Genetic Variation in FADS Genes and Plasma Cholesterol Levels in 2-Year-Old Infants

Single nucleotide polymorphisms (SNPs) in genes involved in fatty acid metabolism (FADS1 FADS2 gene cluster) are associated with plasma lipid levels. We aimed to investigate whether these associations are already present early in life and compare the relative contribution of FADS SNPs vs traditional (non-genetic) factors as determinants of plasma lipid levels. Information on infants' plasma total cholesterol levels, genotypes of five FADS SNPs (rs174545, rs174546, rs174556, rs174561, and rs3834458), anthropometric data, maternal characteristics, and breastfeeding history was available for 521 2-year-old children from the KOALA Birth Cohort Study. For 295 of these 521 children, plasma HDLc and non-HDLc levels were also known. Multivariable linear regression analysis was used to study the associations of genetic and non-genetic determinants with cholesterol levels. All FADS SNPs were significantly associated with total cholesterol levels. Heterozygous and homozygous for the minor allele children had about 4% and 8% lower total cholesterol levels than major allele homozygotes. In addition, homozygous for the minor allele children had about 7% lower HDLc levels. This difference reached significance for the SNPs rs174546 and rs3834458. The associations went in the same direction for non-HDLc, but statistical significance was not reached. The percentage of total variance of total cholesterol levels explained by FADS SNPs was relatively low (lower than 3%) but of the same order as that explained by gender and the non-genetic determinants together. FADS SNPs are associated with plasma total cholesterol and HDLc levels in preschool children. This brings a new piece of evidence to explain how blood lipid levels may track from childhood to adulthood. Moreover, the finding that these SNPs explain a similar amount of variance in total cholesterol levels as the non-genetic determinants studied reveals the potential importance of investigating the effects of genetic variations in early life

Algorithm for tracking peaks amongst numerous datasets in comprehensive two-dimensional chromatography to enhance data analysis and interpretation

Analytical data processing often requires the comparison of data, i.e. finding similarities and differences within separations. In this context, a peak-tracking algorithm was developed to compare multiple datasets in one-dimensional (1D) and two-dimensional (2D) chromatography. Two application strategies were investigated: i) data processing where all chromatograms are produced in one sequence and processed simultaneously, and ii) method optimization where chromatograms are produced and processed cumulatively. The first strategy was tested on data from comprehensive 2D liquid chromatography and comprehensive 2D gas chromatography separations of academic and industrial samples of varying compound classes (monoclonal-antibody digest, wine volatiles, polymer granulate headspace, and mayonnaise). Peaks were tracked in up to 29 chromatograms at once, but this could be upscaled when necessary. However, the peak-tracking algorithm performed less accurate for trace analytes, since, peaks that are difficult to detect are also difficult to track. The second strategy was tested with 1D liquid chromatography separations, that were optimized using automated method-development. The strategy for method optimization was quicker to detect peaks that were still poorly separated in earlier chromatograms compared to assigning a target chromatogram, to which all other chromatograms are compared. Rendering it a useful tool for automated method optimization.</p

Decay resistance variability of European wood species thermally modified by industrial process

Thermal modification is now considered as a new ecofriendly industrial wood modification process improving mainly the material decay resistance and its dimensional stability. Most industrial thermal treatment processes use convection heat transfer which induces sometimes heterogeneous treatment temperature propagation within the oven and lead to the heterogeneity in treatment efficiency. Thus, it is common that treatment is not completely effective on several stack boards, in a same batch. The aim of this paper was to study the decay resistance variability of various European wood species thermally modified. Thermal modifications were performed around 240°C during 4h, on about 10 m3 of 27 x 152 x 2000 mm3 wood planks placed in an industrial oven having a volume of 20 m3, on the following wood species: spruce, ash, beech and poplar. All of the tests concerning the decay resistance were carried out in the laboratory using untreated beech and pine woods as reference materials. An agar block test was used to determine the resistance of thermally modified woods, leached beforehand according to EN 84 standard or not, to brown-rot and white-rot fungi, according to XP CEN/TS 15083-1. A large selection of treated wood samples was tested in order to estimate the variability of treatment efficiency. Thermal treatment increased the biological durability of all leached and un-leached modified wood samples, compared with native wood species. The treatment temperature of 240°C used in this study is sufficient to reach durability classes ''durable'' or ''very durable'' for the four wood species. However, the dispersion of weight loss values, due to the fungal attacks was very important and showed a large variability of the durability of wood which has been treated in a single batch. These results showed that there is a substantial need to develop process control and² indicator in order to insure that the quality of treated timber is properly evaluated with a view to putting this modified timber on the market under a chain of custody. (Résumé d'auteur

Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study

Background: Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. Methods: We did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0.3 mg/kg to 2.4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. Findings: Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2.4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1.5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1.2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20.4-48.4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13.8-46.8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16.3-67.6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0.2-30.2) of 16 patients with gastric cancer, four (25%, 7.3-52.4) of 16 patients with urothelial cancer, and five (39%, 13.9-68.4) of 13 patients with endometrial cancer. Interpretation: Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. Copyright (C) 2019 Elsevier Ltd. All rights reserved

Mode of Delivery and Asthma at School Age in 9 European Birth Cohorts

Evidence on the association between mode of delivery and asthma at school age is inconclusive. We assessed the associations between specific modes of delivery and asthma in children from 9 European birth cohorts that enrolled participants between 1996 and 2006. Cohort-specific crude and adjusted risk ratios for asthma at ages 5–9 years were calculated using Poisson regression models and pooled. A sensitivity analysis was carried out in children born at term to reduce confounding due to perinatal factors. The study included 67,613 participants. Cohortspecific rates of cesarean delivery varied from 9.4% to 37.5%. Cesarean delivery, as opposed to vaginal delivery, was associated with an increased risk of asthma (adjusted risk ratio (aRR) = 1.22, 95% confidence interval (CI): 1.02, 1.46). Compared with spontaneous vaginal delivery, the adjusted risk ratio was 1.33 (95% CI: 1.02, 1.75) for elective cesarean delivery, 1.07 (95% CI: 0.94, 1.22) for emergency cesarean delivery, and 0.97 (95% CI: 0.84, 1.12) for operative vaginal delivery. In children born at term, the associations were strengthened only for elective cesarean delivery (aRR = 1.49, 95% CI: 1.13, 1.97). The large sample size allowed analysis of the associations between specific modes of delivery and asthma at school age. The increased risk of asthma associated with elective cesarean delivery, especially among children born at term, is relevant in counteracting the increasing use of this procedure, which is often performed without a clear medical indication.This work was supported by the European Community’s Seventh Framework Programme (FP7/2009–2013) under a grant agreement (grant 241604) and by the University of Turin and the San Paolo Foundation (Turin, Italy). Data collection was funded and the study teams of all participating birth cohorts were supported by local and/or national research organizations

META Score: An International Consensus Scoring System on Mesh-Tissue Adhesions

Background: Currently, the lack of consensus on postoperative mesh-tissue adhesion scoring leads to incomparable scientific results. The aim of this study was to develop an adhesion score recognized by experts in the field of hernia surgery. Methods: Authors of three or more previously published articles on both mesh-tissue adhesion scores and postoperative adhesions were marked as experts. They were queried on seven items using a modified Delphi method. The items concerned the utility of adhesion scoring models, the appropriateness of macroscopic and microscopic variables, the range and use of composite scores or subscores, adhesion-related complications and follow-up length. This study comprised two questionnaire-based rounds and one consensus meeting. Results: The first round was completed by 23 experts (82%), the second round by 18 experts (64%). Of those 18 experts, ten were able to participate in the final consensus meeting and all approved the final proposal. From a total of 158 items, consensus was reached on 90 items. The amount of mesh surface covered with adhesions, tenacity and thickness of adhesions and organ involvement was concluded to be a minimal set of variables to be communicated separately in each future study on mesh adhesions. Conclusion: The MEsh Tissue Adhesion scoring system is the first consensus-based scoring system with a wide backing of renowned experts and can be used to assess mesh-related adhesions. By including this minimal set of variables in future research interstudy comparability and objectivity can be increased and eventually linked to clinically relevant outcomes

Smith-Waterman peak alignment for comprehensive two-dimensional gas chromatography-mass spectrometry

