| 1. |
- Andreasson, Ulrika, et al.
(författare)
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Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples.
- 2010
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 85:6, s. 418-425
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Tidskriftsartikel (refereegranskat)abstract
- Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment.
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| 2. |
- Carlsson, Anders, et al.
(författare)
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Molecular serum portraits in patients with primary breast cancer predict the development of distant metastases.
- 2011
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 108:34, s. 14252-14257
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Tidskriftsartikel (refereegranskat)abstract
- The risk of distant recurrence in breast cancer patients is difficult to assess with current clinical and histopathological parameters, and no validated serum biomarkers currently exist. Using a recently developed recombinant antibody microarray platform containing 135 antibodies against 65 mainly immunoregulatory proteins, we screened 240 sera from 64 patients with primary breast cancer. This unique longitudinal sample material was collected from each patient between 0 and 36 mo after the primary operation. The velocity for each serum protein was determined by comparing the samples collected at the primary operation and then 3-6 mo later. A 21-protein signature was identified, using leave-one-out cross-validation together with a backward elimination strategy in a training cohort. This signature was tested and evaluated subsequently in an independent test cohort (prevalidation). The risk of developing distant recurrence after primary operation could be assessed for each patient, using her molecular portraits. The results from this prevalidation study showed that patients could be classified into high- versus low-risk groups for developing metastatic breast cancer with a receiver operating characteristic area under the curve of 0.85. This risk assessment was not dependent on the type of adjuvant therapy received by the patients. Even more importantly, we demonstrated that this protein signature provided an added value compared with conventional clinical parameters. Consequently, we present here a candidate serum biomarker signature able to classify patients with primary breast cancer according to their risk of developing distant recurrence, with an accuracy outperforming current procedures.
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| 3. |
- Fend, Falko, et al.
(författare)
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Early lesions in lymphoid neoplasia : Conclusions based on the Workshop of the XV. Meeting of the European Association of Hematopathology and the Society of Hematopathology, in Uppsala, Sweden
- 2012
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Ingår i: Journal of hematopathology. - : Springer Science and Business Media LLC. - 1865-5785 .- 1868-9256. ; 5:3, s. 169-199
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Tidskriftsartikel (refereegranskat)abstract
- The increasing use of immunophenotypic and molecular techniques on lymphoid tissue samples without obvious involvement by malignant lymphoma has resulted in the increased detection of "early" lymphoid proliferations, which show some, but not all the criteria necessary for a diagnosis of malignant lymphoma. In most instances, these are incidental findings in asymptomatic individuals, and their biological behaviour is uncertain. In order to better characterize these premalignant conditions and to establish diagnostic criteria, a joint workshop of the European Association for Haematopathology and the Society of Hematopathology was held in Uppsala, Sweden, in September 2010. The panel reviewed and discussed more than 130 submitted cases and reached consensus diagnoses. Cases representing the nodal equivalent of monoclonal B-cell lymphocytosis (MBL) were discussed, as well as the "in situ" counterparts of follicular lymphoma (FL) and mantle cell lymphoma (MCL), topics that also stimulated discussions concerning the best terminology for these lesions. The workshop also addressed the borderland between reactive hyperplasia, and clonal proliferations such as pediatric marginal zone lymphoma and pediatric FL, which may have very limited capacity for progression. Virus-driven lymphoproliferations in the grey zone between reactive lesions and manifest malignant lymphoma were covered. Finally, early manifestations of T-cell lymphoma, both nodal and extranodal, and their mimics were addressed. This workshop report summarizes the most important conclusions concerning diagnostic features, as well as proposals for terminology and classification of early lymphoproliferations and tries to give some practical guidelines for diagnosis and reporting.
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| 4. |
- Gore, C., et al.
