| 1. |
- George, Julie, et al.
(författare)
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Comprehensive genomic profiles of small cell lung cancer
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73
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Tidskriftsartikel (refereegranskat)abstract
- We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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| 2. |
- Abgrall, N., et al.
(författare)
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The large enriched germanium experiment for neutrinoless double beta decay (LEGEND)
- 2017
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Ingår i: AIP Conference Proceedings. - : Author(s). - 1551-7616 .- 0094-243X. ; 1894
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Konferensbidrag (refereegranskat)abstract
- The observation of neutrinoless double-beta decay (0νββ) would show that lepton number is violated, reveal that neu-trinos are Majorana particles, and provide information on neutrino mass. A discovery-capable experiment covering the inverted ordering region, with effective Majorana neutrino masses of 15 - 50 meV, will require a tonne-scale experiment with excellent energy resolution and extremely low backgrounds, at the level of ∼0.1 count /(FWHM·t·yr) in the region of the signal. The current generation 76Ge experiments GERDA and the Majorana Demonstrator, utilizing high purity Germanium detectors with an intrinsic energy resolution of 0.12%, have achieved the lowest backgrounds by over an order of magnitude in the 0νββ signal region of all 0νββ experiments. Building on this success, the LEGEND collaboration has been formed to pursue a tonne-scale 76Ge experiment. The collaboration aims to develop a phased 0νββ experimental program with discovery potential at a half-life approaching or at 1028 years, using existing resources as appropriate to expedite physics results.
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| 3. |
- Schulze, Jule, et al.
(författare)
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Design, implementation and test of a serious online game for exploring complex relationships of sustainable land management and human well-being
- 2015
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Ingår i: Environmental Modelling & Software. - : Elsevier BV. - 1364-8152 .- 1873-6726. ; 65, s. 58-66
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Tidskriftsartikel (refereegranskat)abstract
- Land is a limited resource providing various services. Decisions on land use shape the distribution of these life support functions and thus require understanding of complex feedbacks between decisions on land use and human resource appropriation. Due to multiple nonlinear feedbacks between management, productivity, environmental quality, and human well-being, complexity is an inherent property of land systems. We present an educational game, which aims at illustrating options of sustainable land management to the interested public, students and stakeholders. The game provides the opportunity to govern a country by exploring how contrasting dimensions of sustainability (economy, environment and social conditions), can be harmonized regionally, while continuously being threatened by global trade fluctuations. The game was tested by several groups of students from high schools and universities. The feedback shows that the game is a valuable tool in environmental education initiating learning the complexity of feedbacks in land use and resources appropriation.
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| 4. |
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| 5. |
- Abe, K., et al.
(författare)
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J-PARC Neutrino Beamline Upgrade Technical Design Report
- 2019
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Rapport (refereegranskat)abstract
- In this document, technical details of the upgrade plan of the J-PARC neutrino beamline for the extension of the T2K experiment are described. T2K has proposed to accumulate data corresponding to 2×1022 protons-on-target in the next decade, aiming at an initial observation of CP violation with 3σ or higher significance in the case of maximal CP violation. Methods to increase the neutrino beam intensity, which are necessary to achieve the proposed data increase, are described.
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| 6. |
- Chien, Yin-Hsiu, et al.
(författare)
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Mudd's disease (MAT I/III deficiency) : a survey of data for MAT1A homozygotes and compound heterozygotes
- 2015
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine beta-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. Purpose of the study: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. Results and Discussion: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 mu M or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.
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| 7. |
- Fagernäs, Simon, et al.
(författare)
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Moderating effects of presence and adherence in internetbased CBT with virtual reality exposure therapy for public speaking anxiety
- 2017
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Konferensbidrag (refereegranskat)abstract
- Introduction: Previous research has revealed that Virtual Reality Exposure Therapy (VRET) is an effective method for reducing symptoms of public speaking anxiety (PSA). Research about presence in the virtual environment indicates a moderating effect on physiological arousal, but more ambiguous effect on treatment effects where some research indicates a small effect while other indicate no effect. Furthermore, previous research has found adherence to home work assignments to moderate treatment outcome. In this treatment study which aimed for treating public speaking anxiety with VRET and a internetbased CBT-program, we investigated whether presence in the virtual environment and adherence to home work moderated treatment effects.Methods: N=25 adult participants from the general public with clinically significant PSA were recruited to a wait-list to another study. After five weeks on waitlist, they started the treatment with a self-guided in virtuo exposure session followed by a four week online maintenance promoting in-vivo exposure. Participants got a simple VR headset by post. The three-hour exposure session included psychoeducation in text, and the participants conducted speech exercises, framed as behavioral experiments targeting idiosyncratic catastrophic beliefs, in front of virtual audiences, and listening to audio recording afterwards. Primary outcome measure was self-reported PSA. To measure moderating effects of presence on the primary outcome measure a self-reported validated scale with subscales for presence (iGroup Presence Questionnaire, IPQ) were used, and for adherence a score were manually calculated based on the number of completed home-work assignments in both a linear model and a binary model dividing participants in two groups: one with at least one completed home work assignment and one with no completed home work assignment. The analysis on presence included both the effects of the VRET-session alone and in combination with the internetbased CBT-program. Data were analyzed using mixed effects modeling.Results: No significant results were found in moderating effects of presence with its subscales on the primary outcome measure for either the VRET-session (p = .375-.616) nor in combination with the internetbased CBT-program (p = .454 - .877). Moderating effects of adherence on primary outcome measure neither revealed no significant results in the linear model (p = .368) nor the binary model (p = .113).Conclusions: The findings of this study indicate, in line with some previous research, that presence in the virtual environment has no significant moderating effect on treatment outcome. Furthermore, in contrast to previous research, this study found no significant moderating effect on adherence to home work assignments on primary treatment outcome. Internal- and external validity and other potential explanations are discussed in detail in the poster.