<p>Abstract</p> <p>Background</p> <p>Comprehensive two-dimensional gas chromatography coupled with mass spectrometry (GC × GC-MS) is a powerful technique which has gained increasing attention over the last two decades. The GC × GC-MS provides much increased separation capacity, chemical selectivity and sensitivity for complex sample analysis and brings more accurate information about compound retention times and mass spectra. Despite these advantages, the retention times of the resolved peaks on the two-dimensional gas chromatographic columns are always shifted due to experimental variations, introducing difficulty in the data processing for metabolomics analysis. Therefore, the retention time variation must be adjusted in order to compare multiple metabolic profiles obtained from different conditions.</p> <p>Results</p> <p>We developed novel peak alignment algorithms for both homogeneous (acquired under the identical experimental conditions) and heterogeneous (acquired under the different experimental conditions) GC × GC-MS data using modified Smith-Waterman local alignment algorithms along with mass spectral similarity. Compared with literature reported algorithms, the proposed algorithms eliminated the detection of landmark peaks and the usage of retention time transformation. Furthermore, an automated peak alignment software package was established by implementing a likelihood function for optimal peak alignment.</p> <p>Conclusions</p> <p>The proposed Smith-Waterman local alignment-based algorithms are capable of aligning both the homogeneous and heterogeneous data of multiple GC × GC-MS experiments without the transformation of retention times and the selection of landmark peaks. An optimal version of the SW-based algorithms was also established based on the associated likelihood function for the automatic peak alignment. The proposed alignment algorithms outperform the literature reported alignment method by analyzing the experiment data of a mixture of compound standards and a metabolite extract of mouse plasma with spiked-in compound standards.</p

Identification of biomarkers in ductal carcinoma in situ of the breast with microinvasion

<p>Abstract</p> <p>Background</p> <p>Widespread use of mammography in breast cancer screening has led to the identification of increasing numbers of patients with ductal carcinoma <it>in situ </it>(DCIS). DCIS of the breast with an area of focal invasion 1 mm or less in diameter is defined as DCIS with microinvasion, DCIS-Mi. Identification of biological differences between DCIS and DCIS-Mi may aid in understanding of the nature and causes of the progression of DCIS to invasiveness.</p> <p>Methods</p> <p>In this study, using resected breast cancer tissues, we compared pure DCIS (52 cases) and DCIS-Mi (28 cases) with regard to pathological findings of intraductal lesions, biological factors, apoptosis-related protein expression, and proliferative capacity through the use of immunohistochemistry and the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method.</p> <p>Results</p> <p>There were no differences in biological factors between DCIS and DCIS-Mi, with respect to levels of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The frequency of necrosis and positive expression ratio of survivin and Bax were significantly higher in DCIS-Mi than in DCIS. In addition, apoptotic index, Ki-67 index, and positive Bcl-2 immunolabeling tended to be higher in DCIS-Mi than in DCIS. Multivariate analysis revealed that the presence of necrosis and positive survivin expression were independent factors associated with invasion.</p> <p>Conclusion</p> <p>Compared with DCIS, DCIS-Mi is characterized by a slightly elevated cell proliferation capacity and enhanced apoptosis within the intraductal lesion, both of which are thought to promote the formation of cell necrotic foci. Furthermore, the differential expression of survivin may serve in deciding the response to therapy and may have some prognostic significance.</p

Dairy consumption and ovarian cancer risk in the Netherlands Cohort Study on Diet and Cancer

Ovary cancer risk in relation to consumption of dairy products was investigated using a self-administered questionnaire on dietary habits and other risk factors for cancer, which was completed in 1986 by 62 573 postmenopausal women participating in the Netherlands Cohort Study. Follow-up for cancer was implemented by annual record linkage with the Netherlands Cancer Registry and a nationwide pathology registry. After 11.3 years of follow-up, data of 252 incident epithelial ovarian cancer cases and 2216 subcohort members were available for analysis. No association was seen between consumption of milk, yoghurt, cheese or fermented dairy products and ovarian cancer risk. The multivariable adjusted relative risk of epithelial ovarian cancer for women in the highest compared to the lowest quintile of intake of lactose or dairy fat was 0.93 (95% confidence interval (CI)=0.60–1.45; Ptrend=0.32) and 1.53 (95% CI=1.00–2.36; Ptrend=0.11), respectively. Lactose or dairy fat intakes were not associated with serous ovarian cancer risk. Our results do not support an association between consumption of dairy products or lactose intake and ovarian cancer