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1.
Scand J Rheumatol ; 53(2): 94-103, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38031733

ABSTRACT

OBJECTIVE: While considerable focus has been placed on pain due to inflammation in psoriatic arthritis (PsA), less is reported on pain despite inflammation control. Here, we aimed to investigate the occurrence/predictors of persistent pain, including non-inflammatory components, after starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Bionaïve PsA patients starting a first anti-TNF therapy 2004-2010 were identified (South Swedish Arthritis Treatment Group register; N = 351). Outcomes included unacceptable pain [visual analogue scale (VAS) pain > 40 mm], and unacceptable pain despite inflammation control (refractory pain; VAS pain > 40 mm + C-reactive protein < 10 mg/L + ≤ 1 swollen joint of 28), assessed at 0, 3, 6, and 12 months. Baseline predictors were estimated by logistic regression. RESULTS: Upon starting anti-TNF therapy, 85% of patients reported unacceptable pain, falling to 43% at 3 months and then remaining stable. After 12 months, refractory pain constituted 63% of all unacceptable pain. Higher baseline VAS pain/global, worse physical function and lower health-related quality-of-life were associated with a higher risk of unacceptable/refractory pain at 12 months. More swollen joints and higher evaluator's global assessment were associated with a lower risk of 12-month refractory pain. CONCLUSIONS: A substantial proportion of PsA patients reported unacceptable pain throughout the first anti-TNF treatment year. At 12 months, refractory pain constituted about two-thirds of this remaining pain load. More objective signs of inflammation at anti-TNF initiation were associated with less future refractory pain. This highlights insufficient effect of biologics in patients with inflammation-independent pain, warranting alternative treatments.


Subject(s)
Antirheumatic Agents , Arthritis, Psoriatic , Pain, Intractable , Humans , Arthritis, Psoriatic/complications , Antirheumatic Agents/therapeutic use , Pain, Intractable/chemically induced , Pain, Intractable/complications , Pain, Intractable/drug therapy , Tumor Necrosis Factor Inhibitors/therapeutic use , Treatment Outcome , Tumor Necrosis Factor-alpha , Inflammation/drug therapy , Necrosis/chemically induced , Necrosis/complications , Necrosis/drug therapy , Severity of Illness Index
2.
Eur J Pain ; 24(3): 649-658, 2020 03.
Article in English | MEDLINE | ID: mdl-31797468

ABSTRACT

BACKGROUND: Pain is a common complaint presented in healthcare, but most epidemiological pain research has focused either on single pain conditions or on the adult population. The aim of this study was to investigate the 2017 consultation prevalence of a wide range of pain conditions in the general population of young people. METHODS: We used the Skåne Healthcare Register, covering prospectively collected data on all healthcare delivered (primary and secondary care) to the population in the region of Skåne, southern Sweden (population 2017 n = 1,344,689). For individuals aged 1-24 in 2017 (n = 373,178), we calculated the consultation prevalence, stratified by sex and age, and the standardised morbidity ratio (SMR) to assess overall healthcare consultation. RESULTS: A total of 58,981 (15.8%) individuals consulted at least once for any of the predefined pain conditions. Of these, 13.5% (n = 7,996) consulted four or more times for pain. Abdominal pain, joint pain/myalgia, headache and back/neck pain were the most common complaints. Overall, females had higher consultation prevalence than males: 17.6% versus 14.1% (p < .0001). SMR was 1.82 (95% CI = 1.74-1.87) for females with pain and 1.51 (95% CI = 1.42-1.56) for males with pain. Consultation prevalence increased with age, but this pattern varied between sex and pain condition. CONCLUSIONS: Among individuals under the age of 25, a significant proportion consult for pain already in early ages, and they also have high healthcare consultation rates for conditions other than pain. The even higher consultation rates among young females need additional attention, both in the clinic and in research. SIGNIFICANCE: We present comprehensive 1-year healthcare consultation prevalence data covering all levels of care. A significant proportion of children, adolescents and young adults consult for different pain conditions at multiple occasions warranting greater clinical awareness.


