| 1. |
- Chen, Yihong, et al.
(författare)
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Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis
- 2024
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Ingår i: Pharmacological Research. - 1096-1186. ; 205
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Tidskriftsartikel (refereegranskat)abstract
- The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.
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| 2. |
- Felberg, Anna, et al.
(författare)
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Elevated expression of complement factor I in lung cancer cells associates with shorter survival–Potentially via non-canonical mechanism
- 2024
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Ingår i: Translational Research. - 1931-5244. ; 269, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- While numerous membrane-bound complement inhibitors protect the body's cells from innate immunity's autoaggression, soluble inhibitors like complement factor I (FI) are rarely produced outside the liver. Previously, we reported the expression of FI in non-small cell lung cancer (NSCLC) cell lines. Now, we assessed the content of FI in cancer biopsies from lung cancer patients and associated the results with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining intensity did not correlate with age, smoking status, tumor size, stage, differentiation grade, and T cell infiltrates, but was associated with progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS). Multivariate Cox analysis of low vs. high FI content revealed HR 0.55, 95 % CI 0.32-0.95, p=0.031 for PFS, HR 0.51, 95 % CI 0.25-1.02, p=0.055 for OS, and HR 0.32, 95 % CI 0.12-0.84, p=0.021 for DSS. Unfavorable prognosis might stem from the non-canonical role of FI, as the staining pattern did not correlate with C4d - the product of FI-supported degradation of active complement component C4b. To elucidate that, we engineered three human NSCLC cell lines naturally expressing FI with CRISPR/Cas9 technology, and compared the transcriptome of FI-deficient and FI-sufficient clones in each cell line. RNA sequencing revealed differentially expressed genes engaged in intracellular signaling pathways controlling proliferation, apoptosis, and responsiveness to growth factors. Moreover, in vitro colony-formation assays showed that FI-deficient cells formed smaller foci than FI-sufficient NSCLC cells, but their size increased when purified FI protein was added to the medium. We postulate that a non-canonical activity of FI influences cellular physiology and contributes to the poor prognosis of lung cancer patients.
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| 3. |
- Felberg, Anna, et al.
(författare)
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Monitoring of the Complement System Status in Patients With B-Cell Malignancies Treated With Rituximab
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Rituximab is a pioneering anti-CD20 monoclonal antibody that became the first-line drug used in immunotherapy of B-cell malignancies over the last twenty years. Rituximab activates the complement system in vitro, but there is an ongoing debate on the exact role of this effector mechanism in therapeutic effect. Results of both in vitro and in vivo studies are model-dependent and preclude clear clinical conclusions. Additional confounding factors like complement inhibition by tumor cells, loss of target antigen and complement depletion due to excessively applied immunotherapeutics, intrapersonal variability in the concentration of main complement components and differences in tumor burden all suggest that a personalized approach is the best strategy for optimization of rituximab dosage and therapeutic schedule. Herein we critically review the existing knowledge in support of such concept and present original data on markers of complement activation, complement consumption, and rituximab accumulation in plasma of patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHL). The increase of markers such as C4d and terminal complement complex (TCC) suggest the strongest complement activation after the first administration of rituximab, but not indicative of clinical outcome in patients receiving rituximab in combination with chemotherapy. Both ELISA and complement-dependent cytotoxicity (CDC) functional assay showed that a substantial number of patients accumulate rituximab to the extent that consecutive infusions do not improve the cytotoxic capacity of their sera. Our data suggest that individual assessment of CDC activity and rituximab concentration in plasma may support clinicians’ decisions on further drug infusions, or instead prescribing a therapy with anti-CD20 antibodies like obinutuzumab that more efficiently activate effector mechanisms other than complement.
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| 4. |
- McMahon, Colin J, et al.
(författare)
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Paediatric and adult congenital cardiology education and training in Europe.
- 2022
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Ingår i: Cardiology in the young. - 1467-1107. ; 32:12, s. 1966-1983
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Tidskriftsartikel (refereegranskat)abstract
- Limited data exist on training of European paediatric and adult congenital cardiologists.A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries.Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87-9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63-10.72 million), and one training centre per 4.29 million population (range 1.63-10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1-17), and duration of training was 3 years (range 2-5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R2 = 0.41).Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.
