| 1. |
- Englund, Ulrica, et al.
(författare)
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The use of a recombinant lentiviral vector for ex vivo gene transfer into the rat CNS
- 2000
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Ingår i: NeuroReport. - : Lippincott Williams & Wilkins. - 0959-4965 .- 1473-558X. ; 11:18, s. 3973-3977
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Tidskriftsartikel (refereegranskat)abstract
- A major obstacle in ex vivo gene transfer has been the loss of transgene expression soon after implantation of the grafted transduced cells. Recently, a lentiviral vector system has been developed which has proven to express high levels of transgenes in vivo after direct injection into the tissue. In this study, we have investigated the use of such a vector for ex vivo gene transfer to the brain. A number of neural cell types were found to be permissive to transduction by the lentiviral vector in vitro and a majority of them expressed the transgene after transplantation to the rat brain. Transgene expression was detected up to 8 weeks post-grafting. These findings suggest that recombinant lentiviral vectors may be used for further development of ex vivo gene therapy protocols to the CNS.
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| 2. |
- Ericson, Cecilia, et al.
(författare)
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Ex vivo and in vitro studies of transgene expression in rat astrocytes transduced with lentiviral vectors.
- 2002
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 173:1, s. 22-30
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Tidskriftsartikel (refereegranskat)abstract
- Implantation of cells genetically modified to express therapeutic genes into the brain has been proposed as a potential treatment for neurodegenerative diseases. In the current study embryonic rat-derived astrocytes were cultured and transduced with a lentiviral vector expressing the reporter gene green fluorescent protein (GFP) and subsequently grafted into the adult rat brain. The proportion of GFP expressing cells was stable, albeit small (1%), at all survival times, up to 6 weeks, the longest time point studied. In parallel in vitro studies, the astrocytes were lentivirally transduced to express either one of the two isoforms of glutamate decarboxylase (GAD(65) or GAD(67)) or glial cell line-derived neurotrophic factor (GDNF). When transducing 293T cells with the two GAD vectors, released GABA could be measured using high-performance liquid chromatography. Further studies of rat astrocytes transduced with the same vectors resulted in a level of GAD activity about 10 times higher than the activity of an intact rat striatum. One hundred thousand astrocytes transduced with LV-GDNF released approximately 27 ng of GDNF per hour. Thus, taken together, our observations provide support for the use of rat astrocytes in ex vivo gene transfer of these proteins in animal models of CNS disorders, e.g., Parkinson's disease or epilepsy.
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| 3. |
- Ericson, Cecilia, et al.
(författare)
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Ex vivo gene delivery of GDNF using primary astrocytes transduced with a lentiviral vector provides neuroprotection in a rat model of Parkinson's disease.
- 2005
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 22:11, s. 2755-2764
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes are, as normal constituents of the brain, promising vehicles for ex vivo gene delivery to the central nervous system. In the present study, we have used a lentiviral vector encoding glial cell line-derived neurotrophic factor (GDNF) to transduce rat-derived primary astrocytes, in order to evaluate their potential for long-term transgene expression in vivo and neuroprotection in a rat model of Parkinson's disease. Following transplantation of GDNF-transduced astrocytes to the intact striatum, the level of released GDNF was 2.93 +/- 0.28 ng/mg tissue at 1 week post-grafting, reduced to 0.42 +/- 0.12 ng/mg tissue at 4 weeks, and thereafter was maintained at this level throughout the experiment (12 weeks; 0.53 +/- 0.068 ng/mg tissue). Similarly, grafting to the substantia nigra (SN) resulted in a significant overexpression of GDNF ( approximately 0.20 ng/mg tissue) at 1 week. Intact animals receiving transplants of GDNF-transduced astrocytes displayed an increased contralateral turning (5.39 +/- 1.19 turns/min) in the amphetamine-induced rotation test, which significantly correlated with the GDNF tissue levels measured in the striatum, indicating a stimulatory effect of GDNF on the dopaminergic function. Transplantation of GDNF-transduced astrocytes to the SN 1 week prior to an intrastriatal 6-hydroxydopamine lesion provided a significant protection of nigral tyrosine hydroxylase-positive cells. By contrast, when the cells were transplanted to the striatum, the level of released GDNF was not sufficient to rescue the striatal fibers and, hence, to protect the nigral dopaminergic neurons. Overall, our results suggest that genetically modified astrocytes expressing GDNF can provide neuroprotection in a rat model of Parkinson's disease following transplantation to the SN.
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| 4. |
- Georgievska, Biljana, et al.
(författare)
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Regulated delivery of glial cell line-derived neurotrophic factor into rat striatum, using a tetracycline-dependent lentiviral vector.
