| 1. |
- Ahearn, Thomas U., et al.
(författare)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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| 2. |
- Ahn, CM, et al.
(författare)
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A leukocyte elastase inhibitor reduces thrombin-induced pulmonary oedema in the rat : mechanisms of action
- 1998
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1094-5539 .- 1522-9629. ; 11:4, s. 291-299
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Tidskriftsartikel (refereegranskat)abstract
- The effect of a selective leukocyte elastase inhibitor, ICI 200,355, on thrombin-induced pulmonary oedema was studied in rats. Thrombin administration produced an increase in lung weight (P < 0.05), wet weight/ dry weight ratio (P < 0.05), and relative lung water content (P < 0.05). The lung weight increase was reduced by the elastase inhibitor in doses of 2000, 200 and 20 micrograms/kg per h (P < 0.05), but not by 2 micrograms/kg per h. A dose of 20 micrograms/ kg per h seems to be optimal, since 10-fold and 100-fold increases in dose did not further improve the effect. Free elastase activity in lung tissue was higher after thrombin infusion than in controls, but was not depleted by the elastase inhibitor in vivo (P < 0.05). This elastase activity in the lung was, however, inhibited by the elastase inhibitor in vitro, indicating that the inhibitor can block extracellular, but not intracellular elastase activity. Thrombin infusion resulted in a significant decrease in plasma elastase inhibitory capacity (P < 0.05), which was depleted by the elastase inhibitor (20 micrograms/kg per h) (P < 0.05). Myeloperoxidase activity was significantly increased in lung tissue after thrombin infusion (P < 0.05). Lung myeloperoxidase activity 5 min after thrombin infusion was not affected by the elastase inhibitor, but the inhibitor induced a further increase in myeloperoxidase as seen 90 min after thrombin infusion, indicating that the effect of this inhibitor on pulmonary oedema is not due to reduction of leukocyte infiltration in the lungs, but may partly be exerted by prevention of neutrophil destruction.
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| 3. |
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| 4. |
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| 5. |
- Ahn, Chul Min, et al.
(författare)
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Decreased lung hyaluronan in a model of ARDS in the rat : Effect of an inhibitor of leukocyte elastase
- 2012
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 117:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background. Hyaluronan (HA) is a component of the extracellular matrix in lung tissue and is normally present at low concentrations in blood. HA is rapidly cleared from blood by the liver. Increased concentrations of plasma HA have been found in patients with acute respiratory distress syndrome (ARDS). We investigated changes in HA levels in plasma, bronchoalveolar lavage fluid (BALF), and lung, and their relationship to pretreatment with a leukocyte elastase inhibitor in a rat model of ARDS. Methods. Rats were randomly assigned to three groups: control, thrombin, and thrombin plus elastase inhibitor. By use of a radiometric assay, HA was measured in lungs, BALF, and plasma. Tissue samples from the lungs were stained for HA and examined microscopically. Liver circulation and cardiac output were monitored using radiolabeled microspheres. Results. Infusion of thrombin produced a pronounced increase in wet weight to dry weight ratio, and relative lung water content. This increase was blunted by a leukocyte elastase inhibitor. A decrease in lung HA and increases in both BALF and plasma HA were found. The leukocyte elastase inhibitor counteracted not only the decrease in lung tissue HA, but also the increase in plasma HA. Histologically, there was decreased HA-staining of peribronchial and perivascular areas in the injured rat lung. Decreased liver perfusion was observed after infusion of thrombin. Conclusions. The decrease in lung HA may be involved in the development of pulmonary edema in this ARDS model, and leukocyte elastase may be one cause of this decrease. In addition, an elevated plasma HA level may be an indicator of lung injury.
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| 6. |
- Ahn, C.M., et al.
