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| 3. |
- Matuozzo, D, et al.
(författare)
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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
- 2022
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2],P=2.1×10−4). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years;P=1.68×10−5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
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| 9. |
- Hoenigl, M., et al.
(författare)
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Guideline adherence and survival of patients with candidaemia in Europe: results from the ECMM Candida III multinational European observational cohort study
- 2023
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Ingår i: Lancet. Infectious Diseases. - : Elsevier BV. - 1473-3099 .- 1474-4457. ; 23:6, s. 751-761
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Tidskriftsartikel (refereegranskat)abstract
- Background The European Confederation of Medical Mycology (ECMM) collected data on epidemiology, risk factors, treatment, and outcomes of patients with culture-proven candidaemia across Europe to assess how adherence to guideline recommendations is associated with outcomes.Methods In this observational cohort study, 64 participating hospitals located in 20 European countries, with the number of eligible hospitals per country determined by population size, included the first ten consecutive adults with culture-proven candidaemia after July 1, 2018, and entered data into the ECMM Candida Registry (FungiScope CandiReg). We assessed ECMM Quality of Clinical Candidaemia Management (EQUAL Candida) scores reflecting adherence to recommendations of the European Society of Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of America guidelines.Findings 632 patients with candidaemia were included from 64 institutions. Overall 90-day mortality was 43% (265/617), and increasing age, intensive care unit admission, point increases in the Charlson comorbidity index score, and Candida tropicalis as causative pathogen were independent baseline predictors of mortality in Cox regression analysis. EQUAL Candida score remained an independent predictor of mortality in the multivariable Cox regression analyses after adjusting for the baseline predictors, even after restricting the analysis to patients who survived for more than 7 days after diagnosis (adjusted hazard ratio 1 & BULL;08 [95% CI 1 & BULL;04-1 & BULL;11; p<0 & BULL;0001] in patients with a central venous catheter and 1 & BULL;09 [1 & BULL;05-1 & BULL;13; p<0 & BULL;0001] in those without one, per one score point decrease). Median duration of hospital stay was 15 days (IQR 4-30) after diagnosis of candidaemia and was extended specifically for completion of parenteral therapy in 100 (16%) of 621 patients. Initial echinocandin treatment was associated with lower overall mortality and longer duration of hospital stay among survivors than treatment with other antifungals.Interpretation Although overall mortality in patients with candidaemia was high, our study indicates that adherence to clinical guideline recommendations, reflected by higher EQUAL Candida scores, might increase survival. New antifungals, with similar activity as current echinocandins but with longer half-lives or oral bioavailability, are needed to reduce duration of hospital stay.
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| 10. |
- Nap, M, et al.
(författare)
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Specificity and affinity of monoclonal antibodies against carcinoembryonic antigen.
- 1992
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 52:8, s. 2329-39
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Tidskriftsartikel (refereegranskat)abstract
- The binding specificities of 52 well-characterized monoclonal antibodies (Mabs) against carcinoembryonic antigen (CEA) from 12 different research groups were studied by immunohistochemistry and immuno flow cytometry. In addition, the binding constant for the interaction between Mab and CEA was determined by a solution-phase assay. Cryostat sections of colon carcinoma and normal colon, stomach, liver, pancreas, and spleen were studied by immunohistochemistry. Peripheral blood granulocytes, monocytes, and lymphocytes were assayed by immuno flow cytometry. The Mabs used here have previously been classified into five essentially nonoverlapping epitope groups (GOLD 1-5) (Cancer Res., 49: 4852-4858, 1989). Most Mabs cross-reacted with different normal tissues, ranging from highly cross-reactive Mabs (positive reaction with 8 of 9 discriminating tissues) to relatively specific Mabs (positive reaction with 1 of 9 discriminating tissues). Five Mabs (10%) were specific, reacting only with colon carcinoma, normal colon mucosa, and normal gastric foveola. There was a correlation between epitope group and binding specificity. Mabs with a high degree of CEA specificity almost exclusively belonged to epitope groups 1, 2, and 3, while highly cross-reactive Mabs belonged to epitope groups 4 and 5. There was no correlation between antibody specificity and affinity for CEA. Specific Mabs with high as well as low affinity were found.
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| 11. |
- Söderlund, A, et al.
(författare)
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Allergen induced cytokine profiles in type I allergic individuals before and after immunotherapy.
