| 1. |
- Askman, Sandra, et al.
(författare)
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Decreased neutrophil function in newly diagnosed multiple myeloma patients is restored with lenalidomide therapy
- 2024
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Ingår i: EUROPEAN JOURNAL OF HAEMATOLOGY. - 0902-4441 .- 1600-0609.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesBacterial infections are common and a major cause of morbidity and mortality in multiple myeloma (MM). We have investigated the function of polymorphonuclear leukocyte (PMN), the immune system's first line of defense against bacteria, in peripheral blood (PB) and bone marrow (BM) samples from patients with newly diagnosed MM (NDMM), smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS) and healthy controls.MethodsPhagocytosis and oxidative burst in PMN cells from patients and healthy donors were investigated using PhagoTest and PhagoBurst assay.ResultsPMN from NDMM, SMM, and MGUS patients had reduced phagocytosis and oxidative burst ability compared with healthy controls. The dysfunction was most prominent in BM samples from MM, SMM, and MGUS patients. Importantly the reduced phagocytosis in MM patients was restored in patients on lenalidomide therapy. Consistently the ability of Escherichia coli stimulated oxidative burst in BM was reduced for the MM, SMM, and MGUS cohort in contrast to the healthy controls and the patients on lenalidomide treatment.ConclusionOur results show that MM patients have neutrophil dysfunction that could contribute to susceptibility for bacterial infections and that lenalidomide therapy was associated with restored PMN function.
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| 2. |
- Belfrage, Emma, et al.
(författare)
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Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE) : Protocol for a Translational Study
- 2024
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Ingår i: JMIR Research Protocols. - 1929-0748. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a rare group of lymphomas that primarily affects the skin. Mycosis fungoides (MF) is the most common form of CTCL and Sézary syndrome (SS) is more infrequent. Early stages (IA-IIA) have a favorable prognosis, while advanced stages (IIB-IVB) have a worse prognosis. Around 25% of patients with early stages of the disease will progress to advanced stages. Malignant skin-infiltrating T-cells in CTCL are accompanied by infiltrates of nonmalignant T-cells and other immune cells that produce cytokines that modulate the inflammation. Skin infection, often with Staphylococcus aureus, is frequent in advanced stages and can lead to sepsis and death. S. aureus has also been reported to contribute to the progression of the disease. Previous reports indicate a shift from Th1 to Th2 cytokine production and dysfunction of the skin barrier in CTCL. Treatment response is highly variable and often unpredictable, and there is a need for new predictive and prognostic biomarkers.OBJECTIVE: This prospective translational study aims to identify prognostic biomarkers in the blood and skin of patients with MF and SS.METHODS: The Predictive and Prognostic Biomarkers in Patients With MF and SS (BIO-MUSE) study aims to recruit 120 adult patients with MF or SS and a control group of 20 healthy volunteers. The treatments will be given according to clinical routine. The sampling of each patient will be performed every 3 months for 3 years. The blood samples will be analyzed for lactate dehydrogenase, immunoglobulin E, interleukins, thymus and activation-regulated chemokine, and lymphocyte subpopulations. The lymphoma microenvironment will be investigated through digital spatial profiling and single-cell RNA sequencing. Microbiological sampling and analysis of skin barrier function will be performed. The life quality parameters will be evaluated. The results will be evaluated by the stage of the disease.RESULTS: Patient inclusion started in 2021 and is still ongoing in 2023, with 18 patients and 20 healthy controls enrolled. The publication of selected translational findings before the publication of the main results of the trial is accepted.CONCLUSIONS: This study aims to investigate blood and skin with a focus on immune cells and the microbiological environment to identify potential new prognostic biomarkers in MF and SS.TRIAL REGISTRATION: ClinicalTrials.gov NCT04904146; https://www.clinicaltrials.gov/study/NCT04904146.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55723.