(författare)
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Effect of ibuprofen on thrombin-induced pulmonary edema in the rat
- 1994
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Ingår i: Pulmonary pharmacology. - : Elsevier BV. - 0952-0600. ; 7:6, s. 393-399
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Tidskriftsartikel (refereegranskat)abstract
- The effect of ibuprofen on thrombin-induced pulmonary edema was studied in rats. Thrombin infusion produced a significant increase in lung weight, wet weight/dry weight ratio and relative lung water content, a rise in mean pulmonary arterial pressure and a fall in mean systemic arterial pressure. It also caused a progressive decrease in PaO2 and a continuous increase in pH and PaCO2. Administration of either the S-isomer or R-isomer of ibuprofen at doses of 5 mg/kg body weight prior to thrombin infusion resulted in significant reduction in lung weight, wet weight/dry weight ratio and water content. The wet weight/dry weight ratio and the water content were somewhat lower after infusion of the S-isomer than of the R-isomer. Ibuprofen diminished the thrombin-induced increase in mean pulmonary arterial pressure and attenuated the early and late decrease in mean systemic arterial pressure caused by thrombin. Ibuprofen also stabilized thrombin-induced impairments in PaO2, PaCO2 and pH. The results thus indicate that ibuprofen effectively counteracts hemodynamic changes, stabilizes impairments in arterial blood gas variables and attenuates the increase in lung vascular permeability to protein with pulmonary edema caused by thrombin. The results also indicate a substantial R to S chiral inversion of ibuprofen in vivo in the rat.
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| 7. |
- Ahn, Chut Min, et al.
(författare)
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Effect of indomethacin on thrombin-induced pulmonary edema in the rat
- 1995
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 100:2, s. 125-135
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Tidskriftsartikel (refereegranskat)abstract
- The preventive effect of indomethacin on thrombin-induced pulmonary edema was studied in rats. Administration of thrombin caused a significant increase in lung weight, wet weight to dry weight ratio (WW/DW), and relative lung water content. During infusion of thrombin, mean pulmonary artery pressure rose and mean systemic artery pressure fell, PaO2 decreased progressively and there was a continuous rise in pH and PaCO2.An inhibitor of cyclooxygenase, indomethacin, at a dose of 1 mg/kg body weight, induced a significant further increase in lung weight (p<0.05), and a tendency towards an increase in WW/DW and water content compared with animals given thrombin alone. Treatment with indomethacin, however, counteracted the elevated pulmonary artery pressure occurring in the early phase after thrombin infusion, but not that in the late phase. Systemic artery pressure was not affected by indomethacin. The increases in pH and PaCO2 after thrombin infusion were attenuated and remained stable almost at baseline level after indomethacin administration. Indomethacin did not prevent the hypoxemia induced by thrombin infusion.In conclusion, although indomethacin prevented the early increase in pulmonary artery pressure due to thrombin and the decrease in pH and the increase in PaCO2, it caused lung vascular permeability to protein to increase more than with thrombin alone.
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| 8. |
- Andersson, Jacob
(författare)
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Aetiologies and Epidemiology of Subdural Haematoma in Infancy
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- According to scientific studies, subdural haematoma (SDH) in combination with retinal haemorrhage and encephalopathy (usually denoted as the triad) during infancy is highly specific for abusive head trauma/shaken baby syndrome, if a fall from over one meter, a traffic accident and certain medical conditions have been excluded. Other studies have challenged this notion since there are witnessed falls from less than one meter which has caused acute SDH, birth-related SDH which have been confirmed to develop into chronic SDH, and external hydrocephalus that can be complicated by a spontaneous SDH or an SDH from minor trauma.These aetiologies have not been taken into consideration in prior studies on abusive head trauma. An independent review on infant abusive shaking from the Swedish Agency for Health Technology Assessment concluded that there was insufficient evidence for determining the specificity of the triad for isolated shaking. The aim of this thesis was to increase the understanding of the aetiologies and the epidemiology of infant SDH. This was accomplished by studying registry data (Paper I and II), descriptive reviews of infants with SDH (paper I, III and IV) and infants subjected to witnessed or spontaneously admitted shaking (paper V).The maximum incidence of fatal AHT in Sweden, 0.6/100 000, was at least 10 times lower than in other Western countries and the risk of unreported fatal AHT was low (Paper I). A majority of the deceased infants had neonatal conditions, several were twins and/or preterm, one had a cerebral vascular condition, and one signs of metabolic disorder (Paper I). Approximately 12 infants every year are diagnosed with SDH beyond the first week of life and the case-fatality rate for all SDH diagnosis categories is 6.2% (Paper II). Males, preterm born and twins have a higher risk to develop SDH in general, and those having an abuse diagnosis had increased odds of being born preterm and small-for-gestational age (Paper II). Chronic SDH has a higher freqency of male and premature infants and a lower mortality rate than acute SDH (Paper III). Infants with chronic CSDH, but not with acute SDH, tend to have findings on neuroimaging and a head circumference that are suggestive of external hydrocephalus complicated by spontaneous SDH or SDH from minor trauma (Paper IV). Intracranial and ocular findings in infants subjected to abusive shaking were rare, seen in 2 out of 36 infants, both with pre-existing intracranial pathology, and of non-specific character (Paper V).In conclusion this thesis provides evidence that non-abusive aetiologies for SDH in infancy may have been overlooked in previous research.
