| 1. |
- Ling Lundström, Maria, et al.
(author)
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Faecal biomarkers for diagnosis and prediction of disease course in treatment-naïve patients with IBD.
- 2024
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In: Alimentary Pharmacology and Therapeutics. - 0269-2813 .- 1365-2036.
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Journal article (peer-reviewed)abstract
- BACKGROUND: Faecal biomarkers can be used to assess inflammatory bowel disease (IBD).AIM: To explore the performance of some promising biomarkers in diagnosing and predicting disease course in IBD.METHODS: We included 65 patients with treatment-naïve, new-onset Crohn's disease (CD), 90 with ulcerative colitis (UC), 67 symptomatic controls (SC) and 41 healthy controls (HC) in this prospective observational study. We analysed faecal samples for calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein ECP and eosinophil-derived neurotoxin (EDN) and compared markers among groups. We assessed the diagnostic capability of biomarkers with receiver operating characteristic curves. Clinical disease course was determined for each patient with IBD and analysed the association with biomarkers by logistic regression.RESULTS: All markers were elevated at inclusion in patients with IBD compared with HC (p < 0.001) and SC (p < 0.001). FC (AUC 0.85, 95% CI: 0.79-0.89) and MPO (AUC 0.85, 95% CI: 0.80-0.89) showed the highest diagnostic accuracy in distinguishing IBD from SC. The diagnostic ability of biomarkers differed between IBD subtypes with the highest performance for FC and MPO in CD. The diagnostic accuracy was further improved by combining FC and MPO (p = 0.02). Levels of FC, MPO and HNL at inclusion were predictive of an aggressive disease course with MPO showing the strongest association (p = 0.006).CONCLUSIONS: This study provides new insight into the diagnostic and prognostic capability of neutrophil and eosinophil biomarkers in IBD and suggests that MPO, alone or in combination with FC, may add to the diagnostic power of faecal biomarkers.
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| 2. |
- Ling Lundström, Maria, et al.
(author)
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Fecal Biomarkers of Neutrophil and Eosinophil Origin Reflect the Response to Biological Therapy and Corticosteroids in Patients With Inflammatory Bowel Disease
- 2023
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In: Clinical and Translational Gastroenterology. - : Nature Publishing Group. - 2155-384X. ; 14:8
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Journal article (peer-reviewed)abstract
- Introduction: Fecal calprotectin (FC) is anoninvasive tool for examining response to biologics in inflammatory boweldisease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown.Methods: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated.Results: In patients achieving clinical remission (n = 27), a decrease in levels of FC (P = 0.005), MPO (P < 0.001), HNL (P < 0.001), and EDN (P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO (P = 0.01) and HNL (P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (P = 0.01) and EDN (P < 0.001) at baseline, compared with patients without corticosteroids.Discussion: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO.
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| 3. |
- Moraes Holst, Luiza, et al.
(author)
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Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis
- 2022
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In: Clinical and Experimental Gastroenterology. - : DOVE MEDICAL PRESS LTD. - 1178-7023. ; 15, s. 129-144
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Journal article (peer-reviewed)abstract
- Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn's disease (CD active).Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways.Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed.Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.
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| 4. |
- Ling Lundström, Maria, et al.
(author)
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The utility of faecal biomarkers in the discrimination between acute gastroenteritis and inflammatory bowel diseases
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Other publication (other academic/artistic)abstract
- Background: Inflammatory bowel disease (IBD) and acute infectious gastroenteritis (GE) may have similar clinical characteristics at onset, and discrimination between these two diagnoses can initially be challenging. We aimed to explore faecal biomarkers reflecting neutrophil, eosinophil, and epithelial activity to distinguish between IBD onset and acute GE. Material and method: Faecal samples were collected from patients presenting with acute GE (n=28), treatment-naïve patients with newly onset IBD (n=40), and healthy controls, HC (n=40). Faecal biomarkers including faecal calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL) 763/764, eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) were assessed by ELISA. The Kruskal-Wallis test was used for biomarker comparison. To evaluate the discriminative capability of biomarkers, receiver operating curves (ROC) were established. Result: Patients with acute GE displayed elevated levels of all the tested biomarkers compared with HC (p<0.001). Higher levels of faecal HNL (p<0.001), EDN (p<0.01) and MPO (p<0.05) were seen in acute GE patients than in patients with new onset IBD. The highest discriminative capability between acute GE and IBD was yielded by HNL with AUC 0.74, 95%CI: 0.62-0.84. Subgrouping patients with GE based on the infectious aetiology did not reveal differences in biomarker levels between groups. Conclusion: This overview suggests faecal HNL as a biomarker to differentiate acute GE from new-onset IBD and proposes that infectious GE can be detected by markers that reflect epithelial cell damage. However, although biomarkers may guide the clinician, clinical judgment is still crucial in making a final diagnosis for these patients.