- 2004
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Ingår i: Human Gene Therapy. - : Mary Ann Liebert Inc. - 1043-0342 .- 1557-7422. ; 15:10, s. 934-944
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Tidskriftsartikel (refereegranskat)abstract
- In this study, a tetracycline-regulated lentiviral vector system, based on the tetracycline-dependent transactivator rtTA2S-M2, was developed for controlled expression of glial cell line-derived neurotrophic factor (GDNF) in the rat brain. Expression of the marker gene green fluorescent protein (GFP) and GDNF was tightly regulated in a dose-dependent manner in neural cell lines in vitro. Injection of high-titer lentiviral vectors into the rat striatum resulted in a 7-fold induction of GDNF tissue levels (1060 pg/mg tissue), when doxycycline (a tetracycline analog) was added to the drinking water. However, low levels of GDNF (150 pg/mg tissue) were also detected in animals that did not receive doxycycline, indicating a significant background leakage from the vector system in vivo. The level of basal expression was markedly reduced when a 10-fold lower dose of the tetracycline-regulated GDNF vector was injected into the striatum (3–11 pg/mg tissue), and doxycycline- induced GDNF tissue levels obtained in these animals were about 190 pg/mg tissue. Doxycycline-induced expression of GDNF resulted in a significant downregulation of the tyrosine hydroxylase (TH) protein in the intact striatum. Removal of doxycycline from the drinking water rapidly (within 3 days) turned off transgenic GDNF mRNA expression and GDNF protein levels in the tissue were completely reduced by 2 weeks, demonstrating the dynamics of the system in vivo. Accordingly, TH protein expression returned to normal by 2–8 weeks after removal of doxycycline, indicating that GDNF-induced downregulation of TH is a reversible event.
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| 5. |
- Häggmark, Anna, et al.
(författare)
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Proteomic Profiling Reveals Autoimmune Targets in Sarcoidosis
- 2015
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 191:5, s. 574-583
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: There is a need to further characterize the antibody repertoire in relation to sarcoidosis and potentially related autoantigens. Objectives: We investigated bronchoalveolar lavage (BAL) and serum samples from patients with sarcoidosis and healthy and diseased control subjects to discover sarcoidosis-associated autoantigens. Methods: Antigen microarrays built on 3,072 protein fragments were used to screen for IgG reactivity in 73 BAL samples from subjects with sarcoidosis, subjects with asthma, and healthy subjects. A set of 131 targets were selected for subsequent verification on suspension bead arrays using 272 additional BAL samples and 141 paired sera. Reactivity to four antigens was furthermore analyzed in 22 unprocessed BAL samples from patients with fibrosis and 269 plasma samples from patients diagnosed with myositis. Measurements and Main Results: Reactivity toward zinc finger protein 688 and mitochondrial ribosomal protein L43 were discovered with higher frequencies in patients with sarcoidosis, for mitochondrial ribosomal protein L43 especially in patients with non-Lofgren syndrome. Increased reactivity toward nuclear receptor coactivator 2 was also observed in patients with non-Lofgren syndrome as compared with patients with Lofgren syndrome. The antigen representing adenosine diphosphate-ribosylation factor GTPase activating protein 1 revealed high reactivity frequency in all sample groups but with significantly higher level of IgG reactivities in patients with sarcoidosis. Conclusions: Autoantigen reactivity was present in most BAL and serum samples analyzed, and the results revealed high interindividual heterogeneity, with most of the reactivities observed in single individuals only. Four proteins are here proposed as sarcoidosis-associated autoimmune targets and of interest for further validation in independent cohorts.
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| 6. |
- Jakobsson, Johan, et al.
(författare)
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Lentiviral vectors.
- 2003
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Ingår i: International Review of Neurobiology. - 0074-7742. ; 55, s. 111-122
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Forskningsöversikt (refereegranskat)
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| 7. |
- Jakobsson, Johan, et al.
(författare)
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Lesion-dependent regulation of transgene expression in the rat brain using a human glial fibrillary acidic protein-lentiviral vector.
- 2004
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Ingår i: European Journal of Neuroscience. - 1460-9568. ; 19:3, s. 761-765
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Tidskriftsartikel (refereegranskat)abstract
- The ability to regulate transgene expression will be crucial for development of gene therapy to the brain. The most commonly used systems are based on a transactivator in combination with a drug, e.g. the tetracycline-regulated system. Here we describe a different method of transgene regulation by the use of the human glial fibrillary acidic protein (GFAP) promoter. We constructed a lentiviral vector that directs transgene expression to astrocytes. Using toxin-induced lesions we investigated to what extent transgene expression could be regulated in accordance with the activation of the endogenous GFAP gene. In animals receiving excitotoxic lesions of the striatum we detected an eightfold increase of green fluorescent protein (GFP)-expressing cells. The vast majority of these cells did not divide, suggesting that the transgene was indeed regulated in a similar fashion as the endogenous GFAP gene. This finding will lead to the development of lentiviral vectors with autoregulatory capacities that may be very useful for gene therapy to the brain.
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| 8. |
- Jakobsson, Johan, et al.
(författare)
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Targeted transgene expression in rat brain using lentiviral vectors.
- 2003
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 73:6, s. 876-885
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Tidskriftsartikel (refereegranskat)abstract
- Direct gene transfer to the adult brain is dependent on vectors that transduce non-dividing cells, such as lentiviral vectors. Another aspect of the development of gene therapy to the brain is the need for cell-specific transgene expression. Expression from vesicular stomatitis virus G-protein (VSV-G) pseudotyped lentiviral vectors has been reported to be mainly neuron specific in the brain. We constructed cell-specific lentiviral vectors using the neuron-specific enolase (rNSE) or the glial fibrillary acidic protein (hGFAP) promoters and compared them to the ubiquitous human cytomegalovirus promoter (hCMV), a hybrid CMV/-actin promoter (CAG) and the promoter for human elongation factor 1 (EF1). Our results showed that the hGFAP promoter was expressed only in glial cells, whereas rNSE was purely neuron specific, showing that VSV-G is pantropic in the rat striatum. We conclude that the VSV-G allows transduction of both glial and neuronal cells and the promoter dictates in what cell type the transgene will be expressed. The expression of transgenes exclusively in astrocytes would allow for local delivery of secreted transgene products, such as glial cell line-derived neurotrophic factor (GDNF), circumventing the anterograde transport that may induce unwanted side effects.
