| 1. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 2. |
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| 3. |
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| 4. |
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| 6. |
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| 7. |
- Berger, Susanne, et al.
(författare)
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WASP and SCAR have distinct roles in activating the Arp2/3 complex during myoblast fusion
- 2008
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 121:Pt 8, s. 1303-1313
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Tidskriftsartikel (refereegranskat)abstract
- Myoblast fusion takes place in two steps in mammals and in Drosophila. First, founder cells (FCs) and fusion-competent myoblasts (FCMs) fuse to form a trinucleated precursor, which then recruits further FCMs. This process depends on the formation of the fusion-restricted myogenic-adhesive structure (FuRMAS), which contains filamentous actin (F-actin) plugs at the sites of cell contact. Fusion relies on the HEM2 (NAP1) homolog Kette, as well as Blow and WASP, a member of the Wiskott-Aldrich-syndrome protein family. Here, we show the identification and characterization of schwächling--a new Arp3-null allele. Ultrastructural analyses demonstrate that Arp3 schwächling mutants can form a fusion pore, but fail to integrate the fusing FCM. Double-mutant experiments revealed that fusion is blocked completely in Arp3 and wasp double mutants, suggesting the involvement of a further F-actin regulator. Indeed, double-mutant analyses with scar/WAVE and with the WASP-interacting partner vrp1 (sltr, wip)/WIP show that the F-actin regulator scar also controls F-actin formation during myoblast fusion. Furthermore, the synergistic phenotype observed in Arp3 wasp and in scar vrp1 double mutants suggests that WASP and SCAR have distinct roles in controlling F-actin formation. From these findings we derived a new model for actin regulation during myoblast fusion.
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| 8. |
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| 9. |
- Bignert, Anders, et al.
(författare)
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Comments Concerning the National Swedish Contaminant Monitoring Programme in Marine Biota, 2015
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The environmental toxicants examined in this report can be classified into five groups – heavy metals, chlorinated compounds, brominated flame retardants, polyaromatic hydrocarbons and perfluorinated compounds. Each of these contaminants have been examined from various sites for up to six different fish species, in blue mussels, and in guillemot eggs, for varying lengths of time. The following summary examines overall trends, spatial and temporal, for the five groups.Condition and Fat ContentCondition and fat content in different species tended to follow the same pattern at the same sites, with a few exceptions. Most of the fish species generally displayed a decreasing trend in both condition and fat content at most sites examined. Exceptions to this were increases in condition factor seen in cod liver at Fladen, perch muscle at Kvädöfjärden, and for herring at Ängskärsklubb in spring. Also, an increase in fat content was seen during the most recent ten years for herring at Ängskärsklubb in spring. There were also some sites where no log linear trends were seen.Heavy MetalsDue to a change in methods for metal analysis (not mercury) in 2004, values between 2003 and 2007 should be interpreted with care. From 2009 metals are analyzed at ACES, Stockholm University.Generally, higher mercury concentrations are found in the Bothnian Bay, but also from one station in the Northern parts of Baltic Proper, compared to other parts of the Swedish coastline. The time series show varying concentrations over the study period. The longer time series in guillemot egg and spring-caught herring from the southern Bothnian Sea and southern Baltic Proper show significant decreases of mercury. On the other hand, increasing concentrations are seen in e.g., cod muscle, but the concentrations are fairly low compared to measured concentrations in perch from fresh water and coastal sites. In most cases, the mercury concentrations are above the EQSbiota of 20 ng/g wet weight.Lead is generally decreasing over the study period (in time series of sufficient length), supposedly due to the elimination of lead in gasoline. The highest concentrations are seen in the southern part of the Baltic Sea. Elevated lead concentrations between 2003 and 2007 (e.g. Harufjärden) should be viewed with caution (see above regarding change in analysis methods). Lead concentrations are below the suggested target level at all stations.Cadmium concentrations show varying non-linear trends over the monitored period. It is worth noting that despite several measures taken to reduce discharges of cadmium, generally the most recent concentrations are similar to concentrations measured 30 yearsago in the longer time series. Cadmium concentrations in herring and perch are all below the suggested target level of 160 μg/kg wet weight.The reported nickel concentrations show no consistent decreasing trends. Some series begin with two elevated values that exert a strong