| 1. |
- Bensberg, Maike, et al.
(författare)
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TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:34
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Tidskriftsartikel (refereegranskat)abstract
- Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggres-sive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methyl-ation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improv-ing prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respec-tively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Impor-tantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2-silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous ret-roviruses (HERVs), which was further enhanced by the addition of phys-iological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2-silenced T-ALL.
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| 2. |
- Eriksson, Carl, 1981-, et al.
(författare)
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Real-world effectiveness of vedolizumab in inflammatory bowel disease : week 52 results from the Swedish prospective multicentre SVEAH study
- 2021
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Ingår i: Therapeutic Advances in Gastroenterology. - : Sage Publications. - 1756-283X .- 1756-2848. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prospectively and systematically collected real-world data on vedolizumab are scarce. We aimed to assess the long-term clinical effectiveness of vedolizumab in inflammatory bowel disease (IBD).Methods: This study was a prospective, observational, multicentre study. Overall, 286 patients with active IBD were included (Crohn's disease, n = 169; ulcerative colitis, n = 117). The primary outcomes were clinical response at week 12 and clinical remission at week 52, based on the Harvey Bradshaw Index and the partial Mayo Clinic score. Secondary outcomes included clinical remission at week 12, clinical response at week 52, corticosteroid-free clinical remission at week 52, changes in biochemical measures, and health-related quality of life (HRQoL).Results: At baseline, 88% of the patients were exposed to anti-TNF and 41% of the patients with Crohn's disease had undergone ⩾1 surgical resection. At week 12, clinical response was 27% and remission 47% in Crohn's disease; corresponding figures in ulcerative colitis were 52% and 34%. Clinical response, remission and corticosteroid-free remission at week 52 were 22%, 41% and 40% in Crohn's disease and 49%, 47% and 46% in ulcerative colitis, respectively. A statistically significant decrease in median faecal-calprotectin and C-reactive protein was observed at 12 and 52 weeks in patients with Crohn's disease and ulcerative colitis. The HRQoL measures Short Health Scale and EuroQol 5-Dimensions improved in both Crohn's disease and ulcerative colitis patients (p < 0.001). Clinical disease activity at baseline was inversely associated with clinical remission at week 52.Conclusion: Vedolizumab proved effective for the treatment of refractory IBD in clinical practice.
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| 3. |
- Hellberg, Sandra, et al.
(författare)
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Progesterone Dampens Immune Responses in In Vitro Activated CD4(+) T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induced effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4(+) T cell activation, key event in pregnancy and disease. We report profound dampening effects of P4 on T cell activation, altering the gene and protein expression profile and reversing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the disease-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12 beta, CXCL10 and OSM, which were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and support its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation and highlight the need for further studies evaluating P4 as a future treatment option.
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| 4. |
- Magnusson, Rasmus, et al.
(författare)
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RNA-sequencing and mass-spectrometry proteomic time-series analysis of T-cell differentiation identified multiple splice variants models that predicted validated protein biomarkers in inflammatory diseases
- 2022
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Profiling of mRNA expression is an important method to identify biomarkers but complicated by limited correlations between mRNA expression and protein abundance. We hypothesised that these correlations could be improved by mathematical models based on measuring splice variants and time delay in protein translation. We characterised time-series of primary human naive CD4(+) T cells during early T helper type 1 differentiation with RNA-sequencing and mass-spectrometry proteomics. We performed computational time-series analysis in this system and in two other key human and murine immune cell types. Linear mathematical mixed time delayed splice variant models were used to predict protein abundances, and the models were validated using out-of-sample predictions. Lastly, we re-analysed RNA-seq datasets to evaluate biomarker discovery in five T-cell associated diseases, further validating the findings for multiple sclerosis (MS) and asthma. The new models significantly out-performing models not including the usage of multiple splice variants and time delays, as shown in cross-validation tests. Our mathematical models provided more differentially expressed proteins between patients and controls in all five diseases. Moreover, analysis of these proteins in asthma and MS supported their relevance. One marker, sCD27, was validated in MS using two independent cohorts for evaluating response to treatment and disease prognosis. In summary, our splice variant and time delay models substantially improved the prediction of protein abundance from mRNA expression in three different immune cell types. The models provided valuable biomarker candidates, which were further validated in MS and asthma.