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| 5. |
- Papadakos, Konstantinos S., et al.
(författare)
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High levels of expression of cartilage oligomeric matrix protein in lymph node metastases in breast cancer are associated with reduced survival
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:23
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Tidskriftsartikel (refereegranskat)abstract
- Cartilage oligomeric matrix protein (COMP) is a regulator of the extracellular matrix and is expressed primarily in the cartilage. Recently, COMP expression was also documented in breast cancer patients both in sera and tumor biopsies, in both of which it could serve as an independent prognostic marker. This study aimed to assess COMP as a potential biomarker in the group of metastatic breast cancer patients. Levels of COMP were measured by ELISA in serum samples of 141 metastatic breast cancer patients. Biopsies from primary tumors, synchronous lymph node metastases, and distant metastases were stained for COMP expression. The levels of serum COMP were higher in patients with ER‐ and HER2‐positive tumors when compared to triple‐negative tumors and correlated with the presence of bone and lung metastases, circulating tumor cell count, and clusters. Most of the primary tumors expressing COMP (70%) retained the expression also in the lymph node metastases, which correlated with visceral metastases and reduced survival. In conclusion, COMP appears as a valuable biomarker in metastatic breast cancer patients indicating a more severe stage of the disease. Serum COMP levels were associated with specific types of metastases in patients with metastatic breast cancer emphasizing that further studies are warranted to elucidate its potential role as a monitoring marker.
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| 6. |
- Papp, Alexandra, et al.
(författare)
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Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Components of the extracellular matrix (ECM), when exposed to body fluids may promote local complement activation and inflammation. Pathologic complement activation at the glomerular basement membrane and at the Bruch’s membrane is implicated in renal and eye diseases, respectively. Binding of soluble complement inhibitors to the ECM, including factor H (FH), is important to prevent excessive complement activation. Since the FH-related (FHR) proteins FHR1 and FHR5 are also implicated in these diseases, our aim was to study whether these FHRs can also bind to ECM components and affect local FH activity and complement activation. Both FH and the FHRs showed variable binding to ECM components. We identified laminin, fibromodulin, osteoadherin and PRELP as ligands of FHR1 and FHR5, and found that FHR1 bound to these ECM components through its C-terminal complement control protein (CCP) domains 4-5, whereas FHR5 bound via its middle region, CCPs 3-7. Aggrecan, biglycan and decorin did not bind FH, FHR1 and FHR5. FHR5 also bound to immobilized C3b, a model of surface-deposited C3b, via CCPs 3-7. By contrast, soluble C3, C3(H2O), and the C3 fragments C3b, iC3b and C3d bound to CCPs 8-9 of FHR5. Properdin, which was previously described to bind via CCPs 1-2 to FHR5, did not bind in its physiologically occurring serum forms in our assays. FHR1 and FHR5 inhibited the binding of FH to the identified ECM proteins in a dose-dependent manner, which resulted in reduced FH cofactor activity. Moreover, both FHR1 and FHR5 enhanced alternative complement pathway activation on immobilized ECM proteins when exposed to human serum, resulting in the increased deposition of C3-fragments, factor B and C5b-9. Thus, our results identify novel ECM ligands of FH family proteins and indicate that FHR1 and FHR5 are competitive inhibitors of FH on ECM and, when bound to these ligands, they may enhance local complement activation and promote inflammation under pathological conditions.
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| 7. |
- Stasiłojć, Grzegorz, et al.
