediagnostic total IgE levels among CLL and MM cases compared with matched controls. This corresponds to the clinical immunodeficiency state often observed in CLL patients prior to diagnosis. No support for an inverse association between prediagnostic levels of specific IgE and NHL risk was found.
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Primary Hormonal Therapy for Elderly Breast Cancer Patients: Single Institution Experience.
Gynecol. Obstet. Invest.
PUBLISHED: 09-08-2014
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Aims: Breast cancer is the most frequently diagnosed cancer among women. Up to 50% of breast cancer cases occur in patients over the age of 65 years. Hormonal therapy as a single alternative treatment has been used in this population. The aim of this study was to analyze the oncological outcomes in breast cancer patients who received hormonal therapy alone as a primary treatment. Methods: We retrospectively reviewed our database to find all patients with breast cancer from 2006 to 2011 who were treated with hormonal therapy only at our center. The collected data included patients and tumor characteristics, type of drug administered, follow-up details and type of response obtained using RECIST criteria. Results: We included 44 breast cancer patients. The mean age was 83.5 ± 6.0 years. The majority of patients had tumors with less aggressive immunohistochemical characteristics and 100% of them presented positive estrogen receptors. The pharmacological treatment included exemestane, anastrozole, tamoxifen, letrozole and fulvestrant. The effectiveness rate was 60%, evaluated according to tumor reduction or no progression. Conclusion: The efficacy of hormonal therapy in older patients is reasonably high to justify its use in selected patients. Therefore, it is a sensible alternative for patients who refuse or are unfit for surgery. © 2014 S. Karger AG, Basel.
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Circulating 25-Hydroxyvitamin D3 in Relation to Renal Cell Carcinoma Incidence and Survival in the EPIC Cohort.
Am. J. Epidemiol.
PUBLISHED: 09-08-2014
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Normal renal function is essential for vitamin D metabolism, but it is unclear whether circulating vitamin D is associated with risk of renal cell carcinoma (RCC). We assessed whether 25-hydroxyvitamin D3 (25(OH)D3) was associated with risk of RCC and death after RCC diagnosis in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC recruited 385,747 participants with blood samples between 1992 and 2000. The current study included 560 RCC cases, 557 individually matched controls, and 553 additional controls. Circulating 25(OH)D3 was assessed by mass spectrometry. Conditional and unconditional logistic regression models were used to calculate odds ratios and 95% confidence intervals. Death after RCC diagnosis was assessed using Cox proportional hazards models and flexible parametric survival models. A doubling of 25(OH)D3 was associated with 28% lower odds of RCC after adjustment for season of and age at blood collection, sex, and country of recruitment (odds ratio = 0.72, 95% confidence interval: 0.60, 0.86; P = 0.0004). This estimate was attenuated somewhat after additional adjustment for smoking status at baseline, circulating cotinine, body mass index (weight (kg)/height (m)(2)), and alcohol intake (odds ratio = 0.82, 95% confidence interval: 0.68, 0.99; P = 0.038). There was also some indication that both low and high 25(OH)D3 levels were associated with higher risk of death from any cause among RCC cases.
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Fruit and vegetable intake and cause-specific mortality in the EPIC study.
Eur. J. Epidemiol.
PUBLISHED: 08-26-2014
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Consumption of fruits and vegetables is associated with a lower overall mortality. The aim of this study was to identify causes of death through which this association is established. More than 450,000 participants from the European Prospective Investigation into Cancer and Nutrition study were included, of which 25,682 were reported deceased after 13 years of follow-up. Information on lifestyle, diet and vital status was collected through questionnaires and population registries. Hazard ratios (HR) with 95% confidence intervals (95% CI) for death from specific causes were calculated from Cox regression models, adjusted for potential confounders. Participants reporting consumption of more than 569 g/day of fruits and vegetables had lower risks of death from diseases of the circulatory (HR for upper fourth 0.85, 95% CI 0.77-0.93), respiratory (HR for upper fourth 0.73, 95% CI 0.59-0.91) and digestive system (HR for upper fourth 0.60, 95% CI 0.46-0.79) when compared with participants consuming less than 249 g/day. In contrast, a positive association with death from diseases of the nervous system was observed. Inverse associations were generally observed for vegetable, but not for fruit consumption. Associations were more pronounced for raw vegetable consumption, when compared with cooked vegetable consumption. Raw vegetable consumption was additionally inversely associated with death from neoplasms and mental and behavioral disorders. The lower risk of death associated with a higher consumption of fruits and vegetables may be derived from inverse associations with diseases of the circulatory, respiratory and digestive system, and may depend on the preparation of vegetables and lifestyle factors.
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Identification of the Structural Basis of Thermal Lability of a Virus Provides a Rationale for Improved Vaccines.
Structure
PUBLISHED: 07-10-2014
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Virus stability and dynamics play critical roles during infection. Some viruses, including foot-and-mouth disease virus (FMDV), are surprisingly prone to thermal dissociation outside the cell. The structural bases and functional implications of this distinctive trait were essentially unknown. This study (1) uncovers the structural determinants of FMDV thermolability, (2) investigates the relationship between virus thermolability and infectivity, and (3) provides a structure-based rationale for engineering thermostable virus particles to develop improved vaccines and nanocontainers. The results reveal that negatively charged residues close to protein-protein interfaces exert electrostatic repulsions between capsid subunits and mediate the sensitivity of the virion to thermal dissociation, even at neutral pH. Based on these results, a series of fully infectious virions of increased thermostability were engineered by individually removing different carboxylates involved in intersubunit repulsions. The implications for virus biology and the design of thermostable vaccines are discussed.
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Stability Analysis of a Run-of-River Diversion Hydropower Plant with Surge Tank and Spillway in the Head Pond.