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| 9. |
- Andersson, M.G., et al.
(författare)
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Application of the Bayesian framework for forensic interpretation to casework involving postmortem interval estimates of decomposed human remains
- 2019
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Ingår i: Forensic Science International. - : Elsevier BV. - 1872-6283 .- 0379-0738. ; 301, s. 402-414
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier B.V. We demonstrate how the Bayesian framework for forensic interpretation can be adapted for casework involving postmortem intervals (PMI) utilizing taphonomic data as well as how to overcome some of the limitations of current approaches for estimating and communicating uncertainty. A model is implemented for indoor cases based on partial body scores from three different anatomical regions as correlated functions of accumulated temperature (AT). The multivariate model enables estimation of PMI for human remains also when one or two local body scores are missing or undetermined, e.g. as a result of burns, scars or covered body parts. The model was trained using the expectation maximization algorithm, enabling us to account for uncertainty of PMI and/or ambient temperature in the training data. Alternative approaches reporting the results are presented, including the likelihood curve, likelihood ratios for competing hypotheses and posterior probability distributions and credibility intervals for PMI. The applicability or the approaches in different forensic scenarios is discussed.
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| 10. |
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| 11. |
- Ceciliason, Ann-Sofie, 1971-
(författare)
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Forensic taphonomy in an indoor setting : Implications for estimation of the post-mortem interval
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to determine if and how taphonomic data can be used to expand our knowledge concerning the decompositional process in an indoor setting, as well as adapting scoring-based methods for quantification of human decomposition, to increase the precision of post-mortem interval (PMI) estimates.In the first paper, the established methods of Total Body Score (TBS) and Accumulated Degree-Days (ADD) were investigated in an indoor setting, with results indicating a fairly low precision. The PMI was often underestimated in cases with desiccation and overestimated in cases with presence of insect activity. This suggests that the TBS method needs to be slightly modified to better reflect the indoor decompositional process.In the second paper, a novel method for PMI estimation was developed using histological assessment of decompositional changes in the human liver. The scoring-based method created, the Hepatic Decomposition Score, was a statistically robust way to quantify the degree of decomposition, with the potential to improve the precision of PMI estimates.In the third paper, the indoor decomposition process was further investigated regarding microbial neoformation of volatiles in relation to the degree of decomposition and the PMI. A higher decomposition degree was observed in cases with neoformation (i.e., presence of N-propanol and/or 1-butanol in femoral vein blood) than in cases without signs of neoformation. Microbial neoformation may be an indicator of decomposition rate, which may make it possible to improve the precision of PMI estimates based on the TBS/ADD method.In the fourth paper, a novel constructed Bayesian framework allowed a qualified estimate of PMI based on observed taphonomic findings. This framework provided a unique possibility to report results, express the uncertainties in assumptions and calculations, as well as to evaluate competing hypotheses regarding PMI periods or time of death.Taken as a whole, the results indicate that using taphonomic data derived from an indoor setting could improve scoring-based methods, as well as highlighting benefits of incorporating such data into a Bayesian framework for interpretational purposes and for reporting PMI estimates.
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| 12. |
- Ceciliason, Ann-Sofie, 1971-, et al.
(författare)
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Histological quantification of decomposed human livers : a potential aid for estimation of the post-mortem interval?