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| 3. |
- Schmitz, Daniel, 1995-
(författare)
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Beyond GWAS : Novel Methods and Resources for Genetic Epidemiology
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since the first human genome assembly’s release, our knowledge of the genetic architecture of complex traits and diseases has grown steadily. Genome-wide association studies (GWAS) played a major role but are limited to common traits and single-nucleotide polymorphisms (SNPs). Technologies and resources like next-generation sequencing, Mendelian Randomization (MR), long-read sequencing and improved reference genomes enable the investigation of variants inaccessible to GWAS, such as copy number variations (CNVs), rare variants and variants in previously unresolved regions.In project I, we performed a GWAS of estradiol measurements using data from UK Biobank and quantified estradiol’s effect on bone mineral density (BMD) using MR. 14 loci were associated with estradiol levels in males, of which one was also significant in females and an additional female-specific locus. We found a significant effect of estradiol on BMD, confirming previous research of estrogen’s importance for skeletal health.In project II, we used the GWAS results from project I to investigate the effect of endogenous estradiol on breast, endometrial and ovarian cancer using MR. Estradiol was associated with ovarian cancer and nominally associated with estrogen receptor-positive breast cancer, demonstrating the effect of endogenous estrogen on cancer risk. In project III, we quantified the effect of 184,182 CNVs on 438 blood plasma proteins using whole-genome sequencing (WGS) data from a Northern Swedish cohort and validated our findings using long-read sequencing in a subcohort. 15 CNVs were associated with 16 proteins of which four could be validated using long reads and three more were more complex variation. Our findings show the effects of CNVs on the plasma proteome and highlight the application different sequencing technologies for CNV detection.In project IV, we evaluated the use of T2T-CHM13 as reference for the SweGen cohort. Compared to GRCh38, mapping quality improved and we identified 9.8 million more variants. Sensitivity for rare, singleton and functionally relevant variants was higher. These findings show how research and clinical applications benefit from T2T-CHM13 by improving detection of previously unknown functionally relevant variation.This thesis demonstrates the application of novel technologies and resources in genomics to detect variation and study its impact on quantitative traits. By using genotyping and WGS variants from short and long reads, I showed how we can leverage these technologies for research beyond GWAS.
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| 4. |
- Smargianaki, Sofia, et al.
(författare)
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Disease Activity and Tendency to Relapse in ANCA-Associated Vasculitis Are Reflected in Neutrophil and Intermediate Monocyte Frequencies
- 2024
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Ingår i: Journal of Immunology Research. - 2314-7156. ; 2024
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Tidskriftsartikel (refereegranskat)abstract
- Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases with inflammation affecting small blood vessels and includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). In this study, we investigated granulocyte and monocyte subsets in a large cohort of AAV patients with emphasis on disease activity and tendency to relapse. A cohort of 105 patients with GPA or MPA and 126 healthy controls (HCs) were included. Clinical and laboratory data were collected for all patients, including disease activity, tendency to relapse, and pharmacological treatment. Using flow cytometry, circulating eosinophils, basophils, neutrophils, and monocytes were assessed. The monocytes were subdivided into classical (CD14 ++CD16 -), intermediate (CD14 ++CD16 +), and nonclassical (CD14 -CD16 +) monocytes. Mature (CD16 high) or newly released (CD16 dim) neutrophils were defined, as well as the frequency of CD177 + neutrophils. AAV patients displayed increased frequencies of intermediate monocytes, mature and newly released neutrophils, and an expanded population of CD177 + neutrophils compared to HC. MPA patients differed from GPA patients in terms of lower frequency of classical monocytes. No differences in cell frequencies regarding ANCA phenotype were observed. Paired data from 23 patients demonstrated that active disease was associated with an increased frequency of mature neutrophils and a decreased frequency of monocytes, in particular intermediate monocytes. Moreover, GPA patients with a tendency to relapse displayed an increased frequency of mature neutrophils with increased expression of CD177 +. Relapsing MPA patients, on the other hand, showed decreased frequency of intermediate monocytes. Finally, rituximab treatment was associated with increased frequencies of classical and intermediate monocytes. In conclusion, AAV patients exhibit a skewing of different neutrophil and monocyte subpopulations that are associated with disease subtypes, disease activity, rituximab treatment, and propensity to relapse. These changes may contribute to the inflammatory process and could potentially be used as biomarkers for relapse prediction.
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| 5. |
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| 6. |
- Edsjö, Anders, et al.