ScientificWorldJournal
PUBLISHED: 06-27-2014
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Run-of-river hydropower plants usually lack significant storage capacity; therefore, the more adequate control strategy would consist of keeping a constant water level at the intake pond in order to harness the maximum amount of energy from the river flow or to reduce the surface flooded in the head pond. In this paper, a standard PI control system of a run-of-river diversion hydropower plant with surge tank and a spillway in the head pond that evacuates part of the river flow plant is studied. A stability analysis based on the Routh-Hurwitz criterion is carried out and a practical criterion for tuning the gains of the PI controller is proposed. Conclusions about the head pond and surge tank areas are drawn from the stability analysis. Finally, this criterion is applied to a real hydropower plant in design state; the importance of considering the spillway dimensions and turbine characteristic curves for adequate tuning of the controller gains is highlighted.
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The consensus-based approach for gene/enzyme replacement therapies and crystallization strategies: the case of human alanine-glyoxylate aminotransferase.
Biochem. J.
PUBLISHED: 06-25-2014
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Protein stability is a fundamental issue in biomedical and biotechnological applications of proteins. Among these applications, gene- and enzyme-replacement strategies are promising approaches to treat inherited diseases that may benefit from protein engineering techniques, even though these beneficial effects have been largely unexplored. In the present study we apply a sequence-alignment statistics procedure (consensus-based approach) to improve the activity and stability of the human AGT (alanine-glyoxylate aminotransferase) protein, an enzyme which causes PH1 (primary hyperoxaluria type I) upon mutation. By combining only five consensus mutations, we obtain a variant (AGT-RHEAM) with largely enhanced in vitro thermal and kinetic stability, increased activity, and with no side effects on foldability and peroxisomal targeting in mammalian cells. The structure of AGT-RHEAM reveals changes at the dimer interface and improved electrostatic interactions responsible for increased kinetic stability. Consensus-based variants maintained the overall protein fold, crystallized more easily and improved the expression as soluble proteins in two different systems [AGT and CIPK24 (CBL-interacting serine/threonine-protein kinase) SOS2 (salt-overly-sensitive 2)]. Thus the consensus-based approach also emerges as a simple and generic strategy to increase the crystallization success for hard-to-get protein targets as well as to enhance protein stability and function for biomedical applications.
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Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.
Diabetes
PUBLISHED: 06-19-2014
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We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (? in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and ?-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
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Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort.
Blood
PUBLISHED: 06-04-2014
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It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.
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Molecular determinants of expansivity of native globular proteins: a pressure perturbation calorimetry study.
J Phys Chem B
PUBLISHED: 06-02-2014
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There is a growing interest in understanding how hydrostatic pressure (P) impacts the thermodynamic stability (?G) of globular proteins. The pressure dependence of stability is defined by the change in volume upon denaturation, ?V = (??G/?P)T. The temperature dependence of change in volume upon denaturation itself is defined by the changes in thermal expansivity (?E), ?E = (??V/?T)P. The pressure perturbation calorimetry (PPC) allows direct experimental measurement of the thermal expansion coefficient, ? = E/V, of a protein in the native, ?N(T), and unfolded, ?U(T), states as a function of temperature. We have shown previously that ?U(T) is a nonlinear function of temperature but can be predicted well from the amino acid sequence using ?(T) values for individual amino acids (J. Phys. Chem. B 2010, 114, 16166-16170). In this work, we report PPC results on a diverse set of nine proteins and discuss molecular factors that can potentially influence the thermal expansion coefficient, ?N(T), and the thermal expansivity, EN(T), of proteins in the native state. Direct experimental measurements by PPC show that ?N(T) and EN(T) functions vary significantly for different proteins. Using comparative analysis and site-directed mutagenesis, we have eliminated the role of various structural or thermodynamic properties of these proteins such as the number of amino acid residues, secondary structure content, packing density, electrostriction, dynamics, or thermostability. We have also shown that ?N(T) and EN,sp(T) functions for a given protein are rather insensitive to the small changes in the amino acid sequence, suggesting that ?N(T) and EN(T) functions might be defined by a topology of a given protein fold. This conclusion is supported by the similarity of ?N(T) and EN(T) functions for six resurrected ancestral thioredoxins that vary in sequence but have very similar tertiary structure.
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Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study.
PLoS Med.
PUBLISHED: 05-01-2014
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Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.
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Aromatic adducts and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort.
Carcinogenesis
PUBLISHED: 04-29-2014
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In this case-cohort study, we examined the association between bulky DNA adducts and the risk of lung cancer within the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort with an average 7-year follow-up, including 98 cases of primary lung cancer and 296 subjects randomly selected from the cohort. Aromatic adducts were measured using (32)P-postlabeling in leukocyte DNA from blood samples collected at enrollment. The association between DNA adducts and the risk of lung cancer was estimated using a Cox proportional hazards model with a modified partial likelihood. There was an overall significant increased risk for developing lung cancer when DNA adduct concentrations were doubled, with relative risk (RR) adjusting for all relevant confounders of 1.36 with 95% confidence interval (CI) 1.18-157. There was a significant increased risk for developing lung cancer when DNA adduct concentrations were doubled for current smokers and among subjects exposed to PAH at work; there was also a slightly higher increase among males than females. However, no statistically significant differences were observed for the effect of adduct levels across smoking status, sex or occupational exposure to PAH. A meta-analysis combined four prospective studies, including this study, resulting in a significant association among current smokers, with an overall estimate of 34% increase in the risk of lung cancer when doubling the level of aromatic DNA adducts in leukocytes.
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Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort.