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| 9. |
- Mulder, Hindrik, et al.
(författare)
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Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact.
- 2003
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Ingår i: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 278:38, s. 36380-36388
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Tidskriftsartikel (refereegranskat)abstract
- Lipid metabolism plays an important role in glucose homeostasis under normal and pathological conditions. In adipocytes, skeletal muscle, and pancreatic beta-cells, lipids are mobilized from acylglycerides by the hormone-sensitive lipase (HSL). Here, the consequences of a targeted disruption of the HSL gene for glucose homeostasis were examined. HSL null mice were slightly hyperglycemic in the fasted, but not fed state, which was accompanied by moderate hyperinsulinemia. During glucose challenges, however, disposal of the sugar was not affected in HSL null mice, presumably because of release of increased amounts of insulin. Impaired insulin sensitivity was further indicated by retarded glucose disposal during an insulin tolerance test. A euglycemic hyperinsulinemic clamp revealed that hepatic glucose production was insufficiently blocked by insulin in HSL null mice. In vitro, insulin-stimulated glucose uptake into soleus muscle, and lipogenesis in adipocytes were moderately reduced, suggesting additional sites of insulin resistance. Morphometric analysis of pancreatic islets revealed a doubling of beta-cell mass in HSL null mice, which is consistent with an adaptation to insulin resistance. Insulin secretion in vitro, examined by perifusion of isolated islets, was not impacted by HSL deficiency. Thus, HSL deficiency results in a moderate impairment of insulin sensitivity in multiple target tissues of the hormone but is compensated by hyperinsulinemia.
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| 10. |
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| 11. |
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| 12. |
- Riving, Cecilia, et al.
(författare)
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Lars och litteraturen
- 2018
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Ingår i: Från Malmö till Minneapolis : Kulturhistoriska undersökningar tillägnade Lars Edgren - Kulturhistoriska undersökningar tillägnade Lars Edgren. - 9789179243104 ; , s. 85-92
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Bokkapitel (populärvet., debatt m.m.)
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| 13. |
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| 14. |
- Tengvall, Katarina, 1980-, et al.
(författare)
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Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:34, s. 16955-16960
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 x 10(-36)) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95% CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15: 01 carriage, absence of HLA-A*02: 01, and high anti-EBNA1 antibody levels (OR = 24.9; 95% CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLADRB1*04: 01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95% CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.
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| 15. |
- Yamada, Takashi, et al.
(författare)
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Nitrosative modifications of the Ca2+ release complex and actin underlie arthritis-induced muscle weakness.
- 2015
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 74:10, s. 1907-1914
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca(2+) handling and specific force production.
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| 16. |
- Adhikari, Subash, et al.
(författare)
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A high-stringency blueprint of the human proteome
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Forskningsöversikt (refereegranskat)abstract
- The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.
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| 17. |
- Albrecht, Inka, et al.
(författare)
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Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
- 2015
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 125:12, s. 4612-4624
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Tidskriftsartikel (refereegranskat)abstract
- Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
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| 18. |
- Araghi, Marzieh, et al.
(författare)
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No association between moist oral snuff (snus) use and oral cancer : pooled analysis of nine prospective observational studies
- 2021
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Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 49:8, s. 833-840
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Worldwide, smokeless-tobacco use is a major risk factor for oral cancer. Evidence regarding the particular association between Swedish snus use and oral cancer is, however, less clear. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between snus use and oral cancer.Methods: A total of 418,369 male participants from nine cohort studies were followed up for oral cancer incidence through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors.Results: During 9,201,647 person-years of observation, 628 men developed oral cancer. Compared to never-snus use, ever-snus use was not associated with oral cancer (adjusted HR 0.90, 95% CI: 0.74, 1.09). There were no clear trends in risk with duration or intensity of snus use, although lower intensity use (<= 4 cans/week) was associated with a reduced risk (HR 0.65, 95% CI: 0.45, 0.94). Snus use was not associated with oral cancer among never smokers (HR 0.87, 95% CI: 0.57, 1.32).Conclusions: Swedish snus use does not appear to be implicated in the development of oral cancer in men.
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| 19. |
- Araghi, Marzieh, et al.
(författare)
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Smokeless tobacco (snus) use and colorectal cancer incidence and survival : Results from nine pooled cohorts
- 2017
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 45:8, s. 741-748
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Although smoking is considered to be an established risk factor for colorectal cancer, the current evidence on the association between smokeless tobacco and colorectal cancer is scant and inconclusive. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess this association.METHODS: A total of 417,872 male participants from nine cohort studies across Sweden were followed up for incidence of colorectal cancer and death. Outcomes were ascertained through linkage to health registers. We used shared frailty models with random effects at the study level to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).RESULTS: During 7,135,504 person-years of observation, 4170 men developed colorectal cancer. There was no clear association between snus use and colorectal cancer overall. Exclusive current snus users, however, had an increased risk of rectal cancer (HR 1.40: 95% CI 1.09, 1.79). There were no statistically significant associations between snus use and either all-cause or colorectal cancer-specific mortality after colorectal cancer diagnosis.CONCLUSIONS: Our findings, from a large sample, do not support any strong relationships between snus use and colorectal cancer risk and survival among men. However, the observed increased risk of rectal cancer is noteworthy, and in merit of further attention.
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| 20. |
- Araghi, Marzieh, et al.