- 1997
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Ingår i: Immunology Letters. - 0165-2478 .- 1879-0542. ; 57:1-3, s. 177-81
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Tidskriftsartikel (refereegranskat)abstract
- Allergen immunotherapy (IT) involves subcutaneous injections of increasing doses of specific allergen over a period of time. It is recognised as highly effective in the treatment of patients with allergic rhinitis. However, the specific immunological mechanisms by which IT achieves its effect have not been fully elucidated. Recent studies, have shown that the clinical effects following IT of allergic individuals is concomitant with a reduced production of IL-4 by allergen specific CD4+ T-cells. The aim of the present study was to gain better knowledge about the immunological mechanisms by which IT exerts its beneficial effects. For this purpose, peripheral blood mononuclear cells (PBMC) from ten individuals receiving birch allergen or placebo in an IT-study performed in a double-blind manner, were analysed for IL-4, IFN-gamma, IL-5 and IL-10 mRNA expression at the onset of the study and during the pollen season, during treatment. Both spontaneous and in vitro allergen-induced cytokine mRNA expression was analysed using reverse transcriptase-polymerase chain reaction (RT-PCR). Spontaneous expression of IL-4 mRNA could be detected in most of the allergic patients, but not in healthy donors. The IT-treated patients showed a decrease in the spontaneous expression of IL-4 mRNA during the pollen season as compared to at the onset of the study, while in patients receiving placebo the IL-4 mRNA expression increased or remained unchanged. Similar results were obtained after in vitro stimulation with allergen. This was in contrast to the results for IFN-gamma, which was readily detected in both patient groups with no significant differences between the groups at either timepoint. IL-5 was shown to be increased during the pollen season in both groups and thereby presumably not affected by allergen IT. Taken together, these observations suggest that the cytokine profiles in circulating T lymphocytes change as a consequence of allergen IT.
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| 12. |
- Willadsen, E., et al.
(författare)
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Scandcleft randomized trials of primary surgery for unilateral cleft lip and palate: Speech proficiency at 10 years of age
- 2023
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Ingår i: International journal of language and communication disorders. - : WILEY. - 1368-2822 .- 1460-6984. ; 58:3, s. 892-909
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Tidskriftsartikel (refereegranskat)abstract
- Background & AimTo assess consonant proficiency and velopharyngeal function in 10-year-old children born with unilateral cleft lip and palate (UCLP) within the Scandcleft project. Methods & ProceduresThree parallel group, randomized, clinical trials were undertaken as an international multicentre study by nine cleft teams in five countries. Three different surgical protocols for primary palate repair (Arm B-Lip and soft palate closure at 3-4 months, hard palate closure at 36 months, Arm C-Lip closure at 3-4 months, hard and soft palate closure at 12 months, and Arm D-Lip closure at 3-4 months combined with a single-layer closure of the hard palate using a vomer flap, soft palate closure at 12 months) were tested against a common procedure (Arm A-Lip and soft palate closure at 3-4 months followed by hard palate closure at 12 months) in the total cohort of 431 children born with a non-syndromic UCLP. Speech audio and video recordings of 399 children were available and perceptually analysed. Percentage of consonants correct (PCC) from a naming test, an overall rating of velopharyngeal competence (VPC) (VPC-Rate), and a composite measure (VPC-Sum) were reported. Outcomes & ResultsThe mean levels of consonant proficiency (PCC score) in the trial arms were 86-92% and between 58% and 83% of the children had VPC (VPC-Sum). Only 50-73% of the participants had a consonant proficiency level with their peers. Girls performed better throughout. Long delay of the hard palate repair (Arm B) indicated lower PCC and simultaneous hard and soft palate closure higher (Arm C). However, the proportion of participants with primary VPC (not including velopharyngeal surgeries) was highest in Arm B (68%) and lowest in Arm C (47%). Conclusions & ImplicationsThe speech outcome in terms of PCC and VPC was low across the trials. The different protocols had their pros and cons and there is no obvious evidence to recommend any of the protocols as superior. Aspects other than primary surgical method, such as time after velopharyngeal surgery, surgical experience, hearing level, language difficulties and speech therapy, need to be thoroughly reviewed for a better understanding of what has affected speech outcome at 10 years. WHAT THIS PAPER ADDSWhat is already known on the subjectSpeech outcomes at 10 years of age in children treated for UCLP are sparse and contradictory. Previous studies have examined speech outcomes and the relationship with surgical intervention in 5-year-olds. What this study adds to the existing knowledgeSpeech outcomes based on standardized assessment in a large group of 10-year-old children born with UCLP and surgically treated according to different protocols are presented. While speech therapy had been provided, a large proportion of the children across treatment protocols still needed further speech therapy. What are the potential or actual clinical implications of this work?Aspects other than surgery and speech function might add to the understanding of what affects speech outcome. Effective speech therapy should be available for children in addition to primary surgical repair of the cleft and secondary surgeries if needed.
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| 15. |
- Bas, A, et al.
(författare)
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Utility of the housekeeping genes 18S rRNA, beta-actin and glyceraldehyde-3-phosphate-dehydrogenase for normalization in real-time quantitative reverse transcriptase-polymerase chain reaction analysis of gene expression in human T lymphocytes.