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| 7. |
- Salihovic, Samira, Associate Senior Lecturer, 1985-, et al.
(author)
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Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making.
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| 8. |
- Salihovic, Samira, Associate Senior Lecturer, 1985-, et al.
(author)
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Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease
- 2024
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In: Nature Communications. - : NATURE PORTFOLIO. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-na & iuml;ve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making. Diagnostic blood-based biomarkers of pediatric IBD are limited. Here, the authors demonstrate a diagnostic lipidomic signature, comprising only of two molecular lipids. Translation of this signature into a scalable test has the potential to support clinical decision making.
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| 9. |
- Carlson, Lena-Maria, et al.
(author)
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Differentiation induced by physiological and pharmacological stimuli leads to increased antigenicity of human neuroblastoma cells
- 2008
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In: Cell Research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 18:3, s. 398-411
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Journal article (peer-reviewed)abstract
- Sympathetic neuronal differentiation is associated with favorable prognosis of neuroblastoma (NB), the most common extra-cranial solid tumor of early childhood. Differentiation agents have proved useful in clinical protocols of NB treatment, but using them as a sole treatment is not sufficient to induce tumor elimination in patients. Therefore, complementary approaches, such as immunotherapy, are warranted. Here we demonstrate that differentiation of NB cell lines and ex vivo isolated tumor cells in response to physiological or pharmacological stimuli is associated with acquisition of increased antigenicity. This manifests as increased expression of surface major histocompatibility class I complexes and ICAM-1 molecules and translates into increased sensitivity of NB cells to lysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The latter is paralleled by enhanced ability of differentiated cells to form immune conjugates and bind increased amounts of granzyme B to the cell surface. We demonstrate, for the first time, that, regardless of the stimulus applied, the differentiation state in NBs is associated with increased tumor antigenicity that enables more efficient elimination of tumor cells by cytotoxic lymphocytes and paves the way for combined application of differentiation-inducing agents and immunotherapy as an auxiliary approach in NB patients.
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| 10. |
- Carlson, Lena-Maria
(author)
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Interactions between neuroblastoma and the immune system : cellular pathways and mediators
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Neuroblastoma (NB) is an embryonal tumor of early childhood arising in tissues of the sympathetic nervous system, such as the adrenal gland and paraspinal ganglia. It is the most common extra-cranial solid tumor of childhood, and 10-20 children are diagnosed with NB each year in Sweden. The overall survival rate is about 70%, but 50% of the children in the high-risk group succumb in spite of intense multimodal therapy. This warrants the search for alternative treatment strategies. One upcoming treatment option is immunotherapy, which represents a specific treatment modality with the possibility of minimizing long-term side effects in survivors. Cellular therapies for NB have previously been discouraged due to the notion that NB is a tumor of low immunogenicity. This thesis demonstrates that differentiating agents alter the immune phenotype of primary NB tumors and cell lines such as to enhance the expression of classical HLA molecules and the adhesion molecule ICAM-1. This was paralleled by an increased ability of differentiated NB cells to bind granzyme B at the cell surface and translated into enhanced killing by natural killer (NK) cells and T-cells. These results argue in favor of differentiation and cellular immunotherapy as a combined auxiliary approach for NB patients (paper I). Furthermore, the work presented in this thesis demonstrates that tumor-non-specific activated cytotoxic T lymphocytes (CTLs) release effector molecules which facilitate immune-mediated recognition of NB. Effector molecules from CTLs upregulated HLA class I, ICAM-1 and Fas at the cell surface and restored the expression and activity of caspase-8 in primary NB tumors and cell lines. This rendered NB cells more susceptible to death receptor-mediated killing (paper II). This thesis also demonstrates that primary human NB samples, representing all genetical subtypes, harbor tumor-infiltrating T-cells which proliferate in situ. Tumor-infiltrating lymphocytes were preferentially CD8+, expressed high levels of the activation marker CD25 and exhibited a phenotype of memory cells. Autologous peripheral blood lymphocytes were exposed to tumor cells in vitro and their production of IFN-γ and TNF-α was increased, while an activated phenotype was obtained. This indicates that human NB cells do not prevent the generation of active T-cell responses (paper III). In the transgenic TH-MYCN mouse model of NB, tumor-associated inflammation was investigated and NB tumor progression was shown to be paralleled by a gradual suppression of intratumoral T-cell responses in favor of immature cells of the innate immune system. Anti-inflammatory treatment with low-dose aspirin displayed a promising efficacy in delaying tumor outgrowth with a concomitant abrogation of an inflammatory switch (paper IV). Taken together, the work presented in this thesis demonstrates that NB can serve as a proper target for cellular immunotherapy. It argues for an early implementation of immunotherapy in clinical protocols, where differentiating agents and/or the attraction of activated CTLs to the NB microenvironment could enhance immune-mediated tumor recognition.
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