(författare)
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Use of moist oral snuff (snus) and pancreatic cancer : Pooled analysis of nine prospective observational studies
- 2017
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 141:4, s. 687-693
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Tidskriftsartikel (refereegranskat)abstract
- While smoking is a well-established risk factor for pancreatic cancer, the effect of smokeless tobacco is less well understood. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between Swedish snus use and the risk of pancreatic cancer. A total of 424,152 male participants from nine cohort studies were followed up for risk of pancreatic cancer through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. During 9,276,054 person-years of observation, 1,447 men developed pancreatic cancer. Compared to never-snus use, current snus use was not associated with risk of pancreatic cancer (HR 0.96, 95% CI 0.83-1.11) after adjustment for smoking. Swedish snus use does not appear to be implicated in the development of pancreatic cancer in men. Tobacco smoke constituents other than nicotine or its metabolites may account for the relationship between smoking and pancreatic cancer. What's new? While smoking is a well-established risk factor for pancreatic cancer, the effect of smokeless tobacco is less well understood. Smokeless tobacco like snus yields lower exposure to tobacco carcinogens compared with smoking, because it does not undergo combustion, but delivers an equivalent dose of nicotine. Using pooled individual data from the Swedish Collaboration on Health Effects of Snus Use, here the authors show that Swedish snus use does not appear to be implicated in the development of pancreatic cancer in men. Tobacco smoke constituents other than nicotine or its metabolites may account for the relationship between smoking and pancreatic cancer.
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| 21. |
- Arefalk, Gabriel, et al.
(författare)
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Smokeless Tobacco (Snus) and Risk of Heart Failure of Ischemic and Non-Ischemic Origin: a Pooled Analysis of Eight Prospective Cohort Studies
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundSnus, a Swedish type of smokeless tobacco, has potent acute hemodynamic effects, which could provoke stress on the cardiovascular system, including the myocardium. Snus has, however, not been linked to risk of ischemic heart disease. Therefore, we hypothesized that snus use increases the risk for heart failure of non-ischemic origin.MethodsWe conducted a pooled analysis of eight Swedish prospective cohort studies involving individual participant data from 350,711 men. Shared frailty models with random effects at the cohort level, were used to estimate hazard ratios (HRs) with 95 % confidence intervals (CIs) of heart failure in relation to snus use. We investigated dose-response associations, and association with ischemic and non-ischemic heart failure in separate. For positive control purposes, we also investigated associations between smoking and risk of heart failure.ResultsDuring a median follow-up time of 16 years, 5,404 men were hospitalized for heart failure. In models adjusting for age, smoking, previous myocardial infarction and educational level, current snus use was associated with a higher risk of heart failure (HR 1.27, 95 % CI 1.07-1.50), relative to non-current snus use. A dose-response pattern was observed, with higher risk with more snus cans used per week. We observed an association of snus use with non-ischemic heart failure, HR 1.34 (95 % CI 1.11-1.63), but not with ischemic heart failure, HR 1.01 (95 % CI 0.72-1.42). Smoking was more strongly associated with heart failure, particularly of ischemic origin, than snus use.ConclusionsSnus use was associated with a modestly increased risk for heart failure of non-ischemic origin in a dose-response manner. This finding has public health implications for the risk assessment of snus use, and potentially other modes of smokeless use of nicotine.
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| 22. |
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| 23. |
- Azul, David, et al.
(författare)
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Supporting Well-Being in Gender-Diverse People : A Tutorial for Implementing Conceptual and Practical Shifts Toward Culturally Responsive, Person-Centered Care in Speech-Language Pathology
- 2022
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Ingår i: American Journal of Speech-Language Pathology. - 1558-9110. ; 31:4, s. 1574-1587
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Gender dysphoria is commonly conceptualized as a mental disorder in gender-diverse people who do not identify with the gender assigned to them at birth. Direct support for well-being tends to be delegated to the field of mental health (MH), whereas speech-language pathology (SLP) practice is charged with modifying gender-diverse people's voice and communication in the belief that well-being will improve as a byproduct. However, with the introduction of the minority stress model, gender dysphoria is now understood as the result of sociocultural processes of stigmatization, pathologization, coping, and resilience, and it is to be addressed by all professions providing transgender health services. The purposes of this tutorial are to examine practices in SLP in light of the current conceptualization of gender dysphoria and guide speech-language pathologists in their role in supporting the well-being of gender-diverse people.Method: We reviewed the SLP and MH literature in the topic area to compare the two disciplines' conceptualizations and approaches to professional support for gender-diverse people.Results: We propose a transdisciplinary, person-centered, and culturally responsive approach to SLP practice that directly attends to minority stress, microaggressions, coping skills, and resilience factors.Conclusions: It is not sufficient for speech-language pathologists to delegate support for well-being in gender-diverse people to MH practitioners. Rather, speech-language pathologists need to be proactive in taking responsibility for supporting their clients' well-being based on each individual clinician's knowledge, skills, and capacity to do so. We recommend addressing barriers and facilitators of gender-diverse people's well-being both within SLP as a professional culture and by adapting the clinician's own professional practice.
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| 24. |
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| 25. |
- Bergqvist, Rita, et al.
(författare)
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HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden : A registry-based cohort study
- 2021
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 18:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality.Methods and findings: This cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins.In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%).A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens.Conclusions: Statin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.
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| 26. |
- Bergström, Ulf, et al.