- 2004
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 59:6, s. 566-73
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Tidskriftsartikel (refereegranskat)abstract
- The accuracy of 18S rRNA, beta-actin mRNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA as indicators of cell number when used for normalization in gene expression analysis of T lymphocytes at different activation stages was investigated. Quantitative real-time reverse transcriptase-polymerase chain reaction was used to determine the expression level of 18S rRNA, beta-actin mRNA, GAPDH mRNA and mRNA for six cytokines in carefully counted samples of resting human peripheral blood mononuclear cells (PBMCs), intestinal lymphocytes and PBMCs subjected to polyclonal T-cell activation. The 18S rRNA level in activated and resting PBMCs and intestinal lymphocytes was essentially the same, while the levels of beta-actin and GAPDH mRNAs fluctuated markedly upon activation. When isolated gammadeltaTCR(+), CD4(+) and CD8(+) subpopulations were studied, 18S rRNA levels remained unchanged after 21 h of activation but increased slightly after 96 h. In contrast, there was a 30-70-fold increase of GAPDH mRNA/cell in these cell populations upon activation. Cytokine analysis revealed that only normalization to 18S rRNA gave a result that satisfactorily reflected their mRNA expression levels per cell. In conclusion, 18S rRNA was the most stable housekeeping gene and hence superior for normalization in comparative analyses of mRNA expression levels in human T lymphocytes.
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| 16. |
- Egger, M., et al.
(författare)
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Predictors for Prolonged Hospital Stay Solely to Complete Intravenous Antifungal Treatment in Patients with Candidemia: Results from the ECMM Candida III Multinational European Observational Cohort Study
- 2023
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Ingår i: Mycopathologia. - 0301-486X. ; 188:6, s. 983-994
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Tidskriftsartikel (refereegranskat)abstract
- Background To date, azoles represent the only viable option for oral treatment of invasive Candida infections, while rates of azole resistance among non-albicans Candida spp. continue to increase. The objective of this sub-analysis of the European multicenter observational cohort study Candida III was to describe demographical and clinical characteristics of the cohort requiring prolonged hospitalization solely to complete intravenous (iv) antifungal treatment (AF Tx). Methods Each participating hospital (number of eligible hospitals per country determined by population size) included the first * 10 blood culture proven adult candidemia cases occurring consecutively after July 1st, 2018, and treating physicians answered the question on whether hospital stay was prolonged only for completion of intravenous antifungal therapy. Descriptive analyses as well as binary logistic regression was used to assess for predictors of prolonged hospitalization solely to complete iv AF Tx. Findings Hospital stay was prolonged solely for the completion of iv AF Tx in 16% (100/621) of candidemia cases by a median of 16 days (IQR 8 - 28). In the multivariable model, initial echinocandin treatment was a positive predictor for prolonged hospitalization to complete iv AF Tx (aOR 2.87, 95% CI 1.55 - 5.32, p < 0.001), while (i) neutropenia, (ii) intensive care unit admission, (iii) catheter related candidemia, (iv) total parenteral nutrition, and (v) C. parapsilosis as causative pathogen were found to be negative predictors (aOR 0.22 - 0.45; p < 0.03). Interpretation Hospital stays were prolonged due to need of iv AF Tx in 16% of patients with candidemia. Those patients were more likely to receive echinocandins as initial treatment and were less severely ill and less likely infected with C. parapsilosis.
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| 17. |
- Fahlgren, A, et al.
(författare)
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Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis.
- 2003
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Ingår i: Clinical and Experimental Immunology. - 0009-9104 .- 1365-2249. ; 131:1
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Tidskriftsartikel (refereegranskat)abstract
- The impact of chronic inflammation on the expression of human alpha-defensins 5 and 6 (HD-5, HD-6), beta-defensins 1 and 2 (hBD-1, hBD-2) and lysozyme in epithelial cells of small and large intestine was investigated. Intestinal specimens from 16 patients with ulcerative colitis (UC), 14 patients with Crohn's disease (CD) and 40 controls with no history of inflammatory bowel disease were studied. mRNA expression levels of the five defence molecules were determined in freshly isolated epithelial cells by real-time quantitative RT-PCR. Specific copy standards were used allowing comparison between the expression levels of the different defensins. HD-5 and lysozyme protein expression was also studied by immunohistochemistry. Colonic epithelial cells from patients with UC displayed a significant increase of hBD-2, HD-5, HD-6 and lysozyme mRNA as compared to epithelial cells in controls. Lysozyme mRNA was expressed at very high average copy numbers followed by HD-5, HD-6, hBD-1 and hBD-2 mRNA. HD-5 and lysozyme protein was demonstrated in metaplastic Paneth-like cells in UC colon. There was no correlation between hBD-2 mRNA levels and HD-5 or HD-6 mRNA levels in colon epithelial cells of UC patients. Colonic epithelial cells of Crohn's colitis patients showed increased mRNA levels of HD-5 and lysozyme mRNA whereas ileal epithelial cells of Crohn's patients with ileo-caecal inflammation did not. Chronic inflammation in colon results in induction of hBD-2 and alpha-defensins and increased lysozyme expression. hBD-1 expression levels in colon remain unchanged in colitis. The high antimicrobial activity of epithelial cells in chronic colitis may be a consequence of changes in the epithelial lining, permitting adherence of both pathogenic bacteria and commensals directly to the epithelial cell surface.