- 2021
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Ingår i: International journal of legal medicine. - : Springer Nature. - 0937-9827 .- 1437-1596. ; 135:1, s. 253-267
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to determine if a novel scoring-based model for histological quantification of decomposed human livers could improve the precision of post-mortem interval (PMI) estimation for bodies from an indoor setting. The hepatic decomposition score (HDS) system created consists of five liver scores (HDS markers): cell nuclei and cell structure of hepatocytes, bile ducts, portal triad, and architecture. A total of 236 forensic autopsy cases were divided into a training dataset (n = 158) and a validation dataset (n = 78). All cases were also scored using the total body score (TBS) method. We specified a stochastic relationship between the log-transformed accumulated degree-days (log10ADD) and the taphonomic findings, using a multivariate regression model to compute the likelihood function. Three models were applied, based on: (i) five HDS markers, (ii) three partial body scores (head, trunk, limbs), or (iii) a combination of the two. The predicted log10ADD was compared with the true log10ADD for each case. The fitted models performed equally well in the training dataset and the validation dataset. The model comprising both scoring methods had somewhat better precision than either method separately. Our results indicated that the HDS system was statistically robust. Combining the HDS markers with the partial body scores resulted in a better representation of the decomposition process and might improve PMI estimation of decomposed human remains.
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| 13. |
- Ceciliason, Ann-Sofie, et al.
(författare)
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Microbial neoformation of volatiles : implications for the estimation of post-mortem interval in decomposed human remains in an indoor setting
- 2021
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Ingår i: International journal of legal medicine. - : Springer Nature. - 0937-9827 .- 1437-1596. ; 135:1, s. 223-233
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to determine if a relationship between microbial neoformation of volatiles and the post-mortem interval (PMI) exists, and if the volatiles could be used as a tool to improve the precision of PMI estimation in decomposed human remains found in an indoor setting. Chromatograms from alcohol analysis (femoral vein blood) of 412 cases were retrospectively assessed for the presence of ethanol, N-propanol, 1-butanol, and acetaldehyde. The most common finding was acetaldehyde (83% of the cases), followed by ethanol (37%), N-propanol (21%), and 1-butanol (4%). A direct link between the volatiles and the PMI or the degree of decomposition was not observed. However, the decomposition had progressed faster in cases with microbial neoformation than in cases without signs of neoformation. Microbial neoformation may therefore act as an indicator of the decomposition rate within the early decomposition to bloating stages. This may be used in PMI estimation based on the total body score (TBS) and accumulated degree days (ADD) model, to potentially improve the model's precision.
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| 14. |
- Ceciliason, Ann-Sofie, 1971-, et al.
(författare)
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Microbial neoformation of volatiles: implications for the estimation of post-mortem interval in decomposed human remains in an indoor setting
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The objective of this study was to determine if a relationship between microbial neoformation of volatiles and the post-mortem interval (PMI) exists, and if the volatiles could be used as a tool to improve the precision of PMI estimation in decomposed human remains found in an indoor setting. Chromatograms from alcohol analysis (femoral vein blood) of 412 cases were retrospectively assessed for presence of ethanol, N-propanol, 1-butanol, and acetaldehyde. The most common finding was acetaldehyde (83% of the cases), followed by ethanol (37%), N-propanol (21%) and 1-butanol (4%). A direct link between the volatiles and the PMI or the degree of decomposition was not observed. However, the decomposition had progressed faster in cases with microbial neoformation than in cases without signs of neoformation. Microbial neoformation may therefore act as an indicator of the decomposition rate within the early decomposition to bloating stages. This may be used in PMI estimation based on the total body score (TBS) and accumulated-degree days (ADD) model, to potentially improve the model’s precision.
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| 15. |
- Ceciliason, Ann-Sofie, et al.
