| 1. |
- Al-Saadi, Jonathan, et al.
(författare)
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Endovascular transplantation of mRNA-enhanced mesenchymal stromal cells results in superior therapeutic protein expression in swine heart
- 2024
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Ingår i: Molecular therapy. Methods & clinical development. - : Elsevier BV. - 2399-6951 .- 2329-0501. ; 32:2
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure has a poor prognosis and no curative treatment exists. Clinical trials are investigating gene- and cell-based therapies to improve cardiac function. The safe and efficient delivery of these therapies to solid organs is challenging. Herein, we demonstrate the feasibility of using an endovascular intramyocardial delivery approach to safely administer mRNA drug products and perform cell transplantation procedures in swine. Using a trans-vessel wall (TW) device, we delivered chemically modified mRNAs (modRNA) and mRNA-enhanced mesenchymal stromal cells expressing vascular endothelial growth factor A (VEGF-A) directly to the heart. We monitored and mapped the cellular distribution, protein expression, and safety tolerability of such an approach. The delivery of modRNA-enhanced cells via the TW device with different flow rates and cell concentrations marginally affect cell viability and protein expression in situ. Implanted cells were found within the myocardium for at least 3 days following administration, without the use of immunomodulation and minimal impact on tissue integrity. Finally, we could increase the protein expression of VEGF-A over 500-fold in the heart using a cell-mediated modRNA delivery system compared with modRNA delivered in saline solution. Ultimately, this method paves the way for future research to pioneer new treatments for cardiac disease.
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| 2. |
- Arruda, Lucas C. M., et al.
(författare)
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A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells in vitro and in vivo
- 2022
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 107:8, s. 1786-1795
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Tidskriftsartikel (refereegranskat)abstract
- Less than a third of patients with acute myeloid leukemia (AML) are cured by chemotherapy and/or hematopoietic stem cell transplantation, highlighting the need to develop more efficient drugs. The low efficacy of standard treatments is associated with inadequate depletion of CD34(+) blasts and leukemic stem cells, the latter a drug-resistant subpopulation of leukemia cells characterized by the CD34(+)CD38(-) phenotype. To target these drug-resistant primitive leukemic cells better, we have designed a CD34/CD3 bi-specific T-cell engager (BTE) and characterized its anti-leukemia potential in vitro, ex vivo and in vivo. Our results show that this CD34-specific BTE induces CD34-dependent T-cell activation and subsequent leukemia cell killing in a dose-dependent manner, further corroborated by enhanced T-cell-mediated killing at the singlecell level. Additionally, the BTE triggered efficient T-cell-mediated depletion of CD34(+) hematopoietic stem cells from peripheral blood stem cell grafts and CD34(+) blasts from AML patients. Using a humanized AML xenograft model, we confirmed that the CD34-specific BTE had in vivo efficacy by depleting CD34(+) blasts and leukemic stem cells without side effects. Taken together, these data demonstrate that the CD34-specific BTE has robust antitumor effects, supporting development of a novel treatment modality with the aim of improving outcomes of patients with AML and myelodysplastic syndromes.
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| 3. |
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| 4. |
- Broström (red), Tor, et al.