Int. J. Cancer
PUBLISHED: 04-24-2014
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Suboptimal intakes of the micronutrient selenium (Se) are found in many parts of Europe. Low Se status may contribute to colorectal cancer (CRC) development. We assessed Se status by measuring serum levels of Se and Selenoprotein P (SePP) and examined the association with CRC risk in a nested case-control design (966 CRC cases; 966 matched controls) within the European Prospective Investigation into Cancer and Nutrition. Se was measured by total reflection X-ray fluorescence and SePP by immunoluminometric sandwich assay. Multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Respective mean Se and SePP levels were 84.0 ?g/L and 4.3 mg/L in cases and 85.6 ?g/L and 4.4 mg/L in controls. Higher Se concentrations were associated with a non-significant lower CRC risk (IRR?=?0.92, 95% CI: 0.82-1.03 per 25 ?g/L increase). However, sub-group analyses by sex showed a statistically significant association for women (ptrend ?=?0.032; per 25 ?g/L Se increase, IRR?=?0.83, 95% CI: 0.70-0.97) but not for men. Higher SePP concentrations were inversely associated with CRC risk (ptrend ?=?0.009; per 0.806 mg/L increase, IRR?=?0.89, 95% CI: 0.82-0.98) with the association more apparent in women (ptrend ?=?0.004; IRR?=?0.82, 95% CI: 0.72-0.94 per 0.806 mg/L increase) than men (ptrend ?=?0.485; IRR?=?0.98, 95% CI: 0.86-1.12 per 0.806 mg/L increase). The findings indicate that Se status is suboptimal in many Europeans and suggest an inverse association between CRC risk and higher serum Se status, which is more evident in women.
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Adherence to the Spanish dietary guidelines and its association with obesity in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Granada study.
Public Health Nutr
PUBLISHED: 04-24-2014
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Dietary guidelines are intended to prevent chronic diseases and obesity. The aim of the present study was to develop a diet quality index based on the Spanish Food Pyramid (SFP) and to further explore its association with obesity in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Granada study.
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Healthy lifestyle and risk of breast cancer among postmenopausal women in the European Prospective Investigation into Cancer and Nutrition cohort study.
Int. J. Cancer
PUBLISHED: 04-11-2014
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Breast cancer is the most common cancer among women and prevention strategies are needed to reduce incidence worldwide. A healthy lifestyle index score (HLIS) was generated to investigate the joint effect of modifiable lifestyle factors on postmenopausal breast cancer risk. The study included 242,918 postmenopausal women from the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, with detailed information on diet and lifestyle assessed at baseline. The HLIS was constructed from five factors (diet, physical activity, smoking, alcohol consumption and anthropometry) by assigning scores of 0-4 to categories of each component, for which higher values indicate healthier behaviours. Hazard ratios (HR) were estimated by Cox proportional regression models. During 10.9 years of median follow-up, 7,756 incident breast cancer cases were identified. There was a 3% lower risk of breast cancer per point increase of the HLIS. Breast cancer risk was inversely associated with a high HLIS when fourth versus second (reference) categories were compared [adjusted HR?=?0.74; 95% confidence interval (CI): 0.66-0.83]. The fourth versus the second category of the HLIS was associated with a lower risk for hormone receptor double positive (adjusted HR?=?0.81, 95% CI: 0.67-0.98) and hormone receptor double negative breast cancer (adjusted HR?=?0.60, 95% CI: 0.40-0.90). Findings suggest having a high score on an index of combined healthy behaviours reduces the risk of developing breast cancer among postmenopausal women. Programmes which engage women in long term health behaviours should be supported.
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Dietary fat intake and development of specific breast cancer subtypes.
J. Natl. Cancer Inst.
PUBLISHED: 04-09-2014
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We prospectively evaluated fat intake as predictor of developing breast cancer (BC) subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2), in a large (n = 337327) heterogeneous cohort of women, with 10062 BC case patients after 11.5 years, estimating BC hazard ratios (HRs) by Cox proportional hazard modeling. High total and saturated fat were associated with greater risk of ER(+)PR(+) disease (HR = 1.20, 95% confidence interval [CI] = 1.00 to 1.45; HR = 1.28, 95% CI = 1.09 to 1.52; highest vs lowest quintiles) but not ER(-)PR(-) disease. High saturated fat was statistically significantly associated with greater risk of HER2(-) disease. High saturated fat intake particularly increases risk of receptor-positive disease, suggesting saturated fat involvement in the etiology of this BC subtype.
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t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma.
J. Clin. Oncol.
PUBLISHED: 03-31-2014
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The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL.
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Phenotypic comparisons of consensus variants versus laboratory resurrections of Precambrian proteins.
Proteins
PUBLISHED: 03-13-2014
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Consensus-sequence engineering has generated protein variants with enhanced stability, and sometimes, with modulated biological function. Consensus mutations are often interpreted as the introduction of ancestral amino acid residues. However, the precise relationship between consensus engineering and ancestral protein resurrection is not fully understood. Here, we report the properties of proteins encoded by consensus sequences derived from a multiple sequence alignment of extant, class A ?-lactamases, as compared with the properties of ancient Precambrian ?-lactamases resurrected in the laboratory. These comparisons considered primary sequence, secondary, and tertiary structure, as well as stability and catalysis against different antibiotics. Out of the three consensus variants generated, one could not be expressed and purified (likely due to misfolding and/or low stability) and only one displayed substantial stability having substrate promiscuity, although to a lower extent than ancient ?-lactamases. These results: (i) highlight the phenotypic differences between consensus variants and laboratory resurrections of ancestral proteins; (ii) question interpretations of consensus proteins as phenotypic proxies of ancestral proteins; and (iii) support the notion that ancient proteins provide a robust approach toward the preparation of protein variants having large numbers of mutational changes while possessing unique biomolecular properties.
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Anthropometric measures and bladder cancer risk: A prospective study in the EPIC cohort.
Int. J. Cancer
PUBLISHED: 03-10-2014
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Anthropometric measures have been related to risk of several cancers. For bladder cancer, however, evidence is sparse. Comparability of existing studies is hampered by use of different obesity-measures, inadequate control for smoking, and few female cases. This study examined associations between height, weight, waist and hip circumference, waist-hip ratio, waist-height ratio, body mass index (BMI), recalled weight at age 20 and bladder cancer, and investigated effect modification by age, tumor aggressiveness and smoking. The study was conducted in the European Prospective Investigation into Cancer and Nutrition cohort, in 390,878 participants. Associations were calculated using Cox Proportional Hazards Models. During follow-up, 1,391 bladder cancers (1,018 male; 373 female) occurred. Height was unrelated to bladder cancer in both genders. We found a small but significant positive association with weight [1.04 (1.01-1.07) per 5 kilo], BMI [1.05 (1.02-1.08) per 2 units], waist circumference [1.04 (1.01-1.08) per 5 cm], waist-hip ratio (1.07 (1.02-1.13) per 0.05 unit] and waist-height ratio [1.07 (1.01-1.13) per 0.05 unit] in men. Stratification by smoking status confined associations in men to former smokers. In never smokers, we found no significant associations, suggesting residual confounding by smoking. Results did not differ with tumor aggressiveness and age. Residual analyses on BMI/waist circumference showed a significantly higher disease risk with BMI in men (p?=?0.01), but no association with waist circumference. In conclusion, in this large study, height was unrelated to bladder cancer, whereas overweight was associated with a slightly higher bladder cancer risk in men. This association may, however, be distorted by residual confounding by smoking.
