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| 7. |
- Morgan, Daniel, et al.
(författare)
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
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- Ernst, Kathleen M., et al.
(författare)
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Identifying climate service production constraints to adaptation decision-making in Sweden
- 2019
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Ingår i: Environmental Science and Policy. - : ELSEVIER SCI LTD. - 1462-9011 .- 1873-6416. ; 93, s. 83-91
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Tidskriftsartikel (refereegranskat)abstract
- Climate change adaptation efforts continue to increase as the impacts of climate change increase, intensify, and become more apparent. However, many adaptation efforts fail to result in adaptation actions. This inaction has been linked to several constraining factors including a lack of actionable information for adaptation decision-making processes. We wonder if climate service producers face constraints as they try to create and deliver actionable information for adaptation decision-making efforts? This paper draws on semi-structured interviews and participant-observations across climate service production environments in Sweden to answer our research question and fords that climate service producers engage in research, coordination, and communication to varying degrees and experience constraints related to the production and dissemination of actionable information and stakeholder engagement, as well as funding, professional, and institutional constraints. Some constraints are experienced differently by climate service producers depending on their specific role, institutional affiliation, agency, and experience. Additionally, some climate service production constraints create or exacerbate additional constraints for adaptation decision-making stakeholders. Therefore, climate service production constraints limit the effectiveness of climate services, and overcoming them would help make progress towards more adaptation implementation in specific contexts. However, for adaptation actions to be widespread, the production and dissemination of climate services must be met with additional support and guidance for adaptation efforts beyond the provision of actionable information.
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| 15. |
- Gerger Swartling, Åsa, et al.
(författare)
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Theory and Methodology for EPI analysis
- 2007
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Ingår i: Environmental Policy Integration in Practice. - : Earthscan, London. ; , s. 49-65
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Bokkapitel (refereegranskat)
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| 16. |
- Hill, Rebecca M., et al.
(författare)
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Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease
- 2015
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 27:1, s. 72-84
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Tidskriftsartikel (refereegranskat)abstract
- We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.
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| 17. |
- Huang, Miller, et al.
(författare)
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Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
- 2019
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Ingår i: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:3, s. 433-
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Tidskriftsartikel (refereegranskat)abstract
- Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predis- posed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.
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| 18. |
- Kebbon, L, et al.
(författare)
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Psychiatric symptoms and psychosocial problems in primary health care as seen by doctors
- 1985
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Ingår i: Scandinavian Journal of Primary Health Care. - 0281-3432 .- 1502-7724. ; 3:1, s. 23-30
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Tidskriftsartikel (refereegranskat)abstract
- All visits at a primary health care centre in Sweden were studied during four weeks. The frequency of psychiatric symptoms or psychosocial problems noted by the doctors was recorded on a special form in addition to routine registration of diagnoses. Such problems were noted in 553 out of 3 205 visits, corresponding to 17.3%. Considerable variation in registering problems was found between individual physicians and between different categories of doctors. The most common problems were nervousness, anxiety, psychosomatic disorders, and depression. Mental problems were especially common in connection with gastritis, precordial pain, and abdominal pain. There was a difference between the sexes: 20% of the female patients had mental problems registered compared with 14% of the male patients. Psychiatric diagnoses, however, were registered in only 6% of all cases. Of the 553 patients with mental problems, 16% were considered in need of a specialist, 52% could be dealt with at the health centre, and for 32% no special treatment for the mental problems was regarded necessary. One conclusion is that the routine registration of diagnoses at the health centre covers only some of the mental problems and is therefore insufficient in terms of planning psychiatric resources and the training of doctors. Possible reasons for the differences found are discussed.
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- Levitz, D, et al.
(författare)
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Determination of optical scattering properties of highly-scattering media in optical coherence tomography images
- 2004
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Ingår i: Optics Express. - 1094-4087. ; 12:2, s. 249-259
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Tidskriftsartikel (refereegranskat)abstract
- We developed a new algorithm that fits optical coherence tomography (OCT) signals as a function of depth to a general theoretical OCT model which takes into account multiple scattering effects. With use of this algorithm, it was possible to extract both the scattering coefficient and anisotropy factor from a particular region of interest in an OCT image. The extraction algorithm was evaluated against measurements from an integrating sphere on a set of tissue phantoms and yielded valid results. Finally, a preliminary ex vivo OCT investigation on human aortic specimen indicated that the algorithm may contribute importantly to differentiation between normal and atherosclerotic arteries. We conclude that this algorithm may facilitate tissue characterization by OCT. (C) 2004 Optical Society of America.
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| 22. |
- Lundgren, Markus, et al.
(författare)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 29. |
- Swartling, L., et al.
(författare)
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Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients
- 2020
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 55:7, s. 1255-63
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis E virus (HEV) can cause chronic infection and liver cirrhosis in immunocompromised individuals. The frequency and clinical importance of HEV was studied retrospectively in a cohort of 236 Swedish allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In blood samples collected at 6 months after HSCT, HEV RNA was identified in 8/236 (3.4%) patients, and 11/236 (4.7%) patients had detectable anti-HEV IgG and/or IgM, eight of whom were HEV RNA negative. Two of the patients with positive HEV RNA died with ongoing signs of hepatitis: one of acute liver and multiple organ failure, the other of unrelated causes. The remaining six patients with HEV RNA had cleared the infection at 7-24 (median 8.5) months after HSCT. HEV infection was associated with elevated alanine aminotransferase at 6 months after HSCT (OR 15, 1.3-174, p = 0.03). Active graft-versus-host disease of the liver at 6 months after HSCT was present in 3/8 (38%) patients with HEV RNA, but was not significantly associated with HEV infection. In conclusion, HEV infection is an important differential diagnosis in patients with elevated liver enzymes after HSCT. Although spontaneous clearance was common, the clinical course may be severe.