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| 5. |
- Nestor, Colm, et al.
(författare)
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5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells
- 2016
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 16:2, s. 559-570
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Tidskriftsartikel (refereegranskat)abstract
- 5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment.
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| 6. |
- Rundquist, Olof, 1991-
(författare)
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Multi-omic time-series analysis of T-cells as a model for identification of biomarkers, treatments and upstream disease regulators
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CD4+ T-cell function and their process of differentiation is a central piece of the puzzle in a multitude of diseases. CD4+ T-cells are part of the adaptive immune system and function by directing other immune cells to the site of infection and instructing B-cells to produce antibodies, among many other functions. CD4+ T-cells may differentiate into several different sub-types, such as T-helper 1, 2 and 17, with differing functions within the immune system. T-helper 1 (Th1) cells are most closely associated with the elimination of viral infections but are also associated with autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). T-cells develop in the thymus first as double-negative T-cells, that express neither CD4 nor CD8, going through multiple development stages before becoming double-positive T-cell that express both CD4 and CD8, before eventually giving rise to single positive CD4+ and CD8+ T-cells. This process of development is under tight control and if this control fails, cancer may result. Once CD4+ T-cells are fully developed, they may specialize as outlined above and if said process is not properly controlled, autoimmunity may result. As such, the proper understanding of these control mechanisms is of great importance for the understanding of diseases of the immune system and the discovery of biomarkers and treatments against said diseases. These control processes are often studied in a singular fashion using one omic technique, e.g., RNA sequencing (RNA-seq), with the assumption that a signal in one omic layer will be reflected in another. Recent studies attempting to integrate multiple omics have however cast doubt on this and it is becoming increasingly apparent that to gain a complete understanding of a system, the system needs to be studied at multiple levels of regulation, i.e., multiple omics.The aim of this thesis was to use multi-omics to investigate the development and differentiation process of CD4+ T-helper cells and relate it to disease mechanisms. To start, we studied T-cell development through the model of T-cell acute lymphoblastic leukaemia (T-ALL). More specifically, we studied the TET2 gene and investigated its importance in T-ALL for treatment susceptibility and mechanism in vitro. TET2 is a demethylase and functions through the removal of cytosine methylation on the DNA, a marker of gene silencing. Through treatment with decitabine, an inhibitor of DNA-methylation, and Vitamin C, a co-factor for TET2, we showed that TET2 deficient cancer cell lines were more vulnerable to treatment targeting DNA methylation and investigated the mechanistic effects of said treatment by RNA sequencing. We then moved on to study primary human naïve CD4+ T-cells and their differentiation into Th1-cells. First, we focused on T-cell activation and its importance to MS to understand the role of T-cells in mediating the lowered disease activity usually observed during pregnancy in MS. This showed that the major pregnancy hormone progesterone significantly dampens T-cell activation, providing a possible explanation for the beneficial effects of pregnancy on MS. Then, using ATAC sequencing (ATAC-seq), RNA-seq and proteomics we studied Th1-differentiation as a time series to elucidate regulatory events throughout the differentiation process and to study their implications for MS with the inclusion of progesterone treatment. The integration of several omic techniques presents unique challenges as one does not necessarily directly translate to the other. As such, we first focused on the integration of RNA-seq and proteomics by designing a model for the prediction of protein abundance from RNA-seq and validated it through biomarker discovery. Next, we focused on the integration of ATAC-seq and RNA-seq using correlation between time series of the two techniques. This thesis provides a thorough investigation of Th1-cell differentiation and its potential involvement in disease. Time series datasets were produced to study gene regulation (ATAC-seq), gene expression (RNA-seq) and protein expression (mass spectrometry) and the work focused on their integration. This profoundly showed that through combining multiple omic techniques it was possible to gain new insights that were not possible to discover with one or the other. Multi-omic analyses are becoming more and more common in medicine today as their power to produce new insight into the complexity of complex diseases is being increasingly recognized. As such, this work forms an important foundation for future discovery of biomarkers and treatments in such diseases.
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| 7. |
- Rundquist, Olof, et al.
(författare)
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Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- T(H)1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human T(H)1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during T(H)1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.