(författare)
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Building a precision medicine infrastructure at a national level : The Swedish experience
- 2023
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Ingår i: Cambridge Prisms: Precision Medicine. - : Cambridge University Press. - 2752-6143. ; 1
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine has the potential to transform healthcare by moving from one-size-fits-all to personalised treatment and care. This transition has been greatly facilitated through new high-throughput sequencing technologies that can provide the unique molecular profile of each individual patient, along with the rapid development of targeted therapies directed to the Achilles heels of each disease. To implement precision medicine approaches in healthcare, many countries have adopted national strategies and initiated genomic/precision medicine initiatives to provide equal access to all citizens. In other countries, such as Sweden, this has proven more difficult due to regionally organised healthcare. Using a bottom-up approach, key stakeholders from academia, healthcare, industry and patient organisations joined forces and formed Genomic Medicine Sweden (GMS), a national infrastructure for the implementation of precision medicine across the country. To achieve this, Genomic Medicine Centres have been established to provide regionally distributed genomic services, and a national informatics infrastructure has been built to allow secure data handling and sharing. GMS has a broad scope focusing on rare diseases, cancer, pharmacogenomics, infectious diseases and complex diseases, while also providing expertise in informatics, ethical and legal issues, health economy, industry collaboration and education. In this review, we summarise our experience in building a national infrastructure for precision medicine. We also provide key examples how precision medicine already has been successfully implemented within our focus areas. Finally, we bring up challenges and opportunities associated with precision medicine implementation, the importance of international collaboration, as well as the future perspective in the field of precision medicine.
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| 7. |
- Hadizadeh, Fatemeh, et al.
(författare)
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Effects of oral contraceptives and menopausal hormone therapy on the risk of rheumatoid arthritis : a prospective cohort study.
- 2023
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Ingår i: Rheumatology. - 1462-0324 .- 1462-0332.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Oral contraceptives (OC) and menopausal hormone therapy (MHT) contain exogenous sex hormones and are used by millions of women around the world. However, their effect on development of rheumatoid arthritis (RA) is still debated and the current literature suggests that they may exert opposite effects on the risk of RA. The present study aimed to estimate the effects of exogenous hormones on development of RA, both during the reproductive lifespan and later in life.METHODS: The association between OC and RA, as well as between MHT and late-onset RA (LORA), was investigated using time-dependent Cox regression modelling in white British women from the UK Biobank (N = 236 602 and N = 102 466, respectively) and replicated in women from all ethnic groups.RESULTS: OC use was associated with a decreased risk of RA in ever-users (hazard ratio [HR]=0.89; 95% CI = 0.82-0.96), as well as in current (HR = 0.81; 0.73-0.91) and former users (HR = 0.92; 0.84 -1.00), compared with never-users. In contrast, MHT use was associated with an increased risk of LORA in ever-users (HR = 1.16; 1.06-1.26) as well as in former users (HR = 1.13; 1.03-1.24) compared with never-users.CONCLUSION: OC use appears to protect against RA, while MHT may increase the risk of LORA. This study provides new insights into the possible inverse effect of exposure to different exogenous sex hormones on the risk of RA.
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| 8. |
- Johansson Palmkvist, Åsa, 1980-
(författare)
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Tekniker i människans tjänst : En feministisk analys av återskapande och förändring inom forskning på inflytelserik teknik
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis takes its starting point in the massive attention paid to artificial intelligence (AI) in recent years, especially the reporting on how AI maintains and reinforces power imbalances linked to gender and other categories. The aim is to examine and problematize relations between influential technology and gender from a feminist perspective. More specifically, the focus is on how co-productions of technology and gender are reproduced and changed in contemporary technology research that in various ways links to AI. The theoretical framework consists primarily of feminist science and technology studies (STS). Thus, the overall theoretical starting point is that technology and gender are “done” in relation to each other in ways that involve notions, and values about what is important. In addition, some concepts and perspectives from feminist organization studies are used, especially the concept of gender structure and centre-construction. Empirically, the study is based on semi-structured interviews with researchers and doctoral students in two academic technology research environments, and on observations of their everyday research practices. At both of these environments’ respective universities, the work on gender equality was extensive by international standards. The gender structure of the environments differed: where one of the environments was numerically male-dominated in general and had no female assistant professors, associate professors or full professors, the other environment had a relatively high proportion of women, especially among the full professors.Central to the thesis is how the researchers and doctoral students made a distinction between traditional and new/contemporary AI. Whereas traditional AI was articulated as a delimited technology discipline with the aim of imitating humans, the new form of AI was articulated as disciplinarily vaguer and as striving to support humans; the new AI was articulated as technologies in the service of humans. Based on this division, the thesis examines which technologies, which humans and what kinds of services the articulation of the new AI refers to. It also explores the norms and ideals of being a researcher or doctoral student in the two technology research environments. The thesis highlights some specific ways in which structural and discursive aspects can impact upon how gendered norms and ideals are reproduced and challenged in technology research on influential technologies. The findings indicate that a disruption of the conventional male-dominated gender structure of technology research enables alternative understandings and ways of conducting such research. By examining how interviewees from different gendered technology research directions described their research’s relationship with AI, the thesis also illustrates how researchers’ and doctoral students’ ways of relating to emerging technological phenomena can be understood as parts of wider negotiations about the status of gendered research directions. Furthermore, the thesis discusses how the interviewees’ articulations of the potential benefits of influential technology were influenced by both power-blind and power-critical discourses. This highlights nuances in how researchers and doctoral students engaged in technology research on influential technology understand the relationship between technology research and the wider context of technology. These nuances enable a situated criticism, with greater potential to be heard from within the field itself.