(författare)
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Effects of adalimumab treatment on endothelial cell activation markers in the skeletal muscle of patients with rheumatoid arthritis.
- 2014
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Ingår i: Clinical and Experimental Rheumatology. - 1593-098X .- 0392-856X. ; 32:6, s. 883-890
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with rheumatoid arthritis (RA), particularly those with severe disease, have increased risk of cardiovascular disease (CVD). Previous studies suggest that endothelial cell activation may contribute to this co-morbidity, and that treatment with tumour necrosis factor (TNF) inhibitors could reduce the risk of CVD in these patients. The aim of this study was to investigate endothelial cell activation markers in muscle tissue of patients after adalimumab treatment.
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| 27. |
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| 28. |
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| 29. |
- Björklund, Anders, et al.
(författare)
-
Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model
- 2000
-
Ingår i: Brain Research. - 1872-6240. ; 886:1-2, s. 82-98
-
Tidskriftsartikel (refereegranskat)abstract
- During the last few years, recombinant viral vectors derived from adenovirus (Ad), adeno-associated virus (AAV) or lentivirus (LV) have been developed into highly effective vehicles for gene transfer to the adult central nervous system. In recent experiments, in the rat model of Parkinson's disease, all three vector systems have been shown to be effective for long-term delivery of glial cell line-derived neurotrophic factor (GDNF) at biologically relevant levels in the nigrostriatal system. Injection of the GDNF encoding vectors into either striatum or substantia nigra thus makes it possible to obtain a regionally restricted over-expression of GDNF within the nigrostriatal system that is sufficient to block the toxin-induced degeneration of the nigral dopamine neurons. Injection of GDNF vectors in the striatum, in particular, is effective not only in rescuing the cell bodies in the substantia nigra, but also in preserving the nigrostriatal projection and a functional striatal dopamine innervation in the rat Parkinson model. Long-term experiments using AAV-GDNF and LV-GDNF vectors show, moreover, that sustained GDNF delivery over 3-6 months can promote regeneration and significant functional recovery in both 6-OHDA-lesioned rats and MPTP-lesioned monkeys. The impressive efficacy of the novel AAV and LV vectors in rodent and primate Parkinson models suggests that the time may now be ripe to explore these vector systems as tools for neuroprotective treatments in patients with Parkinson's disease.
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| 30. |
- Blixt Wojciechowski, Anita, et al.
(författare)
-
Long-term survival and glial differentiation of the brain-derived precursor cell line RN33B after subretinal transplantation to adult normal rats
- 2002
-
Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 20:2, s. 163-173
-
Tidskriftsartikel (refereegranskat)abstract
- The potential use of in vitro-expanded precursor cells or cell lines in repair includes transplantation of such cells for cell replacement purposes and the activation of host cells to provide "self-repair." Recently, we have reported that cells from the brain-derived cell line RN33B (derived from the embryonic rat medullary raphe and immortalized through retroviral transduction of the temperature-sensitive mutant of the simian virus 40 ([SV40] large T-antigen) survive for at least 4 weeks, integrate, and differentiate after subretinal grafting to normal adult rats. Here, we demonstrate that grafts of these cells survive for at least 4 months after subretinal transplantation to adult, normal immunosuppressed rats. Implanted cells integrate into the retinal pigment epithelium and the inner retinal layers, and the anterior part of the optic nerve. In addition, the RN33B cells migrate within the retina, occupying the whole retina from one eccentricity to the other. A large fraction of the grafted cells differentiate into glial cells, as shown by double labeling of the reporter genes LacZ or green fluorescent protein, and several glial markers, including oligodendrocytes. However, the cells did not differentiate into retinal neurons, judging from their lack of expression of retinal neuronal phenotypic markers. A significant number of the implanted cells in the host retina were in a proliferative stage, judging from proliferative cell nuclear antigen and SV40 large T-antigen immunohistochemistry. To conclude, the cells survived, integrated, and migrated over long distances within the host. Therefore, our results may be advantageous for future design of therapeutic strategies, since such cells may have the potential of being a source of, for example, growth factor delivery in experimental models of retinal degeneration.
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| 31. |
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| 32. |
- Blixt Wojciechowski, Anita, et al.
(författare)
-
Migratory capacity of the cell line RN33B and the host glial cell response after subretinal transplantation to normal adult rats
- 2004
-
Ingår i: Glia. - : John Wiley & Sons. - 0894-1491 .- 1098-1136. ; 47:1, s. 58-67
-
Tidskriftsartikel (refereegranskat)abstract
- As previously reported, the brain-derived precursor cell line RN33B has a great capacity to migrate when transplanted to adult brain or retina. This cell line is immortalized with the SV40 large T-antigen and carries the reporter gene LacZ and the green fluorescent protein GFP. In the present study, the precursor cells were transplanted to the subretinal space of adult rats and investigated early after grafting. The purpose was to demonstrate the migration of the grafted cells from the subretinal space into the retina and the glial cell response of the host retina. Detachment caused by the transplantation method was persistent up to 4 days after transplantation, and then reattachment occurred. The grafted cells were shown to migrate in between the photoreceptor cells before entering into the plexiform layers. Molecules involved in migration of immature neuronal cells as the polysialylated neural cell adhesion molecule (PSA-NCAM) and the collapsing response-mediated protein 4 (TUC-4) was found in the plexiform layers of the host retina, but not in the grafted cells. The expression of the intermediate filaments GFAP, vimentin, and nestin was intensely upregulated immediately after transplantation. A less pronounced upregulation was observed on sham-operated animals. In summary, the RN33B cell line migrated promptly posttransplantation and settled preferably into the plexiform layers of the retina, the same layers where the migration cues PSA-NCAM and TUC-4 were established. In addition, both the transplantation method per se and the implanted cells caused an intense glial cell response by the host retina.
