| 1. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
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| 3. |
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| 4. |
- Adam, A, et al.
(författare)
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Abstracts from Hydrocephalus 2016.
- 2017
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14:Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 6. |
- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 12. |
- Amendola, L., et al.
(författare)
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Cosmology and fundamental physics with the Euclid satellite
- 2018
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Ingår i: Living Reviews in Relativity. - : Springer. - 1433-8351 .- 2367-3613. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Euclid is a European Space Agency medium-class mission selected for launch in 2020 within the cosmic vision 2015–2025 program. The main goal of Euclid is to understand the origin of the accelerated expansion of the universe. Euclid will explore the expansion history of the universe and the evolution of cosmic structures by measuring shapes and red-shifts of galaxies as well as the distribution of clusters of galaxies over a large fraction of the sky. Although the main driver for Euclid is the nature of dark energy, Euclid science covers a vast range of topics, from cosmology to galaxy evolution to planetary research. In this review we focus on cosmology and fundamental physics, with a strong emphasis on science beyond the current standard models. We discuss five broad topics: dark energy and modified gravity, dark matter, initial conditions, basic assumptions and questions of methodology in the data analysis. This review has been planned and carried out within Euclid’s Theory Working Group and is meant to provide a guide to the scientific themes that will underlie the activity of the group during the preparation of the Euclid mission.
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| 13. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 14. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 15. |
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| 16. |
- Murumagi, A, et al.
(författare)
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Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma
- 2023
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 128:4, s. 678-690
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Tidskriftsartikel (refereegranskat)abstract
- Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.
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| 17. |
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| 18. |
- Leinonen, V, et al.
(författare)
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Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.
- 2013
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 20:7, s. 1043-52
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical biopsy.METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain.RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-β levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003).CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-β in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-β pathology, both in patients with possible NPH and among the wider population.
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| 19. |
- Kemppinen, A, et al.
(författare)
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MYO9B polymorphisms in multiple sclerosis
- 2009
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 17:6, s. 840-843
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Tidskriftsartikel (refereegranskat)
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| 20. |
- Janhunen, P., et al.
(författare)
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Invited Article: Electric solar wind sail : Toward test missions
- 2010
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 81:11, s. 111301-
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Tidskriftsartikel (refereegranskat)abstract
- The electric solar wind sail (E-sail) is a space propulsion concept that uses the natural solar wind dynamic pressure for producing spacecraft thrust. In its baseline form, the E-sail consists of a number of long, thin, conducting, and centrifugally stretched tethers, which are kept in a high positive potential by an onboard electron gun. The concept gains its efficiency from the fact that the effective sail area, i.e., the potential structure of the tethers, can be millions of times larger than the physical area of the thin tethers wires, which offsets the fact that the dynamic pressure of the solar wind is very weak. Indeed, according to the most recent published estimates, an E-sail of 1 N thrust and 100 kg mass could be built in the rather near future, providing a revolutionary level of propulsive performance (specific acceleration) for travel in the solar system. Here we give a review of the ongoing technical development work of the E-sail, covering tether construction, overall mechanical design alternatives, guidance and navigation strategies, and dynamical and orbital simulations.
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| 21. |
- Leinonen, V., et al.
(författare)
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S- F-18 THK-5117-PET and C-11 PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-beta Plaques and Tau in Brain Biopsies
- 2018
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 64:1, s. 171-179
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Tidskriftsartikel (refereegranskat)abstract
- Background: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[F-18] THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[F-18] THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. Objective: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[F-18] THK-5117, and [C-11] PIB PET against tau and amyloid lesions in brain biopsy. Methods: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF A beta(1-42), total tau, and P-tau(181) measures, underwent brain MRI, [C-11] PIB PET, and S-[F-18] THK-5117 PET imaging. Results: Seven patients had amyloid-beta(A beta, 4G8) plaques, two both A beta and phosphorylated tau (P tau, AT8) and one only P tau in biopsy. As expected, increased brain biopsy A beta was well associated with higher [C-11] PIB uptake in PET. However, S-[F-18] THK-5117 uptake did not show any statistically significant correlation with either brain biopsy P tau or CSF P-tau(181) or total tau. Conclusions: S-[F-18] THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous A beta and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.