(författare)
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Calcein release assay as a method for monitoring serum complement activity during monoclonal antibody therapy in patients with B-cell malignancies
- 2020
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Ingår i: Journal of Immunological Methods. - : Elsevier BV. - 0022-1759 .- 1872-7905. ; 476, s. 1-5
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Tidskriftsartikel (refereegranskat)abstract
- Monoclonal antibodies ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) which are approved for usage in patients with chronic lymphocytic leukemia (CLL), efficiently activate the classical complement pathway. However complement is an exhaustible component and high doses of its activators may deplete complement-dependent cytotoxicity (CDC) potential, thus reducing the effect of repeated mAb dosing. Widely used method to measure CDC activity of patients' serum is hemolytic assay (CH50) on sheep erythrocytes. Despite its simplicity, such CH50 assay may not reflect pivotal interactions between patient serum and human complement inhibitors on the surface of target cells. We propose calcein release assay performed on tumor cells similar to those targeted by therapeutic antibodies as an alternative method. We analyzed serum samples collected from 12 patients participating in the clinical study, receiving s.c. 30 mg alemtuzumab three times per week combined with i.v. ofatumumab at an initial dose of 300 mg in week 3 further escalated to 2000 mg every other week. All serum samples were measured by hemolytic assay on sheep erythrocytes as well as using calcein release assay on CD20-positive Raji cells. Our data show that results obtained from both assays are related to each other at the level of the whole group (n = 96 samples, Spearman r = 0.504, p < .001) but may substantially differ when analyzing individual patients. Furthermore, by using CDC assay on Raji cells, we found that in the presented clinical study CDC serum potential was not significantly affected when measured before consecutive administrations in most of the patients.
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| 8. |
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| 9. |
- Baglioni, Chiara, et al.
(författare)
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The European Academy for Cognitive Behavioural Therapy for Insomnia : An initiative of the European Insomnia Network to promote implementation and dissemination of treatment
- 2020
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Ingår i: Journal of Sleep Research. - : Wiley. - 0962-1105 .- 1365-2869. ; 29:2
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Tidskriftsartikel (refereegranskat)abstract
- Insomnia, the most prevalent sleep disorder worldwide, confers marked risks for both physical and mental health. Furthermore, insomnia is associated with considerable direct and indirect healthcare costs. Recent guidelines in the US and Europe unequivocally conclude that cognitive behavioural therapy for insomnia (CBT-I) should be the first-line treatment for the disorder. Current treatment approaches are in stark contrast to these clear recommendations, not least across Europe, where, if any treatment at all is delivered, hypnotic medication still is the dominant therapeutic modality. To address this situation, a Task Force of the European Sleep Research Society and the European Insomnia Network met in May 2018. The Task Force proposed establishing a European CBT-I Academy that would enable a Europe-wide system of standardized CBT-I training and training centre accreditation. This article summarizes the deliberations of the Task Force concerning definition and ingredients of CBT-I, preconditions for health professionals to teach CBT-I, the way in which CBT-I should be taught, who should be taught CBT-I and to whom CBT-I should be administered. Furthermore, diverse aspects of CBT-I care and delivery were discussed and incorporated into a stepped-care model for insomnia.
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| 10. |
- Barghouth, Mohammad, et al.
(författare)
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The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Exocytosis in excitable cells is essential for their physiological functions. Although the exocytotic machinery controlling cellular secretion has been well investigated, the function of the vesicular cargo, i.e. secretory granular content remains obscure. Here we combine dSTORM imaging and single-domain insulin antibody, to dissect the in situ structure of insulin granule cores (IGCs) at nano level. We demonstrate that the size and shape of the IGCs can be regulated by the juxta-granular molecules Nucleobindin-2 and Enolase-1, that further contribute to the stimulated insulin secretion. IGCs located at the plasma membrane are larger than those in the cytosol. The IGCs size is decreased by ∼20% after glucose stimulation due to the release of the peripheral part of IGCs through incomplete granule fusion. Importantly, the reduction of the IGCs size is also observed in non-stimulatory pancreatic β-cells from diabetic db/db mice, Akita (Ins2+/-) mice and human Type-2 diabetic donors, in accordance with impaired secretion. These findings overall highlight the structure of exocytotic insulin cores as a novel modality amenable to targeting in the stimulated exocytosis in β-cells with impaired insulin secretion.Competing Interest StatementThe authors have declared no competing interest.
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| 11. |
- Bettoni, Serena, et al.