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| 18. |
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| 19. |
- He, W., et al.
(författare)
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CYP2D6 genotype predicts tamoxifen discontinuation and drug response : a secondary analysis of the KARISMA trial
- 2021
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 32:10, s. 1286-1293
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Tidskriftsartikel (refereegranskat)abstract
- Background: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status isa associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. Patients and methods: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. Results: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were −0.8 cm2, −4.5 cm2, −4.1 cm2, and −8.0 cm2 respectively. Conclusions: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.
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| 20. |
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| 22. |
- Huber, M., et al.
(författare)
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Phase memory relaxation times of spin labels in human carbonic anhydrase II : Pulsed EPR to determine spin label location
- 2001
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Ingår i: Biophysical Chemistry. - 0301-4622 .- 1873-4200. ; 94:3, s. 245-256
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Tidskriftsartikel (refereegranskat)abstract
- Phase memory relaxation times (TM or T2) of spin labels in human carbonic anhydrase II (HCA II) are reported. Spin labels (N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidinyl)iodoacetamide, IPSL) were introduced at cysteines, by site-directed mutagenesis at seven different positions in the protein. By two pulse electron paramagnetic resonance (EPR), electron spin echo decays at 45 K are measured and fitted by stretched exponentials, resulting in relaxation parameters TM and x. TM values of seven positions are between 1.6 ╡s for the most buried residue (L79C) and 4.7 ╡s for a residue at the protein surface (W245C). In deuteriated buffer, longer TM are found for all but the most buried residues (L79C and W97C), and electron spin echo envelop modulation (ESEEM) of deuterium nuclei is observed. Different deuterium ESEEM patterns for W95C and W16C (surface residue) indicate differences in the local water concentration, or accessibility, of the spin label by deuterium. We propose TM as a parameter to determine the spin label location in proteins. Furthermore, these systems are interesting for studying the pertaining relaxation mechanism. ⌐ 2001 Elsevier Science B.V. All rights reserved.
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| 23. |
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| 24. |
- Lundqvist, Carina, et al.
(författare)
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Cytokine profile and ultrastructure of intraepithelial gamma delta T cells in chronically inflamed human gingiva suggest a cytotoxic effector function
- 1994
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 153:5, s. 2302-2312
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Tidskriftsartikel (refereegranskat)abstract
- We have shown that gamma delta T cells in human gingiva have an intraepithelial location and, that in the chronic inflammatory disease periodontitis, the expression of CD45RO and CD8 or CD4 is induced on gamma delta T cells. To study the role of gamma delta T cells in local antibacterial responses, we determined the cytokine profiles of isolated human gingival cells. Different T cell subpopulations, isolated by positive selection with mAb-coated magnetic beads and macrophages, as well as epithelial cells, were analyzed for expression of mRNA for 15 cytokines by reverse transcriptase-PCR. The ultrastructure of gingival gamma delta T cells was also studied. The gamma delta T cells expressed mRNA for IFN-gamma, TNF-alpha, TGF-beta 1, and IL-6. Expression of IFN-gamma was a consequence of inflammation. CD4+ gamma delta T cells expressed IFN-gamma only, whereas CD8+ gamma delta T cells expressed all four cytokines. CD8+ cells expressing IFN-gamma, TNF-alpha, and IL-6 in combination suggest a cytotoxic effector function. Gingival gamma delta T cells contained cytoplasmic electron-dense membrane-bound granules and multivesicular bodies that are ultrastructural characteristics of cytotoxic cells. Epithelial cells from inflamed gingiva expressed HLA-DR, CD1a, CD1c, and heat shock protein 60 on the cell surface. They also expressed mRNA for IL-1 beta, IL-6, IL-8, TNF-alpha, and TGF-beta 1. Thus, epithelial cells may function as accessory cells in immune activation and, at the same time, be target cells for CD8+ gamma delta T cells reactive with CD1 Ag or heat shock protein. These results suggest that gamma delta T cells constitute a first line of defense in gingiva, preventing entrance of pathogens by cytotoxicity against infected and stressed epithelial cells, and by control of epithelial cell growth through secretion of regulatory cytokines.
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| 25. |
- Lundqvist, C, et al.
(författare)
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Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions.