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| 22. |
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| 23. |
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| 24. |
- Pyykkö, O. T., et al.
(författare)
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APOE4 predicts amyloid-β in cortical brain biopsy but not idiopathic normal pressure hydrocephalus
- 2012
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 83:11, s. 1119-1124
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the association of apolipoprotein E (APOE) genotype, especially the APOE4 allele, to (1) idiopathic normal pressure hydrocephalus (iNPH) and (2) amyloid-β (Aβ) plaques in cortical brain biopsies of presumed NPH patients with and without a final clinical diagnosis of Alzheimer's disease (AD). Methods: 202 patients with presumed NPH were evaluated by intraventricular pressure monitoring and frontal cortical biopsy immunostained against Aβ (134 semiquantified by Aβ plaques/mm 2). The 202 patients and 687 cognitively healthy individuals were genotyped for APOE. The final clinical diagnoses in a median follow-up of 3.9 years were: 113 iNPH (94 shunt responsive, 16 shunt non-responsive, three not shunted); 36 AD (12 mixed iNPH + AD); 53 others. Results: The APOE genotypes distributed similarly in the 94 shunt responsive and 16 non-responsive iNPH patients and healthy controls. In multivariate analysis, the APOE4 allele correlated independently with Aβ plaques in the cortical biopsies (OR 8.7, 95% CI 3.6 to 20, p<0.001). The APOE4 allele in presumed NPH predicted later AD as follows: sensitivity 61%; specificity 77%; positive predictive value 37%; negative predictive value 90%. Conclusion: In presumed NPH patients, APOE4 associates independently with the presence of Aβ plaques in the frontal cortical biopsy. APOE4 is not a risk factor for iNPH and does not predict the response to shunt. Our data further support the view that the iNPH syndrome is a distinct dementing disease.
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| 25. |
- Vanninen, A., et al.
(författare)
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Cerebrospinal Fluid Diagnostics of Alzheimer's Disease in Patients with Idiopathic Normal Pressure Hydrocephalus
- 2023
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Ingår i: Journal of Alzheimers Disease. - 1387-2877. ; 94:2, s. 727-736
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide and a frequent comorbidity in idiopathic normal pressure hydrocephalus (iNPH). The presence of AD pathology is associated with worse outcomes after a shunt procedure in iNPH. Preoperative diagnosis of AD is challenging in patients with iNPH, which involves reduced concentrations of the cerebrospinal fluid (CSF) AD biomarkers. Objective: Our aim was to estimate the effect size of iNPH as a factor in CSF levels of AD biomarkers and to test if correction could be used to improve diagnostic value. Methods: Our cohort included 222 iNPH patients with data in the Kuopio NPH registry and brain biopsy and CSF samples available. We divided the patients into groups according to AD pathology per brain biopsy. For control cohorts, we had CSF samples from cognitively healthy individuals (n = 33) and patients with diagnosed AD and no iNPH (n = 39). Results: Levels of all investigated biomarkers differed significantly between groups, with the exception of t-Tau levels between healthy individuals and iNPH patients with AD pathology. Applying a correction factor for each biomarker (0.842*A beta(1-42), 0.779*t-Tau, and 0.610*P-Tau181) for the effect of iNPH yielded a sensitivity of 2.4% and specificity of 100%. The ratio of P-Tau(181) to A beta(1-42) was moderately effective in aiding recognition of AD pathology in iNPH patients (sensitivity 0.79, specificity 0.76, area under the curve 0.824). Conclusion: Correcting for iNPH as a factor failed to improve diagnostic effectiveness, but the P-Tau(181)/A beta(1-42) ratio showed some utility in the diagnosis of AD in iNPH patients.
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| 26. |
- Walther, G, et al.