(författare)
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Serum Complement Activation by C4BP-IgM Fusion Protein Can Restore Susceptibility to Antibiotics in Neisseria gonorrhoeae
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Neisseria gonorrhoeae is the etiological agent of gonorrhea, the second most common bacterial sexually transmitted infection worldwide. Reproductive sequelae of gonorrhea include infertility, ectopic pregnancy and chronic pelvic pain. Most antibiotics currently in clinical use have been rendered ineffective due to the rapid spread of antimicrobial resistance among gonococci. The developmental pipeline of new antibiotics is sparse and novel therapeutic approaches are urgently needed. Previously, we utilized the ability of N. gonorrhoeae to bind the complement inhibitor C4b-binding protein (C4BP) to evade killing by human complement to design a chimeric protein that linked the two N-terminal gonococcal binding domains of C4BP with the Fc domain of IgM. The resulting molecule, C4BP-IgM, enhanced complement-mediated killing of gonococci. Here we show that C4BP-IgM induced membrane perturbation through complement deposition and membrane attack complex pore insertion facilitates the access of antibiotics to their intracellular targets. Consequently, bacteria become more susceptible to killing by antibiotics. Remarkably, C4BP-IgM restored susceptibility to azithromycin of two azithromycin-resistant clinical gonococcal strains because of overexpression of the MtrC-MtrD-MtrE efflux pump. Our data show that complement activation can potentiate activity of antibiotics and suggest a role for C4BP-IgM as an adjuvant for antibiotic treatment of drug-resistant gonorrhea.
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| 12. |
- Bettoni, Serena, et al.
(författare)
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Serum complement activation by C4BP-IgM fusion protein can restore susceptibility to antibiotics in Neisseria gonorrhoeae
- 2022
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Ingår i: Molecular Immunology. - : Elsevier. - 0161-5890 .- 1872-9142. ; 141, s. 215-215
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: The sexually transmitted infection gonorrhea is a common health problem worldwide causing critical reproductive sequelae such as infertility. An effective vaccine remains elusive and antibiotics used in clinics are becoming ineffective because of the rapid spread of resistance among Neisseria gonorrhoeae, the causative organism of gonorrhea. We previously created a human fusion protein called C4BP-IgM to mark and eliminate bacteria by activating host complement. C4BP-IgM links the two N-terminal domains of C4BP, which bind to gonococci, with the Fc domain of IgM to increase complement activation on and kill bacteria. We documented that C4BP-IgM enhances bactericidal activity of serum against clinical C4BP-binding gonococcal isolates from patients, and markedly attenuated the duration and burden of gonococcal infection in a mouse vaginal colonizationmodel 1. Here, we explore the activity of C4BP-IgM as an adjuvant to several antibiotics (spectinomycin, azithromycin, cefixime, ceftriaxone and ciprofloxacin) currently or previously used to treat gonorrhea.Materials and methods: Cooperative bactericidal activity between C4BP-IgM, complement and antibiotics was evaluated by monitoring survival and membrane alterations of a laboratory isolate and two clinical azithromycin-resistant gonococcal strains, which also resisted killing by normal human serum. Effect of complement and C4BP-IgM on uptake and intracellular activity of selected antibiotics was also assessed.Results: We found that human serum, as source of complement components, reduced MIC values of antibiotics against N. gonorrhoeae. Addition of C4BP-IgM at concentrations which only partially reduced survival, induced complete killing of bacteria when both serum and antibiotics were present. Bactericidal cooperation between complement and antimicrobials was revealed to be triggered by membrane damage induced by C4BP-IgM complement activation. Formation of membrane attack complex pores on bacteria facilitated uptake of antimicrobials, which in turn enhanced their intracellular concentration and activity. Remarkably, C4BP-IgM restored susceptibility to azithromycin of two azithromycin-resistant clinical gonococcal strains that overexpressed the MtrC-MtrD-MtrE efflux pump.Conclusion: We provide proof-of-principle for the use of C4BP-IgM fusion protein as an adjuvant to antibiotics, which could be re-purposed for clinical use pending the development of effective new treatments.
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| 13. |
- Bierschenk, Damien, et al.