(författare)
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Treatment and secondary prevention effects of the probiotics Lactobacillus paracasei or Bifidobacterium lactis on early infant eczema : randomized controlled trial with follow-up until age 3 years
- 2012
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 42:1, s. 112-122
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Tidskriftsartikel (refereegranskat)abstract
- Background Allergic disease has been associated with altered intestinal microbiota. Therefore, probiotics have been suggested as a potential treatment for eczema. Objective We investigated whether dietary supplementation of infants with eczema at age 3-6 months with Lactobacillus paracasei CNCM I-2116 or Bifidobacterium lactis CNCM I3446 had a treatment effect or altered allergic disease progression. Methods Primary outcome included eczema severity (SCORing Atopic Dermatitis, SCORAD) 3 months post-randomization. Secondary: SCORAD (other visits); infant dermatitis quality of life (IDQoL); gastrointestinal permeability; urinary eosinophilic protein X; allergen- sensitization; allergic symptoms (age 12, 18, 36 months). A total of 208 infants aged 3-6 months with physician-diagnosed eczema were recruited; 137/208 (SCORAD >= 10, consuming >= 200 mL standard formula/day) were randomized to daily supplements containing L. paracasei or B. lactis or placebo for a 3-month period, while receiving extensively hydrolysed whey-formula (dairy-free diet). There were two open observational groups, one group exclusively breastfed (n = 22) and the other, standard formula-fed (n = 49). Trial number: ISRCTN41490500. Results Eczema severity decreased significantly over time in all groups. No significant difference was observed between randomized groups after 12-week treatment-period (SCORAD-score pre-/post-intervention: B. lactis 25.9 [95% CI: 22.8-29.2] to 12.8 [9.416.6]; L. paracasei 25.4 [22.1-29] to 12.5 [9.2-16.4]; placebo 26.9 [23.4-30.6] to 11.8 [9.6-14.3]; P = 0.7). Results were similar when analysis was controlled for allergen-sensitization, or when only sensitized infants were analysed. No differences were found for secondary outcomes. No difference was observed in SCORAD-score between randomized and observational groups. Conclusion and Clinical Relevance We found no benefit from supplementation with B. lactis or L. paracasei in the treatment of eczema, when given as an adjunct to basic topical treatment, and no effect on the progression of allergic disease from age 1 to 3 years.
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| 5. |
- Haglund, Sofie, et al.
(författare)
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The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease.
- 2011
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Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 33:2, s. 200-208
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities. RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001). CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.
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| 6. |
- Karawajczyk, Malgorzata, et al.
(författare)
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An Extragranular Compartment of Blood Eosinophils Contains Eosinophil Protein X/Eosinophil-Derived Neurotoxin (EPX/EDN)
- 2013
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Ingår i: Inflammation. - : Springer Science and Business Media LLC. - 0360-3997 .- 1573-2576. ; 36:2, s. 320-329
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Tidskriftsartikel (refereegranskat)abstract
- Serum and plasma profiles of eosinophil protein X (EPX/EDN) and those of other eosinophil proteins differ in various conditions, suggesting a different mobilisation from storage granules. This work studied the subcellular localisation of EPX/EDN in non-primed and in vivo primed blood eosinophils from healthy and allergic subjects, during and out of the pollen season. Primed eosinophils contain easily mobilisable secretory proteins. By fractionation on sucrose density gradients, EPX/EDN localised in the specific granules as well as in a cytoplasmic extra-granular compartment of low equilibrium density that partially overlapped with vesicular structures, cytosolic proteins and plasma membranes. This compartment was clearly separate from the low density peak of ECP that increases during the pollen season. There were no significant differences in the amounts of EPX/EDN present in the low density peak of healthy and allergic subjects. Immuno-gold labelling electron microscopy showed EPX/EDN in specific granules, cytoplasm and associated to plasma membranes. In conclusion, substantial amounts of EPX/EDN localise in an extra-granular, low equilibrium density compartment of human eosinophils.
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| 7. |
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| 8. |
- Wagner, Michael, 1957-, et al.
(författare)
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Fecal eosinophil cationic protein as a marker of active disease and treatment outcome in collagenous colitis : A pilot study
- 2011
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 46:7-8, s. 849-854
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims. Fecal calprotectin (FC) is used as a marker for intestinal inflammation in inflammatory bowel disease (IBD) but there is no reliable marker for collagenous colitis (CC). We have previously demonstrated that the mucosal inflammation in CC is characterized by eosinophil activation, which is restored during budesonide treatment, but there is no enhanced neutrophil activity. The aim of this study was to evaluate the use of fecal eosinophil cationic protein (F-ECP) and eosinophil protein X (F-EPX) compared with the neutrophil-derived myeloperoxidase (F-MPO) and FC in patients treated for active CC. Methods. Patients with active CC (n = 12) were studied before and after 3, 7, 28 and 56 days of budesonide treatment. Clinical symptoms and stool frequency were recorded, fecal samples were collected, and F-ECP, F-EPX, F-MPO and FC were measured at each occasion. Results. All but one patient achieved remission. On inclusion 92%, 67%, 67% and 75% of the patients had elevated F-ECP, F-EPX, F-MPO and FC levels, respectively. All markers decreased during the treatment, particularly F-ECP and F-EPX, which decreased after only 3 days. At the end of the study 100%, 92%, 83% and 75% of the patients had normal F-ECP, F-EPX, F-MPO and FC values, respectively. Conclusion. F-ECP demonstrated the best discriminating capacity in detecting active CC. A normalized F-ECP and F-EPX may further be studied as a marker for successful treatment. During budesonide treatment there is a rapid fall in F-ECP and F-EPX, accompanied by clinical improvement, indicating an essential role for the eosinophil participating in the pathophysiology of CC.