(författare)
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Report on challenges for SCIs
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report discusses the challenges posed by four types of threats – terrorist attacks, cyber-attacks, extreme weather and social unrest – on the following eight smart critical infrastructure systems:a.ALPHA - Finance (financial system): The analysis focuses on disturbed information flow and disabling/manipulating IT and communication systems, including attacks on the “physical layer” using the example of IEMI/HPEM threats, as well as the software layer.b. BRAVO - Energy supply (system): The analysis focuses on disruption of “smart” energy supply in a “smart city”, caused by natural hazards, in this case flooding, leading to cascading effects and severe consequences for other energy-depending SCIs.c. CHARLIE - Health care (system):Focus of the analysis is on all threats that might cause large increases in the numbers of injuries or sick patients within a densely populated area. This will include indirect impacts, e.g. large numbers of injuries caused by a disaster or terrorist attacks or disease epidemics, but also direct impacts, e.g. service disruptions in critical health infrastructures, such as hospitals, due to attacks or disasters hitting the infrastructure itself.d.DELTA - Transportation (system) – airports: According to the framework situation, threats on Smart Airports will be assessed under circumstances of (i) blocked traffic, (ii) passenger and airplane traffic exceeding capacity (iii) flood.e. ECHO - Industry (in zones in cities) "Industrial Production Plants":The analysis focuses mainly on technological accidents within the refinery complex, but also accidents caused by natural hazards affecting refinery property outside the main refinery complex, e.g. accident on jetty belonging to refinery on the river Danube during unloading/loading oil products from barge to a tank, damages by a gale or storm on process installations (pipes, hoses) resulting in river pollution. Both scenarios could lead to cascading effects for other SCIs in close vicinity.f. FOXTROT - Water supply (systems): The analysis focuses on three cases of local and regional drinking water supply chains, with different kinds of vulnerabilities in terms of climate threats, ICT challenges, security issues and human error.g.GOLF - Urban flood protection (systems): The analysis focuses in the disruption of water and transport caused through tidal and fluvial flooding events.h. HOTEL: City of Helsinki - Flooding underground coal storage. Resilience of the energy infrastructure (city environment).The way this analysis was conducted was by assessing these threats using a 5x5 framework matrix. The two axes of the matrix were phases (understand risks, anticipate/prepare, absorb/withstand, respond/recover, adapt/learn) and dimensions (system/physical, information/data, organizational/business, societal/political, cognitive/decision-making).Each individual matrix block was discussed by subject experts who identified specific challenges and implications for each matrix element and rated its relevance (high, medium, low).In terms of the results, the system/physical dimension received the highest number of important challenges.Overall, the most important singular element was to understand risks in the organizational/business dimension. The least importance was attributed to the adapt/learn phase.
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| 27. |
- Ciavola, G., et al.
(författare)
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Status report of the MS-ECRIS construction
- 2007
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Ingår i: High Energy Physics & Nuclear Physics - Chinese Edition. - 0254-3052. ; 31, s. 13-17
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Tidskriftsartikel (refereegranskat)abstract
- The design of each component of the Multipurpose Superconducting ECR Ion Source (MS-ECRIS) has been completed and some items are ready. The magnets and the cryostat are under construction at ACCEL and the commissioning is scheduled for March 2007. The mechanical have been optimized and their construction is under way, the microwave system is under refurbishment and the 65kV power supply is available and upgraded for afterglow operations. Pumping and extraction system were adapted to the EIS testbench of GSI Darmstadt. The description of,each part will be given in the paper along with a schedule of the forthcoming development and experiments.
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| 28. |
- Ciavola, G., et al.