Subject(s)
Referral and Consultation , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Morbidity , Prevalence , Sex Factors , Sweden/epidemiology , Young Adult
3.
Ann Rheum Dis ; 76(7): 1245-1252, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28073801

ABSTRACT

OBJECTIVES: To examine predictors of work ability gain and loss after anti-tumour necrosis factor (TNF) start, respectively, in working-age patients with rheumatoid arthritis (RA) with a special focus on disease duration. METHODS: Patients with RA, aged 19-62 years, starting their first TNF inhibitor 2006-2009 with full work ability (0 sick leave/disability pension days during 3 months before bio-start; n=1048) or no work ability (90 days; n=753) were identified in the Swedish biologics register (Anti-Rheumatic Treatment In Sweden, ARTIS) and sick leave/disability pension days retrieved from the Social Insurance Agency. Outcome was defined as work ability gain ≥50% for patients without work ability at bio-start and work ability loss ≥50% for patients with full work ability, and survival analyses conducted. Baseline predictors including disease duration, age, sex, education level, employment, Health Assessment Questionnaire, Disease Activity Score 28 and relevant comorbidities were estimated using Cox regression. RESULTS: During 3 years after anti-TNF start, the probability of regaining work ability for totally work-disabled patients was 35% for those with disease duration <5 years and 14% for disease duration ≥5 years (adjusted HR 2.1 (95% CI 1.4 to 3.2)). For patients with full work ability at bio-start, disease duration did not predict work ability loss. Baseline disability pension was also a strong predictor of work ability gain after treatment start. CONCLUSIONS: A substantial proportion of work-disabled patients with RA who start anti-TNF therapy regain work ability. Those initiating treatment within 5 years of symptom onset have a more than doubled 3-year probability of regaining work ability compared with later treatment starts. This effect seems largely due to the impact of disease duration on disability pension status.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Registries , Return to Work/statistics & numerical data , Sick Leave/statistics & numerical data , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Arthritis, Rheumatoid/physiopathology , Female , Humans , Male , Middle Aged , Pensions , Proportional Hazards Models , Sweden , Young Adult
4.
J Dairy Sci ; 99(4): 2940-2944, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26830735

ABSTRACT

Despite the increasing knowledge of prevention and control strategies, bovine mastitis remains one of the most challenging diseases in the dairy industry. This study investigated the antimicrobial activity of 13 species of lactic acid bacteria (LAB), previously isolated from the honey crop of the honeybee, on several mastitis pathogens. The viable LAB were first reintroduced into a sterilized heather honey matrix. More than 20 different bovine mastitis isolates were tested against the mixture of the 13 LAB species in the honey medium using a dual-culture overlay assay. The mastitis isolates were identified through bacteriological culturing, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Additionally, the mastitis isolates were subjected to antimicrobial susceptibility testing through disk diffusion. Growth of all tested mastitis pathogens, including the ones displaying antimicrobial resistance to one or more antimicrobial compounds, were inhibited to some extent by the honey and LAB combination. The antibacterial effect of these LAB opens up new perspectives on alternative treatment and prevention of bovine mastitis.


Subject(s)
Antibiosis , Bacterial Physiological Phenomena , Bees/microbiology , Bifidobacterium/physiology , Honey/microbiology , Lactobacillus/physiology , Mastitis, Bovine/prevention & control , Animals , Anti-Bacterial Agents/therapeutic use , Bacteria/isolation & purification , Cattle , Female , Mastitis, Bovine/microbiology , Mastitis, Bovine/therapy
5.
Leukemia ; 27(7): 1520-6, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23328954

ABSTRACT

Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38-) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P=0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P=0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.


Subject(s)
Benzamides/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Neoplastic Stem Cells/pathology , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Adult , Aged , Antineoplastic Agents/therapeutic use , Dasatinib , Female , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Middle Aged , Pilot Projects , Predictive Value of Tests , Prognosis , Protein Kinase Inhibitors/therapeutic use , Treatment Outcome
6.
Br J Cancer ; 104(11): 1747-54, 2011 May 24.
Article in English | MEDLINE | ID: mdl-21559010

ABSTRACT

BACKGROUND: The clinical course of World Health Organisation grade II gliomas remains variable and their time point of transformation into a more malignant phenotype is unpredictable. Identification of biological markers that can predict prognosis in individual patients is of great clinical value. PROX1 is a transcription factor that has a critical role in the development of various organs. PROX1 has been ascribed both oncogenic and tumour suppressive functions in human cancers. We have recently shown that PROX1 may act as a diagnostic marker for high-grade gliomas. The aim of this study was to address the prognostic value of PROX1 in grade II gliomas. METHODS: A total of 116 samples were evaluated for the presence of PROX1 protein. The number of immunopositive cells was used as a variable in survival analysis, together with established prognostic factors for this patient group. RESULTS: Higher PROX1 protein was associated with poor outcome. In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours. CONCLUSION: PROX1 is a novel predictor of survival for grade II gliomas.