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| 33. |
- Blixt Wojciechowski, Anita, et al.
(författare)
-
Subretinal Transplantation of Brain-derived Precursor Cells to Young RCS Rats Promotes Photoreceptor Cell Survival☆
- 2002
-
Ingår i: Experimental Eye Research. - : Elsevier. - 0014-4835 .- 1096-0007. ; 75:1, s. 23-37
-
Tidskriftsartikel (refereegranskat)abstract
- The potential use of in vitro-expanded precursor cells or cell lines in brain repair includes transplantation of such cells for cell replacement purposes and the activation of host cells to provide 'self-repair'. Recently, it has been reported that the immortalized brain-derived cell line RN33B (derived from the embryonic rat medullary raphe) survive, integrate and differentiate after subretinal grafting to normal adult rats. Here, it is demonstrated that grafts of these cells survive for at least 6 weeks after implantation into postnatal days 21 and 35 retinas of normal and Royal College of Surgeons rats, a model of retinal degeneration. Implanted cells integrate into the retinal pigment epithelium and the inner retinal layers, and the anterior part of the optic nerve of both normal and Royal College of Surgeons rats. The RN33B cells migrate within the retina, occupying the whole retina from one eccentricity to the other. A significant number of the grafted cells differentiate into glial cells, as shown by the double labelling of the reporter genes LacZ or green fluorescent protein, with several glial markers, including oligodendrocytic markers. Many implanted cells in the host retina were in a proliferative stage judging from proliferative cell nuclear antigen and SV40 large T-antigen immunohistochemistry. Interestingly, there was a promotion of photoreceptor survival, extending over more than 2/3 of the superior hemisphere, in Royal College of Surgeons rats transplanted at postnatal day 21, but not at postnatal day 35. In addition, grafted cells were found in the surviving photoreceptor layer in these rats.
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| 34. |
- Blixt Wojciechowski, Anita, et al.
(författare)
-
Survival and long distance migration of brain-derived precursor cells transplanted to adult rat retina
- 2004
-
Ingår i: Stem Cells. - : AlphaMed Press. - 1549-4918 .- 1066-5099. ; 22:1, s. 27-38
-
Tidskriftsartikel (refereegranskat)abstract
- Neural precursor cells transplanted to adult retina can integrate into the host. This is especially true when the neural precursor rat cell line RN33B is used. This cell line carries the reporter genes LacZ and green fluorescent protein (GFP). In grafted rat eyes, RN33B cells are localized from one eccentricity to the other of the host retina. In the present study, whole-mounted retinas were analyzed to obtain a more appropriate evaluation of the amount of transgene-expressing cells and the migratory capacity of these cells 3 and 8 weeks post-transplantation. Quantification was made of the number of beta-galactosidase- and GFP-expressing cells with a semiautomatized stereological cell counting system. With the same system, delineation of the distribution area of the grafted cells was also performed. At 3 weeks, 68% of the grafted eyes contained marker-expressing cells, whereas at 8 weeks only 35% of the eyes contained such cells. Counting of marker-expressing cells demonstrated a lower number of transgene-expressing cells at 3 weeks compared with 8 weeks post-transplantation. The distribution pattern of marker gene-expressing cells revealed cells occupying up to 21% at 3 weeks and up to 68% at 8 weeks of the entire host retina post-grafting. The precursor cells survived well in the adult retina although the most striking feature of the RN33B cell line was its extraordinary migratory capacity. This capability could be useful if precursor cells are used to deliver necessary genes or gene products that need to be distributed over a large diseased area.
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| 35. |
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| 36. |
- Bostrom, E. A., et al.
(författare)
-
Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines
- 2015
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
-
Tidskriftsartikel (refereegranskat)abstract
- Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-alpha (TNF-alpha and interleukin-1 beta (IL-1 beta), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-kappa B pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss.
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| 37. |
- Breger, Ludivine, et al.
(författare)
-
Regulated Gene Therapy.
- 2016
-
Ingår i: Methods in Molecular Biology. - New York, NY : Springer New York. - 1940-6029. ; 1382, s. 57-66
-
Tidskriftsartikel (refereegranskat)abstract
- Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system.
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| 38. |
- Byhamre, Marja Lisa, et al.
(författare)
-
Swedish snus use is associated with mortality : a pooled analysis of eight prospective studies
- 2020
-
Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 49:6, s. 2041-2050
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The health consequences of the use of Swedish snus, including its relationship with mortality, have not been fully established. We investigated the relationship between snus use and all-cause and cause-specific mortality (death due to cardiovascular diseases, cancer diseases and all other reasons, respectively) in a nationwide collaborative pooling project.METHODS: We followed 169 103 never-smoking men from eight Swedish cohort studies, recruited in 1978-2010. Shared frailty models with random effects at the study level were used in order to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of mortality associated with snus use.RESULTS: Exclusive current snus users had an increased risk of all-cause mortality (aHR 1.28, 95% CI 1.20-1.35), cardiovascular mortality (aHR 1.27, 95% CI 1.15-1.41) and other cause mortality (aHR 1.37, 95% CI 1.24-1.52) compared with never-users of tobacco. The risk of cancer mortality was also increased (aHR 1.12, 95% CI 1.00-1.26). These mortality risks increased with duration of snus use, but not with weekly amount.CONCLUSIONS: Snus use among men is associated with increased all-cause mortality, cardiovascular mortality, with death from other causes and possibly with increased cancer mortality.