leverage effect on the regression line and may give a false impression of decreasing trends. Chromium generally shows decreasing concentrations, possibly explained by a shift in analytical method. The essential trace metals, copper and zinc, show no consistent trends during the monitored period.Generally higher concentrations of arsenic and silver are found along the west coast compared to other parts of the Sweadish coast line. However for silver a few stations in the Bothnian Sea and Bothnian Bay show comparable concentrations to the west coast stations.Chlorinated CompoundsGenerally, a decreasing concentrations were observed for all compounds (DDT’s, PCB’s, HCH’s, HCB) in all species examined, with a few exceptions, such as no change in TCDD-equivalents being seen in herring muscle (except at Änskärsklubb where very high concentrations at the beginning of the sampling period were seen and also at the west coast station Fladen). The longer time-series in guillemot also show a marked decrease in TCDD-equivalents from the start in the late 1960s until about 1985 from where no change occurred for many years, however, during the most recent ten years a decrease in the concentration is seen. Concentrations of DDE and CB-118 are for some species and sites still above their respective target levels.The chlorinated compounds generally show higher concentrations in the Bothnian Sea and/or Baltic Proper when compared to the Bothnian Bay and the Swedish west coast.Brominated Flame RetardantsElevated levels of HBCDD are seen in sites from the Baltic Proper, while the investigated PBDEs show higher concentrations in the Bothnian Bay. In addition, lower concentrations of all investigated PBDEs and HBCDD are seen on the Swedish west coast compared to the east coast. Temporally, significant increases in BDE-47, -99 and -100 have been seen in guillemot eggs since the late 1960s until the early 1990s, where concentrations then began to show decreases. Also, the concentration of HBCDD in guillemot eggs shows a decrease during the most recent ten years. For fish and blue mussels, BDE-47, -99, and -153 decreased at some sites and showed no trend at other sites. The concentration of HBCDD in fish and blue mussels showed inconsistent trends. The concentration of HBCDD is below the EQSbiota of 167 μg/kg wet weight for all fish species from all areas, while the concentration of BDE-47 alone is above the EQSbiota for sumPBDE of 0.0085 ng/g wet weight.PAHsOnly blue mussels have been examined for spatial differences in PAH concentrations. Concentration of ΣPAH was found to be higher from Kvädöfjärden in the Baltic Proper compared to stations at the West coast, but individual PAHs showed varying spatial patterns. Over time, acenaphthalene was rarely found above the detection limit. Significant decreasing trends were observed for ΣPAH, chrysene, fluoranthene and pyrene at Fjällbacka; for naphthalene at Kvädöfjärden; and for pyrene at Fladen.All time series where concentrations of various PAHs were compared with the target value based on OSPAR Ecological Assessment Criteria, or EC Environmental Quality Standards were below the target value.PFASsPFHxS and PFOS show a similar spatial pattern, but PFOS concentrations were approximately 25 times higher than PFHxS levels. The distribution of PFOS is quite homogenous along the Swedish coast but with somewhat higher concentrations in the Baltic Proper. PFOS concentrations in guillemot eggs are about 100-200 times higher than in herring liver. An overall increasing concentration of PFOS in guillemot eggs has been observed throughout the whole time period, however, during the most recent ten years, a change of direction is detected. The longer herring time series from Harufjärden, Landsort, and Utlängan show increasing concentrations for PFOS and most carboxylates. For FOSA, on the other hand, decreasing concentrations are seen during the most recent ten years.Organotin compoundsThe majority of the analysed tinorganic compounds showed concentrations below LOQ. However TBT and DPhT showed concentrations above LOQ at all stations with highest reported concentrations in fish from Örefjärden in the northern part of Bothnian Sea.
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| 10. |
- Galon, Jerome, et al.
(författare)
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Cancer classification using the Immunoscore : a worldwide task force
- 2012
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 10, s. 205-
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Forskningsöversikt (refereegranskat)abstract
- Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the ` Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
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| 11. |
- Galon, Jerome, et al.
(författare)
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Towards the introduction of the 'Immunoscore' in the classification of malignant tumours
- 2014
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Ingår i: Journal of Pathology. - : Wiley-Blackwell. - 0022-3417 .- 1096-9896. ; 232:2, s. 199-209
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Forskningsöversikt (refereegranskat)abstract
- The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
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| 12. |
- Kohls, Mirjam, et al.