Subject(s)
Brain Neoplasms/diagnosis , Glioma/diagnosis , Homeodomain Proteins/metabolism , Isocitrate Dehydrogenase/analysis , Isocitrate Dehydrogenase/genetics , Tumor Suppressor Proteins/metabolism , Adult , Biomarkers, Tumor/analysis , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Female , Glioma/mortality , Glioma/pathology , Humans , Loss of Heterozygosity , Male , Middle Aged , Mutation , Prognosis , Survival Analysis
7.
Leukemia ; 24(5): 992-1000, 2010 May.
Article in English | MEDLINE | ID: mdl-20237505

ABSTRACT

Wilms' tumor gene 1 (WT1) is a transcription factor involved in developmental processes. In adult hematopoiesis, only a small portion of early progenitor cells express WT1, whereas most leukemias show persistently high levels, suggesting an oncogenic role. We have previously characterized oncogenic BCR/ABL1 tyrosine kinase signaling pathways for increased WT1 expression. In this study, we show that overexpression of BCR/ABL1 in CD34+ progenitor cells leads to reduced expression of interferon regulatory factor 8 (IRF8), in addition to increased WT1 expression. Interestingly, IRF8 is known as a tumor suppressor in some leukemias and we investigated whether WT1 might repress IRF8 expression. When analyzed in four leukemia mRNA expression data sets, WT1 and IRF8 were anticorrelated. Upon overexpression in CD34+ progenitors, as well as in U937 cells, WT1 strongly downregulated IRF8 expression. All four major WT1 splice variants induced repression, but not the zinc-finger-deleted WT1 mutant, indicating dependence on DNA binding. A reporter construct with the IRF8 promoter was repressed by WT1, dependent on a putative WT1-response element. Binding of WT1 to the IRF8 promoter was demonstrated by chromatin immunoprecipitation. Our results identify IRF8 as a direct target gene for WT1 and provide a possible mechanism for oncogenic effects of WT1 in leukemia.


Subject(s)
Gene Expression Regulation, Neoplastic , Hematopoietic Stem Cells/physiology , Interferon Regulatory Factors/genetics , Leukemia/genetics , WT1 Proteins/metabolism , Antigens, CD34/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Blotting, Western , Chromatin Immunoprecipitation , DNA Methylation , Down-Regulation , Fetal Blood , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Gene Expression Profiling , Genes, Tumor Suppressor , Humans , Interferon Regulatory Factors/antagonists & inhibitors , Interferon Regulatory Factors/metabolism , Leukemia/metabolism , Mutagenesis, Site-Directed , Mutation/genetics , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Response Elements/physiology , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , U937 Cells , WT1 Proteins/genetics
8.
Oncogene ; 28(23): 2266-75, 2009 Jun 11.
Article in English | MEDLINE | ID: mdl-19421151

ABSTRACT

Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2',3'-cyclic nucleotide 3'-phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.


Subject(s)
Glioma/pathology , Neoplasms, Experimental/pathology , Oligodendroglia/cytology , Stem Cells/cytology , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase , Animals , Avian Proteins/genetics , Cell Proliferation/drug effects , Cells, Cultured , Chickens , Genetic Vectors/genetics , Glioma/genetics , Glioma/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Immunohistochemistry , Mice , Mice, Transgenic , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Oligodendroglia/metabolism , Phosphoric Diester Hydrolases/metabolism , Platelet-Derived Growth Factor/genetics , Platelet-Derived Growth Factor/metabolism , Platelet-Derived Growth Factor/pharmacology , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Receptors, Virus/genetics , Stem Cells/metabolism , Transfection , Vimentin/metabolism , ras Proteins/genetics , ras Proteins/metabolism
9.
Int J Food Microbiol ; 118(3): 233-40, 2007 Sep 30.
Article in English | MEDLINE | ID: mdl-17765348