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Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition.
Int. J. Cancer
PUBLISHED: 03-05-2014
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The role of endogenous androgens and sex hormone-binding globulin (SHBG) in ovarian carcinogenesis is poorly understood. Epithelial invasive ovarian cancer (EOC) is a heterogeneous disease and there are no prospective data on endogenous androgens and EOC risk by tumor characteristics (histology, grade, stage) or the dualistic model of ovarian carcinogenesis (i.e. type I vs. type II, leading to less or more aggressive tumors). We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluating androgens and SHBG and invasive EOC risk by tumor characteristics. Female participants who provided a blood sample and were not using exogenous hormones at blood donation were eligible (n = 183,257). A total of 565 eligible women developed EOC; two controls (n = 1,097) were matched per case. We used multivariable conditional logistic regression models. We observed no association between androgens, SHBG and EOC overall. A doubling of androstenedione reduced risk of serous carcinomas by 21% (odds ratio (OR)log2?=?0.79, 95% confidence interval [CI]?=?[0.64-0.97]). Moreover, associations differed for low-grade and high-grade carcinomas, with positive associations for low-grade and inverse associations for high-grade carcinomas (e.g. androstenedione: low grade: ORlog2 ?=?1.99 [0.98-4.06]; high grade: ORlog2 ?=?0.75 [0.61-0.93], phet ???0.01), similar associations were observed for type I/II tumors. This is the first prospective study to evaluate androgens, SHBG and EOC risk by tumor characteristics and type I/II status. Our findings support a possible role of androgens in ovarian carcinogenesis. Additional studies exploring this association are needed.
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Risk factors for cancers of unknown primary site: Results from the prospective EPIC cohort.
Int. J. Cancer
PUBLISHED: 03-04-2014
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Cancer of unknown primary site (CUP) may be called an "orphan" disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N=476,940). During prospective follow-up, a total of 651 cases of incident cases of CUP were detected (ICD-O-2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24-5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09-8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking-related tumors, in particular.
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Pre-diagnostic anthropometry and survival after colorectal cancer diagnosis in Western European populations.
Int. J. Cancer
PUBLISHED: 02-25-2014
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General and abdominal adiposity are associated with a high risk of developing colorectal cancer (CRC), but the role of these exposures on cancer survival has been less studied. The association between pre-diagnostic anthropometric characteristics and CRC-specific and all-cause death was examined among 3,924 men and women diagnosed with CRC between 1992 and 2009 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Over a mean follow-up period of 49 months, 1,309 deaths occurred of which 1,043 (79.7%) were due to CRC. In multivariable analysis, pre-diagnostic BMI ? 30 kg/m(2) was associated with a high risk for CRC-specific (HR = 1.26, 95% CI = 1.04-1.52) and all-cause (HR = 1.32, 95% CI = 1.12-1.56) death relative to BMI <25 kg/m(2). Every 5 kg/m(2) increase in BMI was associated with a high risk for CRC-specific (HR = 1.10, 95% CI = 1.02-1.19) and all-cause death (HR = 1.12, 95% CI = 1.05-1.20); and every 10 cm increase in waist circumference was associated with a high risk for CRC-specific (HR = 1.09, 95% CI = 1.02-1.16) and all-cause death (HR = 1.11, 95% CI = 1.05-1.18). Similar associations were observed for waist-to-hip and waist-to-height ratios. Height was not associated with CRC-specific or all-cause death. Associations tended to be stronger among men than in women. Possible interactions by age at diagnosis, cancer stage, tumour location, and hormone replacement therapy use among postmenopausal women were noted. Pre-diagnostic general and abdominal adiposity are associated with lower survival after CRC diagnosis.
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Fish consumption and mortality in the European Prospective Investigation into Cancer and Nutrition cohort.
Eur. J. Epidemiol.
PUBLISHED: 02-21-2014
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Fish is a source of important nutrients and may play a role in preventing heart diseases and other health outcomes. However, studies of overall mortality and cause-specific mortality related to fish consumption are inconclusive. We examined the rate of overall mortality, as well as mortality from ischaemic heart disease and cancer in relation to the intake of total fish, lean fish, and fatty fish in a large prospective cohort including ten European countries. More than 500,000 men and women completed a dietary questionnaire in 1992-1999 and were followed up for mortality until the end of 2010. 32,587 persons were reported dead since enrolment. Hazard ratios and their 99 % confidence interval were estimated using Cox proportional hazard regression models. Fish consumption was examined using quintiles based on reported consumption, using moderate fish consumption (third quintile) as reference, and as continuous variables, using increments of 10 g/day. All analyses were adjusted for possible confounders. No association was seen for fish consumption and overall or cause-specific mortality for both the categorical and the continuous analyses, but there seemed to be a U-shaped trend (p < 0.000) with fatty fish consumption and total mortality and with total fish consumption and cancer mortality (p = 0.046).
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Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Br. J. Nutr.
