| 1. |
- Aevarsson, Arnthór, et al.
(författare)
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Going to extremes - a metagenomic journey into the dark matter of life
- 2021
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Ingår i: FEMS Microbiology Letters. - : Oxford University Press (OUP). - 1574-6968. ; 368:12
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Forskningsöversikt (refereegranskat)abstract
- The Virus-X-Viral Metagenomics for Innovation Value-project was a scientific expedition to explore and exploit uncharted territory of genetic diversity in extreme natural environments such as geothermal hot springs and deep-sea ocean ecosystems. Specifically, the project was set to analyse and exploit viral metagenomes with the ultimate goal of developing new gene products with high innovation value for applications in biotechnology, pharmaceutical, medical, and the life science sectors. Viral gene pool analysis is also essential to obtain fundamental insight into ecosystem dynamics and to investigate how viruses influence the evolution of microbes and multicellular organisms. The Virus-X Consortium, established in 2016, included experts from eight European countries. The unique approach based on high throughput bioinformatics technologies combined with structural and functional studies resulted in the development of a biodiscovery pipeline of significant capacity and scale. The activities within the Virus-X consortium cover the entire range from bioprospecting and methods development in bioinformatics to protein production and characterisation, with the final goal of translating our results into new products for the bioeconomy. The significant impact the consortium made in all of these areas was possible due to the successful cooperation between expert teams that worked together to solve a complex scientific problem using state-of-the-art technologies as well as developing novel tools to explore the virosphere, widely considered as the last great frontier of life.
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| 2. |
- Lira-Junior, Ronaldo, et al.
(författare)
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S100A12 Expression Is Modulated During Monocyte Differentiation and Reflects Periodontitis Severity
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- S100A12 is a calcium-binding protein of the S100 subfamily of myeloid-related proteins that acts as an alarmin to induce a pro-inflammatory innate immune response. It has been linked to several chronic inflammatory diseases, however its role in the common oral immunopathology periodontitis is largely unknown. Previous in vitro monoculture experiments indicate that S100A12 production decreases during monocyte differentiation stages, while the regulation within tissue is poorly defined. This study evaluated S100A12 expression in monocyte subsets, during monocyte-to-macrophage differentiation and following polarization, both in monoculture and in a tissue context, utilizing a three-dimensional co-culture oral tissue model. Further, we explored the involvement of S100A12 in periodontitis by analyzing its expression in peripheral circulation and gingival tissue, as well as in saliva. We found that S100A12 expression was higher in classical than in non-classical monocytes. S100A12 expression and protein secretion declined significantly during monocyte-to-macrophage differentiation, while polarization of monocyte-derived macrophages had no effect on either. Peripheral monocytes from periodontitis patients had higher S100A12 expression than monocytes from controls, a difference particularly observed in the intermediate and non-classical monocyte subsets. Further, monocytes from periodontitis patients displayed an increased secretion of S100A12 compared with monocytes from controls. In oral tissue cultures, monocyte differentiation resulted in increased S100A12 secretion over time, which further increased after inflammatory stimuli. Likewise, S100A12 expression was higher in gingival tissue from periodontitis patients where monocyte-derived cells exhibited higher expression of S100A12 in comparison to non-periodontitis tissue. In line with our findings, patients with severe periodontitis had significantly higher levels of S100A12 in saliva compared to non-periodontitis patients, and the levels correlated to clinical periodontal parameters. Taken together, S100A12 is predominantly secreted by monocytes rather than by monocyte-derived cells. Moreover, S100A12 is increased in inflamed tissue cultures, potentially as a result of enhanced production by monocyte-derived cells. This study implicates the involvement of S100A12 in periodontitis pathogenesis, as evidenced by increased S100A12 expression in inflamed gingival tissue, which may be due to altered circulatory monocytes in periodontitis.
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| 3. |
- Mattsson, Jenny, et al.
(författare)
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Sequence enrichment profiles enable target-agnostic antibody generation for a broad range of antigens
- 2023
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Ingår i: Cell reports methods. - 2667-2375. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- Phenotypic drug discovery (PDD) enables the target-agnostic generation of therapeutic drugs with novel mechanisms of action. However, realizing its full potential for biologics discovery requires new technologies to produce antibodies to all, a priori unknown, disease-associated biomolecules. We present a methodology that helps achieve this by integrating computational modeling, differential antibody display selection, and massive parallel sequencing. The method uses the law of mass action-based computational modeling to optimize antibody display selection and, by matching computationally modeled and experimentally selected sequence enrichment profiles, predict which antibody sequences encode specificity for disease-associated biomolecules. Applied to a phage display antibody library and cell-based antibody selection, ∼105 antibody sequences encoding specificity for tumor cell surface receptors expressed at 103–106 receptors/cell were discovered. We anticipate that this approach will be broadly applicable to molecular libraries coupling genotype to phenotype and to the screening of complex antigen populations for identification of antibodies to unknown disease-associated targets.