(författare)
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Status report of the multipurpose superconducting electron cyclotron resonance ion source
- 2008
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 79:2, s. 02A326-
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Tidskriftsartikel (refereegranskat)abstract
- Intense heavy ion beam production with electron cyclotron resonance (ECR) ion sources is a common requirement for many of the accelerators under construction in Europe and elsewhere. An average increase of about one order of magnitude per decade in the performance of ECR ion sources was obtained up to now since the time of pioneering experiment of R. Geller at CEA, Grenoble, and this trend is not deemed to get the saturation at least in the next decade, according to the increased availability of powerful magnets and microwave generators. Electron density above 1013 cm(-3) and very high current of multiply charged ions are expected with the use of 28 GHz microwave heating and of an adequate plasma trap, with a B-minimum shape, according to the high B mode concept [S. Gammino and G. Ciavola, Plasma Sources Sci. Technol. 5, 19 (1996)]. The MS-ECRIS ion source has been designed following this concept and its construction is underway at GSI, Darmstadt. The project is the result of the cooperation of nine European institutions with the partial funding of EU through the sixth Framework Programme. The contribution of different institutions has permitted to build in 2006-2007 each component at high level of expertise. The description of the major components will be given in the following with a view on the planning of the assembly and commissioning phase to be carried out in fall 2007. An outline of the experiments to be done with the MS-ECRIS source in the next two years will be presented.
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| 29. |
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| 30. |
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| 31. |
- Kainu, T, et al.
(författare)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Barenkamp, Stephen J., et al.
(författare)
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Panel 4 : Report of the Microbiology Panel
- 2017
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Ingår i: Otolaryngology - Head and Neck Surgery. - : Wiley. - 0194-5998 .- 1097-6817. ; 156:4_suppl, s. 51-62
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To perform a comprehensive review of the literature from July 2011 until June 2015 on the virology and bacteriology of otitis media in children. Data Sources: PubMed database of the National Library of Medicine. Review Methods: Two subpanels comprising experts in the virology and bacteriology of otitis media were created. Each panel reviewed the relevant literature in the fields of virology and bacteriology and generated draft reviews. These initial reviews were distributed to all panel members prior to meeting together at the Post-symposium Research Conference of the 18th International Symposium on Recent Advances in Otitis Media, National Harbor, Maryland, in June 2015. A final draft was created, circulated, and approved by all panel members. Conclusions: Excellent progress has been made in the past 4 years in advancing our understanding of the microbiology of otitis media. Numerous advances were made in basic laboratory studies, in animal models of otitis media, in better understanding the epidemiology of disease, and in clinical practice. Implications for Practice: (1) Many viruses cause acute otitis media without bacterial coinfection, and such cases do not require antibiotic treatment. (2) When respiratory syncytial virus, metapneumovirus, and influenza virus peak in the community, practitioners can expect to see an increase in clinical otitis media cases. (3) Biomarkers that predict which children with upper respiratory tract infections will develop otitis media may be available in the future. (4) Compounds that target newly identified bacterial virulence determinants may be available as future treatment options for children with otitis media.
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| 37. |
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| 38. |
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| 39. |
- Herukka, S. K., et al.
(författare)
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Amyloid-beta and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus
- 2015
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 46:1, s. 261-269
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyloid-beta (A beta(1-42)), total tau (T-tau), and phosphorylated tau (P-tau(181)) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble A beta decreases with increasing age and advanced A beta pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. A beta(1-42) and P-tau(181) remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while A beta(1-42) levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau(181) (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF A beta(1-42) levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF A beta and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.
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| 40. |
- Karvonen, H, et al.
(författare)
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Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness
- 2020
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:9, s. 790-
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.
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| 41. |
- Kiviluoma, J., et al.
(författare)
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Flexibility from the Electrification of Energy : How Heating, Transport, and Industries Can Support a 100% Sustainable Energy System
- 2022
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Ingår i: IEEE Power and Energy Magazine. - : Institute of Electrical and Electronics Engineers (IEEE). - 1540-7977 .- 1558-4216. ; 20:4, s. 55-65
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Tidskriftsartikel (refereegranskat)abstract
- Energy production and consumption activities account for 76% of global greenhouse gas (GHG) emissions, according to the Historical GHG Emissions database by Climate Watch. Power and heat plants cause 42% of energy-related GHG emissions, while other sectors, like transport, other energy use in buildings, and industry, cause 22%, 8%, and 24% of energy-related GHG emissions, respectively.