PUBLISHED: 02-13-2014
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Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products. In the present study, we analysed the plasma concentrations of five AR homologues in 2845 participants from ten European countries from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition. High concentrations of plasma total AR were found in participants from Scandinavia and Central Europe and lower concentrations in those from the Mediterranean countries. The geometric mean plasma total AR concentrations were between 35 and 41 nmol/l in samples drawn from fasting participants in the Central European and Scandinavian countries and below 23 nmol/l in those of participants from the Mediterranean countries. The whole-grain source (wheat or rye) could be determined using the ratio of two of the homologues. The main source was wheat in Greece, Italy, the Netherlands and the UK, whereas rye was also consumed in considerable amounts in Germany, Denmark and Sweden. The present study demonstrates a considerable variation in the plasma concentrations of total AR and concentrations of AR homologues across ten European countries, reflecting both quantitative and qualitative differences in the intake of whole-grain wheat and rye.
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Bladder cancer index: cross-cultural adaptation into Spanish and psychometric evaluation.
Health Qual Life Outcomes
PUBLISHED: 02-11-2014
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The Bladder Cancer Index (BCI) is so far the only instrument applicable across all bladder cancer patients, independent of tumor infiltration or treatment applied. We developed a Spanish version of the BCI, and assessed its acceptability and metric properties.
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Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study.
Hepatology
PUBLISHED: 02-10-2014
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The association between vitamin D status and hepatocellular carcinoma (HCC) has not been well investigated, despite experimental evidence supporting an important role of vitamin D in liver pathophysiology. Our objective was to investigate the association between prediagnostic circulating 25-hydroxyvitamin D [25(OH)D] serum levels and the risk of HCC in a prospective, nested case-control study among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Each case (n?=?138) diagnosed between 1992 and 2010 was matched to one control by age, sex, study center, date and time of blood collection, and fasting status. Serum baseline levels of 25(OH)D were measured by liquid chromatography/tandem mass spectrometry. Multivariable incident rate ratios (IRRs) of HCC associated with continuous (per 10 nmol/L) or categorical levels (tertiles or a priori-defined categories) of prediagnostic 25(OH)D were calculated using conditional logistic regression. Higher 25(OH)D levels were associated with a 49% reduction in the risk of HCC (highest versus lowest tertile: multivariable IRR?=?0.51, 95% confidence interval [CI], 0.26 to 0.99; Ptrend ?=?0.04; per 10 nmol/L increase: IRR?=?0.80, 95% CI, 0.68-0.94). The finding did not vary substantially by time from enrolment to diagnosis, and did not change after adjustment for biomarkers of preexisting liver damage, nor chronic infection with hepatitis B or C viruses. The findings were not modified by body size or smoking status.
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Virtual sensors for on-line wheel wear and part roughness measurement in the grinding process.
Sensors (Basel)
PUBLISHED: 02-08-2014
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Grinding is an advanced machining process for the manufacturing of valuable complex and accurate parts for high added value sectors such as aerospace, wind generation, etc. Due to the extremely severe conditions inside grinding machines, critical process variables such as part surface finish or grinding wheel wear cannot be easily and cheaply measured on-line. In this paper a virtual sensor for on-line monitoring of those variables is presented. The sensor is based on the modelling ability of Artificial Neural Networks (ANNs) for stochastic and non-linear processes such as grinding; the selected architecture is the Layer-Recurrent neural network. The sensor makes use of the relation between the variables to be measured and power consumption in the wheel spindle, which can be easily measured. A sensor calibration methodology is presented, and the levels of error that can be expected are discussed. Validation of the new sensor is carried out by comparing the sensor's results with actual measurements carried out in an industrial grinding machine. Results show excellent estimation performance for both wheel wear and surface roughness. In the case of wheel wear, the absolute error is within the range of microns (average value 32 ?m). In the case of surface finish, the absolute error is well below Ra 1 ?m (average value 0.32 ?m). The present approach can be easily generalized to other grinding operations.
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A prospective study of one-carbon metabolism biomarkers and cancer of the head and neck and esophagus.
Int. J. Cancer
PUBLISHED: 01-29-2014
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Experimental and epidemiological data suggest that factors of one-carbon metabolism are important in the pathogenesis of several cancers, but prospective data on head and neck cancer (HNC) and esophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants from 10 countries who donated a blood sample. The current study included 516 cancer cases of the head and neck and esophagus and 516 individually matched controls. Plasma levels of vitamins B2, B6, B9 (folate), B12, and methionine and homocysteine were measured in pre-diagnostic plasma samples and analyzed in relation to HNC and esophagus cancer risk, as well as post-diagnosis all-cause mortality. After controlling for risk factors, study participants with higher levels of homocysteine had elevated risk of HNC, the odds ratio (OR) in conditional analysis when comparing the top and bottom quartiles of homocysteine [ORQ4 vs. Q1 ] being 2.13 (95% confidence interval [95% CI] 1.13-4.00, p for trend 0.009). A slight decrease in HNC risk was also seen among subjects with higher levels of folate (ORQ4 vs. Q1 0.63, 95% CI 0.35-1.16, p for trend 0.02). Subgroup analyses by anatomical sub-site indicated particularly strong associations with circulating homocysteine for oral cavity and gum cancer (p for trend 8 × 10(-4) ), as well as for oropharynx cancer (p for trend 0.008). Plasma concentrations of the other investigated biomarkers did not display any clear association with risk or survival. In conclusion, study participants with elevated circulating levels of homocysteine had increased risk of developing squamous cell carcinoma of the head and neck.
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Tea and coffee consumption and risk of esophageal cancer: the European prospective investigation into cancer and nutrition study.