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| 8. |
- Rundquist, Sara, 1992-, et al.
(författare)
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Clinical effectiveness of golimumab in Crohn's disease : an observational study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG)
- 2018
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 53:10-11, s. 1257-1263
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The effectiveness of golimumab in Crohn's disease (CD) is largely unknown as it is not approved for the treatment of the disease. We aimed to identify the population of CD patients treated with golimumab in Sweden, to assess the effectiveness of golimumab (defined as the drug retention rate), and to identify predictors of drug discontinuation.METHODS: Patients with CD who received at least one injection of golimumab were identified through the Swedish National Quality Registry for Inflammatory Bowel Disease, which includes prospectively collected clinical information. Cox regression models were used to identify predictors of golimumab discontinuation.RESULTS: The study cohort involved 94 patients of whom the majority (96.8%) had previously discontinued at least one anti-tumour necrosis factor (anti-TNF) agent. The drug retention rate at 12 weeks was 85.1%. Predictors of golimumab discontinuation at 12 weeks were previous surgery (adjusted HR = 7.52, 95% CI: 1.12-50.36), concomitant corticosteroid use at baseline (adjusted HR = 5.70, 95% CI: 1.13-28.68) and female sex (adjusted HR = 6.59; 95% CI: 1.04-41.62). The median duration of follow-up was 89 (IQR: 32-158) weeks. The drug retention at the most recent follow-up was 35.1%. Predictors of golimumab discontinuation at the most recent follow-up were corticosteroid use at baseline (adjusted HR = 2.60, 95% CI: 1.17-5.79) and female sex (adjusted HR = 2.24; 95% CI: 1.19-4.23).CONCLUSION: Patients with CD treated with golimumab were a treatment-refractory group. Despite this, more than one-third of the patients appeared to have had clinical benefit after a median follow-up of more than 1.5 years.
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| 9. |
- Zenere, Alberto, 1992-, et al.
(författare)
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Multi-omics protein-coding units as massively parallel Bayesian networks : Empirical validation of causality structure
- 2022
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Ingår i: iScience. - : Cell press. - 2589-0042. ; 25:4
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Tidskriftsartikel (refereegranskat)abstract
- In this article we use high-throughput epigenomics, transcriptomics, and proteomics data to construct fine-graded models of the "protein-coding units"gathering all transcript isoforms and chromatin accessibility peaks associated with more than 4000 genes in humans. Each protein-coding unit has the structure of a directed acyclic graph (DAG) and can be represented as a Bayesian network. The factorization of the joint probability distribution induced by the DAGs imposes a number of conditional independence relationships among the variables forming a protein-coding unit, corresponding to the missing edges in the DAGs. We show that a large fraction of these conditional independencies are indeed verified by the data. Factors driving this verification appear to be the structural and functional annotation of the transcript isoforms, as well as a notion of structural balance (or frustration-free) of the corresponding sample correlation graph, which naturally leads to reduction of correlation (and hence to independence) upon conditioning.
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| 10. |
- Zenere, Alberto, et al.
(författare)
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Using high-throughput multi-omics data to investigate structural balance in elementary gene regulatory network motifs
- 2022
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Ingår i: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811. ; 38:1, s. 173-178
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: The simultaneous availability of ATAC-seq and RNA-seq experiments allows to obtain a more in-depth knowledge on the regulatory mechanisms occurring in gene regulatory networks. In this article, we highlight and analyze two novel aspects that leverage on the possibility of pairing RNA-seq and ATAC-seq data. Namely we investigate the causality of the relationships between transcription factors, chromatin and target genes and the internal consistency between the two omics, here measured in terms of structural balance in the sample correlations along elementary length-3 cycles. Results: We propose a framework that uses the a priori knowledge on the data to infer elementary causal regulatory motifs (namely chains and forks) in the network. It is based on the notions of conditional independence and partial correlation, and can be applied to both longitudinal and non-longitudinal data. Our analysis highlights a strong connection between the causal regulatory motifs that are selected by the data and the structural balance of the underlying sample correlation graphs: strikingly, >97% of the selected regulatory motifs belong to a balanced subgraph. This result shows that internal consistency, as measured by structural balance, is close to a necessary condition for 3-node regulatory motifs to satisfy causality rules.
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