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  • 1
    Keywords: TUMOR-SUPPRESSOR GENE ; MASS-SPECTROMETRY ; DISEASE PROGRESSION ; histone modifications ; DNA METHYLATION PATTERNS ; RISK MYELODYSPLASTIC SYNDROMES ; PLURIPOTENT STEM-CELLS ; METHYLTRANSFERASE GENE EZH2 ; CONVENTIONAL CARE REGIMENS ; H3K79 METHYLATION
    Abstract: Research over the past decade has confirmed that epigenetic alterations act in concert with genetic lesions to deregulate gene expression in acute myeloid leukemia and myelodysplastic syndromes. Epigenetic alterations may serve as markers of disease, and may potentially be used for classification, prognostication and to monitor minimal residual disease. In addition, we now have the capability to pharmaceutically target epigenetic modifications, and there is an urgent need for early validation of the efficacy of the drugs. Also, an improved understanding of the functionality of epigenetic modifications may further pave the road towards individualized therapy. The recent advances in biotechnology and bioinformatics provide a plethora of novel tools for characterizing the epigenome in clinical samples, but at this point the practical, clinical utility of these methodologies needs further exploration. Here, we provide the pros and cons of the currently most feasible methods used for characterizing the methylome in clinical samples, and give a brief introduction to novel approaches to sequencing that may revolutionize our abilities to characterize the genomes and epigenomes in acute myeloid leukemia and myelodysplastic syndrome patients.
    Type of Publication: Journal article published
    PubMed ID: 22491733
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  • 2
    Abstract: We recently reported a truncating deletion in the NFKBIE gene, which encodes IkappaB, a negative feedback regulator of NF-kappaB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (〈2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIE aberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-kappaB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.
    Type of Publication: Journal article published
    PubMed ID: 27670424
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  • 3
    ISSN: 1432-1041
    Keywords: Zinc supplementation ; Antipyrine clearance ; Liver cirrhosis ; alcoholic liver disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Methods: The effect of zinc supplementation on antipyrine clearance was evaluated in 14 outpatients with stable alcoholic liver disease, of whom nine had biopsy proven alcoholic cirrhosis. Results: There was no change in antipyrine clearance after 14 days of zinc supplementation (median 12.5 vs 12.9 ml · min−1). However, a significant increase in P-prothrombin-proconvertin was found. There was a positive correlation between S-zinc and antipyrine clearance at inclusion (rs=0.76) as well as after zinc supplementation (rs=0.72). Conclusion: No effect of zinc supplementation on antipyrine clearance was found. The positive correlation between S-zinc and antipyrine clearance could be due to the confounding effect of alcoholic liver disease.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1041
    Keywords: Key words Zinc supplementation ; Antipyrine clearance ; Liver cirrhosis; alcoholic liver disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Methods: The effect of zinc supplementation on antipyrine clearance was evaluated in 14 out-patients with stable alcoholic liver disease, of whom nine had biopsy proven alcoholic cirrhosis. Results: There was no change in antipyrine clearance after 14 days of zinc supplementation (median 12.5 vs 12.9 ml ⋅ min−1). However, a significant increase in P-prothrombin-proconvertin was found. There was a positive correlation between S-zinc and antipyrine clearance at inclusion (rs = 0.76) as well as after zinc supplementation (rs = 0.72). Conclusion: No effect of zinc supplementation on antipyrine clearance was found. The positive correlation between S-zinc and antipyrine clearance could be due to the confounding effect of alcoholic liver disease.