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| 39. |
- Carreras-Puigvert, Jordi, et al.
(författare)
-
A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
- 2017
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.
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| 40. |
- Cheng, Wing-Shing, 1974-
(författare)
-
TARP Promoter-Based Prostate Cancer Gene Therapy : From Development to Application
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer is one leading cause of cancer-related death among men in Western countries. The standard therapies for localized prostate cancer include radical prostatectomy and radiation therapy. Such measures are relatively effective in the short term, but many patients ultimately relapse. These patients may benefit from a combination of standard therapy and oncolytic virus therapy. My work aimed to develop viruses for this purpose.TARP is a protein that in males is specifically expressed in prostate epithelial and cancer cells. In my thesis, I characterized the TARP promoter and showed that TARP expression is regulated at the transcriptional level by testosterone through binding of the androgen receptor in the proximal TARP promoter. I further developed TARP promoter-based regulatory sequences for prostate-specific gene expression. A sequence comprising a PSA enhancer, a PSMA enhancer and the TARP promoter was constructed and designated PPT. An adenoviral vector containing the PPT sequence shielded from transcriptional interference by an H19 insulator showed high prostate-specific transcriptional activity in human cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer the PPT sequence is not active. Therefore, a two-step transcriptional amplification (TSTA) system was used together with the PPT sequence to develop an adenovirus that confers prostate-specific transgene expression also in murine cells.I constructed a conditionally replicating adenovirus where the E1A gene expression is controlled by an H19 insulator-shielded PPT regulatory sequence, Ad[I/PPT-E1A]. This virus exhibited absolute prostate specificity in terms of E1A expression, viral replication and cytolysis in vitro and in vivo. Importantly, our virus is active both in the presence and absence of testosterone, which may prove beneficial for patients treated by hormonal withdrawal. Hopefully, my work will improve existing gene therapy strategies for prostate cancer and in the long term improve the prognosis for patients with prostate cancer.
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| 41. |
- Chtarto, Abdelwahed, et al.
(författare)
-
A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses
- 2016
-
Ingår i: Molecular Therapy - Methods and Clinical Development. - : Elsevier BV. - 2329-0501. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat PD. The main challenge is finding a combination of a genetic switch and a drug which, when administered at a clinically-approved dose, reaches the brain in sufficient amounts to induce a therapeutic effect. We describe a highly-sensitive doxycycline-inducible adeno-associated virus (AAV) vector. This vector allowed for the first time a longitudinal analysis of inducible transgene expression in the brain using bioluminescence imaging. To evaluate the dose range of GDNF biological activity, the inducible AAV vector (8.0 × 10(9) viral genomes) was injected in the rat striatum at four delivery sites and increasing doxycycline doses administered orally. ERK/Akt signaling activation as well as tyrosine hydroxylase downregulation, a consequence of long-term GDNF treatment, were induced at plasmatic doxycycline concentrations of 140 and 320 ng/ml respectively, which are known not to increase antibiotic-resistant microorganisms in patients. In these conditions, GDNF covered the majority of the striatum. No behavioral abnormalities or weight loss were observed. Motor asymmetry resulting from unilateral GDNF treatment only appeared with a 2.5-fold higher vector and a 13-fold higher inducer doses. Our data suggest that using the herein-described inducible AAV vector, biological effects of GDNF can be obtained in response to sub-antimicrobial doxycycline doses.
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| 42. |
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| 43. |
- Danielsson, Frida, et al.
(författare)
-
Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia
- 2018
-
Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 9:28, s. 19730-19744
-
Tidskriftsartikel (refereegranskat)abstract
- In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing their surrounding vasculature network. Transformed cancer cells are known to exhibit phenotypic alterations, enabling continuous proliferation despite a limited oxygen supply. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines of the BJ model responded strikingly different to hypoxia. Besides corroborating many of the known responses to hypoxia, we demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.
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| 44. |
- Davidsson, Marcus, et al.
(författare)
-
Molecular barcoding of viral vectors enables mapping and optimization of mRNA trans-splicing
- 2018
-
Ingår i: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 24:5, s. 673-687
-
Tidskriftsartikel (refereegranskat)abstract
- Genome editing has proven to be highly potent in the generation of functional gene knockouts in dividing cells. In the CNS however, efficient technologies to repair sequences are yet to materialize. Reprogramming on the mRNA level is an attractive alternative as it provides means to perform in situ editing of coding sequences without nuclease dependency. Furthermore, de novo sequences can be inserted without the requirement of homologous recombination. Such reprogramming would enable efficient editing in quiescent cells (e.g., neurons) with an attractive safety profile for translational therapies. In this study, we applied a novel molecular-barcoded screening assay to investigate RNA trans-splicing in mammalian neurons. Through three alternative screening systems in cell culture and in vivo, we demonstrate that factors determining trans-splicing are reproducible regardless of the screening system. With this screening, we have located the most permissive trans-splicing sequences targeting an intron in the Synapsin I gene. Using viral vectors, we were able to splice full-length fluorophores into the mRNA while retaining very low off-target expression. Furthermore, this approach also showed evidence of functionality in the mouse striatum. However, in its current form, the trans-splicing events are stochastic and the overall activity lower than would be required for therapies targeting loss-of-function mutations. Nevertheless, the herein described barcode-based screening assay provides a unique possibility to screen and map large libraries in single animals or cell assays with very high precision.