(författare)
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Impact of cumulative body mass index and cardiometabolic diseases on survival among patients with colorectal and breast cancer : a multi-centre cohort study
- 2022
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Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Body mass index (BMI) and cardiometabolic comorbidities such as cardiovascular disease and type 2 diabetes have been studied as negative prognostic factors in cancer survival, but possible dependencies in the mechanisms underlying these associations remain largely unexplored. We analysed these associations in colorectal and breast cancer patients.Methods: Based on repeated BMI assessments of cancer-free participants from four European countries in the European Prospective Investigation into Cancer and nutrition (EPIC) study, individual BMI-trajectories reflecting predicted mean BMI between ages 20 to 50 years were estimated using a growth curve model. Participants with incident colorectal or breast cancer after the age of 50 years were included in the survival analysis to study the prognostic effect of mean BMI and cardiometabolic diseases (CMD) prior to cancer. CMD were defined as one or more chronic conditions among stroke, myocardial infarction, and type 2 diabetes. Hazard ratios (HRs) and confidence intervals (CIs) of mean BMI and CMD were derived using multivariable-adjusted Cox proportional hazard regression for mean BMI and CMD separately and both exposures combined, in subgroups of localised and advanced disease.Results: In the total cohort of 159,045 participants, there were 1,045 and 1,620 eligible patients of colorectal and breast cancer. In colorectal cancer patients, a higher BMI (by 1 kg/m2) was associated with a 6% increase in risk of death (95% CI of HR: 1.02–1.10). The HR for CMD was 1.25 (95% CI: 0.97–1.61). The associations for both exposures were stronger in patients with localised colorectal cancer. In breast cancer patients, a higher BMI was associated with a 4% increase in risk of death (95% CI: 1.00–1.08). CMDs were associated with a 46% increase in risk of death (95% CI: 1.01–2.09). The estimates and CIs for BMI remained similar after adjustment for CMD and vice versa.Conclusions: Our results suggest that cumulative exposure to higher BMI during early to mid-adulthood was associated with poorer survival in patients with breast and colorectal cancer, independent of CMD prior to cancer diagnosis. The association between a CMD diagnosis prior to cancer and survival in patients with breast and colorectal cancer was independent of BMI.
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| 13. |
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| 14. |
- Koponen, Jani, et al.
(författare)
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Longitudinal trends of per- and polyfluoroalkyl substances in children's serum
- 2018
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 121, s. 591-599
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Tidskriftsartikel (refereegranskat)abstract
- Studies suggest negative health impacts from early life exposure to per- and polyfluoroalkyl substances (PFASs). However, information on longitudinal exposure to PFASs during childhood is scarce for background-exposed individuals. This study sought to fill this gap by investigating children's longitudinal exposure trends through measurement of PFAS serum concentrations and calculation of body burdens (mu g, total in body). Blood of 54 Finnish children was sampled 2005-2015 and analyzed for 20 PFASs at 1, 6 and 10.5 years of age. The body burden was calculated by multiplying the serum concentration by the volume of distribution and the bodyweight for each individual. Associations between serum concentrations or body burdens and parameters, such as sex, breastfeeding duration, body mass index as well as indoor dust and air PFAS concentrations, were evaluated. Serum concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) decreased significantly (p < 0.001) with age. In contrast to serum concentrations, body burdens stayed unchanged or even increased significantly (p < 0.05), except for PFOA in female children. Breastfeeding duration was positively correlated (p < 0.001) with serum concentrations of PFHxS, PFOS, PFOA and PFNA at 1 year of age. Some associations were found at 10.5 years with sex and indoor PFAS concentrations. Observations of longitudinal decreasing trends of serum concentrations can be misleading for understanding exposure levels from external media during childhood, as the serum concentration is influenced by parallel temporal changes and growth dilution. Body burdens account for growth dilution and thus better reflect differences in early-life to adolescence exposure than serum concentrations.
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| 15. |
- Laskar, Tanmoy, et al.