(författare)
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Brandsäkerhet för byggnader med kulturvärden: En kunskapsöversikt
- 2021
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Abstract [sv] Arbetet med brandsäkerhet för byggnader med kulturvärden kräver anpassade lösningar som också kan tillgodose ett bevarande av byggnaderna och deras kulturvärden. Det finns, utspritt, mycket kunskap och erfarenhet inom det här området både i Sverige och internationellt. För att tillgodose ett behov av samlad kunskap inom detta område initierade Brandforsk en kunskapsöversikt tillsammans med Akademiska hus, Fortifikationsverket, Kammarkollegiet, Kyrkans försäkring, Riksantikvarieämbetet och Statens fastighetsverk. Den här kunskapsöversikten syftar till att sammanställa och presentera den kunskap som finns. Ett kompletterande syfte är att definiera områden där kunskap saknas. Kunskapsöversikten är indelad i sex områden: 2. Skydd mot brands uppkomst 3. Spridning av brand inom byggnad 4. Spridning av brand till byggnad 5. Brandens påverkan på byggnadens stomme 6. Utrymning 7. Räddningstjänstens insats Med utgångspunkt från workshops har en sammanställning av behovsbilden gjorts. Kunskapsöversikten och behovsbilden ligger till grund för en gap-analys vilken pekar på behov av fortsatt forskning och utveckling. Abstract [en] Working with fire safety in historic buildings requires adapted solutions that can also satisfy the preservation of the buildings and their cultural values. There is a lot of knowledge and experience in this area both in Sweden and internationally. In order to make this available to end users, Brandforsk initiated a literature review together with a group of national sponsors. This literature review aims to compile and present the documented knowledge in the field. A complementary purpose is to define knowledge gaps. The review is divided into six areas: 2. Fire prevention 3. Fire spread within buildings 4. Fire spread between structures 5. Structural fire resistance 6. Evacuation 7. Fire and rescue service activities Based on workshops the needs of end users have been compiled. A comparison of the outcome of the review and the end user needs defines a knowledge gap pointing to the need for continued research and development.
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| 5. |
- Carlsten, Mattias
(författare)
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Molecular specificities of NK cell-mediated recognition of human tumor cells
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Natural killer (NK) cells have been implicated in tumor immune surveillance and can reject transformed cells expressing ligands for activating NK cell receptors and low levels of HLA class I. Although NK cells are well known for their ability to kill tumor cells, relatively few studies have addressed the molecular specificity of NK cell-mediated recognition of freshly isolated human tumor cells. The rational for conducting such studies is based on the fact that tumor cell lines display altered molecular expression compared to their origin. In this thesis, we have assessed the role for NK cells in solid and hematological malignancies. We show that freshly isolated metastatic ovarian carcinoma (OC) cells express low levels of HLA class I. In one patient, we identified a genomic HLA class I haplotype loss that was associated with a HLA-A2 restricted Her2/neu specific T cell response. The low HLA class I levels, in combination with the presence of ligands for activating NK cell receptors, resulted in a significant killing of the metastatic OC cells by allogeneic NK cells, while sparing normal cells. Experiments masking activating NK cell receptors revealed a dominant role for the DNAM-1 receptor with a minor contribution from the NKG2D receptor. Studies of the receptor repertoire and functional integrity of NK cells associated to the tumor in vivo substantiated a role for DNAM-1 since a marked loss of DNAM-1 as well as 2B4 and CD16 were observed and resulted in significantly reduced natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) against autologous carcinoma cells. The DNAM-1 loss was likely caused by chronic ligand exposure, since physical interactions between the receptor and its ligand CD155 induced down-regulation. Suppressed NK cell function due to loss of DNAM-1 and NKG2D expression was also identified in the bone marrow and blood of patients with myelodysplastic syndromes (MDS). Relative to NK cells in peripheral blood, bone marrow-derived NK cells associated to the tumor cells displayed a more severe loss of the two receptors as well as a reduced effector cell function. The receptor loss was most prominent in patients with more than 5% blasts in the bone marrow, suggesting that poor NK cell function may be associated with an increased risk of progression to acute myeloid leukemia (AML). Tumor cells may also evade NK cell-mediated lysis by up-regulation of HLA-E that inhibits NK cell activity through signaling via the CD94/NKG2A receptor. Drugs have been used to manipulate the NK cell receptor ligand repertoire on tumor cells to render them more susceptible to NK cells. Selenite, a highly reactive oxidative agent, is known to selectively kill tumor cells when used in high concentrations. We show that selenite also reduced the expression of HLA-E and rendered the tumor cells more susceptible to killing by CD94/NKG2A expressing NK cells. Given the emerging evidence for NK cell-mediated tumor immune surveillance, our data indicate that tumor progression may be promoted by perturbed activating NK cell receptor repertoires and poor function of tumor-associated NK cells. The data imply that OC could be targeted by NK cell-based immunotherapy and that MDS patients having more than 5% blasts in the bone marrow could be considered as potential candidates for NK cell-based immunotherapy. Data also indicate that selenite may be used to improve the results of NK cell-based immunotherapies by rendering HLA-E expressing tumor cells more susceptible to NK cells. Thus, a better comprehension of the molecular specificity of NK cells targeting fresh human tumor cells and the role for combinatorial treatments can hopefully advance NK cell-based immunotherapies.