(författare)
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Mummification in a forensic context : an observational study of taphonomic changes and the post-mortem interval in an indoor setting
- 2023
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Ingår i: International journal of legal medicine. - : Springer Nature. - 0937-9827 .- 1437-1596. ; 137:4, s. 1077-1088
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate the presence of mummification in an indoor setting, with an emphasis on the forensic perspective. A dataset of 102 forensic autopsy cases was assessed for distribution of desiccation of skin and soft tissue (i.e., subcutaneous fat and musculature) and for moist decompositional (i.e., putrefactive) changes. Further, possible correlation with the post-mortem interval (PMI) was evaluated, as well as the effects of clothing coverage of the body. The results indicated that yellow to orange parchment-like desiccated skin was found at significantly shorter PMIs than reddish brown to black leathery desiccated skin, even when soft tissue desiccation was included in the comparative analysis. Clothing appeared to have a significant decelerating effect on the extent of desiccation on the legs, but findings in regard to whole body or torso/arms were inconclusive. A large variation in PMIs was evident as regards fully desiccated skin (PMI 18-217 days), indicating difficulties in PMI estimation due to a variable repressive effect on the decompositional process per se in an indoor setting. For the specific case in forensic practice, no definite conclusion can be drawn from the observed desiccation changes to the PMI. One way forward might be creating a systematic and standardized method for describing different desiccation types, as well as other cooccurring decompositional changes and how they relate to the PMI, as a foundation for a future quantification model.
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| 16. |
- Ceciliason, Ann-Sofie, et al.
(författare)
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Quantifying human decomposition in an indoor setting and implications for postmortem interval estimation
- 2018
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Ingår i: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 283, s. 180-189
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Tidskriftsartikel (refereegranskat)abstract
- This study's objective is to obtain accuracy and precision in estimating the postmortem interval (PMI) for decomposing human remains discovered in indoor settings. Data were collected prospectively from 140 forensic cases with a known date of death, scored according to the Total Body Score (TBS) scale at the post-mortem examination. In our model setting, it is estimated that, in cases with or without the presence of blowfly larvae, approximately 45% or 66% respectively, of the variance in TBS can be derived from Accumulated Degree-Days (ADD). The precision in estimating ADD/PMI from TBS is, in our setting, moderate to low. However, dividing the cases into defined subgroups suggests the possibility to increase the precision of the model. Our findings also suggest a significant seasonal difference with concomitant influence on TBS in the complete data set, possibly initiated by the presence of insect activity mainly during summer. PMI may be underestimated in cases with presence of desiccation. Likewise, there is a need for evaluating the effect of insect activity, to avoid overestimating the PMI. Our data sample indicates that the scoring method might need to be slightly modified to better reflect indoor decomposition, especially in cases with insect infestations or/and extensive desiccation. When applying TBS in an indoor setting, the model requires distinct inclusion criteria and a defined population.
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| 17. |
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| 18. |
- Coignard, J, et al.
(författare)
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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 1078-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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| 19. |
- Dareng, EO, et al.
(författare)
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- 2022
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 30:3, s. 349-362
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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| 20. |
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| 21. |
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| 22. |
- Jiang, X., et al.
(författare)
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Shared heritability and functional enrichment across six solid cancers
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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| 23. |
- Johansson, Anna, et al.
(författare)
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A non-fatal intoxication and seven deaths involving the dissociative drug 3-MeO-PCP
- 2017
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Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 275, s. 76-82
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: 3-methoxyphencyclidine (3-MeO-PCP) appeared on the illicit drug market in 2011 and is an analogue of phencyclidine, which exhibits anesthetic, analgesic and hallucinogenic properties. In this paper, we report data from a non-fatal intoxication and seven deaths involving 3-MeO-PCP in Sweden during the period March 2014 until June 2016. Case descriptions: The non-fatal intoxication case, a 19-year-old male with drug problems and a medical history of depression, was found awake but tachycardic, hypertensive, tachypnoeic and catatonic at home. After being hospitalized, his condition worsened as he developed a fever and lactic acidosis concomitant with psychomotor agitation and hallucinations. After 22 h of intensive care, the patient had made a complete recovery. During his hospitalization, a total of four blood samples were collected at different time points. The seven autopsy cases, six males and one female, were all in their twenties to thirties with psychiatric problems and/or an ongoing drug abuse. Methods: 3-MeO-PCP was identified with liquid chromatography (LC)/time-of-flight technology and quantified using LC-tandem mass spectrometry. Results: In the clinical case, the concentration of 3-MeO-PCP was 0.14 mu g/g at admission, 0.08 mu g/g 2.5 h after admission, 0.06 mu g/g 5 h after admission and 0.04 mu g/g 17 h after admission. The half-life of 3-MeO-PCP was estimated to 11 h. In the autopsy cases, femoral blood concentrations ranged from 0.05 mu g/g to 0.38 mu g/g. 3-MeO-PCP was the sole finding in the case with the highest concentration and the cause of death was established as intoxication with 3-MeO-PCP. In the remaining six autopsy cases, other medications and drugs of abuse were present as well. Conclusion: Despite being scheduled in January 2015, 3-MeO-PCP continues to be abused in Sweden. Exposure to 3-MeO-PCP may cause severe adverse events and even death, especially if the user does not receive life-supporting treatment.