ABSTRACT

The composition of the dominating population of freshly cut beef, and beef stored at 4 degrees C for 8 d, was studied by direct analysis of the 16S rRNA gene (PCR amplification, cloning and sequencing) and compared with pure culture technique where the isolates picked from the viable plate count were identified by sequencing of the 16S rRNA gene. The composition of the bacterial population was recorded at two different time points, at the start when the viable plate count of the meat was 4 x 10(2) colony forming unit (cfu) per cm(2) and when it was 5 x 10(7) cfu per cm(2). Direct gene analysis by PCR amplification generated 30 clones, and 79 isolates were picked from the plate count, and identified by 16S rRNA gene sequencing. At the low initial bacterial load of the beef, the two sampling strategies showed variations in the composition of species. Direct 16S rRNA gene analysis revealed a domination of Bacillus-like sequences while no such sequences were found in isolates from the viable plate count. Instead the population of the plate count was dominated by Chryseobacterium spp. In contrast, the two sampling strategies matched on the multiplying beef population, where both methods indicated Pseudomonas spp. as the dominating group (99% of the population-sequences), irrespectively of sampling strategy. Pseudomonas panacis/Pseudomons brennerii was the dominating taxon (99% similarity to type strain), but sequences with highest similarity to Pseudomonas lundensis (99%), Pseudomonas beteli (99%) and Pseudomonas koreensis (100%) were also found.


Subject(s)
Chryseobacterium/isolation & purification , Food Contamination/analysis , Meat/microbiology , Pseudomonas/isolation & purification , Refrigeration , Animals , Cattle , Chryseobacterium/growth & development , Colony Count, Microbial/methods , DNA, Bacterial/analysis , DNA, Ribosomal/analysis , Food Microbiology , Gene Amplification , Humans , Polymerase Chain Reaction/methods , Pseudomonas/growth & development , RNA, Bacterial/analysis , RNA, Ribosomal, 16S/chemistry , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Species Specificity
10.
Leukemia ; 21(12): 2485-94, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17728783

ABSTRACT

The Wilms' tumour gene 1 (WT1) protein is highly expressed in most leukaemias. Co-expression of WT1 and the fusion protein AML1-ETO in mice rapidly induces acute myeloid leukaemia (AML). Mechanisms behind expression of WT1, as well as consequences thereof, are still unclear. Here, we report that the fusion protein BCR/ABL1 increases expression of WT1 mRNA and protein via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway. Inhibition of BCR/ABL1 or PI3K activity strongly suppressed transcription from WT1 promoter/enhancer reporters. Forced expression of BCR/ABL1 in normal human progenitor CD34+ cells increased WT1 mRNA and protein, further supporting the notion of BCR/ABL1-driven expression of WT1 in human haematopoietic cells. Forced expression of WT1 in K562 cells provided protection against cytotoxic effects of the ABL1 tyrosine kinase inhibitor imatinib, as judged by effects on viability measured by trypan blue exclusion, metabolic activity, annexin V and DAPI (4', 6-diamidino-2-phenylindole) staining. None of the isoforms provided any detectable protection against apoptosis induced by arsenic trioxide and only very weak protection against etoposide, indicating that WT1 interferes with specific apoptotic signalling pathways. Our data demonstrate that WT1 expression is induced by oncogenic signalling from BCR/ABL1 and that WT1 contributes to resistance against apoptosis induced by imatinib.


Subject(s)
Drug Resistance, Neoplasm/genetics , Fusion Proteins, bcr-abl/physiology , Genes, Wilms Tumor , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Neoplasm Proteins/physiology , Piperazines/pharmacology , Pyrimidines/pharmacology , WT1 Proteins/physiology , Apoptosis/drug effects , Benzamides , Cell Line, Tumor/drug effects , Cell Line, Tumor/metabolism , Cells, Cultured/drug effects , Cells, Cultured/metabolism , Chromones/pharmacology , Etoposide/pharmacology , Fusion Proteins, bcr-abl/antagonists & inhibitors , Gene Expression Regulation, Leukemic , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Imatinib Mesylate , Inositol/analogs & derivatives , Inositol/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Morpholines/pharmacology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Phosphatidylinositol 3-Kinases/physiology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/physiology , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Recombinant Fusion Proteins/physiology , Signal Transduction/drug effects , Transduction, Genetic , WT1 Proteins/biosynthesis
11.
J Appl Microbiol ; 103(1): 109-19, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17584457