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| 4. |
- Svensson, Maria C, et al.
(författare)
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High infiltration of CD68+/CD163- macrophages is an adverse prognostic factor after neoadjuvant chemotherapy in esophageal and gastric adenocarcinoma
- 2022
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 14:6, s. 615-628
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-associated macrophages (TAMs) have emerged as key players in tumor immunology but demonstrate a continuum of functional states being either tumor suppressive or promoting. Moreover, chemotherapeutic agents have been shown to alter the tumor microenvironment. Perioperative chemotherapy is a standard treatment option for resectable esophageal and gastric (EG) adenocarcinoma. The aim of this study was to investigate the influence of neoadjuvant chemotherapy (NAC) on TAMs to improve the prognostication and treatment course for these patients. The study cohort comprised 148 patients, all of whom were diagnosed with resectable EG adenocarcinoma and treated with NAC. Immunohistochemistry was applied to assess the total infiltration and infiltration into tumor nests (TN) of CD68+/CD163−, CD68+/CD163+, and MARCO+ TAMs, on paired biopsies from primary tumors (PT) pre-NAC, and resected PT and lymph node metastases post-NAC. In pre-NAC specimens, high CD68+/CD163+ infiltration into TN was an unfavorable prognostic factor. No association was found between TAM density in PT pre-NAC and histopathological regression. The density of CD68+/CD163+ TAMs was increased in PT post-NAC, while the density of MARCO+ TAMs was decreased. CD68+/CD163− TAM density was not altered. In post-NAC specimens, higher total as well as TN infiltration of CD68+/CD163−TAMs were adverse prognostic factors. In conclusion, these results suggest that NAC may alter certain TAM subsets in EG adenocarcinoma, along with their functional properties and thus their prognostic value.
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| 5. |
- Afghahi, Henri, 1966, et al.
(författare)
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Long-term glycemic variability and the risk of mortality in diabetic patients receiving peritoneal dialysis.
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- The large amount of glucose in the dialysate used in peritoneal dialysis (PD) likely affects the glycemic control. The aim of this study was to investigate the association between HbA1c variability, as a measure of long-term glycemic variability, and the risk of all-cause mortality in diabetic patients with PD.325 patients with diabetes and ESRD were followed (2008-2018) in the Swedish Renal Registry. Patients were separated in seven groups according to level of HbA1c variability. The group with the lowest variability was denoted the reference. The ratio of the standard deviation (SD) to the mean of HbA1c, HbA1c (SD)/HbA1c (mean), i.e. the coefficient of variation (CV), was defined as HbA1c variability. Hazard ratios (HR) and 95% confidence intervals (CI) were examined using Cox regression analyses.During follow-up, 170 (52%) deaths occurred. The highest mortality was among patients with the second highest HbA1c variability, CV≥2.83 [n = 44 of which 68% patients died]. In the multivariate analyses where lowest HbA1c variability (CV≤0.51) was used as the reference group, HbA1c CV 2.83-4.60 (HR 3.15, 95% CI 1.78-5.55; p<0.001) and CV> 4.6 (HR 2.48, 95% CI 1.21-5.11; p = 0.014) were associated with increased risk of death.The high risk of all-cause mortality in patients with diabetes and PD increased significantly with elevated HbA1c variability, as measure of long-term glycemic control. This indicates that stable glycemia is associated with an improvement of survival; whereas more severe glycemic fluctuations, possibly caused by radical changes in dialysis regimes or peritonitis, are associated with a higher risk of mortality in diabetic patients with PD.
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| 6. |
- Afghahi, Henri, 1966, et al.
(författare)
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The association between long-term glycemic control and all-cause mortality is different among older versus younger patients with diabetes mellitus and maintenance hemodialysis treatment.