- 1996
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 157:5, s. 1926-34
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Tidskriftsartikel (refereegranskat)abstract
- The functional properties of intraepithelial lymphocytes (IEL) in normal human jejunum, ileum, and colon were investigated. Cytokine mRNA expression in IEL and enterocytes was determined by reverse transcriptase-PCR and IFN-gamma+ IEL by immunohistochemistry. Polyclonal activators were used to study proliferation and IFN-gamma secretion of IEL, and an anti-CD3-mediated redirected cytotoxicity assay was used to determine the lytic potential of IEL. Freshly isolated IEL at all three gut levels expressed mRNA for IL-1 beta, IL-2, IL-8, IFN-gamma, and TNF-alpha. Approximately 10% of IEL produced IFN-gamma, suggesting that IEL are immunologically active in vivo, performing similar functions along the intestine. IEL could be stimulated further in vitro to express IL-10, TNF-beta, and TGF-beta 1, while no Th2-type cytokines were induced, suggesting suppressive and cytolytic functions for IEL. All three jejunal IEL subpopulations (CD4-CD8-TCR-gamma delta+, CD4+TCR-alpha beta+, CD8+TCR-alpha beta+) expressed the same four cytokines, IL-2, IL-8, IFN-gamma, and TNF-alpha, indicating that CD4+TCR-alpha beta+ IEL are Th1 cells and that TCR-gamma delta+ IEL and CD8+TCR-alpha beta+ IEL include cytotoxic effector cells. Indeed, freshly isolated jejunal IEL displayed cytolytic activity. IEL were induced to proliferation by anti-CD3/TCR complex mAbs and leukoagglutinin, but not by Con A. There was no correlation between the magnitude of the proliferative response and the amounts of secreted IFN-gamma. Enterocytes expressed IL-1 beta and IL-8, and sometimes TNF-alpha. Although jejunal enterocytes express HLA-DR and hsp60, Ag presentation by these cells may induce anergy since their cytokine profile is different from that of classical APCs.
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| 26. |
- Manry, Jérémy, et al.
(författare)
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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| 27. |
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| 28. |
- Melgar, S, et al.
(författare)
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Cytolytic capabilities of lamina propria and intraepithelial lymphocytes in normal and chronically inflamed human intestine
- 2004
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 60:1-2, s. 167-177
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Tidskriftsartikel (refereegranskat)abstract
- Cell-mediated lymphocyte cytotoxicity in ileum and colon of patients with ulcerative colitis (UC), Crohn's disease (CD) and controls was investigated. Frequencies of cells expressing perforin and Fas-ligand (FasL) were determined by immunomorphometry. mRNA expression of perforin, granzyme B and FasL in T cells and subsets was assayed by reverse transcriptase-polymerase chain reaction. Cytotoxicity of intraepithelial and lamina propria lymphocytes was analysed without ex vivo activation in three functional assays: (1) anti-CD3-dependent T-cell receptor (TCR)-/CD3-mediated redirected cytotoxicity, (2) Fas-/FasL-mediated TCR-/CD3-independent cytotoxicity and (3) natural killer (NK) cell cytotoxicity. Inflammation in ileum of CD patients caused increased frequency of perforin-expressing cells and enhanced perforin-dependent TCR-/CD3-mediated cytotoxicity. In contrast, lymphocytes in the inflamed colon of UC or Crohn's colitis patients did not display this cytotoxicity nor did lymphocytes of normal colon. Normal colon lymphocytes showed spontaneous Fas-/FasL-mediated cytotoxicity. This activity was retained but not enhanced in inflamed UC colon. In contrast, a significant increase of FasL-expressing cells was seen in situ. Inflammation did not induce NK cell activity in colonic lymphocytes. Intestinal lymphocytes comprise effectors active in two different cytolytic processes. 'Classical' cytotoxic T lymphocytes in small intestine and lymphocytes executing TCR-/CD3-independent FasL-/Fas-mediated killing of unknown biological role present throughout the intestinal mucosa. Ongoing normal cytolytic processes seem to be enhanced by chronic inflammation.
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| 29. |
- Melgar, S, et al.
(författare)
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Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis.
- 2003
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Ingår i: Clinical and Experimental Immunology. - 0009-9104 .- 1365-2249. ; 134:1, s. 127-37
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Tidskriftsartikel (refereegranskat)abstract
- Ulcerative colitis (UC), a chronic inflammatory bowel disease, exhibits pronounced increase of T lymphocytes in the inflamed mucosa. To understand the role of intestinal T lymphocytes in the pathogenesis of UC their cytokine production in the mucosa was analysed. Intestinal T lymphocytes of UC, Crohn's disease and control patients were analysed for cytokine mRNA levels by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) directly after isolation without in vitro stimulation. Frequencies of cytokine positive cells were determined in UC and control colon by immunomorphometry. T lymphocytes in normal colon expressed interleukin (IL)-2, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1, but not IL-4, IL-5 or IL-10. In UC, a highly significant increase in IL-10 mRNA levels in T lymphocytes and an increased frequency of IL-10 positive cells was seen in colon. IL-10 mRNA levels were also elevated in T lymphocytes of the non-inflamed ileum and correlated with disease activity at both locations. CD4+ T lymphocytes were the major source of IL-10 mRNA. IL-2, IFN-gamma and TNF-alpha mRNA levels were decreased in colonic T lymphocytes, and virtually no IL-2, IFN-gamma, TNF-alpha or TGF-beta positive cells were detected in basal lymphoid aggregates. However, scattered IL-10 positive cells were found here. Lamina propria outside the aggregates contained IL-10-, IFN-gamma, TNF-alpha and TGF-beta but not IL-2 positive cells. T cells of UC patients did not express IL-4 or IL-5. Taken, together the data suggest a generalized activation of IL-10 producing CD4+ T cells along the intestine of UC patients. The local environment seems to determine the biological consequences of elevated IL-10.