ABSTRACT

AIMS: The indigenous flora of freshly chilled cold-smoked salmon just after the vacuum packaging, and the spoilage flora after storage, in vacuum package at 7 degrees C for 19 days, were to be investigated with two different sampling strategies. METHODS AND RESULTS: Identification was performed using 16S rRNA sequencing of both isolated bacteria and bacterial DNA from tissue extract. The indigenous flora of fresh cold-smoked vacuum-packed salmon was dominated by, in order, Brochothrix thermosphacta, Yersinia ruckeri, Photobacterium and Carnobacterium, whereas the spoilage flora of the same product stored at 7 degrees C for 19 days was dominated by Lactobacillus and Photobacterium. The two sampling strategies showed similar results on the fish flora. Several new types of Photobacterium sequences, closely related to Photobacterium iliopiscarium and Photobacterium phosphoreum, were found from both the freshly processed and the stored salmon, indicating that smoked salmon harbours at least three different, as yet unknown, Photobacterium species. CONCLUSIONS: Ten per cent of the bacterial flora multiplying on chilled, vacuum-packed, cold-smoked salmon comprised unknown species. The two sampling strategies complement each other. SIGNIFICANCE AND IMPACT OF THE STUDY: As cold-smoked salmon is consumed without heat-treatment, the presence of undefined bacteria in high numbers should be considered in public health assessments.


Subject(s)
Bacteria/isolation & purification , Food Microbiology , Food Packaging/methods , Salmon/microbiology , Seafood/microbiology , Animals , Bacteria/classification , Bacterial Typing Techniques/methods , Cold Temperature , Food Handling/methods , Food Preservation/methods , Phylogeny , Polymerase Chain Reaction/methods , RNA, Bacterial/analysis , RNA, Ribosomal, 16S/analysis , Vacuum
12.
Leukemia ; 21(6): 1198-203, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17410184

ABSTRACT

Gene expression analyses were performed on 121 consecutive childhood leukemias (87 B-lineage acute lymphoblastic leukemias (ALLs), 11 T-cell ALLs and 23 acute myeloid leukemias (AMLs)), investigated during an 8-year period at a single center. The supervised learning algorithm k-nearest neighbor was utilized to build gene expression predictors that could classify the ALLs/AMLs according to clinically important subtypes with high accuracy. Validation experiments in an independent data set verified the high prediction accuracies of our classifiers. B-lineage ALLs with uncharacteristic cytogenetic aberrations or with a normal karyotype displayed heterogeneous gene expression profiles, resulting in low prediction accuracies. Minimal residual disease status (MRD) in T-cell ALLs with a high (>0.1%) MRD at day 29 could be classified with 100% accuracy already at the time of diagnosis. In pediatric leukemias with uncharacteristic cytogenetic aberrations or with a normal karyotype, unsupervised analysis identified two novel subgroups: one consisting mainly of cases remaining in complete remission (CR) and one containing a few patients in CR and all but one of the patients who relapsed. This study of a consecutive series of childhood leukemias confirms and extends further previous reports demonstrating that global gene expression profiling provides a valuable tool for genetic and clinical classification of childhood leukemias.


Subject(s)
Leukemia/classification , Leukemia/genetics , Neoplasm, Residual/diagnosis , Oligonucleotide Array Sequence Analysis/methods , Acute Disease , Algorithms , Child , Gene Expression Profiling , Genes, cdc , Humans , Leukemia, B-Cell , Leukemia, Myeloid , Leukemia, T-Cell , Predictive Value of Tests , Recurrence , Remission Induction
13.
Leukemia ; 20(2): 224-9, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16357831

ABSTRACT

Although many of the chromosomal abnormalities in hematologic malignancies are identifiable cytogenetically, some are only detectable using molecular methods. We describe a novel cryptic t(7;21)(p22;q22) in acute myeloid leukemia (AML). FISH, 3'RACE, and RT-PCR revealed a fusion involving RUNX1 and the ubiquitin-specific protease (USP) gene USP42. The genomic breakpoint was in intron 7 of RUNX1 and intron 1 of USP42. The reciprocal chimera was not detected - neither on the transcriptional nor on the genomic level - and FISH showed that the 5' part of USP42 was deleted. USP42 maps to a 7p22 region characterized by segmental duplications. Notably, 17 kb duplicons are present 1 Mb proximal to USP42 and 3 Mb proximal to RUNX1; these may be important in the genesis of t(7;21). This is the second cryptic RUNX1 translocation in hematologic malignancies and the first in AML. The USPs have not previously been reported to be rearranged in leukemias. The cellular context in which USP42 is active is unknown, but we here show that it is expressed in normal bone marrow, in primary AMLs, and in cancer cell lines. Its involvement in the t(7;21) suggests that deregulation of ubiquitin-associated pathways may be pathogenetically important in AML.