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| 24. |
- Johansson, Anna, et al.
(författare)
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Quantitation of seven sedative and analgesic drugs in whole blood from intensive care patients using liquid chromatography mass spectrometry
- 2021
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Ingår i: TOXICOLOGIE ANALYTIQUE ET CLINIQUE. - : Elsevier. - 2352-0078 .- 2352-0086. ; 33:4, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- We present the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of clonidine, dexmedetomidine, fentanyl, ketamine, ketobemidone, midazolam and morphine in whole blood. These are drugs predominately used in intensive care units (ICUs) but they are also encountered in forensic investigations. The analytes were recovered from 0.25 g of blood by protein precipitation with a mixture of acetonitrile and ethanol. Separation was performed on a BEH phenyl column. Mobile phases consisted of 0.05% formic acid in 10 mM ammonium formate and 0.05% formic acid in methanol, respectively, and the flow rate was 600 mu L/min. The mass spectrometer was operated in positive electrospray ionization mode with multiple reaction monitoring. Validation included selectivity, qualitative matrix effects, calibration model, limit of detection, lower limit of quantification, within- and between-day accuracy and precision, process efficiency, dilution integrity, carry over and stability. Selectivity was high and no ion suppression or enhancementwas observed in the areas were the analytes eluted. Calibration curves were linear over arange of 0.25-50 ng/g for dexmedetomidine, 0.05-50 ng/g for fentanyl and 5.0-500 ng/g formorphine and quadratic over a range of 0.5-50 ng/g for clonidine, 50-5000 ng/g for ketamine, 5.0-500 ng/g for ketobemidone and midazolam. The method showed acceptable within- and betweenday accuracies and precisions. All analytes were stable in whole blood for three weeksat 4. C. Concentrations in patient samples ranged between 42-760 ng/g for midazolam (n = 15), 0.3-1.5 ng/g for dexmedetomidine (n = 13), 0.6-6.4 ng/g for clonidine (n = 13), 8-62 ng/g for morphine (n = 16), 5-19 ng/g for ketobemidone (n = 5), 0.07-3.1 ng/g for fentanyl (n = 43), and 562000 ng/g for ketamine (n = 10). We conclude that the method was successfully validatedand applied to ante-mortem and post-mortem blood samples from critically ill adult patientsin a general ICU.
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| 25. |
- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 26. |
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| 27. |
- Li, Xiaogai, et al.
(författare)
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Infant skull fractures : Accident or abuse? Evidences from biomechanical analysis using finite element head models
- 2019
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Ingår i: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 294, s. 173-182
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Tidskriftsartikel (refereegranskat)abstract
- Abusive Head Trauma (AHT) is considered by some authors to be a leading cause of traumatic death in children less than two years of age and skull fractures are commonly seen in cases of suspected AHT. Today, diagnosing whether the observed fractures are caused by abuse or accidental fall is still a challenge within both the medical and the legal communities and the central question is a biomechanical question: can the described history explain the observed fractures? Finite element (FE) analysis has been shown a valuable tool for biomechanical analysis accounting for detailed head geometry, advanced material modelling, and case-specific factors (e.g. head impact location, impact surface properties). Here, we reconstructed two well-documented suspected abuse cases (a 3- and a 4-month-old) using subject-specific FE head models. The models incorporate the anatomical details and age-dependent anisotropic material properties of infant cranial bones that reflect the grainy fibres radiating from ossification centres. The impact locations are determined by combining multimodality images. The results show that the skull fracture patterns in both cases of suspected abuse could be explained by the described accidental fall history, demonstrating the inherent potential of FE analysis for providing biomechanical evidence to aid forensic investigations. Increased knowledge of injury mechanisms in children may have enormous medico-legal implications world-wide.