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| 45. |
- Deierborg, Tomas, et al.
(författare)
-
Absence of striatal newborn neurons with mature phenotype following defined striatal and cortical excitotoxic brain injuries.
- 2009
-
Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 219, s. 363-367
-
Tidskriftsartikel (refereegranskat)abstract
- Experimental stroke and excitotoxic brain lesion to the striatum or cortex increase the proliferation of cells residing within the ventricular wall and cause subsequent migration of newborn neuroblasts into the lesioned brain parenchyma. In this study, we clarify the different events of neurogenesis following striatal or cortical excitotoxic brain lesions in adult rats. Newborn cells were labeled by intraperitoneal injection of bromo-deoxy-uridine (BrdU), or by green fluorescent protein (GFP)-expressing lentiviral vectors injected into the subventricular zone (SVZ). We show that only neural progenitors born the first 5 days in the SVZ reside and expand within this neurogenic niche over time, and that these early labeled cells are more prone to migrate towards the striatum as neuroblasts. However, these neuroblasts could not mature into NeuN(+) neurons in the striatum. Furthermore, we found that cortical lesions, close or distant from the SVZ, could not upregulate SVZ cell proliferation nor promote neurogenesis. Our study demonstrates that both the time window for labeling proliferating cells and the site of lesion are crucial when assessing neurogenesis following brain injury.
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| 46. |
- Dolatkhah, Mats, et al.
(författare)
-
Att värdera skolbiblioteksforskning
- 2013
-
Annan publikation (populärvet., debatt m.m.)abstract
- 25 år av tvärvetenskaplig, internationell forskning visar alltjämt att bemannade skolbibliotek som samspelar nära med undervisningen kan ge högst meningsfulla bidrag till elevers lärande. Det menar sex forskare vid institutionen för Biblioteks- och informationsvetenskap vid Högskolan i Borås. I en lång replik (7/10) i debatten om skolbibliotek, där Gabriel H Sahlgren generöst presenterar färdiga och kategoriska lösningar på svåra och omstridda metodologiska problem inom samhällsvetenskaplig och tvärvetenskaplig forskning, bemöts vårt tidigare inlägg (4/10). Vi noterar att Sahlgren, som professionell opinionsbildare med uppdrag att finna argument för en fri skolmarknad, framhärdar i sin övertygelse om att en enda indisk studie är en bättre indikator på hur skolbibliotek i Sverige kan fungera, än den helhetsbild som övrig forskning presenterar. Skälet för detta är att den indiska studien använder sig av en experimentell metoddesign. Studien ifråga finner inget stöd för att anta att orsakssamband finns mellan förekomsten av skolbibliotek och elevers studieresultat.
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| 47. |
- Dolatkhah, Mats, et al.
(författare)
-
"Skolbiblioteken allt annat än meningslösa"
- 2013
-
Ingår i: Dagens nyheter. - : Dagens nyheter. - 1101-2447.
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Relevansen och effektiviteten hos skolbibliotek har diskuterats på DN Debatt de senaste dagarna. Det är glädjande att forskning används som stöd för politisk debatt i detta sammanhang, men forskningsresultaten bör inte användas selektivt för att stödja en viss politisk ståndpunkt, skriver forskare och lärare vid institutionen för Biblioteks- och informationsvetenskap vid Högskolan i Borås.
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| 48. |
- Dou, Diana R., et al.
(författare)
-
Xist ribonucleoproteins promote female sex-biased autoimmunity
- 2024
-
Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 187:3, s. 16-733
-
Tidskriftsartikel (refereegranskat)abstract
- Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
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| 49. |
- Döring, Nora, et al.
(författare)
-
Labour market position of young people and premature mortality in adult life : A 26-year follow-up of 569 528 Swedish 18 year-olds
- 2021
-
Ingår i: The Lancet Regional Health. - : Elsevier BV. - 2666-7762. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Throughout the industrialized world, demand for low skilled labour is falling. The length of schooling is increasing in response, but so is the proportion of individuals not finishing upper secondary school. The objective of this study was to evaluate the associations between labour market positions at age 18 and all-cause and suicide- and accident-specific mortality in later adulthood.Methods: Labour market positions at age 18 were categorized for all Swedes born 1972-77 (n=630 959) into four main groups: employed, successful students, students not about to qualify (SNAQs), and individuals not in employment, education or training (NEETs). Cox proportional hazard models were fitted to assess allcause, suicide and accident mortality up to 2016 (ages 39-44), adjusting for high school grades, parental and own prior psychiatric diagnoses, and childhood socioeconomic status.Findings: SNAQs had substantially increased all-cause (men: HR=2.10; 95% CI 1.92-2.28, women: HR=1.64; 95% CI: 1.44-1.86), suicide (men: HR=2.16; CI: 1.86-2.51, women: HR=2.10; 95% CI 1.64-2.69), and accident specific (men: HR=2.08; 95% CI 1.77-2.44, women: 1.87; 95% CI 1.33;2.62) mortality risks compared to successful students. The risks were similar for NEETs. There was no increased risk among full-time employed compared to successful students.Interpretation: Expanding the educational system may be a natural response to falling demand for low skilled labour but not by far one that corrects the major societal challenge of it. Unless educational systems adequately respond to this challenge, only more inequality is to be expected ahead.
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| 50. |
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