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- Gustavsson, Tobias, et al.
(författare)
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Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease
- 2023
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central (BMC). - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundBrain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer’s disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis.MethodsAppNL−G−F knock-in mice received RmAb158, RmAb158-scFv8D3, or PBS in three treatment regimens. First, to assess the acute therapeutic effect, a single antibody dose was given to 5 months old AppNL−G−F mice, with evaluation after 3 days. Second, to assess the antibodies’ ability to halt the progression of Aβ pathology, 3 months old AppNL−G−F mice received three doses during a week, with evaluation after 2 months. Reduction of RmAb158-scFv8D3 immunogenicity was explored by introducing mutations in the antibody or by depletion of CD4+ T cells. Third, to study the effects of chronic treatment, 7-month-old AppNL−G−F mice were CD4+ T cell depleted and treated with weekly antibody injections for 8 weeks, including a final diagnostic dose of [125I]RmAb158-scFv8D3, to determine its brain uptake ex vivo. Soluble Aβ aggregates and total Aβ42 were quantified with ELISA and immunostaining.ResultsNeither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after a single injection treatment. After three successive injections, Aβ1-42 was reduced in mice treated with RmAb158, with a similar trend in RmAb158-scFv8D3-treated mice. Bispecific antibody immunogenicity was somewhat reduced by directed mutations, but CD4+ T cell depletion was used for long-term therapy. CD4+ T cell-depleted mice, chronically treated with RmAb158-scFv8D3, showed a dose-dependent increase in blood concentration of the diagnostic [125I]RmAb158-scFv8D3, while concentration was low in plasma and brain. Chronic treatment did not affect soluble Aβ aggregates, but a reduction in total Aβ42 was seen in the cortex of mice treated with both antibodies.ConclusionsBoth RmAb158 and its bispecific variant RmAb158-scFv8D3 achieved positive effects of long-term treatment. Despite its ability to efficiently enter the brain, the benefit of using the bispecific antibody in chronic treatment was limited by its reduced plasma exposure, which may be a result of interactions with TfR or the immune system. Future research will focus in new antibody formats to further improve Aβ immunotherapy.
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- Toksvang, LN, et al.
(författare)
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Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol
- 2022
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 22:1, s. 483-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundA critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance.MethodsTEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0–45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5–12.5 mg/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients.DiscussionTEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms.Trial registrationEudraCT, 2018–001795-38. Registered 2020-05-15,Clinicaltrials.gov,NCT04307576. Registered 2020-03-13,https://clinicaltrials.gov/ct2/show/NCT04307576
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| 9. |
- Aben, Ralf C. H., et al.
(författare)
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Cross continental increase in methane ebullition under climate change
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Methane (CH4) strongly contributes to observed global warming. As natural CH4 emissions mainly originate from wet ecosystems, it is important to unravel how climate change may affect these emissions. This is especially true for ebullition (bubble flux from sediments), a pathway that has long been underestimated but generally dominates emissions. Here we show a remarkably strong relationship between CH4 ebullition and temperature across a wide range of freshwater ecosystems on different continents using multi-seasonal CH4 ebullition data from the literature. As these temperature-ebullition relationships may have been affected by seasonal variation in organic matter availability, we also conducted a controlled year-round mesocosm experiment. Here 4 degrees C warming led to 51% higher total annual CH4 ebullition, while diffusion was not affected. Our combined findings suggest that global warming will strongly enhance freshwater CH4 emissions through a disproportional increase in ebullition (6-20% per 1 degrees C increase), contributing to global warming.
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- Fischer, Håkan, et al.
(författare)
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Extraversion, Neuroticism and brain function: A PET study of personality
- 1997
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Ingår i: PERSONALITY AND INDIVIDUAL DIFFERENCES. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0191-8869. ; 23:2, s. 345-352
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Tidskriftsartikel (refereegranskat)abstract
- The personality dimensions Extraversion and Neuroticism seem associated with differences in central nervous system function. We used positron emission tomographic (PET) measures of regional cerebral blood flow (rCBF) to investigate central neural differe
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- Fischer, Håkan, et al.
(författare)
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Functional neuroanatomy of robbery re-experience: Affective memories studied with PET
- 1996
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Ingår i: NEUROREPORT. - : RAPID SCIENCE PUBLISHERS. - 0959-4965. ; 7:13, s. 2081-2086
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Tidskriftsartikel (refereegranskat)abstract
- USING positron emission tomography (PET) and [O-15]butanol, regional cerebral blood flow (rCBF) was determined in six bank officials during exposure to a video of a jointly experienced armed bank robbery, and a control video. Besides elevating subjective
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- Fredrikson, Mats, et al.