(författare)
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C4b-binding protein inhibits particulate- and crystalline-induced NLRP3 inflammasome activation
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulated NLRP3 inflammasome activation drives a wide variety of diseases, while endogenous inhibition of this pathway is poorly characterised. The serum protein C4b-binding protein (C4BP) is a well-established inhibitor of complement with emerging functions as an endogenously expressed inhibitor of the NLRP3 inflammasome signalling pathway. Here, we identified that C4BP purified from human plasma is an inhibitor of crystalline- (monosodium urate, MSU) and particulate-induced (silica) NLRP3 inflammasome activation. Using a C4BP mutant panel, we identified that C4BP bound these particles via specific protein domains located on the C4BP α-chain. Plasma-purified C4BP was internalised into MSU- or silica-stimulated human primary macrophages, and inhibited MSU- or silica-induced inflammasome complex assembly and IL-1β cytokine secretion. While internalised C4BP in MSU or silica-stimulated human macrophages was in close proximity to the inflammasome adaptor protein ASC, C4BP had no direct effect on ASC polymerisation in in vitro assays. C4BP was also protective against MSU- and silica-induced lysosomal membrane damage. We further provide evidence for an anti-inflammatory function for C4BP in vivo, as C4bp-/- mice showed an elevated pro-inflammatory state following intraperitoneal delivery of MSU. Therefore, internalised C4BP is an inhibitor of crystal- or particle-induced inflammasome responses in human primary macrophages, while murine C4BP protects against an enhanced inflammatory state in vivo. Our data suggests C4BP has important functions in retaining tissue homeostasis in both human and mice as an endogenous serum inhibitor of particulate-stimulated inflammasome activation.
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| 14. |
- Bladh, Oscar, et al.
(författare)
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Comparison of SARS-CoV-2 spike-specific IgA and IgG in nasal secretions, saliva and serum
- 2024
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Several novel vaccine platforms aim at mucosal immunity in the respiratory tract to block SARS-CoV-2 transmission. Standardized methods for mucosal sample collection and quantification of mucosal antibodies are therefore urgently needed for harmonized comparisons and interpretations across mucosal vaccine trials and real-world data. Methods: Using commercial electrochemiluminescence antibody panels, we compared SARS-CoV-2 spike-specific IgA and IgG in paired saliva, nasal secretions, and serum from 1048 healthcare workers with and without prior infection. Results: Spike-specific IgA correlated well in nasal secretions and saliva (r>0.65, p<0.0001), but the levels were more than three-fold higher in nasal secretions as compared to in saliva (p<0.01). Correlations between the total population of spike-specific IgA and spike-specific secretory IgA (SIgA) were significantly stronger (p<0.0001) in nasal secretions (r=0.96, p<0.0001) as opposed to in saliva (r=0.77, p<0.0001), and spike-specific IgA correlated stronger (p<0.0001) between serum and saliva (r=0.73, p<0.001) as opposed to between serum and nasal secretions (r=0.54, p<0.001), suggesting transudation of monomeric spike specific IgA from the circulation to saliva. Notably, spike-specific SIgA had a markedly higher SARS-CoV-2 variant cross-binding capacity as compared to the total population of spike specific IgA and IgG in both nasal secretions, saliva and serum, (all p<0.0001), which emphasizes the importance of taking potential serum derived monomeric IgA into consideration when investigating mucosal immune responses. Discussion: Taken together, although spike-specific IgA can be reliably measured in both nasal secretions and saliva, our findings imply an advantage of higher levels and likely also a larger proportion of SIgA in nasal secretions as compared to in saliva. We further corroborate the superior variant cross-binding capacity of SIgA in mucosal secretions, highlighting the potential protective benefits of a vaccine targeting the upper respiratory tract.
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| 15. |
- Bladh, Oscar, et al.
(författare)
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Comparison of SARS-CoV-2 spike-specific IgA and IgG in nasal secretions, saliva and serum
- 2024
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Several novel vaccine platforms aim at mucosal immunity in the respiratory tract to block SARS-CoV-2 transmission. Standardized methods for mucosal sample collection and quantification of mucosal antibodies are therefore urgently needed for harmonized comparisons and interpretations across mucosal vaccine trials and real-world data.Methods: Using commercial electrochemiluminescence antibody panels, we compared SARS-CoV-2 spike-specific IgA and IgG in paired saliva, nasal secretions, and serum from 1048 healthcare workers with and without prior infection.Results: Spike-specific IgA correlated well in nasal secretions and saliva (r>0.65, p<0.0001), but the levels were more than three-fold higher in nasal secretions as compared to in saliva (p<0.01). Correlations between the total population of spike-specific IgA and spike-specific secretory IgA (SIgA) were significantly stronger (p<0.0001) in nasal secretions (r=0.96, p<0.0001) as opposed to in saliva (r=0.77, p<0.0001), and spike-specific IgA correlated stronger (p<0.0001) between serum and saliva (r=0.73, p<0.001) as opposed to between serum and nasal secretions (r=0.54, p<0.001), suggesting transudation of monomeric spike specific IgA from the circulation to saliva. Notably, spike-specific SIgA had a markedly higher SARS-CoV-2 variant cross-binding capacity as compared to the total population of spike specific IgA and IgG in both nasal secretions, saliva and serum, (all p<0.0001), which emphasizes the importance of taking potential serum derived monomeric IgA into consideration when investigating mucosal immune responses.Discussion: Taken together, although spike-specific IgA can be reliably measured in both nasal secretions and saliva, our findings imply an advantage of higher levels and likely also a larger proportion of SIgA in nasal secretions as compared to in saliva. We further corroborate the superior variant cross-binding capacity of SIgA in mucosal secretions, highlighting the potential protective benefits of a vaccine targeting the upper respiratory tract.