Subject(s)
Chromosomes, Human, Pair 21/genetics , Chromosomes, Human, Pair 7/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Endopeptidases/genetics , Leukemia, Myeloid/genetics , Oncogene Proteins, Fusion/genetics , Translocation, Genetic , Acute Disease , Cell Line, Tumor , Child , Cytogenetic Analysis/methods , Gene Expression Profiling , Gene Rearrangement , Humans , In Situ Hybridization, Fluorescence/methods , Male , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Thiolester Hydrolases , Transcription, Genetic , Ubiquitin-Specific Proteases
14.
Bone Marrow Transplant ; 33(5): 559-63, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14716343

ABSTRACT

A 54-year-old RhD-negative male with del(20q)-positive myelodysplastic syndrome was transplanted with bone marrow from an HLA-identical RhD-positive sibling donor. Cytogenetic relapse was detected 21 months after stem cell transplantation (SCT), with reappearance of the original del(20q)-positive clone and reversion to recipient RhD-negative blood group. The patient received sequential donor lymphocyte infusions (DLIs), resulting in mild graft-versus-host disease and pure red cell aplasia. At 2 years post DLI, the patient remains in a stable condition, despite a dominance of recipient-derived erythro- and granulopoiesis originating in del(20q)-carrying progenitor cells. We conclude that reappearance of autologous erythropoiesis, upon relapse after allogeneic SCT, may be predictive of erythropenia after DLI and that re-emerging autologous del(20q)-positive erythropoiesis post DLI can provide a normal peripheral red blood cell count. Furthermore, in patients relapsing after blood-group-mismatched transplantation, a possible reversion to recipient blood group should be considered prior to blood transfusion or DLI.


Subject(s)
Erythroid Precursor Cells/cytology , Hematopoietic Stem Cell Transplantation , Lymphocyte Transfusion , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/therapy , Chromosome Deletion , Chromosomes, Human, Pair 20 , Humans , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Recurrence , Rh-Hr Blood-Group System , Transplantation, Homologous
15.
Leukemia ; 18(3): 538-47, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14712293

ABSTRACT

Chronic myeloid leukemia (CML) is characterized by the expression of the P210 BCR/ABL fusion protein. The molecular mechanisms behind this oncogene-mediated hematological disease are, however, not fully understood. Here, we describe the establishment and phenotypic characterization of U937 cells in which P210 BCR/ABL can be conditionally expressed using tetracycline. The induction of BCR/ABL in the obtained clones resulted in a rapid phosphorylation of the STAT1, STAT3 and STAT5 molecules, consistent with the findings in other model systems. Phenotypic characterization of the clones revealed that BCR/ABL induces a slight decrease in the proliferation and viability, without a marked effect on cell cycle distribution, the rate of apoptosis or on cellular differentiation, as judged by several cell surface markers and capacity to reduce nitro blue tetrazolium. Interestingly, BCR/ABL was found to upregulate the expression of carcinoembryonic-related antigen (CEA)CAM1 (CD66a), which is a plasma membrane-linked glycoprotein belonging to the CEAs and involved in signal transduction and cellular adhesion. The expression of CEACAM1 was reversible upon imatinib treatment in BCR/ABL-expressing U937 cells as well as in BCR/ABL-positive K562 cells. The established cell lines may prove useful in further modeling and dissection of BCR/ABL-induced leukemogenesis.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation/metabolism , Fusion Proteins, bcr-abl/genetics , Leukemia/metabolism , Milk Proteins , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzamides , Carcinoembryonic Antigen/metabolism , Cell Adhesion Molecules , Cell Cycle/drug effects , Cell Differentiation/drug effects , DNA-Binding Proteins/metabolism , Fusion Proteins, bcr-abl/metabolism , Humans , Imatinib Mesylate , K562 Cells , Leukemia/pathology , Phenotype , Piperazines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , STAT1 Transcription Factor , STAT3 Transcription Factor , STAT5 Transcription Factor , Trans-Activators/metabolism , Transfection , U937 Cells , Up-Regulation
16.
Lett Appl Microbiol ; 37(4): 275-80, 2003.
Article in English | MEDLINE | ID: mdl-12969488

ABSTRACT

AIMS: The aim of the study was to screen the Enterobacteriaceae flora of meat for the presence of bacteria harbouring the Yersinia high-pathogenicity island (HPI). METHODS AND RESULTS: Bacteria from 29 meat and 29 liver samples were isolated on violet-red bile glucose agar. A total of 197 isolates were screened for the presence of the irp2 gene, encoded within the HPI, by PCR. One isolate that was positive for irp2 gene was also positive for the fyuA, irp1, ybtP/ybtQ, ybtX/ybtS and int/asn tRNA genes by PCR. The presence of fyuA, irp1 and irp2 genes was confirmed by Southern hybridization. CONCLUSIONS: The isolate was identified as Serratia liquefaciens by sequencing of the 16S rRNA gene and by ribotyping. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of a Serratia harbouring the Yersinia HPI. Serratia is a frequently occurring Enterobacteriaceae genus in chill-stored meat.


