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- Gupta, Dhanu, et al.
(författare)
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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
- 2021
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Ingår i: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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| 3. |
- Li, Chen, et al.
(författare)
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Cutaneous squamous cell carcinoma-derived extracellular vesicles exert an oncogenic role by activating cancer-associated fibroblasts
- 2023
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Ingår i: Cell Death Discovery. - : Springer Nature. - 2058-7716. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Cutaneous squamous cell carcinoma (cSCC) is a fast-increasing cancer with metastatic potential. Extracellular vesicles (EVs) are small membrane-bound vesicles that play important roles in intercellular communication, particularly in the tumor microenvironment (TME). Here we report that cSCC cells secrete an increased number of EVs relative to normal human epidermal keratinocytes (NHEKs) and that interfering with the capacity of cSCC to secrete EVs inhibits tumor growth in vivo in a xenograft model of human cSCC. Transcriptome analysis of tumor xenografts by RNA-sequencing enabling the simultaneous quantification of both the human and the mouse transcripts revealed that impaired EV-production of cSCC cells prominently altered the phenotype of stromal cells, in particular genes related to extracellular matrix (ECM)-formation and epithelial-mesenchymal transition (EMT). In line with these results, co-culturing of human dermal fibroblasts (HDFs) with cSCC cells, but not with normal keratinocytes in vitro resulted in acquisition of cancer-associated fibroblast (CAF) phenotype. Interestingly, EVs derived from metastatic cSCC cells, but not primary cSCCs or NHEKs, were efficient in converting HDFs to CAFs. Multiplex bead-based flow cytometry assay and mass-spectrometry (MS)-based proteomic analyses revealed the heterogenous cargo of cSCC-derived EVs and that especially EVs derived from metastatic cSCCs carry proteins associated with EV-biogenesis, EMT, and cell migration. Mechanistically, EVs from metastatic cSCC cells result in the activation of TGFβ signaling in HDFs. Altogether, our study suggests that cSCC-derived EVs mediate cancer-stroma communication, in particular the conversion of fibroblasts to CAFs, which eventually contribute to cSCC progression.
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- Winkler, Andreas, et al.
(författare)
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Cord clamping beyond 3 minutes : Neonatal short-term outcomes and maternal postpartum hemorrhage
- 2022
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Ingår i: Birth. - : Wiley. - 0730-7659 .- 1523-536X. ; 49:4, s. 783-791
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Delaying cord clamping (CC) for 3-5 minutes reduces iron deficiency and improves neurodevelopment. Data on the effects of CC beyond 3 minutes in relation to short-term neonatal outcomes and maternal risk of postpartum hemorrhage are scarce.METHODS: This was a prospective observational study performed in two delivery departments. Pregnant women with vaginal deliveries were included. Time to CC, estimated postpartum blood loss, and perinatal data were recorded. Spearman's correlation analysis and comparisons between newborns clamped before and after 3 minutes were performed.RESULTS: In total, 904 dyads were included. The mean gestational age ± standard deviation was 40.1 ± 1.2 weeks. CC was performed at a median time of 6 minutes (range 0-23.5). Apgar scores at 5 and 10 minutes were positively correlated with time to CC (correlation coefficient .140, P < .001 and .161, < .001). There was no correlation between CC time and bilirubin level (correlation coefficient .021, P = .54). The median postpartum blood loss was 300 mL (70-2550 mL), with a negative correlation between CC time and postpartum blood loss (-0.115, P = .001). The postpartum blood loss was larger in the group clamped at ≤3 minutes (median [interquartile range] 400 mL [300-600] vs 300 mL [250-450], [P = .003]].CONCLUSIONS: Umbilical CC times beyond 3 minutes in vaginal deliveries were not associated with negative short-term outcomes in newborns and were associated with a smaller maternal postpartum blood loss. Although CC time as long as 6 minutes could be considered as safe, further research is needed to decide the optimal timing.
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- Wåhlén, Karin, 1986-
(författare)
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The pain profile in fibromyalgia : Painomic studies of pain characteristics and proteins in blood
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic widespread pain (CWP), including fibromyalgia (FM), is a complex pain condition, where little is known about the molecular mechanisms contributing to its pathophysiology. To date, there are no established biomarkers for CWP/FM. This thesis has investigated potential molecular mechanisms and biomarkers in blood for chronic pain in women with CWP/FM. Furthermore, investigations are made to evaluate whether common pain characteristics such as pain intensity, sensitivity, and psychological distress in CWP/FM are correlated with specific proteins in blood.The pain profile of CWP/FM, which includes the plasma proteome and clinical characteristics, is analyzed using proteomics, advanced multivariate statistics, and bioinformatics. The results from paper I, III, and IV indicate that there are prominent systemic changes related to immunity, inflammation, and metabolic processes in women with CWP/FM compared to healthy controls. Furthermore, paper II and III show that in CWP/FM, pain intensity is related to protein profiles involved in immunity processes, psychological distress with metabolic and immunity processes, and pain sensitivity with inflammatory processes.In paper IV, the plasma proteome is investigated before and after a 15 weeks resistance exercise intervention in FM and healthy controls. Both at baseline and post exercise in FM and controls, prominent protein alterations are found that are involved in immunity, stress, mRNA stability, and muscle structure development. Exercise seems to influence clinical characteristics and circulating proteins in FM. Furthermore, specific plasma proteome profile is found related to grade of chronification, pain sensitivity, and improved muscle force of the quadriceps muscle.To summarize, the results from this thesis suggest that in CWP/FM there might be a dysregulation in the biological processes involved in the immune system and metabolic processes, which are tightly linked to several proteins in the complement system and blood coagulation cascade. These results shed light on potential ongoing mechanisms involved in the pathophysiology of the complex pain condition CWP/FM. This type of biomarker research has a large potential in increasing knowledge about mechanisms involved in CWP/FM and can hereby open for better clinical understanding and management of this and other chronic pain states. The clinical value of collecting a blood sample and measuring stable pain mechanism markers in combination with evaluation of anamnesis and clinical examination would in the future help clinicians and patients receive a faster and more precise diagnosis and ultimately better treatment strategies.
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