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| 30. |
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| 31. |
- Sul, Young-Taeg, 1960, et al.
(författare)
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Bone tissue responses to Mg-incorporated oxidized implants and machine-turned implants in the rabbit femur
- 2005
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Ingår i: Journal of Applied Biomaterials & Biomechanics 2005. - 1724-6024. ; 3:1, s. 18-28
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have demonstrated a significant improvement in the bone response to oxidized titanium implants. Little is known about the effects of specific oxide properties on the bone tissue responses to titanium implants. This study in-vestigated the bone tissue responses to magnesium (Mg)-incorporated oxidized titanium implants and machine-turned titani-um implants in the rabbit femur. The oxidized implants were prepared using micro arc oxidation (MAO) methods. Surface oxide properties were characterized by using various surface analytic techniques, involving scanning electron microscopy (SEM) equipped with energy dispersive spectrometer (EDS), X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS) and optical interferometry. Screw shaped titanium implants, 10 machine-turned implants (controls) and 10 Mg-incorporated im-plants (tests) were inserted in the femoral condyles of 10 New Zealand white rabbits. After a 6-week healing period, resonance frequency analyses and removal torque measurements of the Mg-incorporated oxidized implants demonstrated significant im-provements in implant integration with bone in comparison to machine-turned implants, p=0.007 and p=0.017, respectively. Bone growth in the pores of the oxidized implants was probably incomplete at a follow-up of 6 weeks, as indicated by SEM and EDS measurements. Mg-incorporated titanium implants significantly improved bone responses as compared with machine-turned control implants. Considering the differences and similarities of the surface oxide properties of controls and test im-plants, the enhanced bone responses to Mg-incorporated implants could be explained by the Mg surface chemistry of the test im-plants. (Journal of Applied Biomaterials & Biomechanics 2005; 3: 18-28)
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| 33. |
- Yeung, M M, et al.
(författare)
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Characterisation of mucosal lymphoid aggregates in ulcerative colitis : immune cell phenotype and TcR-gammadelta expression.
- 2000
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Ingår i: Gut. - 0017-5749 .- 1468-3288. ; 47:2, s. 215-27
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: A histopathological feature considered indicative of ulcerative colitis (UC) is the so-called basal lymphoid aggregates. Their relevance in the pathogenesis of UC is, however, unknown. We have performed a comprehensive analysis of the immune cells in these aggregates most likely corresponding to the lymphoid follicular hyperplasia also described in other colitides.METHODS: Resection specimens of UC and normal colon were analysed by immunomorphometry, immunoflow cytometry, and immunoelectron microscopy, using a large panel of monoclonal antibodies.RESULTS: (1) In all cases of UC, colonic lamina propria contained numerous basal aggregates composed of lymphocytes, follicular dendritic cells, and CD80/B7.1 positive dendritic cells. (2) CD4(+)CD28(-) alphabeta T cells and B cells were the dominant cell types in the aggregates. (3) The aggregates contained a large fraction of cells that are normally associated with the epithelium: that is, gammadelta T cells (11 (7)%) and alpha(E)beta(7)(+) cells (26 (13)%). The gammadelta T cells used Vdelta1 and were CD4(-)CD8(-). Immunoelectron microscopy analysis demonstrated TcR-gammadelta internalisation and surface downregulation, indicating that the gammadelta T cells were activated and engaged in the disease process. (4) One third of cells in the aggregates expressed the antiapoptotic protein bcl-2.CONCLUSIONS: Basal lymphoid aggregates in UC colon are a consequence of anomalous lymphoid follicular hyperplasia, characterised by abnormal follicular architecture and unusual cell immunophenotypes. The aggregates increase in size with severity of disease, and contain large numbers of apoptosis resistant cells and activated mucosal gammadelta T cells. The latter probably colonise the aggregates as an immunoregulatory response to stressed lymphocytes or as a substitute for defective T helper cells in B cell activation. gammadelta T cells in the aggregates may be characteristic of UC.
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| 34. |
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| 37. |
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| 38. |
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| 39. |
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| 40. |
- Banin, U., et al.