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| 16. |
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| 17. |
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| 18. |
- Blom, Anna M, et al.
(författare)
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Expression of Cartilage Oligomeric Matrix Protein in colorectal cancer is an adverse prognostic factor and correlates negatively with infiltrating immune cells and PD-L1 expression
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Cartilage Oligomeric Matrix Protein (COMP) is an oncogenic protein that has been associated with a decrease in infiltrating T-cells in periampullary adenocarcinoma. This study aimed to investigate whether this is also the case for colorectal cancer (CRC) and to evaluate the relationship between COMP expression and clinopathological features.METHODS: Immunohistochemistry was used to determine the expression levels of COMP in tumor cells and stroma in primary tumors from a cohort of 537 CRC patients. The expression of immune cell markers, including CD3+, CD8+, FoxP3+, CD68+, CD56+, CD163+, and PD-L1, was evaluated previously. Tumor fibrosis was assessed by Sirius Red staining and evaluation of collagen fiber organization.RESULTS: COMP expression correlated positively with TNM-stage and grade of differentiation. Patients with CRC expressing high levels of COMP had significantly shorter OS than those with low COMP expression (p<0.0001), and fewer infiltrating T-cells were detected in tumors with high COMP expression. Additionally, a negative correlation was identified between the expression of COMP and PD-L1 on both tumor cells and immune cells. Cox regression analysis showed that tumors expressing high levels of COMP had significantly shorter OS, independent of all evaluated immune cell markers. Tumor fibrosis was correlated with high expression of COMP in the stroma (p<0.0001), and tumors with high levels of COMP expression and denser fibrosis displayed more sparse immune cell infiltration.DISCUSSION: The results suggest that COMP expression in CRC may exert an immune regulatory effect by increasing dense fibrosis and decreasing immune cell infiltration. These findings support the notion that COMP is an important factor in the development and progression of CRC.
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| 19. |
- Blom, Kerstin, et al.
(författare)
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Sleep during pelvic-abdominal radiotherapy for cancer : a longitudinal study with special attention to sleep in relation to nausea and quality of life
- 2021
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Ingår i: Cancer Nursing. - : Wolters Kluwer. - 0162-220X .- 1538-9804. ; 44:4, s. 333-344
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Poor sleep, nausea, psychological distress, and a lowered quality of life are common during radiotherapy for cancer. There is a lack of studies on the relationship between radiotherapy-induced nausea and sleep. This longitudinal study analyzes data from 196 patients who underwent pelvic-abdominal radiotherapy for cancer.OBJECTIVE: The aim of this study was to investigate sleep parameters weekly before, during, and after radiotherapy in relation to nausea and other patient characteristics, clinical characteristics, psychological distress, and quality of life.METHODS: Patients (n = 196, 84% women; mean age, 63 years; 68% had gynecological tumor, 28% had colorectal tumor, and 4% had other tumors) longitudinally answered questionnaires before, during, and after their radiotherapy over the abdominal and pelvic fields.RESULTS: Poor sleep was experienced by 30% of the participants, and sleep (quality and difficulty falling asleep) improved during and after treatment compared with baseline. Experiencing nausea during treatment was associated with worse sleep quality during radiotherapy. Baseline anxiety was associated with worse sleep quality before, during, and after treatment. Poor sleep was associated with worse quality of life.CONCLUSION: Nausea, more than a number of other variables, is a possible predictor of poor sleep in patients during radiotherapy for cancer.IMPLICATIONS FOR PRACTICE: The results indicate that effectively managing nausea may be important for sleep quality, and possibly quality of life, in patients undergoing radiotherapy for cancer. More research is needed before recommendations for practice can be made.