Subject(s)
Bacterial Proteins/genetics , Meat/microbiology , Polymerase Chain Reaction/methods , Serratia liquefaciens/genetics , Serratia liquefaciens/isolation & purification , Yersinia/pathogenicity , Animals , Bacterial Outer Membrane Proteins , Cattle , DNA, Ribosomal/analysis , Iron-Binding Proteins , Liver/microbiology , Molecular Sequence Data , Periplasmic Binding Proteins , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Serratia liquefaciens/classification , Serratia liquefaciens/pathogenicity , Siderophores/metabolism , Virulence/genetics , Yersinia/genetics
17.
Am J Hematol ; 71(1): 15-9, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12221668

ABSTRACT

Acute myeloid leukemia (AML) with inv(16)(p13q22) or the variant t(16;16)(p13;q22), is strongly associated with the FAB subtype M4Eo. A high incidence of CNS involvement was reported in the 1980s, but otherwise little is known about the pattern of extamedullary leukemia (EML) manifestations in this AML type. We have compiled clinical and cytogenetic data on 27 consecutive AML cases with inv(16)/t(16;16) from southern Sweden. In general, these AMLs displayed the clinical features that have previously been described as characteristic for this disease entity: low median age, hyperleukocytosis, M4Eo morphology, and a favorable prognosis. However, CNS leukemia was only seen in relapse in one patient diagnosed in 1980, whereas the most common EML manifestation in our series was lymphadenopathy (5/27, 19%), most often cervical with or without gross tonsillar enlargement. A review of previously published, clinically informative cases corroborates that lymphadenopathy, with preference for the cervical region, is the most common EML at diagnosis in inv(16)-positive AML (58/175, 33%). CNS leukemia, on the other hand, has been reported in only 17% of the cases, mostly in the relapse setting, with a diminishing frequency over time, possibly due to protective effects of high-dose cytarabine. Other reported EML sites include the scalp, ovaries, and the intestine. Cervicotonsillar EML was in our series associated with a shorter duration of first remission, (P < 0.05), and may hence prove to be an important clinical parameter when deciding treatment strategies in AML with inv(16)/t(16;16).


Subject(s)
Chromosome Inversion , Chromosomes, Human, Pair 16/genetics , Leukemia, Myelomonocytic, Acute/epidemiology , Leukemic Infiltration , Lymph Nodes/pathology , Palatine Tonsil/pathology , Adult , Aged , Central Nervous System/pathology , Child , Child, Preschool , Chromosomes, Human, Pair 16/ultrastructure , Female , Humans , Leukemia, Myelomonocytic, Acute/genetics , Leukemia, Myelomonocytic, Acute/pathology , Male , Prognosis , Retrospective Studies , Treatment Outcome
18.
Genes Chromosomes Cancer ; 32(4): 302-10, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11746971

ABSTRACT

Constitutive activation of tyrosine kinases as a consequence of chromosomal translocations, forming fusion genes, plays an important role in the development of hematologic malignancies, in particular, myeloproliferative syndromes (MPSs). In this respect, the t(9;22)(q34;q11) that results in the BCR/ABL fusion gene in chronic myeloid leukemia is one of the best-studied examples. The fibroblast growth factor receptor 1 (FGFR1) gene at 8p11 encodes a transmembrane receptor tyrosine kinase and is similarly activated by chromosomal translocations, in which three alternative genes-ZNF198 at 13q12, CEP110 at 9q34, and FOP at 6q27-become fused to the tyrosine kinase domain of FGFR1. These 8p11-translocations are associated with characteristic morphologic and clinical features, referred to as "8p11 MPS." In this study, we report the isolation and characterization of a novel fusion gene in a hematologic malignancy with a t(8;22)(p11;q11) and features suggestive of 8p11 MPS. We show that the breakpoints in the t(8;22) occur within introns 4 and 8 of the BCR and FGFR1 genes, respectively. On the mRNA level, the t(8;22) results in the fusion of BCR exons 1-4 in-frame with the tyrosine kinase domain of FGFR1 as well as in the expression of a reciprocal FGFR1/BCR chimeric transcript. By analogy with data obtained from previously characterized fusion genes involving FGFR1 and BCR/ABL, it is likely that the oligomerization domain contributed by BCR is critical and that its dimerizing properties lead to aberrant FGFR1 signaling and neoplastic transformation.


