| 1. |
- Fiolet, Thibault, et al.
(författare)
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Dietary intakes of dioxins and polychlorobiphenyls (PCBs) and breast cancer risk in 9 European countries
- 2022
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 163
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dioxins and polychlorobiphenyls (PCBs) are persistent organic pollutants that have demonstrated endocrine disrupting properties. Several of these chemicals are carcinogenic and positive associations have been suggested with breast cancer risk. In general population, diet represents the main source of exposure.Methods: Associations between dietary intake of 17 dioxins and 35 PCBs and breast cancer were evaluated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from nine European countries using multivariable Cox regressions. The present study included 318,607 women (mean ± SD age: 50.7 ± 9.7) with 13,241 incident invasive breast cancers and a median follow-up of 14.9 years (IQR = 13.5–16.4). Dietary intake of dioxins and PCBs was assessed combining EPIC food consumption data with food contamination data provided by the European Food Safety Authority.Results: Exposure to dioxins, dioxins + Dioxin-Like-PCBs, Dioxin-Like-PCBs (DL-PCBs), and Non-Dioxin-Like-PCBs (NDL-PCBs) estimated from reported dietary intakes were not associated with breast cancer incidence, with the following hazard ratios (HRs) and 95% confidence intervals for an increment of 1 SD: HRdioxins = 1.00 (0.98 to 1.02), HRdioxins+DL-PCB = 1.01 (0.98 to 1.03), HRDL-PCB = 1.01 (0.98 to 1.03), and HRNDL-PCB = 1.01 (0.99 to 1.03). Results remained unchanged when analyzing intakes as quintile groups, as well as when analyses were run separately per country, or separating breast cancer cases based on estrogen receptor status or after further adjustments on main contributing food groups to PCBs and dioxins intake and nutritional factors.Conclusions: This large European prospective study does not support the hypothesis of an association between dietary intake of dioxins and PCBs and breast cancer risk.
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| 2. |
- Fiolet, Thibault, et al.
(författare)
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Dietary intakes of dioxins and polychlorobiphenyls (PCBs) and mortality : EPIC cohort study in 9 European countries
- 2024
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Ingår i: International Journal of Hygiene and Environmental Health. - 1438-4639. ; 255
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Tidskriftsartikel (refereegranskat)abstract
- Dioxins and polychlorinated biphenyls (PCBs) are toxic, endocrine disruptors and persistent chemicals for which the main exposure source is diet due to their bioaccumulation and biomagnification in food chains. Cohort studies in the general populations have reported inconsistent associations between these chemicals in serum/plasma and mortality. Our objective was to study the association between dietary intake of 17 dioxins and 35 PCBs and all-cause, cancer-specific and cardiovascular-specific mortalities were assessed in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Dietary intake of dioxins and PCBs was assessed combining EPIC food consumption data with European food contamination data provided by the European Food Safety Authority. We applied multivariable Cox regressions. The analysis included 451,390 adults (mean ± SD age:51.1 ± 9.7 years) with 46,627 deaths and a median follow-up of 17.4 years (IQR = 15.2–19.1). A U-shaped non-linear association with all-cause mortality for dietary intake of dioxins (Pnon-linearity<0.0001), DL-PCB (Pnon-linearity = 0.0001), and NDL-PCBs (Pnon-linearity<0.01) was observed. For example, the hazard ratios (95%Confidance interval) for all-cause mortality obtained with the spline model was equal to 1.03 (1.02–1.05) for low levels of intake to dioxins (7 pg TEQ/day), 0.93 (0.90–0.96) for moderate levels of intake (25 pg TEQ/day), while for high levels of intake (55 pg TEQ/day) it was 1.03 (0.97–1.09). Intake of dioxins, DL-PCBs and NDL-PCBs was not associated with cardiovascular mortality. There was no association between intakes of dioxins and cancer mortality, but a U-shaped association was observed for intake of DL-PCBs and intakes of NDL-PCBs and cancer mortality. The PCBs and dioxins are known to have endocrine disrupting properties which can lead to non-monotonic dose responses. These results need to be interpreted with caution and further studies are needed to better clarify the association between dietary intake of dioxins and PCB and mortality in the general population.