Int. J. Cancer
PUBLISHED: 01-20-2014
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Epidemiological data regarding tea and coffee consumption and risk of esophageal cancer (EC) is still inconclusive. We examined the association of tea and coffee consumption with EC risk among 442,143 men and women without cancer at baseline from 9 countries of the European Prospective Investigation into Cancer and Nutrition. Tea and coffee intakes were recorded using country-specific validated dietary questionnaires. Cox regression models were used to analyze the relationships between tea and coffee intake and EC risk. During a mean follow-up of 11.1 years, 339 participants developed EC, of which 142 were esophageal adenocarcinoma (EAC) and 174 were esophageal squamous cell carcinoma (ESCC). In the multivariable models, no significant associations between tea (mostly black tea), and coffee intake and risk of EC, EAC and ESCC were observed. In stratified analyses, among men coffee consumption was inversely related to ESCC (HR for comparison of extreme tertiles 0.42, 95% CI 0.20-0.88; p-trend=0.022), but not among women. In current smokers, a significant and inverse association was observed between ESCC risk and tea (HR 0.46, 95% CI 0.23-0.93; p-trend=0.053) and coffee consumption (HR 0.37, 95% CI 0.19-0.73; p-trend=0.011). However, no statistically significant findings were observed using the continuous variable (per 100 mL/d). These data did not show a significant association between tea and coffee consumption and EC, EAC and ESCC, although a decreased risk of ESCC among men and current smokers is suggested, but need to be confirmed in further prospective studies including more cases.
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Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study.
Int. J. Cancer
PUBLISHED: 01-17-2014
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Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B-cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case-control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p = 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2-4, respectively, p-trend = 0.001], diffuse large B-cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2-4, respectively, p-trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2-4, respectively, p-trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL.
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Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study.
Int. J. Cancer
PUBLISHED: 01-13-2014
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Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40-50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (-0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83-4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3 : 1.09, 95% CI: 1.01-1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3 : 1.37, 95% CI: 1.02-1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood.
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Active and passive cigarette smoking and breast cancer risk: results from the EPIC cohort.
Int. J. Cancer
PUBLISHED: 01-13-2014
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Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack-years and a dose-response relationship with increasing pack-years of smoking between menarche and first full-term pregnancy (FFTP). Studies with comprehensive quantitative life-time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) [95% confidence interval (CI)] 1.16 [1.05-1.28], 1.14 [1.04-1.25] and 1.10 [1.01-1.20], respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack-years from menarche to FFTP (1.73 [1.29-2.32] for every increase of 20 pack-years) while pack-years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34-0.82 for every increase of 20 pack-years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious.
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Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer.
Hepatology
PUBLISHED: 01-09-2014
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Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), and gallbladder and biliary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Over an average of 7.7 years, 296 participants developed HCC (n=125), GBTC (n=137), or IBD (n=34). Using risk-set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations=1.22; 95% CI=1.02-1.46; P=0.03; 1.90; 95% CI=1.30-2.77; P=0.001; 2.25; 95% CI=1.43-3.54; P=0.0005; and 2.09; 95% CI=1.19-3.67; P=0.01, respectively). CRP was associated also with risk of GBTC (IRR=1.22; 95% CI=1.05-1.42; P=0.01). GLDH was associated with risks of HCC (IRR=1.62; 95% CI=1.25-2.11; P=0.0003) and IBD (IRR=10.5; 95% CI=2.20-50.90; P=0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide, and non-HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers.
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Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 12-19-2013
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Background: Imbalances in tryptophan metabolism have been linked to cancer related immune escape and implicated in several cancers, including lung cancer. Methods: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk. Results: Tryptophan (Ptrend=2x10-5) and the kynurenine/tryptophan ratio (KTR) (Ptrend=4x10-5) were associated with lung cancer risk overall after adjusting for established risk factors. The odds ratios comparing the fifth and first quintiles (OR5thvs.1st) were 0.52 (95% CI: 0.37-0.74) for tryptophan and 1.74 (95% CI: 1.24-2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend=0.13) and KTR (Ptrend=0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5thvs.1st being 2.83 (95% CI: 1.62-4.94, Ptrend=3x10-5) that was only marginally affected by adjusting for methionine. Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. While this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology. Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk.
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Dietary Intakes and Risk of Lymphoid and Myeloid Leukemia in the European Prospective Investigation into Cancer and Nutrition (EPIC).
Nutr Cancer
PUBLISHED: 11-26-2013
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The etiology of leukemias cannot entirely be explained by known risk factors, including ionizing radiation, benzene exposure, and infection with human T cell leukemia virus. A number of studies suggested that diet influences the risk of adult leukemias. However, results have been largely inconsistent. We examined the potential association between dietary factors and risk of leukemias among participants of the European Prospective Investigation into Cancer and Nutrition study. Among the 477,325 participants with mean follow-up of 11.34 yr (SD = 2.47), 773 leukemias (373 and 342 cases of lymphoid and myeloid leukemia, respectively) were identified. Diet over the previous 12 mo was assessed at baseline using a validated country-specific dietary questionnaire. Cox proportional hazards regression was used to explore the association between dietary factors that have previously been associated with leukemia risk, including red and processed meat, poultry, offal, fish, dairy products, vegetables, fruits, and seeds/nuts, and risk of both lymphoid and myeloid leukemias. No significant associations were observed between dietary measures and total, lymphoid, and myeloid leukemias. Additional subtype analyses showed no dietary association with risk of major subtypes of leukemias. In summary, this study did not support a possible link between selected dietary factors and risk of leukemias.
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Single site-specific integration targeting coupled with embryonic stem cell differentiation provides a high-throughput alternative to in vivo enhancer analyses.
Biol Open
PUBLISHED: 11-15-2013
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Comprehensive analysis of cis-regulatory elements is key to understanding the dynamic gene regulatory networks that control embryonic development. While transgenic animals represent the gold standard assay, their generation is costly, entails significant animal usage, and in utero development complicates time-course studies. As an alternative, embryonic stem (ES) cells can readily be differentiated in a process that correlates well with developing embryos. Here, we describe a highly effective platform for enhancer assays using an Hsp68/Venus reporter cassette that targets to the Hprt locus in mouse ES cells. This platform combines the flexibility of Gateway® cloning, live cell trackability of a fluorescent reporter, low background and the advantages of single copy insertion into a defined genomic locus. We demonstrate the successful recapitulation of tissue-specific enhancer activity for two cardiac and two haematopoietic enhancers. In addition, we used this assay to dissect the functionality of the highly conserved Ets/Ets/Gata motif in the Scl+19 enhancer, which revealed that the Gata motif is not required for initiation of enhancer activity. We further confirmed that Gata2 is not required for endothelial activity of the Scl+19 enhancer using Gata2(-/-) Scl+19 transgenic embryos. We have therefore established a valuable toolbox to study gene regulatory networks with broad applicability.