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| 28. |
- Li, Xiaogai, et al.
(författare)
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The importance of nonlinear tissue modelling in finite element simulations of infant head impacts
- 2017
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Ingår i: Biomechanics and Modeling in Mechanobiology. - : Springer Berlin/Heidelberg. - 1617-7959 .- 1617-7940. ; 16:3, s. 823-840
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Tidskriftsartikel (refereegranskat)abstract
- Despite recent efforts on the development of finite element (FE) head models of infants, a model capable of capturing head responses under various impact scenarios has not been reported. This is hypothesized partially attributed to the use of simplified linear elastic models for soft tissues of suture, scalp and dura. Orthotropic elastic constants are yet to be determined to incorporate the direction-specific material properties of infant cranial bone due to grain fibres radiating from the ossification centres. We report here on our efforts in advancing the above-mentioned aspects in material modelling in infant head and further incorporate them into subject-specific FE head models of a newborn, 5- and 9-month-old infant. Each model is subjected to five impact tests (forehead, occiput, vertex, right and left parietal impacts) and two compression tests. The predicted global head impact responses of the acceleration-time impact curves and the force-deflection compression curves for different age groups agree well with the experimental data reported in the literature. In particular, the newly developed Ogden hyperelastic model for suture, together with the nonlinear modelling of scalp and dura mater, enables the models to achieve more realistic impact performance compared with linear elastic models. The proposed approach for obtaining age-dependent skull bone orthotropic material constants counts both an increase in stiffness and decrease in anisotropy in the skull bone-two essential biological growth parameters during early infancy. The profound deformation of infant head causes a large stretch at the interfaces between the skull bones and the suture, suggesting that infant skull fractures are likely to initiate from the interfaces; the impact angle has a profound influence on global head impact responses and the skull injury metrics for certain impact locations, especially true for a parietal impact.
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| 29. |
- Lu, Yingchang, et al.
(författare)
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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
- 2018
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:18, s. 5419-5430
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Tidskriftsartikel (refereegranskat)abstract
- .AbstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
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| 34. |
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| 35. |
- Sandberg, Monica, 1964-
(författare)
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Intracellular Degradation of Insulin in Pancreatic Islets
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is a substantial intracellular degradation of insulin in pancreatic islets. This may be a physiological process, which, in correspondence with biosynthesis and secretion of insulin, would optimize the secretory granule content of the pancreatic β-cell. Insulin degradation may be effected by crinophagy, a process where secretory granules fuse with lysosomes. The general aim of this thesis was to investigate possible control mechanisms for intracellular degradation of insulin and crinophagy in isolated pancreatic islets. In islets incubated at low glucose concentrations there was an insulin degradation and this correlated well with the ultrastructural findings, where a lot of secondary lysosomes containing secretory granules were found. In islets incubated at a high glucose concentration there was no insulin degradation and the ultrastructure revealed only a few insulin granules and mostly primary lysosomes, indicating that there was no crinophagic activity. With interleukin-1β the islet insulin degradation, nitric oxide production and prostaglandin E2 production were increased. The effects were abolished either by inhibition of inducible nitric oxide synthetase by aminoguanidine, or by the specific cyclooxygenase-2 inhibitor rofecoxib. These findings indicate that there is a connection between the intracellular degradation of insulin, production of nitric oxide and cyclooxygenase-2 activation. The nitric oxide donor DETA/NO enhanced the intracellular degradation of insulin and cyclooxygenase-2 activation with subsequent production of prostaglandin E2, suggesting that the link between nitric oxide and insulin degradation may be a cyclooxygenase-2 activation and subsequent prostaglandin E2 production. With corticosterone added to islet incubations the insulin degradation decreased, which paralleled with a diminished crinophagy and formation of prostaglandin E2. With progesterone there was instead an increase in insulin degradation and crinophagy and an increased formation of prostaglandin E2. These effects were abolished by mifepristone, an inhibitor of intracellular corticosterone and progesterone receptors. This suggests that the effects from these steroids are exerted via a change in islet gene expression and cyclooxygenase-2 activation. It was also concluded that phospholipase A2 is involved in insulin degradation and that the isoform secretory phospholipase A2 may be involved in triggering this process. This suggests that cyclooxygenase-2 activation with a subsequent production of prostaglandin E2 may provide a control mechanism for intracellular degradation of insulin and crinophagy in pancreatic islets.