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| 3. |
- Hatos, Andras, et al.
(författare)
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DisProt : intrinsic protein disorder annotation in 2020
- 2020
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:D1, s. D269-D276
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Tidskriftsartikel (refereegranskat)abstract
- The Database of Protein Disorder (DisProt, URL:https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the 'dark' proteome.
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| 4. |
- Horváth, Zsuzsanna, et al.
(författare)
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Development of a food composition database for the intake estimation of total, added and free sugars in different EU countries and age groups
- 2021
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Ingår i: International Conference on Diet and Activity Methods (eICDAM).
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: The database development is a part of the protocol for the Scientific Opinion on the Tolerable Upper Intake Level of dietary sugars of the European Food Safety Authority (EFSA) Panel on Nutrition, Novel Foods and Food Allergens, supported by the ad-hoc Working Group on sugars. Since only total sugars are subject to mandatory labelling in Europe and there are no analytical methods to distinguish between naturally-occurring, added and free sugars present in foods, available data on total sugars was used as starting point. Methods: A single European database for total sugars was developed from the information available in the national food composition databases included in the EFSA Nutrient Composition Database. A comprehensive data cleaning including outlier analysis was performed. Total sugars content of foods and beverages was checked in the online Mintel’s Global New Products Database according to the nutrition information indicated on the labels of the packaging. For each food category, the mean value of the corresponding available total sugar values was taken as a unique value. A systematic procedure developed from previous methods to estimate added and free sugars in foods was used to calculate or assign the best fitting added and free sugars values to the different food categories for which a total sugars value was available. Results: Estimates of intake for total, added and free sugars from all dietary sources will be obtained using food consumption data from the EFSA Comprehensive Food Consumption Database in combination with the developed food composition databases for total, added and free sugars. The intake of total/added/free sugars will be calculated at individual level by multiplying the average daily consumption of each food by the corresponding concentration of total/added/free sugars, summing up the respective intakes throughout the diet. Data on the contribution of different food groups to (total/added/free) sugars intake by survey and age group will also be presented. Discussion: The accuracy and uncertainty of the developed food composition databases is discussed in view of their use to estimate the intake of total, added and free sugars in different EU countries and age groups.
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| 5. |
- Knutsen, Helle Katrine, et al.
(författare)
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Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food.
- 2018
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Ingår i: EFSA journal. European Food Safety Authority. - : Wiley. - 1831-4732. ; 16:11
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Tidskriftsartikel (refereegranskat)abstract
- The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL-PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre- and postnatal exposure. The critical study showed a NOAEL of 7.0pg WHO2005-TEQ/g fat in blood sampled at age 9years based on PCDD/F-TEQs. No association was observed when including DL-PCB-TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panelestablished a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F-TEQ only was on average 2.4- and 2.7-fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL-PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panelwas not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.
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| 6. |
- Szucs, Edina, et al.
(författare)
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Synthesis, biochemical, pharmacological characterization and in silico profile modelling of highly potent opioid orvinol and thevinol derivatives
- 2020
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Ingår i: European Journal of Medicinal Chemistry. - : ELSEVIER. - 0223-5234 .- 1768-3254. ; 191
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Tidskriftsartikel (refereegranskat)abstract
- Morphine and its derivatives play inevitably important role in the m-opioid receptor (MOR) targeted antinociception. A structure-activity relationship study is presented for novel and known orvinol and thevinol derivatives with varying 3-O, 6-O, 17-N and 20-alkyl substitutions starting from agonists, antagonists and partial agonists. In vitro competition binding experiments with [H-3]DAMGO showed low subnanomolar affinity to MOR. Generally, 6-O-demethylation increased the affinity toward MOR and decreased the efficacy changing the pharmacological profile in some cases. In vivo tests in osteoarthritis inflammation model showed significant antiallodynic effects of thevinol derivatives while orvinol derivatives did not. The pharmacological character was modelled by computational docking to both active and inactive state models of MOR. Docking energy difference for the two states separates agonists and antagonists well while partial agonists overlapped with them. An interaction pattern of the ligands, involving the interacting receptor atoms, showed more efficient separation of the pharmacological profiles. In rats, thevinol derivatives showed antiallodynic effect in vivo. The orvinol derivatives, except for 6-O-desmethyl-dihydroetorfin (2c), did not show antiallodynic effect.