(författare)
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Nanotechnology for catalysis and solar energy conversion
- 2021
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Ingår i: Nanotechnology. - : Institute of Physics Publishing (IOPP). - 0957-4484 .- 1361-6528. ; 32:4
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Tidskriftsartikel (refereegranskat)abstract
- This roadmap on Nanotechnology for Catalysis and Solar Energy Conversion focuses on the application of nanotechnology in addressing the current challenges of energy conversion: 'high efficiency, stability, safety, and the potential for low-cost/scalable manufacturing' to quote from the contributed article by Nathan Lewis. This roadmap focuses on solar-to-fuel conversion, solar water splitting, solar photovoltaics and bio-catalysis. It includes dye-sensitized solar cells (DSSCs), perovskite solar cells, and organic photovoltaics. Smart engineering of colloidal quantum materials and nanostructured electrodes will improve solar-to-fuel conversion efficiency, as described in the articles by Waiskopf and Banin and Meyer. Semiconductor nanoparticles will also improve solar energy conversion efficiency, as discussed by Boschloo et al in their article on DSSCs. Perovskite solar cells have advanced rapidly in recent years, including new ideas on 2D and 3D hybrid halide perovskites, as described by Spanopoulos et al 'Next generation' solar cells using multiple exciton generation (MEG) from hot carriers, described in the article by Nozik and Beard, could lead to remarkable improvement in photovoltaic efficiency by using quantization effects in semiconductor nanostructures (quantum dots, wires or wells). These challenges will not be met without simultaneous improvement in nanoscale characterization methods. Terahertz spectroscopy, discussed in the article by Milot et al is one example of a method that is overcoming the difficulties associated with nanoscale materials characterization by avoiding electrical contacts to nanoparticles, allowing characterization during device operation, and enabling characterization of a single nanoparticle. Besides experimental advances, computational science is also meeting the challenges of nanomaterials synthesis. The article by Kohlstedt and Schatz discusses the computational frameworks being used to predict structure-property relationships in materials and devices, including machine learning methods, with an emphasis on organic photovoltaics. The contribution by Megarity and Armstrong presents the 'electrochemical leaf' for improvements in electrochemistry and beyond. In addition, biohybrid approaches can take advantage of efficient and specific enzyme catalysts. These articles present the nanoscience and technology at the forefront of renewable energy development that will have significant benefits to society.
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| 41. |
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| 42. |
- Collins, Ruairi, et al.
(författare)
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Biochemical discrimination between selenium and sulfur 1 : a single residue provides selenium specificity to human selenocysteine lyase
- 2012
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Ingår i: PLoS One. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- Selenium and sulfur are two closely related basic elements utilized in nature for a vast array of biochemical reactions. While toxic at higher concentrations, selenium is an essential trace element incorporated into selenoproteins as selenocysteine (Sec), the selenium analogue of cysteine (Cys). Sec lyases (SCLs) and Cys desulfurases (CDs) catalyze the removal of selenium or sulfur from Sec or Cys and generally act on both substrates. In contrast, human SCL (hSCL) is specific for Sec although the only difference between Sec and Cys is the identity of a single atom. The chemical basis of this selenium-over-sulfur discrimination is not understood. Here we describe the X-ray crystal structure of hSCL and identify Asp146 as the key residue that provides the Sec specificity. A D146K variant resulted in loss of Sec specificity and appearance of CD activity. A dynamic active site segment also provides the structural prerequisites for direct product delivery of selenide produced by Sec cleavage, thus avoiding release of reactive selenide species into the cell. We thus here define a molecular determinant for enzymatic specificity discrimination between a single selenium versus sulfur atom, elements with very similar chemical properties. Our findings thus provide molecular insights into a key level of control in human selenium and selenoprotein turnover and metabolism.
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| 43. |
- Corden, V.A., et al.
(författare)
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Spectroscopic and structural investigations reveal the signaling mechanism of a luminescent molybdate sensor
- 2011
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 50:3, s. 1105-1115
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Tidskriftsartikel (refereegranskat)abstract
- A heteroditopic ligand H 2-L consisting of a dihydroxybenzene (catechol)-unit linked via an amide bond to a pyridyl-unit and its methyl-protected precursor Me 2-L were synthesized, characterized, and their photophysical properties investigated. The three accessible protonation states of the ligand, H 2-L+, H 2-L, and H-L-, showed distinct 1 H NMR, absorption and emission spectroscopic characteristics that allow pH-sensing. The spectroscopic signatures obtained act as a guide to understand the signaling mechanism of the luminescent pH and molybdate sensor [Re-(bpy)(CO) 3(H 2-L)]+. It was found that upon deprotonation of the 2-hydroxy group of H 2-L, a ligand-based absorption band emerges that overlaps with the Re(dπ)-bpy metal-to-ligand charge transfer (MLCT) band of the sensor, reducing the quantum yield for emission on excitation in the 370 nm region. In addition, deprotonation of the catechol-unit leads to quenching of the emission from the Re(dn)→ bpy 3MLCT state, consistent with photoinduced electron transfer from the electron-rich, deprotonated catecholate to the Re-based luminophore. Finally, reaction of 2 equiv of [Re(bpy)(CO) 3(H 2-L)]+ with molybdate was shown to give the zwitterionic Mo(VI) complex [MoO 2{Re(CO) 3-(bpy)(L)} 2], as confirmed by electrospray ionization (ESI) mass spectrometry and X-ray crystallography. The crystal structure determination revealed that two fully deprotonated sensor molecules are bound via their oxygen-donors to a cis-dioxo-MoO 2 center.