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| 9. |
- Wagner, Michael, et al.
(författare)
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Increased Fecal Levels of Chromogranin A, Chromogranin B and Secretoneurine in Collagenous Colitis
- 2013
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Ingår i: Inflammation. - : Springer Science and Business Media LLC. - 0360-3997 .- 1573-2576. ; 36:4, s. 855-861
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between the enteric nervous system and the immune system are suggested to play an important role in the pathophysiology of inflammatory bowel disease (IBD). This study aims to determine if chromogranin A (CgA), chromogranin B (CgB), and secretoneurin (SN) are detectable in feces (F) from patients with collagenous colitis (CC) and to compare the levels found in patients with ulcerative colitis (UC) and Crohn’s disease (CD) before and during treatment. Patients with CC (n = 12) were studied before and after 3, 7, 28, and 56 days of treatment. Patients with IBD (UC, n = 21; CD, n = 11) were studied before and after 28 and 56 days of treatment. Clinical data were recorded, and fecal samples were collected at each occasion. F-CgA, F-CgB, and F-SN were measured by RIA. Eleven patients with CC, 21 with UC, and 10 with CD achieved remission. On inclusion, CC patients had higher levels of F-CgA, F-CgB, and F-SN than patients with IBD and controls. Patients with IBD expressed markedly lower levels of F-SN than controls. During treatment, F-SN in CC patients decreased to control levels but remained low in IBD patients. No change was found in F-CgA or F-CgB in any of the groups. In conclusion, CgA, CgB, and SN are detectable in feces, and CC patients express higher values than patients with IBD and controls. During treatment, F-SN decreased to control levels in CC. These findings suggest that the enteric nervous system is clearly involved in the pathophysiology of CC.
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| 10. |
- Zhulina, Yaroslava, 1973-, et al.
(författare)
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Subclinical Inflammation with Increased Neutrophil Activity in Healthy Twin Siblings Reflect Environmental Influence in the Pathogenesis of Inflammatory Bowel Disease
- 2013
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Ingår i: Inflammatory Bowel Diseases. - Philadelphia, USA : Lippincott Williams & Wilkins. - 1078-0998 .- 1536-4844. ; 19:8, s. 1725-1731
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Tidskriftsartikel (refereegranskat)abstract
- Background: The mechanisms behind increased fecal calprotectin (FC) in healthy relatives of patients with inflammatory bowel disease (IBD) are unknown. Our aims were to explore if there is a subclinical inflammation with increased neutrophil activity in healthy twin siblings in discordant twin pairs with IBD and to assess the influence of genetics in this context.Methods: Nuclear factor kappa B (NF-B) and neutrophil activity, based on myeloperoxidase (MPO) and FC, were analyzed in healthy twin siblings in discordant twin pairs with IBD and compared with healthy controls. NF-B and MPO were assessed by immunohistochemistry and FC by enzyme-linked immunosorbent assay.Results: In total, 33 of 34 healthy twin siblings were histologically normal. Increased NF-B was more often observed in healthy twin siblings in discordant twin pairs with Crohn's disease (13/18 [73%]) and with ulcerative colitis (12/16 [75%]) than in healthy controls (8/45 [18%]). MPO was more often increased in healthy twin siblings in discordant pairs with Crohn's disease (12/18 [67%]) than in healthy controls (11/45 [24%]) and FC more often in healthy twin siblings in discordant pairs with ulcerative colitis (14/21 [67%]) than in healthy controls (6/31 [19%]). Interestingly, the observed differences remained when healthy monozygotic and dizygotic twin siblings were analyzed separately.Conclusions:We observed increased NF-B, MPO, and FC in healthy twins in both monozygotic and dizygotic discordant pairs with IBD. These novel findings speak for an ongoing subclinical inflammation with increased neutrophil activity in healthy first-degree relatives.
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