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| 7. |
- Ternell, Anna, et al.
(författare)
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Possibilities and challenges for landscape observatories
- 2023
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Ingår i: Ecocycles. - : Ecocycles. - 2416-2140. ; 9:1, s. 61-82
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Tidskriftsartikel (refereegranskat)abstract
- The twentieth century saw rapid environmental degradationdue to changes that contributed to increased net GHG emissions, loss of natural ecosystems, and declining biodiversity. Deterioration of unprotected landscapes during swift industrialization, urbanization, increasing monocultures in agriculture, expansion of commercial production significantly contributed to thesenegative consequences. However, a cultural shift occurred during the last two decades in favour of landscape conservation. In response to widespread landscape degradation and loss of ecosystem services, the Council of Europe saw the need to protect, manage, and develop the landscapes, and thus signed the European Landscape Convention (ELC) in 2000. This was the world's first international agreement that described all aspects of landscape management in detail. The European Landscape Convention fully meets the challenges through its goal of correcting a lack of understanding of landscapes as a unique system embracing natural, economic, and social features throughout Europe. It goes beyond simply protecting landscapes and addresses landscape management and development, as well as raising public and government awareness of the importance of paying attention to all types of landscapes, whether exceptional or spoiled. Landscapeobservatories, multifunctionalplatformsand knowledge centres for researchers, technicians, administrators, and citizens,are one of the Council of Europe's instruments for implementing the European Landscape Convention (ELC). They can be established on a variety of scales and can serve as a vital link between administrations, civil society, researchers, and the economic sector. This article discusses the emergenceof landscape observatories and the role they can play as decision support instruments in promoting sustainable landscape developmentthrough a regenerative approach. Additionally, the paper discusses the implementation of ELC in Västra Götaland in Sweden through the establishment of Landscape Observatory Västra Götaland, and its impacts and challenges associated with landscape development.Furthermore, we propose a comprehensive and holistic, to any landscape type adaptable landscape observatory concept, based on multifunctionality of these institutions, emphasizing their decision support roles, social and economic importance.
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| 8. |
- Valko, Zsuzsanna, et al.
(författare)
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Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer
- 2023
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 128:10, s. 1850-1861
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Tidskriftsartikel (refereegranskat)abstract
- Background: No targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies. Methods: Expression of BCL-2 family members in 27 SCLC cell lines representing all known four SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions were calculated using the Combenefit software. Ectopic BAX overexpression was achieved by expression plasmids. Results: The highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas the expression of other BCL-2 family members did not affect therapeutic efficacy. Combination of venetoclax and S63845 resulted in significant, synergistic in vitro and in vivo anti-tumour activity and apoptosis induction in double-resistant cells; however, this was seen only in a subset with detectable BAX. In non-responding cells, ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced synergistic drug interaction. Conclusions: The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.
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| 9. |
- Zhou, Qing, et al.
(författare)
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Persistence of ctDNA in breast cancer patients during neoadjuvant treatment is a significant predictor of poor tumour response.
- 2021
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 28:4, s. 697-707
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Tidskriftsartikel (refereegranskat)abstract
- Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally-invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions.We profiled 93 genes in tissue from 193 early breast cancer patients. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR), residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release.At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR 0.062, 95% CI 0.01-0.48, P=0.0077).Out of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were non-responders (RCB II, n=8; RCB III, n=22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, while 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result.Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.
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