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| 20. |
- Blom Kemdal, Anna, et al.
(författare)
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Incels världsåskådning. Hur många Elliot Rodger finns på ett incelforum?
- 2024
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Konferensbidrag (populärvet., debatt m.m.)abstract
- Skriftlig kommunikation från två typer av Reddit forum - Incels och Politics - jämfördes med varandra och med massmördaren Elliot Rodgers skriftliga manifest. Onlinespråk analyserades med LIWC (Linguistic Inquiry Word Count). Data analyserades med ROC-curve och AUC-curve. Linguistiska variabler som var respresentativa för en incel världsåskådning identifierades, en världsåskådning med socio-biologiska, pseudovetenskapliga teorier och negativa antaganden, uttryckta med ett tydligt stereotypiskt dehumaniserande språk, speciellt gällande kvinnor. Detta är i linje med tidigare studier av incels typiska lingvistiska och psykologiska begrepp. ICC (Intraclass correlation coefficient) användes för att undersöka likheter mellan incels, politics och Elliot Rodger. Det fanns stöd för en viss skillnad o absoluta skillnader mellan Incels och Elliot Rodger å ena sidan och Politics och Elliot Rodger å den andra. Incels visade likheter med Elliot Rodger och använde språk som tidigare forskning identifierat som riskbeteende, kopplat till ensamma våldsverkare. Resultaten är preliminära men visar att det finns behov av ytterligare forskning om incels språk och psykologi, för att medverka till att identifiera individer som riskerar att begå våldsamma brott.
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| 21. |
- Blom Kemdal, Anna, et al.
(författare)
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The Incel World View : How many Incels are there on an incel forum?
- 2024
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Konferensbidrag (populärvet., debatt m.m.)abstract
- Skriftlig kommunikation från två typer av Reddit forum - Incels och Politics - jämfördes med varandra och med massmördaren Elliot Rodgers skriftliga manifest. Onlinespråk analyserades med LIWC (Linguistic Inquiry Word Count). Data analyserades med ROC-curve och AUC-curve. Linguistiska variabler som var respresentativa för en incel världsåskådning identifierades, en världsåskådning med socio-biologiska, pseudovetenskapliga teorier och negativa antaganden, uttryckta med ett tydligt stereotypiskt dehumaniserande språk, speciellt gällande kvinnor. Detta är i linje med tidigare studier av incels typiska lingvistiska och psykologiska begrepp. ICC (Intraclass correlation coefficient) användes för att undersöka likheter mellan incels, politics och Elliot Rodger. Det fanns stöd för en viss skillnad o absoluta skillnader mellan Incels och Elliot Rodger å ena sidan och Politics och Elliot Rodger å den andra. Incels visade likheter med Elliot Rodger och använde språk som tidigare forskning identifierat som riskbeteende, kopplat till ensamma våldsverkare. Resultaten är preliminära men visar att det finns behov av ytterligare forskning om incels språk och psykologi, för att medverka till att identifiera individer som riskerar att begå våldsamma brott.
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| 22. |
- Blom Kemdal, Anna, et al.
(författare)
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The Incel World View : How Many Elliot Rodgers are there on an Incel Forum?