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| 44. |
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| 45. |
- Eltahir, mohmo394, et al.
(författare)
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Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients
- 2021
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Ingår i: International Immunopharmacology. - : Elsevier. - 1567-5769 .- 1878-1705. ; 90
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Tidskriftsartikel (refereegranskat)abstract
- Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods. To better recapitulate an in vivo setting, we implemented a unique human whole blood "loop" system to study patient-specific immune responses to rituximab in blood derived from CLL patients. Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature. Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting.
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| 46. |
- Frantz, S.E.A., et al.
(författare)
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Quantum efficiency and two-photon absorption cross-section of conjugated polyelectrolytes used for protein conformation measurements with applications on amyloid structures
- 2007
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Ingår i: Chemical Physics. - : Elsevier BV. - 0301-0104 .- 1873-4421. ; 336:2-3, s. 121-126
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid diseases such as Alzheimer's and spongiform encephalopathies evolve from aggregation of proteins due to misfolding of the protein structure. Early disease handling require sophisticated but yet simple techniques to follow the complex properties of the aggregation process. Conjugated polyelectrolytes (CPEs) have shown promising capabilities acting as optical biological sensors, since they can specifically bind to polypeptides both in solution and in solid phase. The structural changes in biomolecules can be monitored by changes of the optical spectra of the CPEs, both in absorption and emission modes. Notably, the studied CPEs possess multi-photon excitation capability, making them potential for in vivo imaging using laser scanning microscopy. Aggregation of proteins depends on concentration, temperature and pH. The optical effect on the molecular probe in various environments must also be investigated if applied in these environments. Here we present the results of quantum efficiency and two-photon absorption cross-section of three CPEs: POMT, POWT and PTAA in three different pH buffer systems. The extinction coefficient and quantum efficiency were measured. POMT was found to have the highest quantum efficiency being approximately 0.10 at pH 2.0. The two-photon absorption cross-section was measured for POMT and POWT and was found to be more than 18-25 times and 7-11 times that of Fluorescein, respectively. We also show how POMT fluorescence can be used to distinguish conformational differences between amyloid fibrils formed from reduced and non-reduced insulin in spectrally resolved images recorded with a laser scanning microscope using both one- and two-photon excitation. © 2007 Elsevier B.V. All rights reserved.
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| 47. |
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| 48. |
- Frängsmyr, L., et al.
(författare)
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Evolution of the carcinoembryonic antigen family. Structures of CGM9, CGM11 and pregnancy-specific glycoprotein promoters
- 2000
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Ingår i: Tumor Biology. - 1010-4283 .- 1423-0380. ; 21:2, s. 63-81
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Tidskriftsartikel (refereegranskat)abstract
- Earlier studies have demonstrated that the genes of the human carcinoembryonic antigen (CEA) family can be divided into three subgroups, the CEA subgroup (n = 12), the pregnancy-specific glycoprotein (PSG) subgroup (n = 11), and a third subgroup (n = 6). To further characterize the CEA gene family, we have determined the genomic structures of CGM9 and CGM11, analyzed the promoter regions of all eleven PSGs, studied the CGM15-PSG13 intergenic region and the evolutionary relationships between the CEA family genes. CGM9, a typical CEA subgroup member, was a pseudogene with the exon structure [5'UTR-L-L/N-TM-Cyt-3'UTR]. CGM11 contained a mixture of exons derived from CEA and PSG subgroup genes. The formula of the CGM11 pseudogene was [5'UTRL- L/N-C-3'UTR]. Thus both genes lacked the IgC2-like domains typically found in CEA subfamily members. The upstream promoter regions of all eleven PSGs were characterized. All PSG promoters lacked the classical TATA and CCAAT elements, but had putative PEA3 box(es), CACCC box(es), a RARE box, and poly (dG-dT) repeats of different lengths. Five PSGs also had an SP1 site. The complete 10-kb intergenic region between CGM15 and PSG13 was sequenced. Clusters of different types of repetitive sequences were seen. The time of divergence of the CEA and PSG subfamilies was estimated to be 107.7 ± 17.1 million years, or at about the time of human-rodent divergence. Models for the evolution of CEA and PSG and the third family subgroup genes are proposed.
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| 49. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 50. |
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