- 2022
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Ingår i: Diabetes research and clinical practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 191
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about association between glycated hemoglobin (HbA1c) and risk of all-cause mortality in patients with diabetes mellitus on maintenance hemodialysis (HD)-treatment is sparse. The study aims to investigate association between HbA1c and all-cause mortality in patients with diabetes and maintenance HD-treatment, separately for two age groups- above and below 75years.2487 patients (mean age 66years, 66% men) were separated in two age groups: ≤75years (n=1810) and>75years (n=677) and followed up between 2008 and 2018. Hazard ratios (HR) and 95% confidence intervals (CI) for associations between HbA1c and all-cause mortality were calculated using Cox-regression-models.1295 (52%) patients died and 473 (70%) among the patients above 75years old. In the multivariate analysis, HbA1c5-6% was used as reference. In patients≤75years old, only increased HbA1c>9.7%, HR2.03(CI1.43-2.89) was associated with increased risk of all-cause mortality. In patients>75years, HbA1c≤5%, HR1.67(CI1.16-2.40); HbA1c6.9-7.8%, HR1.41(CI1.03-1.93) and HbA1c8.7-9.7%, HR1.79 (CI1.08-2.96) were associated with increased risk of all-cause mortality.We found a J-shaped association between HbA1c and mortality only in diabetic HD-patients>75years. This probably indicates that in an old population of diabetic HD-patients, both intensive glucose control and hyperglycemia could be harmful and associated with higher risk of death.
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| 7. |
- Agelii, Monica Leu, et al.
(författare)
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Misdiagnosis of Rheumatoid Arthritis in a Long-Term Cohort of Early Arthritis Based on the ACR-1987 Classification Criteria
- 2022
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Ingår i: Open Access Rheumatology: Research and Reviews. - 1179-156X. ; 14, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Correct diagnosis of early rheumatoid arthritis (RA) is essential for optimal treatment choices. No pathognomonic test is available, and diagnosis is based on classification criteria, which can result in misdiagnosis. Here, we examined the differences between actual and misdiagnosed RA cases in a long-term cohort of patients included based on the ACR-1987 classification criteria. Methods: Patients in the BARFOT (Better Anti-Rheumatic PharmacOTherapy) cohort (n=2543) with at least four follow-up visits during the initial 5 years from enrolment were assessed, and a change in diagnosis was reported by the treating rheumatologist. The groups were analysed with respect to the individual classification criteria, antibodies to citrullinated proteins (ACPA), disease activity (DAS28) and radiographic changes from inclusion up to 2 years. Results: Forty-five patients (1.8%) were misdiagnosed (RA-change group). When compared to those in the RA-change group, the patients who kept their diagnosis (RA-keep) were more often RF positive (64% vs 21%, p<0.001) or ACPA positive (59% vs 8%, p<0.001). They were also more likely to fulfil more than four ACR-1987 criteria (64% vs 33%, p<0.001) and to have radiographic changes at inclusion (RA-keep 27% vs RA-change 12%, p=0.04). The groups had a similar evolution of DAS28 and its components as well as of radiological joint destruction. Conclusion: Diagnosis of RA according to the ACR-1987 criteria had a high precision in this long-term cohort. A diagnosis of RA should be re-evaluated in patients who do not fulfil more than four ACR-1987 criteria especially in patients negative for RF.
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| 8. |
- Ajeganova, S., et al.
(författare)
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Long-term fracture risk in rheumatoid arthritis: impact of early sustained DAS28-remission and restored function, progressive erosive disease, body mass index, autoantibody positivity and glucocorticoids. A cohort study over 10 years
- 2023
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Ingår i: BMC Rheumatology. - 2520-1026. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRisk of fragility fractures in patients with rheumatoid arthritis (RA) is increased. Disease-related inflammation in RA is associated with low Bone Mineral Density (BMD). However, effects of specific disease factors on fracture occurrence and whether or not such disease effects are independent of BMD are unknown.MethodsAnalysis of fracture outcome in the prospective cohort of 2557 patients with early RA (67% women, mean age 58.1 & PLUSMN; 15.6 years) during an observation period of 10.6 & PLUSMN; 4.7 years. In 602 patients BMD was measured at baseline. The first major fragility fractures were considered. Kaplan-Meier and Cox regression analysis, adjusted for traditional factors, prior fracture, disease activity and period of inclusion, were used to estimate the risk of the outcome.ResultsDuring follow-up fracture occurred in 352 patients (13.8%), a rate of 13/1000 p-y. A proportional risk reduction for the outcome was associated with Body Mass Index (BMI) at baseline, BMI & GE; 30 kg/m(2), and over the first two years sustained Disease Activity Score (DAS28)-remission, DAS28-low disease activity and Health Assessment Questionnaire (HAQ) & LE; 0.5. The proportional risk elevation for fractures was associated with BMI & LE; 20 kg/m(2), DAS28 at baseline, 6-month and at 1-year, cumulative DAS28 over the two years, RF, erosion score progression at 2-year, HAQ score and HAQ & GE; 1 at 6-month and 1-year and showed a trend for ACPA positivity. The estimated fracture risk was increased in users of glucocorticoids (GC), associated with a higher GC-dosage at follow-ups and a higher cumulative dosage over two years, independently of disease activity. With adjustment for BMD, there was no difference in fracture outcome by exposure to GC. The effects of a higher BMI, DAS28-remission and low HAQ & LE; 0.5 attained at 6-month of treatment initiation and sustained up to 2 years, RF, ACPA, and erosion score progression at 2-year were independent of low BMD.ConclusionsThis analysis supports importance of RA-specific risk factors in early RA for future major fragility fractures. Treat-to-target strategy and restored functional capacity in early RA-disease are important to prevent fractures. Autoantibody positivity, progressively erosive disease, and low weight could have additional value for personalized fracture preventive strategies in early RA.