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| 8. |
- Knabl, Ludwig, et al.
(författare)
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Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets
- 2018
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Ingår i: International Journal of Medical Microbiology. - : Elsevier BV. - 1438-4221 .- 1618-0607. ; 308:7, s. 969-976
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Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli-induced hemolytic uremic syndrome (eHUS) is a life-threatening complication of infection with Shiga toxin (Stx), in particular Stx2a-producing Escherichia coli. Enhanced coagulation activation with formation of microthrombi seems to be a key event in development of eHUS. Platelet activation has been postulated as a possible, but controversially debated mechanism. The present study investigated the effect of Stx2a on plasmatic coagulation and platelets. Binding studies were initially performed with ELISA and co-immunoprecipitation and supported by quartz crystal microbalance with dissipation monitoring (QCM-D). Antithrombin (AT) activity was measured using the automated BCS XP (R) system. ROTEM (R) was used for functional coagulation testing. Platelet binding and activation was studied with FACS and light-transmission aggregometry. We found binding of Stx2a to AT, an important inhibitor of blood coagulation, but only a mild albeit significant reduction of AT activity against FXa in the presence of Stx2a. QCM-D analysis also showed binding of Stx2a to heparin and an impaired binding of AT to Stx2a-bound heparin. ROTEM (R) using Stx2a-treated platelet-poor plasma revealed a significant, but only moderate shortening of clotting time. Neither binding nor activation of platelets by Stx2a could be demonstrated. In summary, data of this study suggest that Stx2a binds to AT, but does not induce major effects on plasmatic coagulation. In addition, no interaction with platelets occurred. The well-known non-beneficial administration of heparin in eHUS patients could be explained by the interaction of Stx2a with heparin.
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| 9. |
- Lindner, Philip, et al.
(författare)
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Combining online Community Reinforcement and Family Training (CRAFT) with a parent-training programme for parents with partners suffering from alcohol use disorder : study protocol for a randomised controlled trial
- 2018
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Partners and children of individuals with alcohol use disorder (AUD) present with impaired quality of life and mental health, yet seldom seek or participate in traditional supportive interventions. Engaging the parent/partner without AUD in treatment is a promising way of supporting behavioural change in both the child and the parent with AUD. Universal parent-training (PT) programmes are effective in increasing children’s well-being and decreasing problem behaviours, but have yet to be tailored for children with a parent with AUD. Community Reinforcement Approach And Family Training (CRAFT) programmes are conceptually similar, and aim to promote behavioural change in individuals with AUD by having a concerned significant other change environmental contingencies. There has been no study on whether these two interventions can be combined and tailored for partners of individuals with AUD with common children, and delivered as accessible, online self-help.Methods and analysis: n=300 participants with a child showing mental health problems and partner (co-parent) with AUD, but who do not themselves present with AUD, will be recruited from the general public and randomised 1:1 to either a four-module, online combined PT and CRAFT programme or a psychoeducation-only comparison intervention. Primary outcome will be the child’s mental health. Additional outcomes will cover the partner’s drinking, the participants own mental health and drinking, the child’s social adjustment, treatment seeking in all three parties and parental self-efficacy. Measures will be collected preintervention, mid-intervention and postintervention, and three times during a 2-year follow-up period. Data will be analysed using mixed-effects modelling.Ethics and dissemination: This study has been approved by the Stockholm Regional Ethical Review Board (2016/2179-31). The results will be presented at conferences and published as peer-reviewed publications.Trial registration number: ISRCTN38702517; Pre-results.
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| 10. |
- Lindner, Philip, et al.
(författare)
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Combining online community reinforcement and family training with a parent training program for parents with partners suffering from alcohol use disorder : Study protocol for a randomized controlled trial
- 2018
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Partners and children of individuals with alcohol use disorder (AUD) present impaired quality of life and mental health, yet seldom seek or participate in traditional supportive interventions. Engaging the parent/partner without AUD in treatment is a promising way of supporting behavior change in both the child and the parent with AUD. Universal parent training (PT) programs are effective in increasing children´s well-being and decreasing problem behaviors, but have yet to be tailored for children with a parent with AUD. Community reinforcement approach and family training (CRAFT) programs are conceptually similar, and aim to promote behavior change in individuals with AUD by having a concerned significant other change environmental contingencies. There has been no study on whether these two interventions can be combined and tailored for partners of individuals with AUD with common children, and delivered as accessible, online self-help. Methods and analysis: N=300 participant who share a child showing mental health problems with a person with AUD, but do not present AUD themselves, will be recruited from the general public and randomized 1:1 to either a four-module, online combined PT and CRAFT program, or a psychoeducation-only comparison intervention. Primary outcome will be the child’s mental health. Additional outcomes will cover the partner’s drinking, the participants own mental health and drinking, the child’s social adjustment, treatment-seeking in all three parties, and parental self-efficacy. Measures will be collected pre-, mid- and post-intervention, and three times during a two-year follow-up period. Data will be analyzed using mixed effects modeling. Trial status: This trial is currently recruiting.
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