(författare)
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The Radio to GeV Afterglow of GRB 221009A
- 2023
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 946:1
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Tidskriftsartikel (refereegranskat)abstract
- GRB 221009A ($z=0.151$) is one of the closest known long $gamma$-ray bursts (GRBs). Its extreme brightness across all electromagnetic wavelengths provides an unprecedented opportunity to study a member of this still-mysterious class of transients in exquisite detail. We present multi-wavelength observations of this extraordinary event, spanning 15 orders of magnitude in photon energy from radio to $gamma$-rays. We find that the data can be partially explained by a forward shock (FS) from a highly-collimated relativistic jet interacting with a low-density wind-like medium. The jet's beaming-corrected kinetic energy ($E_K sim 4times10<^>{50}$ erg) is typical for the GRB population, but its opening angle ($sim2<^>{circ}$) is one of the narrowest. The radio and mm data provide strong limiting constraints on the FS model, but require the presence of an additional emission component. From equipartition arguments, we find that the radio emission is likely produced by a small amount of mass ($lesssim6times10<^>{-7} M_odot$) moving relativistically ($Gammagtrsim9$) with a large kinetic energy ($gtrsim10<^>{49}$ erg). However, the temporal evolution of this component does not follow prescriptions for synchrotron radiation from a single power-law distribution of electrons (e.g. in a reverse shock or two-component jet), or a thermal electron population, perhaps suggesting that one of the standard assumptions of afterglow theory is violated. GRB 221009A will likely remain detectable with radio telescopes for years to come, providing a valuable opportunity to track the full lifecycle of a powerful relativistic jet.
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| 16. |
- Loza, M. J., et al.
(författare)
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Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
- 2016
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration:NCT01274507(ADEPT), registered October 28, 2010 and NCT01982162(U-BIOPRED), registered October 30, 2013.
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| 17. |
- Osorio, Ana, et al.
(författare)
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DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7×10-3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8×10-3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
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| 18. |
- Raschig, Judith, et al.
(författare)
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Ubiquitously expressed Human Beta Defensin 1 (hBD1) forms bacteria-entrapping nets in a redox dependent mode of action
- 2017
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Ingår i: PLoS Pathogens. - : PUBLIC LIBRARY SCIENCE. - 1553-7366 .- 1553-7374. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- Ever since the discovery of endogenous host defense antimicrobial peptides it has been discussed how these evolutionary conserved molecules avoid to induce resistance and to remain effective. Human beta-defensin 1 (hBD1) is an ubiquitously expressed endogenous antimicrobial peptide that exhibits qualitatively distinct activities between its oxidized and reduced forms. Here, we explore these antimicrobial mechanisms. Surprisingly, using electron microscopy we detected a so far unknown net-like structure surrounding bacteria, which were treated with the reduced but not the oxidized form of hBD1. A transmigration assay demonstrated that hBD1-derived nets capture bacteria and inhibit bacterial transmigration independent of bacterial killing. The presence of nets could completely prevent migration of hBD1 resistant pathogens and are stable in the presence of human duodenal secretion with a high amount of proteases. In contrast to HD6, cysteins are necessary for net formation. This redox-dependent function serves as an additional mechanism of action for hBD1 and differs from net formation by other defensins such as Paneth cell-derived human alpha-defensin 6 (HD6). While hBD1red and hBD1ox have distinct antimicrobial profiles and functions, only the reduced form provides additional host protection by entrapping bacteria in extracellular net structures preventing bacterial invasion. Better understanding of the modes of action of endogenous host peptides will help to find new antimicrobial strategies.
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| 19. |
- Urban, Mark C., et al.
(författare)
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When and how can we predict adaptive responses to climate change?