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| 6. |
- Curbo, Sophie, et al.
(författare)
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Regulation of interleukin-4 signaling by extracellular reduction of intramolecular disulfides
- 2009
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 390:4, s. 1272-1277
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-4 (IL-4) contains three structurally important intramolecular disulfides that are required for the bioactivity of the cytokine. We show that the cell surface of HeLa cells and endotoxin-activated monocytes can reduce IL-4 intramolecular disulfides in the extracellular space and inhibit binding of IL-4 to the IL-4R alpha receptor. IL-4 disulfides were in vitro reduced by thioredoxin 1 (Trx1) and protein disulfide isomerase (PDI). Reduction of IL-4 disulfides by the cell surface of HeLa cells was inhibited by auranofin, an inhibitor of thioredoxin reductase that is an electron donor to both Trx1 and PDI. Both Trx1 and PDI have been shown to be located at the cell surface and our data suggests that these enzymes are involved in catalyzing reduction of IL-4 disulfides. The pro-drug N-acetylcysteine (NAC) that promotes T-helper type 1 responses was also shown to mediate the reduction of IL-4 disulfides. Our data provides evidence for a novel redox dependent pathway for regulation of cytokine activity by extracellular reduction of intramolecular disulfides at the cell surface by members of the thioredoxin enzyme family.
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| 7. |
- Deminger, Anna, 1973, et al.
(författare)
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Factors associated with changes in volumetric bone mineral density and cortical area in men with ankylosing spondylitis : a 5-year prospective study using HRpQCT
- 2022
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Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 33:1, s. 205-216
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Patients with ankylosing spondylitis (AS) have impaired volumetric bone mineral density (vBMD) assessed with high-resolution peripheral computed tomography (HRpQCT). This first longitudinal HRpQCT study in AS shows that cortical and trabecular vBMD decreased at tibia and that signs of inflammation were associated with cortical bone loss at tibia and radius.Introduction: Patients with ankylosing spondylitis (AS) have reduced volumetric bone mineral density (vBMD) in the peripheral skeleton assessed with high-resolution peripheral quantitative computed tomography (HRpQCT). The aims were to investigate longitudinal changes in vBMD, cortical area, and microarchitecture and to assess factors associated with changes in vBMD and cortical area in men with AS.Methods: HRpQCT of radius and tibia was performed in 54 men with AS at baseline and after 5 years. Univariate and multivariable linear regression analyses were used.Results: At tibia, there were significant decreases exceeding least significant changes (LSC) in cortical and trabecular vBMD, mean (SD) percent change −1.0 (1.9) and −2.7 (5.0) respectively (p<0.001). In multivariable regression analyses, increase in disease activity measured by ASDAS_CRP from baseline to follow-up was associated with decreases in cortical vBMD (β −0.86, 95% CI −1.31 to −0.41) and cortical area (β −1.66, 95% CI −3.21 to −0.10) at tibia. At radius, no changes exceeded LSC. Nonetheless, increase in ASDAS_CRP was associated with decreases in cortical vBMD, and high time-averaged ESR was associated with decreases in cortical area. Treatment with TNF inhibitor ≥ 4 years during follow-up was associated with increases in cortical vBMD and cortical area at tibia, whereas exposure to bisphosphonates was associated with increases in cortical measurements at radius. No disease-related variables or treatments were associated with changes in trabecular vBMD.Conclusion: The findings in this first longitudinal HRpQCT study in patients with AS strengthen the importance of controlling disease activity to maintain bone density in the peripheral skeleton.
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| 8. |
- Deminger, Anna, 1973, et al.