Subject(s)
Chromosomes, Human, Pair 22/genetics , Chromosomes, Human, Pair 8/genetics , Genes, abl/genetics , Myeloproliferative Disorders/genetics , Oncogene Proteins, Fusion/genetics , Oncogene Proteins/genetics , Protein-Tyrosine Kinases , Proto-Oncogene Proteins , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Fibroblast Growth Factor/genetics , Translocation, Genetic/genetics , Aged , Amino Acid Sequence , Base Sequence , Chromosome Breakage/genetics , Humans , Male , Molecular Sequence Data , Proto-Oncogene Proteins c-bcr , Receptor, Fibroblast Growth Factor, Type 1 , Transcription, Genetic
19.
J Acoust Soc Am ; 109(6): 2831-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11425126

ABSTRACT

In this article deconvolution of ultrasonic pulse-echo data acquired from attenuative layered media is considered. The problem is divided in two subproblems: treating the sparse reflection sequence caused by the layered structure of the media and treating the frequency-dependent attenuation. The first subproblem is solved by means of joint maximum a posteriori estimation of the assumed zero mean, white, nonstationary reflection sequence and its corresponding sequence of unknown standard deviations. This approach leads to an algorithm that seeks minimum entropy solutions for the reflection sequence and therefore the algorithm serves as a novel link between the classical Wiener filter and methods for sparse or minimum entropy deconvolution. The second subproblem is solved by introducing a new signal processing-oriented, linear discrete-time model for frequency-dependent attenuation in isotropic and homogeneous media. The deconvolution algorithm is tested using simulated data and its performance for real normal incidence pulse-echo data from a composite material is also demonstrated. The results show that the algorithm, in combination with the attenuation model, yields estimates that reveal the internal structure of the composite and, thus, simplify the interpretation of the ultrasonic data.

20.
Genes Chromosomes Cancer ; 30(3): 261-6, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11170283

ABSTRACT

Three adult de novo acute myeloid leukemias (AML M1, M2, and M4) with an isochromosome 7p are presented. No additional abnormalities were detected by G-band and multicolor, using combined binary ratio labeling, fluorescence in situ hybridization (FISH) analyses, indicating that the i(7p) was the sole, i.e., the primary, chromosomal aberration. Although the patients were elderly--68, 72, and 78 years old--they all responded very well to chemotherapy, achieving complete remission lasting more than a year. Further FISH analyses, using painting, centromeric, as well as 7q11.2-specific YAC probes, revealed that the i(7p) contained two centromeres and that the breakpoints were located in 7q11.2. Thus, the abnormality should formally be designated idic(7)(q11.2). The detailed mapping disclosed a breakpoint heterogeneity, with the breaks in 7q11.2 varying among the cases, being at least 1,310 kb apart. Furthermore, the breakpoints also differed within one of the cases, being located on both the proximal and the distal side of the most centromeric probe used. Based on our three patients, as well as on a previously reported 82-year-old patient with AML M2 and idic(7)(q11) as the only chromosomal change, we suggest that this abnormality, as the sole anomaly, is associated with AML in elderly patients who display a good response to induction chemotherapy and, hence, have a favorable prognosis. Furthermore, the heterogeneous breakpoints in 7q11.2 suggest that the important functional outcome of the idic(7)(q11.2) is the genomic imbalance incurred, i.e., gain of 7p and loss of 7q material, rather than a rearrangement of a specific gene.


Subject(s)
Aging/genetics , Chromosomes, Human, Pair 7/genetics , Isochromosomes/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosome Banding , Cytarabine/therapeutic use , Female , Humans , Idarubicin/therapeutic use , In Situ Hybridization, Fluorescence/methods , Leukemia, Myelomonocytic, Acute/drug therapy , Leukemia, Myelomonocytic, Acute/genetics , Male , Remission Induction , Thioguanine/therapeutic use
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