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| 9. |
- Johansson, Therese, et al.
(författare)
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Population-based cohort study of oral contraceptive use and risk of depression
- 2023
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Ingår i: Epidemiology and Psychiatric Sciences. - : Cambridge University Press. - 2045-7960 .- 2045-7979. ; 32
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Research on the effect of oral contraceptive (OC) use on the risk of depression shows inconsistent findings, especially in adult OC users. One possible reason for this inconsistency is the omission of women who discontinue OCs due to adverse mood effects, leading to healthy user bias. To address this issue, we aim to estimate the risk of depression that is associated with the initiation of OCs as well as the effect of OC use on lifetime risk of depression.METHODS: This is a population-based cohort study based on data from 264,557 women from the UK Biobank. Incidence of depression was addressed via interviews, inpatient hospital or primary care data. The hazard ratio (HR) between OC use and incident depression was estimated by multivariable Cox regression with OC use as a time-varying exposure. To validate causality, we examined familial confounding in 7,354 sibling pairs.RESULTS: We observed that the first 2 years of OC use were associated with a higher rate of depression compared to never users (HR = 1.71, 95% confidence interval [CI]: 1.55-1.88). Although the risk was not as pronounced beyond the first 2 years, ever OC use was still associated with an increased lifetime risk of depression (HR = 1.05, 95% CI: 1.01-1.09). Previous OC use were associated with a higher rate of depression compared to never users, with adolescent OC users driving the increased hazard (HR = 1.18, 95% CI: 1.12-1.25). No significant association were observed among adult OC users who had previously used OCs (HR = 1.00, 95% CI: 0.95-1.04). Notably, the sibling analysis provided further evidence for a causal effect of OC use on the risk of depression.CONCLUSIONS: Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life. Our results are consistent with a causal relationship between OC use and depression, as supported by the sibling analysis. This study highlights the importance of considering the healthy user bias as well as family-level confounding in studies of OC use and mental health outcomes. Physicians and patients should be aware of this potential risk when considering OCs, and individualized risk-benefit assessments should be conducted.
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| 10. |
- Johansson, Åsa, et al.
(författare)
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Precision medicine in complex diseases - : Molecular subgrouping for improved prediction and treatment stratification
- 2023
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 1365-2796 .- 0954-6820. ; 294:4, s. 378-396
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Forskningsöversikt (refereegranskat)abstract
- Complex diseases are caused by a combination of genetic, lifestyle, and environmental factors and comprise common noncommunicable diseases, including allergies, cardiovascular disease, and psychiatric and metabolic disorders. More than 25% of Europeans suffer from a complex disease, and together these diseases account for 70% of all deaths. The use of genomic, molecular, or imaging data to develop accurate diagnostic tools for treatment recommendations and preventive strategies, and for disease prognosis and prediction, is an important step toward precision medicine. However, for complex diseases, precision medicine is associated with several challenges. There is a significant heterogeneity between patients of a specific disease-both with regards to symptoms and underlying causal mechanisms-and the number of underlying genetic and nongenetic risk factors is often high. Here, we summarize precision medicine approaches for complex diseases and highlight the current breakthroughs as well as the challenges. We conclude that genomic-based precision medicine has been used mainly for patients with highly penetrant monogenic disease forms, such as cardiomyopathies. However, for most complex diseases-including psychiatric disorders and allergies-available polygenic risk scores are more probabilistic than deterministic and have not yet been validated for clinical utility. However, subclassifying patients of a specific disease into discrete homogenous subtypes based on molecular or phenotypic data is a promising strategy for improving diagnosis, prediction, treatment, prevention, and prognosis. The availability of high-throughput molecular technologies, together with large collections of health data and novel data-driven approaches, offers promise toward improved individual health through precision medicine.
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