- 2024
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Ingår i: Evolution Letters. - : Oxford University Press. - 2056-3744. ; 8:1, s. 172-187
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Tidskriftsartikel (refereegranskat)abstract
- Predicting if, when, and how populations can adapt to climate change constitutes one of the greatest challenges in science today. Here, we build from contributions to the special issue on evolutionary adaptation to climate change, a survey of its authors, and recent literature to explore the limits and opportunities for predicting adaptive responses to climate change. We outline what might be predictable now, in the future, and perhaps never even with our best efforts. More accurate predictions are expected for traits characterized by a well-understood mapping between genotypes and phenotypes and traits experiencing strong, direct selection due to climate change. A meta-analysis revealed an overall moderate trait heritability and evolvability in studies performed under future climate conditions but indicated no significant change between current and future climate conditions, suggesting neither more nor less genetic variation for adapting to future climates. Predicting population persistence and evolutionary rescue remains uncertain, especially for the many species without sufficient ecological data. Still, when polled, authors contributing to this special issue were relatively optimistic about our ability to predict future evolutionary responses to climate change. Predictions will improve as we expand efforts to understand diverse organisms, their ecology, and their adaptive potential. Advancements in functional genomic resources, especially their extension to non-model species and the union of evolutionary experiments and "omics," should also enhance predictions. Although predicting evolutionary responses to climate change remains challenging, even small advances will reduce the substantial uncertainties surrounding future evolutionary responses to climate change. Preventing biological impacts from climate change will require accurate predictions about which species and ecosystems are most at risk and how best to protect them. Despite some progress, most predictive efforts still omit the potential for evolution to mediate climate change impacts. Here, we evaluate what is predictable now, in the future, and likely never based on recent literature, a survey of authors, and authors' contributions to a special issue on climate change evolution. Evidence indicates a growing ability to predict at least some components underlying evolutionary dynamics. For instance, the direct effects of climate change often alter natural selection regimes that could elicit evolutionary responses assuming sufficient additive genetic variation. We found no evidence for an increase or decrease in evolvability under future climate conditions, but we did find an overall moderate level of evolvability. However, the specific genetics underlying potential adaptive changes are still a "black box" that remains difficult to predict. We not only discuss the opportunities afforded by new genomic techniques to elucidate these genetic black boxes but also caution that the costs and limitations of such techniques for many species might not warrant their general practicality. We highlight further progress and challenges in predicting gene flow and population persistence, both of which can facilitate evolutionary rescue. We finish by listing ten activities that are needed to accelerate future progress in predicting climate change evolution. Despite the many complexities, we are relatively optimistic that evolutionary responses to climate change are becoming more accurate through time, especially assuming a more focused effort to fill key knowledge gaps in the coming years.
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| 20. |
- van den Oever, Selina R., et al.
(författare)
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Childhood cancer survivorship care during the COVID-19 pandemic : an international report of practice implications and provider concerns
- 2022
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Ingår i: Journal of Cancer Survivorship. - : Springer Science and Business Media LLC. - 1932-2259 .- 1932-2267. ; 16:6, s. 1390-1400
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Long-term follow-up (LTFU) care is essential to optimise health outcomes in childhood cancer survivors (CCS). We aimed to assess the impact of the COVID-19 pandemic on LTFU services and providers. Methods: A COVID-19 working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) distributed a questionnaire to LTFU service providers in 37 countries across Europe, Asia, North America, Central/South America, and Australia. The questionnaire assessed how care delivery methods changed during the pandemic and respondents’ level of worry about the pandemic’s impact on LTFU care delivery, their finances, their health, and that of their family and friends. Results: Among 226 institutions, providers from 178 (79%) responded. Shortly after the initial outbreak, 42% of LTFU clinics closed. Restrictions during the pandemic resulted in fewer in-person consultations and an increased use of telemedicine, telephone, and email consultations. The use of a risk assessment to prioritise the method of LTFU consultation for individual CCS increased from 12 to 47%. While respondents anticipated in-person consultations to remain the primary method for LTFU service delivery, they expected significantly increased use of telemedicine and telephone consultations after the pandemic. On average, respondents reported highest levels of worry about psychosocial well-being of survivors. Conclusions: The pandemic necessitated changes in LTFU service delivery, including greater use of virtual LTFU care and risk-stratification to identify CCS that need in-person evaluations. Implications for Cancer Survivors: Increased utilisation of virtual LTFU care and risk stratification is likely to persist post-pandemic.
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| 21. |
- Verbruggen, Lisanne C., et al.
(författare)
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Guidance regarding COVID-19 for survivors of childhood, adolescent, and young adult cancer : A statement from the International Late Effects of Childhood Cancer Guideline Harmonization Group
- 2020
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Ingår i: Pediatric Blood and Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 67:12
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Tidskriftsartikel (refereegranskat)abstract
- Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19.
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| 22. |
- Vigorito, Elena, et al.
(författare)
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Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
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| 23. |
- Voight, Benjamin F, et al.