(författare)
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Which measuring site in ankylosing spondylitis is best to detect bone loss and what predicts the decline : results from a 5-year prospective study
- 2017
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Ingår i: Arthritis Research & Therapy. - London, United,Kingdom : BioMed Central. - 1478-6354 .- 1478-6362. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies have shown increased prevalence of osteoporosis and increased risk for vertebral fractures in patients with ankylosing spondylitis (AS). Measurements of bone mineral density (BMD) in the lumbar spine anterior-posterior (AP) projection may be difficult to interpret due to the ligamentous calcifications, and the lateral projection might be a better measuring site. Our objectives were to investigate BMD changes after 5 years at different measuring sites in patients with AS and to evaluate disease-related variables and medications as predictors for BMD changes.METHODS: In a longitudinal study, BMD in Swedish AS patients, 50 ± 13 years old, was measured with dual-energy x-ray absorptiometry (DXA) at the hip, the lumbar spine AP and lateral projections, and the total radius at baseline and after 5 years. Patients were assessed with questionnaires, blood samples, and spinal radiographs for grading of AS-related alterations in the spine with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and assessment of vertebral fractures by the Genant score. Multiple linear regression analyses were used to investigate predictors for BMD changes.RESULTS: Of 204 patients included at baseline, 168 (82%) were re-examined after 5 years (92 men and 76 women). BMD decreased significantly at the femoral neck and radius and increased significantly at the lumbar spine, both for AP and lateral projections. Mean C-reactive protein during follow-up predicted a decrease in the femoral neck BMD (change in %, β = -0.15, p = 0.046). Use of bisphosphonates predicted an increase in BMD at all measuring sites (p < 0.001 to 0.013), except for the total radius. Use of tumor necrosis factor inhibitors (TNFi) predicted an increase in AP spinal BMD (β = 3.15, p = 0.012).CONCLUSION: The current study (which has a long follow-up, many measuring sites, and is the first to longitudinally assess the lateral projection of the spine in AS patients) surprisingly showed that lateral projection spinal BMD increased. This study suggests that the best site to assess bone loss in AS patients is the femoral neck and that inflammation has an adverse effect, and the use of bisphosphonates and TNFi has a positive effect, on BMD in AS patients.
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| 9. |
- Drevinge, Christina, 1983, et al.
(författare)
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Intermediate monocytes correlate with CXCR3(+) Th17 cells but not with bone characteristics in untreated early rheumatoid arthritis
- 2021
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Background Rheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients. Methods 78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4(+) helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT. Results Flow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3(+) Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3(+) Th17 cells were associated with bone density or bone microarchitecture measurements. Conclusions Our findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3(+) Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA.
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| 10. |
- Grahnemo, Louise, et al.
(författare)
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Trabecular bone loss in collagen antibody-induced arthritis
- 2015
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Postmenopausal women with rheumatoid arthritis (RA) have increased risk of developing osteoporosis due to chronic inflammation and estrogen deprivation. Collagen antibody-induced arthritis (CAIA), an experimental polyarthritis model representing the effector phase of arthritis, is mainly mediated by the innate immune system. Compared to the widely used collagen-induced arthritis model, CAIA is conveniently short and can be used in C57BL/6 mice, enabling studies with knock-out mice. However, the impact on bone of the CAIA model in C57BL/6 mice has not previously been studied. Therefore, the aim of this study was to determine if CAIA can be used to study postmenopausal arthritis-induced osteoporosis. Methods: CAIA was induced by administration of collagen-type II antibodies and lipopolysaccharide to ovariectomized female C57BL/6J mice. Control mice received lipopolysaccharide, but no antibodies. Nine days later, femurs were collected for high-resolution micro-CT and histomorphometry. Serum was used to assess cartilage breakdown and levels of complement. Frequencies of immune cell subsets from bone marrow and lymph nodes were analyzed by flow cytometery. Results: Trabecular bone mass was decreased and associated with increased number of osteoclasts per bone surface in the CAIA model. Also, the frequency of interleukin-17(+) cells in lymph nodes was increased in CAIA. Conclusion: The present study show that CAIA, a short reproducible arthritis model that is compatible with C57BL/6 mice, is associated with increased number of osteoclasts and trabecular bone loss.
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