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| 42. |
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| 43. |
- Korpas, M., et al.
(författare)
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Addressing Market Issues in Electrical Power Systems with Large Shares of Variable Renewable Energy
- 2022
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Ingår i: International Conference on the European Energy Market, EEM. - : Institute of Electrical and Electronics Engineers (IEEE).
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Konferensbidrag (refereegranskat)abstract
- This paper reports recent findings from IEA Wind TCP Task 25, which compiles international experiences and research related to large-scale integration of wind and other renewable energy. In the paper, we address the main challenges for market integration of variable renewable energy, relating to price formation, cost recovery, balancing and other grid services. The paper gives an overview of recent scenario studies on electricity price impacts of (1) various generation, energy storage and demand types in different markets, and (2) different market designs and energy/climate policies. Studying markets with very high shares of variable renewable energy requires an improved set of analysis tools for forecasting market outcomes, estimating flexibility needs and sources, and assessing resource adequacy. Key market features need to be investigated within these improved analytical capabilities for systems transitioning to high shares of variable renewable energy, storage and flexible demand. System services that can be supported by markets will likely need to be revisited. Finally, this paper identifies open questions and suggested future market design work for supporting systems with very high shares of variable renewable energy, which are to be addressed in follow-up work of Task 25 collaborative research.
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| 44. |
- Moilanen, C., et al.
(författare)
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Modelling and simulation of radial spruce compression to optimize energy efficiency in mechanical pulping
- 2016
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Ingår i: International Mechanical Pulping Conference 2016, IMPC 2016. - : TAPPI Press. - 9781510830738 ; , s. 18-35
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Konferensbidrag (refereegranskat)abstract
- Energy efficiency of mechanical pulping is rather low. One possibility to facilitate design of more energy efficient defibration is to model and simulate wood compression. This paper presents an effort to model the behavior of Norwegian spruce in radial compression at defibration circumstances. To identify strain rate dependent properties, compression tests were conducted at both quasi-static conditions and at high strain rate. All tests were done at relevant moisture content and up to defibration zone temperatures and strain rates. Additionally the tests were performed both on native wood and on pre-fatigued wood to include behavior dependency of fatigue. The compression tests were monitored on fiber level to separately model behavior of early- and latewood. The chosen continuum model structure for earlywood and latewood was Voight-Kelvin to enable explicit viscous behavior conditioned by strain rate in parallel to the elastic behavior. The presented model is the first wood compression behavior model individually for earlywood and latewood that is based on wood experiments at industrial defibration circumstances. The influences of temperature and pre-fatigue rise are both softening as expected, The utilization of the compression model was demonstrated in an initial multilayered wood compression simulation.
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| 45. |
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| 46. |
- Patwary, Muhammad Mainuddin, et al.
(författare)
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Impact of extreme weather events on mental health in South and Southeast Asia : A two decades of systematic review of observational studies
- 2024
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 250
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Forskningsöversikt (refereegranskat)abstract
- Extreme weather events in South and Southeast Asia exert profound psychosocial impacts, amplifying the prevalence of mental illness. Despite their substantial consequences, there is a dearth of research and representation in the current literature. We conducted a systematic review of observational studies published between January 1, 2000, and January 20, 2024, to examine the impact of extreme weather events on the mental health of the South and Southeast Asian population. Quality assessment of the included studies was conducted using the Newcastle-Ottawa Scale (NOS) quality appraisal checklist. The search retrieved 70 studies that met the inclusion criteria and were included in our review. Most were from India (n = 22), and most used a cross-sectional study design (n = 55). Poor mental health outcomes were associated with six types of extreme weather events: floods, storm surges, typhoons, cyclones, extreme heat, and riverbank erosion. Most studies (n = 41) reported short-term outcome measurements. Findings included outcomes with predictable symptomatology, including post-traumatic stress disorder, depression, anxiety, general psychological distress, emotional distress and suicide. Limited studies on long-term effects showed higher mental disorders after floods and typhoons, while cyclone-exposed individuals had more short-term distress. Notably, the review identified over 50 risk factors influencing mental health outcomes, categorized into six classes: demographic, economic, health, disaster exposure, psychological, and community factors. However, the quantitative evidence linking extreme weather events to mental health was limited due to a lack of longitudinal data, lack of control groups, and the absence of objective exposure measurements. The review found some compelling evidence linking extreme weather events to adverse mental health in the South and Southeast Asia region. Future research should focus on longitudinal study design to identify the specific stressors and climatic factors influencing the relationship between climate extremes and mental health in this region.