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The clinical, histological, phenotypic and genotypic features of 21 primary cutaneous B-cell lymphomas (CBCLs) have been investigated. The patients were 13 men and eight women aged 34–91 years (median 67) at diagnosis. Eighteen patients had localized disease, and three had multiple skin lesions at diagnosis. Twelve patients developed cutaneous or extracutaneous recurrences, and five died from malignant lymphoma 7–84 months (median 36) after diagnosis. Histological examination showed features of marginal zone/mucosa-associated lymphoid tissue (MALT)-type lymphoma in 12 cases. Three of these had transformed to diffuse large B-cell lymphoma (DLBCL) in relapse biopsies. The remaining cases were seven primary DLBCLs and two cases tentatively classified as follicle centre cell (FCC) lymphoma. The neoplastic B cells showed similar phenotypes and genotypes in most cases (CD20+, CD79+, CD5–, CD10–, cyclin D1–, bcl-2+, bcl-x–, bax–, t(14;18)-negative). p53 protein was expressed in five cases, and four harboured mis-sense or loss-of-function mutations in the p53 gene. Deletion or promoter region hypermethylation of the p16INK4a gene was detected in two patients with DLBCL. The level of retinoblastoma protein expression and the proliferative fraction were significantly higher in DLBCL (〉 50%) than in MALT- or FCC-type lymphomas (〈 10%). Features associated with an unfavourable prognosis were the presence of multiple skin lesions at diagnosis, transformation from MALT-type lymphoma to DLBCL, and possibly p16INK4a aberrations. It is concluded that most CBCLs are dissimilar from FCC lymphomas and seem to be more closely related to marginal zone/MALT-type lymphomas. It is also suggested that there are fundamental differences between DLBCL and other histological categories of CBCL, indicating that cutaneous DLBCL is a separate entity with an increased growth potential and genetic features similar to DLBCL originating in other anatomical sites.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    ISSN: 0020-7373
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Computer Science
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Introduction : Azathioprine is effective for maintenance of remission in Crohn's disease, however, duration of efficacy and the dose response relationship has not been fully evaluated.Aims : To investigate whether patients kept in remission by azathioprine treatment for 〉2 years benefit from further treatment, and to explore dose–response relationship.Patients and methods : In an open 12-month trial, patients with inactive Crohn's disease after 〉2 years (median 37 months) of azathioprine treatment were randomized to azathioprine withdrawal or continued treatment. Primary end point was relapse defined as: (i) Crohn's disease activity index rise ≥ 75, and Crohn's disease activity index 〉150 or (ii) disease activity requiring intervention.Results : Of 29 patients, 28 completed the observation period or relapsed. Eleven of 13 patients (85%) continuing azathioprine remained in remission compared with seven of 15 (47%) observed without azathioprine (P = 0.043). In patients who had been treated with azathioprine 〉1.60 mg/kg/day the difference was even more pronounced, eight of nine (89%) vs. four of 12 (33%) respectively (P = 0.017).Conclusions : Patients with Crohn's disease in remission after 〉2 years of continuous azathioprine treatment will benefit from further continued treatment. Further controlled studies with azathioprine doses 〈2.0 mg/kg/day are needed.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary  The clinical, histological, phenotypic and genotypic features of a lymphoblastoid natural killer (NK)-cell lymphoma presenting in the skin in a young caucasian woman are described. The disease behaved aggressively, but long-lasting remission was obtained by combination chemotherapy followed by autologous bone marrow transplantation. The blastoid cells were positive for terminal deoxynucleotidyl transferase, CD34, CD56 and CD4. Furthermore, the NK-cell receptor complex CD94/NKG2 was strongly expressed, as shown by examination with reverse transcription–polymerase chain reaction. The T-cell receptor (TCR)-γ genes were in germline, and with the exception of CD4 all T-cell antigens were negative, including CD3, TCR-β, TCR-δ, TIA-1, granzyme B and perforin. Epstein–Barr virus was negative, and no expression was seen of myeloid cell-associated markers. Molecular analysis showed no abnormalities of the CDKN2A (p16), CDKN2B (p15) or TNFRSF6 (Fas) genes. By contrast, a 34-bp deletion in exon 7 of the TP53 (p53) gene was detected. It is suggested that lymphoblastoid NK-cell lymphoma, which is a rare but distinctive disease, originates from NK cell precursors and may be associated with and possibly caused by alterations in the TP53 gene. Experience is too limited to warrant therapeutic suggestions. However, stem cell transplantation may be a useful option in younger patients.
    Type of Medium: Electronic Resource
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