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Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk-Results from the EPIC cohort study.
Int. J. Cancer
PUBLISHED: 11-06-2013
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Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992-2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case-control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.7?±?8.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95% CI 0.95-1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95% CI 0.97-1.26) and decaffeinated coffee (HR 0.96, 95% CI 0.84-1.11) and tea (HR 0.97, 95% CI 0.86-1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggests that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC.
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Developing a longitudinal cancer nursing education program in Honduras.
J Cancer Educ
PUBLISHED: 08-06-2013
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The present paper is a longitudinal study which aims to develop and deliver cancer nursing education conferences in Honduras using volunteer nurse educators. This program intends to (1) perform site assessments of work environments and resources for cancer care in Honduras, (2) develop cancer nursing education programs, (3) survey conference participants continuing education needs, (4) deliver cancer nursing education conferences, and (5) share data with local and global partners for future cancer programs. The study draws on a longitudinal program development with site assessments, data collection, and educational conferences at two time points. Assessments and surveys were used for conference development and delivery by volunteer nurse educators. Site assessments and conferences were delivered twice. Data were collected regarding assessments and surveys to inform program development. Survey data revealed that <4 % had formal training in cancer care and >65 % had internet access. Participants desired more information about handling of chemotherapy, symptom management, and palliative care. Volunteer nurse educators perform site assessments and develop educational programming for cancer nurses. Local and global partners should explore internet-based programs between site visits to create sustainable education programs.
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Cortical laminar necrosis related to migrainous cerebral infarction.
World J Clin Cases
PUBLISHED: 08-01-2013
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We present a 29-year-old woman with a long history of attacks of migraine with and without visual aura. She was a heavy smoker (20 cigarettes/d) and was currently taking oral contraceptives. During a typical migraine attack with aura, she developed dysarthria, left brachial hemiparesis and hemihypoesthesia and brief and autolimited left clonic facial movements. Four hours after onset, vascular headache and focal sensorimotor neurological deficit were the only persisting symptoms and, on seventh day, she was completely recovered. Brain magnetic resonance imaging on day 20 after onset showed a subacute ischemic lesion in the right temporo-parietal cortex compatible with cortical laminar necrosis (CLN). Extensive neurological work-up done to rule out other known causes of cerebral infarct with CLN was unrevealing. Only ten of 3.808 consecutive stroke patients included in our stroke registry over a 19-year period fulfilled the strictly defined International Headache Society criteria for migrainous stroke. The present case is the unique one in our stroke registry that presents CLN related to migrainous cerebral infarction. Migrainous infarction can result in CLN.
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Dietary flavonoid and lignan intake and mortality in a Spanish cohort.
Epidemiology
PUBLISHED: 07-25-2013
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Dietary flavonoids and lignans may protect against several chronic diseases, but there is little evidence on the relationship between flavonoid and lignan intake and mortality. We investigated the association between both all-cause and specific-cause mortality and intake of flavonoids and lignans in the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC-Spain) cohort.
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Premenopausal serum sex hormone levels in relation to breast cancer risk, overall and by hormone receptor status-Results from the EPIC cohort.
Int. J. Cancer
PUBLISHED: 07-12-2013
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Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1 ?=?1.56 (95% CI 1.15-2.13), ptrend ?=?0.02 for testosterone and ORQ4-Q1 ?=?1.33 (95% CI 0.99-1.79), ptrend ?=?0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and -negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1 ?=?1.32 (95% CI 0.87-2.01), ptrend ?=?0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1 ?=?0.94 (95% CI 0.60-1.47), ptrend ?=?0.34, phet ?=?0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen.
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Insulin-like growth factor I and risk of breast cancer by age and hormone receptor status-A prospective study within the EPIC cohort.
Int. J. Cancer
PUBLISHED: 06-18-2013
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Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 ?=?1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR?=?1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend ?=?0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 ?=?1.38 [95% CI 1.01-1.89]; OR?=?1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend ?=?0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet ?=?0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older.
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The effects of startle and non-startle auditory stimuli on wrist flexion movement in Parkinsons disease.
Neurosci. Lett.
PUBLISHED: 05-18-2013
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Startle stimuli lead to shorter reaction times in control subjects and Parkinsons disease (PD) patients. However, non-startle stimuli also enhance movement initiation in PD. We wanted to examine whether a startle-triggered movement would retain similar kinematic and EMG-related characteristics compared to one induced by a non-startle external cue in PD patients. In this study we investigated the electromyography pattern and the reaction time during a wrist flexion movement in response to three different stimuli: a visual imperative stimulus; visual stimulus simultaneous with a non-startle auditory stimulus and with a startle auditory stimulus. Ten PD patients and ten aged matched controls participated in this study. The reaction times were faster for startle and non-startle stimuli in comparison with the visual imperative stimulus, in both patients and control subjects. The startle cue induced a faster reaction than the non-startle cue. The electromyography pattern remained unchanged across the conditions. The results suggest that the startle reaction effect for upper limb movements are unimpaired in PD patients and has different characteristics than the effect of non-startle stimuli.
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Conservation of protein structure over four billion years.
Structure
PUBLISHED: 04-10-2013
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Little is known about the evolution of protein structures and the degree of protein structure conservation over planetary time scales. Here, we report the X-ray crystal structures of seven laboratory resurrections of Precambrian thioredoxins dating up to approximately four billion years ago. Despite considerable sequence differences compared with extant enzymes, the ancestral proteins display the canonical thioredoxin fold, whereas only small structural changes have occurred over four billion years. This remarkable degree of structure conservation since a time near the last common ancestor of life supports a punctuated-equilibrium model of structure evolution in which the generation of new folds occurs over comparatively short periods and is followed by long periods of structural stasis.
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Activation of RISK and SAFE pathways is not involved in the effects of Cx43 deficiency on tolerance to ischemia-reperfusion injury and preconditioning protection.