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- Swartling, L., et al.
(författare)
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Prolonged outbreak of adenovirus A31 in allogeneic stem cell transplant recipients
- 2015
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Ingår i: Transplant Infectious Disease. - : Wiley. - 1398-2273 .- 1399-3062. ; 17:6, s. 785-794
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Tidskriftsartikel (refereegranskat)abstract
- Background: An outbreak of human adenovirus (HAdV) A31 occurred from December 2011 to March 2012 at the Center for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital in Sweden. We analyzed the outbreak, the routes of transmission, and report the medical consequences.Methods: The medical records of all patients admitted to CAST during the outbreak period were studied. Phylogenetic analysis of the patient HAdV strains was performed by sequencing the hexon gene and the more variable E3 gene.Results: We identified 9 cases of HAdV A31. Hygiene measures were implemented, but transmission continued for 2 months. All 9 patients had been admitted to the ward, but 2 had no connection in time to other known HAdV A31 cases. DNA sequencing of the patient strains strongly suggested nosocomial transmission. Transplantation was postponed and then cancelled in 1 patient, and 5 patients were treated with cidofovir because of high levels of viremia. In 7 patients, concomitant graft-versus-host disease (GVHD) grade II–V complicated the clinical picture, as it was difficult to distinguish symptoms of GVHD from those of HAdV infection.Conclusion: An outbreak of HAdV in HSCT recipients can be difficult to control. Although none of the patients had severe disease, the medical consequences were significant. It is possible that unidentified cases with mild symptoms may have caused continuous transmission at the unit. Regular testing of all patients several weeks beyond the last case identified may be an important measure to control transmission.
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| 33. |
- Swartling, P G, et al.
(författare)
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Mental health problems in primary health care as seen by doctors
- 1987
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Ingår i: Scandinavian Journal of Primary Health Care. - 0281-3432 .- 1502-7724. ; 5:4, s. 201-04
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Tidskriftsartikel (refereegranskat)abstract
- Mental health problems in primary health care are much more common than can be concluded by routine registration of diagnoses. This has been shown in a previous study by the authors in 1979. In order to test the consistency of these results (Study I) and the reliability of our method a replication was carried out in 1983 at the same health centre but with mainly other doctors (Study II). All visits to the health centre were studied during a period of four weeks. During the study period all doctors recorded mental health problems of importance for the visit in addition to the routine registration of diagnoses. The results of both studies showed a high degree of consistency. Mental health problems were observed in about 17% of the patients in both studies. Sex differences were similar: 20-21% of female patients and 14% of male patients had mental health problems. Psychiatric diagnoses were only registered in six per cent of patients in Study I and five per cent in Study II. Mental problems were especially common in connection with abdominal and chest disorders. The replication thus confirmed our previous findings that mental health problems are common in primary health care. Such problems should therefore be given more attention in the training of doctors in general practice.
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| 35. |
- Thrane, L, et al.
(författare)
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Extraction of tissue optical properties from optical coherence tomography images for diagnostic purposes
- 2005
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Ingår i: Saratov Fall Meeting 2004: Optical Technologies in Biophysics and Medicine VI. - : SPIE. - 1996-756X .- 0277-786X. - 0819457523 ; 5771, s. 139-150
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Konferensbidrag (refereegranskat)abstract
- The concept of optical coherence tomography (OCT) for high-resolution imaging of tissues in vivo is introduced. Analytical and numerical models for describing and understanding the light propagation in samples imaged by OCT systems are presented. An analytical model for calculating the OCT signal based on the extended Huygens-Fresnel principle and valid both for single and multiple scattering regimes is outlined. From this model, an algorithm for extracting tissue optical properties for multi-layered tissues is derived. The algorithm is first verified for various optical properties and geometries using solid phantoms and numerical simulations. The applicability of the algorithm for extraction of tissue optical properties is then demonstrated for vascular tissue samples ex vivo. With the use of data from numerical phantoms, the validity of the OCT extraction algorithm for a two-layer geometry is further supported. It is concluded that by using optical properties extracted from OCT images of human tissues, the clinical utility of OCT imaging can be substantially increased.
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| 36. |
- Weibring, Petter, et al.
(författare)
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Optical monitoring of volcanic sulphur dioxide emissions - comparison between four different remote-sensing spectroscopic techniques
- 2002
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Ingår i: Optics and Lasers in Engineering. - 0143-8166. ; 37:2-3, s. 267-284
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Tidskriftsartikel (refereegranskat)abstract
- The emissions of sulphur dioxide from the Italian volcanoes Mt. Etna and Stromboli were studied in ship-borne underpasses of their plumes. Four different optical spectroscopy techniques were used and inter-compared. All techniques utilise the absorption signature of the gas in the wavelength region of around 300 nm. A differential absorption lidar was employed in active gas concentration assessment. In parallel, a differential optical absorption spectroscopy system (DOAS) provided spectrally resolved absorption spectra, In one configuration the DOAS used a vertically looking telescope and the absorption of the skylight was studied, while a different DOAS implementation utilised the sun disc as the light source in slant-angle, long-path absorption measurements. Parallel measurements with the customary correlation spectroscopy method were also performed. Path length Monte Carlo simulations of the down-welling radiation through the volcanic plume at different sun altitude and azimuth angles have been performed taking into account also the effects of other geometric parameters as the plume height and extension. The results are discussed with special emphasis on systematic effects due to scattering.
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