- 2024
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Skriftlig kommunikation från två typer av Reddit forum - Incels och Politics - jämfördes med varandra och med massmördaren Elliot Rodgers skriftliga manifest. Onlinespråk analyserades med LIWC (Linguistic Inquiry Word Count). Data analyserades med ROC-curve och AUC-curve. Linguistiska variabler som var respresentativa för en incel världsåskådning identifierades, en världsåskådning med socio-biologiska, pseudovetenskapliga teorier och negativa antaganden, uttryckta med ett tydligt stereotypiskt dehumaniserande språk, speciellt gällande kvinnor. Detta är i linje med tidigare studier av incels typiska lingvistiska och psykologiska begrepp. ICC (Intraclass correlation coefficient) användes för att undersöka likheter mellan incels, politics och Elliot Rodger. Det fanns stöd för en viss skillnad o absoluta skillnader mellan Incels och Elliot Rodger å ena sidan och Politics och Elliot Rodger å den andra. Incels visade likheter med Elliot Rodger och använde språk som tidigare forskning identifierat som riskbeteende, kopplat till ensamma våldsverkare. Resultaten är preliminära men visar att det finns behov av ytterligare forskning om incels språk och psykologi, för att medverka till att identifiera individer som riskerar att begå våldsamma brott.
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| 23. |
- Blom, Lisa, et al.
(författare)
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Little All Children in Focus (Little ACF), evaluation of a parental support program for parents of children aged 1–2 years : study protocol for a randomized controlled trial
- 2023
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Ingår i: Trials. - : BioMed Central (BMC). - 1745-6215. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health and development can be promoted by strengthening and supporting parents. Research on parental support programs based on positive psychology and a health-promoting approach aimed at all parents, and in particular parents of infants is limited. All Children in Focus (ACF) is a parental support program that has been evaluated in a randomized trial in parents of children 3–12 years. The ACF is based on health promotion aiming to increase parents’ confidence and child’s well-being. In the current study, we will study the effects of a revised version of the ACF called Little ACF adapted to parents with children aged 1–2 years.Methods: The study includes a randomized controlled trial (RCT) taking place at several Child Health Centers (CHCs) in Sweden. The RCT will evaluate the efficacy of Little ACF (intervention) in comparison with four digital lectures about child development and parenting (active control). Parents are recruited at the 10-, 12-, or 18-month visits to CHC by CHC-nurses. Data to assess changes in parental competencies and child socio-emotional development are collected through online questionnaires completed by parents at five time points: baseline, post-intervention, after 6 and 12 months, and when the child is 3 years old.Discussion: The paper describes a study protocol of a randomized controlled trial evaluating the effects of a parental support program during infancy. Several issues related to the methodology and implementation are discussed.Trial registration: ClinicalTrials.gov NCT05445141. Registered on 6 July 2022.
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| 24. |
- Colineau, Lucie, et al.
(författare)
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Interaction of Streptococcus pyogenes with extracellular matrix components resulting in immunomodulation and bacterial eradication
- 2020
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Ingår i: Matrix Biology Plus. - : Elsevier BV. - 2590-0285. ; 6-7
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pyogenes is a major human pathogen that causes a variety of diseases ranging from mild skin and throat infections to fatal septicemia. In severe invasive infections, S. pyogenes encounters and interacts with components of the extracellular matrix (ECM), including small leucine rich-proteoglycans (SLRPs). In this study, we report a novel antimicrobial role played by SLRPs biglycan, decorin, fibromodulin and osteoadherin, specifically in promoting the eradication of S. pyogenes in a human sepsis model of infection. SLRPs can be released from the ECM and de novo synthesized by a number of cell types. We reveal that infection of human monocytes by S. pyogenes induces the expression of decorin. Furthermore, we show that the majority of genetically distinct and clinically relevant S. pyogenes isolates interact with SLRPs resulting in decreased survival in blood killing assays. Biglycan and decorin induce TLR2 and TLR4 signaling cascades resulting in secretion of proinflammatory and chemotactic molecules and recruitment of professional phagocytes. Surprisingly, SLRP-mediated elimination of S. pyogenes occurs independently of TLR activation. Our results indicate that SLRPs act in concert with human serum, enhancing deposition of complement activation fragments and the classical activator C1q on the bacterial surface, facilitating efficient microbial eradication. Addition of the complement C3 inhibitor compstatin significantly reverses SLRP-induced blood killing, confirming active complement as a key mediator in SLRP-mediated bacterial destruction. Taken together our results add to the functional repertoire of SLRPs, expanding to encompass their role in controlling bacterial infection.
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| 25. |
- de Jong, Sarah, et al.
(författare)
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Effect of rare coding variants in the CFI gene on Factor I expression levels
- 2020
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 29:14, s. 2313-2324
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Tidskriftsartikel (refereegranskat)abstract
- Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G>A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.
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