Basic Res. Cardiol.
PUBLISHED: 04-09-2013
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Connexin 43 (Cx43) deficiency increases myocardial tolerance to ischemia-reperfusion injury and abolishes preconditioning protection. It is not known whether modifications in baseline signaling through protective RISK or SAFE pathways or in response to preconditioning may contribute to these effects. To answer this question we used Cx43(Cre-ER(T)/fl) mice, in which Cx43 expression is abolished after 4-hydroxytamoxifen (4-OHT) administration. Isolated hearts from Cx43(Cre-ER(T)/fl) mice, or from Cx43(fl/fl) controls, treated with vehicle or 4-OHT, were submitted to global ischemia (40 min) and reperfusion. Cx43 deficiency was associated with reduced infarct size after ischemia-reperfusion (11.17 ± 3.25 % vs. 65.04 ± 3.79, 59.31 ± 5.36 and 65.40 ± 4.91, in Cx43(fl/fl) animals treated with vehicle, Cx43(fl/fl) mice treated with 4-OHT, and Cx43(Cre-ER(T)/fl) mice treated with vehicle, respectively, n = 8-9, p < 0.001). However, the ratio phosphorylated/total protein expression for Akt, ERK-1/2, GSK3? and STAT3 was not increased in normoxic samples from animals lacking Cx43. Instead, a reduction in the phosphorylation state of GSK3? was observed in Cx43-deficient mice (ratio: 0.15 ± 0.02 vs. 0.56 ± 0.11, 0.77 ± 0.15, and 0.46 ± 0.14, respectively, n = 5-6, p < 0.01). Furthermore, ischemic preconditioning (IPC, 4 cycles of 3.5 min of ischemia and 5 min of reperfusion) increased phosphorylation of ERK-1/2, GSK3?, and STAT3 in all hearts without differences between groups (n = 5-6, p < 0.05), although Cx43 deficient mice were not protected by either IPC or pharmacological preconditioning with diazoxide. Our data demonstrate that modification of RISK and SAFE signaling does not contribute to the role of Cx43 in the increased tolerance to myocardial ischemia-reperfusion injury and in preconditioning protection.
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Risk of second primary cancer among women with breast cancer: a population-based study in Granada (Spain).
Gynecol. Oncol.
PUBLISHED: 03-22-2013
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The higher risk of developing new cancers in breast cancer survivors is a public health concern. Our aim was to examine risk of second primary cancers among women diagnosed with breast cancer.
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Plasma carotenoid- and retinol-weighted multi-SNP scores and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 03-20-2013
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Dietary and circulating carotenoids have been inversely associated with breast cancer risk, but observed associations may be due to confounding. Single-nucleotide polymorphisms (SNPs) in ?-carotene 15,15-monooxygenase 1 (BCMO1), a gene encoding the enzyme involved in the first step of synthesizing vitamin A from dietary carotenoids, have been associated with circulating carotenoid concentrations and may serve as unconfounded surrogates for those biomarkers. We determined associations between variants in BCMO1 and breast cancer risk in a large cohort consortium.
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Mediterranean diet and colorectal cancer risk: results from a European cohort.
Eur. J. Epidemiol.
PUBLISHED: 03-15-2013
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The authors investigated the association of adherence to Mediterranean diet with colorectal cancer (CRC) risk in the European Prospective Investigation into Cancer and nutrition study. Adherence to Mediterranean diet was expressed through two 10-unit scales, the Modified Mediterranean diet score (MMDS) and the Centre-Specific MMDS (CSMMDS). Both scales share the same dietary components but differ in the cut-off values that were used for these components in the construction of the scales. Adjusted hazard ratios (HR) for the associations of these scales with CRC incidence were estimated. After 5,296,617 person-years of follow-up, 4,355 incident CRC cases were identified. A decreased risk of CRC, of 8 and 11 % was estimated when comparing the highest (scores 6-9) with the lowest (scores 0-3) adherence to CSMMDS and MMDS respectively. For MMDS the HR was 0.89 (95 % confidence interval (CI): 0.80, 0.99). A 2-unit increment in either Mediterranean scale was associated with a borderline statistically significant 3 to 4 % reduction in CRC risk (HR for MMDS: 0.96; 95 % CI: 0.92, 1.00). These associations were somewhat more evident, among women, were mainly manifested for colon cancer risk and their magnitude was not altered when alcohol was excluded from MMDS. These findings suggest that following a Mediterranean diet may have a modest beneficial effect on CRC risk.
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Different contribution of conserved amino acids to the global properties of triosephosphate isomerases.
Proteins
PUBLISHED: 03-11-2013
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It is generally assumed that the amino acids that exist in all homologous enzymes correspond to residues that participate in catalysis, or that are essential for folding and stability. Although this holds for catalytic residues, the function of conserved noncatalytic residues is not clear. It is not known if such residues are of equal importance and have the same role in different homologous enzymes. In humans, the E104D mutation in triosephosphate isomerase (TIM) is the most frequent mutation in the autosomal diseases named "TPI deficiencies." We explored if the E104D mutation has the same impact in TIMs from four different organisms (Homo sapiens, Giardia lamblia, Trypanosoma cruzi, and T. brucei). The catalytic properties were not significantly affected by the mutation, but it affected the rate and extent of formation of active dimers from unfolded monomers differently. Scanning calorimetry experiments indicated that the mutation was in all cases destabilizing, but the mutation effect on rates of irreversible denaturation and transition-state energetics were drastically dependent on the TIM background. For instance, the E104D mutation produce changes in activation energy ranging from 430 kJ mol(-1) in HsTIM to -78 kJ mol(-1) in TcTIM. Thus, in TIM the role of a conserved noncatalytic residue is drastically dependent on its molecular background. Accordingly, it would seem that because each protein has a particular sequence, and a distinctive set of amino acid interactions, it should be regarded as a unique entity that has evolved for function and stability in the organisms to which it belongs. Proteins 2013; 00:000-000. © 2013 Wiley Periodicals, Inc.
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