(författare)
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Affective and attentive neural networks in humans: A PET study of Pavlovian conditioning
- 1995
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Ingår i: NEUROREPORT. - : RAPID SCIENCE PUBLISHERS. - 0959-4965. ; 7:1, s. 97-101
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Tidskriftsartikel (refereegranskat)abstract
- USING positron emission tomography (PET) and [O-15]butanol we studied regional cerebral blood now (rCBF) to a visual snake stimulus before and after classical conditioning with an unconditioned electric shock delivered to the right hand. Measures of hear
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- Fredrikson, Mats, et al.
(författare)
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Cerebral blood flow during anxiety provocation
- 1997
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Ingår i: JOURNAL OF CLINICAL PSYCHIATRY. - : PHYSICIANS POSTGRADUATE PRESS. - 0160-6689. ; 58, s. 16-21
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that traumatic reactions result from the failure to integrate the trauma with existing cognitive schemata, whereas phobias represent biologically influenced adaptation patterns. This implies that central nervous system (CNS) organiz
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| 34. |
- Fredrikson, Mats, et al.
(författare)
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Gender and age differences in the prevalence of specific fears and phobias
- 1996
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Ingår i: BEHAVIOUR RESEARCH AND THERAPY. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0005-7967. ; 34:1, s. 33-39
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Tidskriftsartikel (refereegranskat)abstract
- Point prevalence of specific fears and phobias was determined in 704 respondents of 1000 randomly selected adults aged 18-70 yr. A phobia for lightning, enclosed spaces, darkness, flying, heights, spiders, snakes, injections, dentists and/or injuries was
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| 36. |
- Fredrikson, Mats, et al.
(författare)
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Higher hypothalamic and hippocampal neural activity in type A than type B women
- 1999
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Ingår i: PERSONALITY AND INDIVIDUAL DIFFERENCES. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0191-8869. ; 26:2, s. 265-270
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Tidskriftsartikel (refereegranskat)abstract
- The type A behavior characterized by hostility, competitiveness and time urgency, as compared to its type B counterpart, is associated with increased responsiveness in peripheral measures of the pituitary adrenal and cortical responses as well as in the
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| 44. |
- Furmark, Tomas, et al.
(författare)
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The amygdala and individual differences in human fear conditioning
- 1997
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Ingår i: NEUROREPORT. - : LIPPINCOTT WILLIAMS & WILKINS. - 0959-4965. ; 8:18, s. 3957-3960
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Tidskriftsartikel (refereegranskat)abstract
- WHILE animal research on fear conditioning suggests crucial involvement of the amygdala, this has not been corroborated in humans when using subtractive neuroimaging methodology. Correlation analyses might be more able to reveal relations between individ
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| 45. |
- Kruger, K, et al.
(författare)
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Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 1089-
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Tidskriftsartikel (refereegranskat)abstract
- We here examined whether Nestin, by protein and mRNA levels, could be a predictor of BRCA1 related breast cancer, a basal-like phenotype, and aggressive tumours. Immunohistochemical staining of Nestin was done in independent breast cancer hospital cohorts (Series I-V, total 1257 cases). Also, TCGA proteomic data (n = 103), mRNA microarray data from TCGA (n = 520), METABRIC (n = 1992), and 6 open access breast cancer datasets (n = 1908) were analysed. Patients with Nestin protein expression in tumour cells more often had BRCA1 germline mutations (OR 8.7, p < 0.0005, Series III), especially among younger patients (<40 years at diagnosis) (OR 16.5, p = 0.003). Nestin protein positivity, observed in 9–28% of our hospital cases (Series I-IV), was independently associated with reduced breast cancer specific survival (HR = 2.0, p = 0.035) and was consistently related to basal-like differentiation (by Cytokeratin 5, OR 8.7–13.8, p < 0.0005; P-cadherin OR 7.0–8.9, p < 0.0005; EGFR staining, OR 3.7–8.2, p ≤ 0.05). Nestin mRNA correlated significantly with Nestin protein expression (ρ = 0.6, p < 0.0005), and high levels were seen in the basal-like intrinsic subtype. Gene expression signalling pathways linked to high Nestin were explored, and revealed associations with stem-like tumour features. In summary, Nestin was strongly associated with germline BRCA1 related breast cancer, a basal-like phenotype, reduced survival, and stemness characteristics.
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| 47. |
- Lekander, M, et al.
(författare)
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Neuroimmune relations in patients with fibromyalgia: a positron emission tomography study
- 2000
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Ingår i: NEUROSCIENCE LETTERS. - : ELSEVIER SCI IRELAND LTD. - 0304-3940. ; 282:3, s. 193-196
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Tidskriftsartikel (refereegranskat)abstract
- To study relations between neural and immune activity in patients with chronic pain, we correlated regional cerebral blood flow measured with [O-15]butanol positron emission tomography to immune function in five patients with fibromyalgia. Partly replicat
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