(författare)
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Plasma HDL cholesterol and risk of myocardial infarction : a mendelian randomisation study
- 2012
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 380:9841, s. 572-580
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
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| 24. |
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| 25. |
- Winkens, Kerstin, et al.
(författare)
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Perfluoroalkyl acids and their precursors in floor dust of children's bedrooms - Implications for indoor exposure
- 2018
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 119, s. 493-502
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Tidskriftsartikel (refereegranskat)abstract
- We analysed floor dust samples from 65 children's bedrooms in Finland collected in 2014/2015 for 62 different per- and polyfluoroalkyl substances (PFASs) with a simple and highly efficient method. Validation results from the analysis of standard reference material (SRM) 2585 were in good agreement with literature data, while 24 PFASs were quantified for the first time. In the dust samples from children's bedrooms, five perfluoroalkyl carboxylic acids (PFCAs) and perfluorooctane sulfonic acid (PFOS) were detected in more than half of the samples with the highest median concentration of 5.26 ng/g for perfluorooctanoic acid (PFOA). However, the dust samples were dominated by polyfluoroalkyl phosphoric acid esters (PAPs) and fluorotelomer alcohols (FTOHs) (highest medians: 53.9 ng/g for 6:2 diPAP and 45.7 ng/g for 8:2 FTOH). Several significant and strong correlations (up to p = 0.95) were found among different PFASs in dust as well as between PFASs in dust and air samples (previously published) from the same rooms. The logarithm of dust to air concentrations (log K-dust/air) plotted against the logarithm of the octanol-air partition coefficient (log K-oa) resulted in a significant linear regression line with R-2 > 0.88. Higher dust levels of PFOS were detected in rooms with plastic flooring material in comparison to wood (p < 0.05). Total estimated daily intakes via dust (EDIdust) and air (EDIair) of perfluoroalkyl acids (PFAA), including biotransformation of precursors to PFAAs, were calculated for 10.5-year-old children. The total EDIdust, for PFOA and PFOS were estimated to be 0.007 ng/kg bw/day and 0.006 ng/kg bw/day, respectively, in an intermediate exposure scenario. The sum of the total EDIs for all PFAAs was slightly higher for dust than air (0.027 and 0.019 ng/kg bw/day). Precursor biotransformation was generally important for total PFOS intake, while for the PFCAs, FTOH biotransformation was estimated to be important for air, but not for dust exposure.
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| 26. |
- Winkens, Kerstin, et al.
(författare)
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Perfluoroalkyl acids and their precursors in indoor air sampled in children's bedrooms
- 2017
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491 .- 1873-6424. ; 222, s. 423-432
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Tidskriftsartikel (refereegranskat)abstract
- The contamination levels and patterns of perfluoroallcyl acids (PFAAs) and their precursors in indoor air of children's bedrooms in Finland, Northern Europe, were investigated. Our study is among the most comprehensive indoor air monitoring studies (n = 57) and to our knowledge the first one to analyse air in children's bedrooms for PFASs (17 PFAAs and 9 precursors, including two acrylates, 6:2 FTAC and 6:2 FTMAC). The most frequently detected compound was 8:2 fluorotelomer alcohol (8:2 FTOH) with the highest median concentration (3570 pg/m(3)). FTOH concentrations were generally similar to previous studies, indicating that in 2014/2015 the impact of the industrial transition had been minor on FTOH levels in indoor air. However, in contrast to earlier studies (with one exception), median concentrations of 6:2 FTOH were higher than 10:2 FTOH. The C8 PFAAs are still the most abundant acids, even though they have now been phased out by major manufacturers. The mean concentrations of FOSE/As, especially MeFOSE (89.9 pg/m(3)), were at least an order of magnitude lower compared to previous studies. Collectively the comparison of FTOHs, PFAAs and FOSE/FOSAs with previous studies indicates that indoor air levels of PFASs display a time lag to changes in production of several years. This is the first indoor air study investigating 6:2 FTMAC, which was frequently detected (58%) and displayed some of the highest maximum concentrations (13 000 pg/m(3)). There were several statistically significant correlations between particular house and room characteristics and PFAS concentrations, most interestingly higher EtFOSE air concentrations in rooms with plastic floors compared to wood or laminate.
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