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| 9. |
- Akerblom, H., et al.
(författare)
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Association of Gastric Bypass Surgery With Risk of Developing Diabetic Retinopathy Among Patients With Obesity and Type 2 Diabetes in Sweden: An Observational Study
- 2021
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Ingår i: Jama Ophthalmology. - : American Medical Association (AMA). - 2168-6165 .- 2168-6173. ; 139:2, s. 200-205
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Knowledge of the incidence and progression of diabetic retinopathy (DR) after gastric bypass surgery (GBP) in patients with obesity and diabetes could guide the management of these patients. OBJECTIVE To investigate the incidence of diabetic ocular complications in patients with type 2 diabetes after GBP compared with the incidence of diabetic ocular complications in a matched cohort of patients with obesity and diabetes who have not undergone GBP. DESIGN, SETTING, AND PARTICIPANTS Data from 2 nationwide registers in Sweden, the Scandinavian Obesity Surgery Registry and the National Diabetes Register, were used for this cohort study. A total of 5321 patients with diabetes from the Scandinavian Obesity Surgery Registry who had undergone GBP from January 1, 2007, to December 31, 2013, were matched with 5321 patients with diabetes from the National Diabetes Register who had not undergone GBP, based on sex, age, body mass index (BMI), and calendar time (2007-2013). Follow-up data were obtained until December 31, 2015. Statistical analysis was performed from October 5, 2018, to September 30, 2019. EXPOSURE Gastric bypass surgery. MAIN OUTCOMES AND MEASURES Incidence of new DR and other diabetic ocular complications. RESULTS The study population consisted of 5321 patients who had undergone GBP (3223 women [60.6%]; mean [SD] age, 49.0 [9.5] years) and 5321 matched controls (3395 women [63.8%]; mean [SD] age, 47.1 [11.5] years). Mean (SD) follow-up was 4.5 (1.6) years. The mean (SD) BMI and hemoglobin A1c concentration at baseline were 42.0 (5.7) and 7.6%(1.5%), respectively, in the GBP group and 40.9 (7.3) and 7.5%(1.5%), respectively, in the control group. The mean (SD) duration of diabetes was 6.8 (6.3) years in the GBP group and 6.4 (6.4) years in the control group. The risk for new DR was reduced in the patients who underwent GBP (hazard ratio, 0.62 [95% CI, 0.49-0.78]; P <.001). The dominant risk factors for development of DR at baseline were diabetes duration, hemoglobin A1c concentration, use of insulin, glomerular filtration rate, and BMI. CONCLUSIONS AND RELEVANCE This nationwide matched cohort study suggests that there is a reduced risk of developing new DR associated with GBP, and no evidence of an increased risk of developing DR that threatened sight or required treatment. (c) 2021 American Medical Association. All rights reserved.
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| 10. |
- Andersson-Assarsson, Johanna C., 1974, et al.
(författare)
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Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity
- 2023
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Ingår i: Ebiomedicine. - 2352-3964. ; 92
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Tidskriftsartikel (refereegranskat)abstract
- Background Haematopoietic clones caused by somatic mutations with >= 2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years.Methods Clonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n = 40) of the individuals treated by usual care.Findings In this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P = 0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range -4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R = -0.68, 1.74 E-04).Interpretation Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care.
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