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| 47. |
- Pettigrew, Melinda M, et al.
(författare)
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Panel 6 : Vaccines
- 2017
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Ingår i: Otolaryngology - Head and Neck Surgery. - : Wiley. - 0194-5998 .- 1097-6817. ; 156:4_suppl, s. 76-87
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To review the literature on progress regarding (1) effectiveness of vaccines for prevention of otitis media (OM) and (2) development of vaccine antigens for OM bacterial and viral pathogens. Data Sources: PubMed database of the National Library of Science. Review Methods: We performed literature searches in PubMed for OM pathogens and candidate vaccine antigens, and we restricted the searches to articles in English that were published between July 2011 and June 2015. Panel members reviewed literature in their area of expertise. Conclusions: Pneumococcal conjugate vaccines (PCVs) are somewhat effective for the prevention of pneumococcal OM, recurrent OM, OM visits, and tympanostomy tube insertions. Widespread use of PCVs has been associated with shifts in pneumococcal serotypes and bacterial pathogens associated with OM, diminishing PCV effectiveness against AOM. The 10-valent pneumococcal vaccine containing Haemophilus influenzae protein D (PHiD-CV) is effective for pneumococcal OM, but results from studies describing the potential impact on OM due to H influenzae have been inconsistent. Progress in vaccine development for H influenzae, Moraxella catarrhalis, and OM-associated respiratory viruses has been limited. Additional research is needed to extend vaccine protection to additional pneumococcal serotypes and other otopathogens. There are likely to be licensure challenges for protein-based vaccines, and data on correlates of protection for OM vaccine antigens are urgently needed. Implications for Practice: OM continues to be a significant health care burden globally. Prevention is preferable to treatment, and vaccine development remains an important goal. As a polymicrobial disease, OM poses significant but not insurmountable challenges for vaccine development.
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| 48. |
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| 49. |
- Seppala, T. T., et al.
(författare)
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CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings
- 2012
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 78:20, s. 1568-1575
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess the relationship between Alzheimer disease (AD)-related pathologic changes in frontal cortical brain biopsy and AD biomarkers in ventricular vs lumbar CSF, and to evaluate the relationships of AD biomarkers in CSF and cortical biopsy with the final clinical diagnosis of AD. Methods: In 182 patients with presumed normal pressure hydrocephalus (152 with known APOE carrier status), A beta plaques and tau in the cortical brain biopsies were correlated with the ventricular and lumbar CSF A beta 42, total tau, and p-tau levels measured by ELISA. In a median follow-up of 2.0 years, 51 patients developed AD dementia. Results: The patients with A beta 42 plaques in the cortical biopsy had lower (p = 0.009) CSF A beta 42 levels than those with no A beta plaques. The patients with tau in the cortical biopsy had lower (p = 0.014) A beta 42 but higher (p = 0.015) p-tau 181 in CSF as compared to those with no tau in the cortical biopsy. The patients with amyloid + tau + biopsies had the lowest A beta 42 and highest tau and p-tau 181 levels in CSF. The A beta 42 levels were lower and the tau and p-tau 181 higher in the ventricular vs corresponding lumbar CSF samples. In multivariate analysis, the presence of cortical A beta was independently predicted by the APOE epsilon 4 carrier status and age but not by CSF A beta 42 or tau levels. Conclusions: Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF A beta 42 and high CSF tau and p-tau levels, respectively. Neurology (R) 2012;78:1568-1575
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