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| 36. |
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| 37. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 38. |
- Smekal, David, et al.
(författare)
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Comparison of computed tomography and autopsy in detection of injuries after unsuccessful cardiopulmonary resuscitation
- 2013
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 84:3, s. 357-360
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Tidskriftsartikel (refereegranskat)abstract
- AIM:Computed tomography (CT) has been suggested as an aid or even a replacement for autopsy. The aim of this trial was to study the conformity of the two methods in finding injuries in non-surviving patients after unsuccessful cardiopulmonary resuscitation.METHODS:In this prospective study, 31 patients were submitted to a CT prior to autopsy after unsuccessful resuscitation attempts. Pathological findings were noted by both the radiologist and the pathologists in a specified protocol. The pathologists and radiologist were blinded from each other's results.RESULTS: CT and autopsy revealed rib fractures in 22 and 24 patients respectively (kappa=0.83). In 8 patients, CT revealed more rib fractures than autopsy; and in 12 patients, autopsy revealed more rib fractures than CT. In 7 patients, neither method showed any rib fractures. The mean difference between the two methods in detecting rib fractures was 0.16 (S.D.: ±3.174, limits of agreement: -6.19 to 6.51). The kappa value for sternal fractures was 0.49. A total of 260 pathological findings were noted by CT and 244 by autopsy. The average patient showed a median of 9 injuries (every fracture counted as one injury), independent of the method used in detecting the injuries.CONCLUSIONS:There was a strong concordance between the two methods in finding rib fractures but not sternal fractures and these results support the concept of CT as a valuable complement to autopsy in detecting rib fractures after unsuccessful cardiopulmonary resuscitation but not as a replacement. Other injuries did not show the same concordance.
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| 39. |
- Smekal, David, 1971-, et al.
(författare)
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CPR related injuries after manual or mechanical chest compressions with the LUCAS™ device : A multicentre study in victims after unsuccessful resuscitation
- 2014
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 85:12, s. 1708-1712
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The reported incidence of injuries due to cardiopulmonary resuscitation using manual chest compressions (manual CPR) varies greatly. Our aim was to elucidate the incidence of CPR-related injuries by manual chest compressions compared to mechanical chest compressions with the LUCAS device (mechanical CPR) in non-survivors after out-of-hospital cardiac arrest.METHODS: In this prospective multicentre trial, including 222 patients (83 manual CPR/139 mechanical CPR), autopsies were conducted after unsuccessful CPR and the results were evaluated according to a specified protocol.RESULTS: Among the patients included, 75.9% in the manual CPR group and 91.4% in the mechanical CPR group (p=0.002) displayed CPR-related injuries. Sternal fractures were present in 54.2% of the patients in the manual CPR group and in 58.3% in the mechanical CPR group (p=0.56). Of the patients in the manual CPR group, there were 64.6% with at least one rib fracture versus 78.8% in the mechanical CPR group (p=0.02). The median number of rib fractures among patients with rib fractures was 7 in the manual CPR group and 6 in the mechanical CPR group. No CPR-related injury was considered to be the cause of death.CONCLUSION: In patients with unsuccessful CPR after out-of-hospital cardiac arrest, rib fractures were more frequent after mechanical CPR but there was no difference in the incidence of sternal fractures. No injury was deemed fatal by the pathologist.
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| 40. |
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| 41. |
- Yang, Yaohua, et al.
(författare)
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Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk
- 2019
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:3, s. 505-517
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 x 10(-7). Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
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| 42. |
- Yang, Yaohua, et al.
(författare)
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Genetically Predicted Levels of DNA Methylation Biomarkers and Breast Cancer Risk : Data From 228 951 Women of European Descent
- 2020
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 112:3, s. 295-304
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women's Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10-7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.
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| 43. |
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