| 1. |
- Andersson, Anna, et al.
(författare)
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Microarray-based classification of a consecutive series of 121 childhood acute leukemias: prediction of leukemic and genetic subtype as well as of minimal residual disease status.
- 2007
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 21:6, s. 1198-1203
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Tidskriftsartikel (refereegranskat)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 (40.1%) 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.
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| 2. |
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| 3. |
- Kempf, Tibor, et al.
(författare)
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Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction
- 2007
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 28:23, s. 2858-2865
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Tidskriftsartikel (refereegranskat)abstract
- Aims Growth-differentiation factor-15 (GDF-15) is a transforming growth factor-beta-related cytokine that is induced in the heart following ischaemia-reperfusion injury. We explored the prognostic utility of GDF-15 in patients with ST-segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy. Methods and results Circulating levels of GDF-15 were determined by an immunoradiometric assay in 741 STEMI patients who were included in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-2 and ASSENT-plus trials. About 72.7% of the patients presented with GDF-15 levels >= 1200 ng/L, the upper limit of normal in apparently healthy elderly individuals. Increased levels of GDF-15 were associated with a higher risk of death during 1-year follow-up. Mortality rates at 1 year were 2.1, 5.0, and 14.0% in patients with GDF-15 levels < 1200, 1200-1800, and > 1800 ng/L, respectively (P < 0.001). GDF-15 remained an independent predictor of mortality after adjustment for clinical variables, troponin T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). GDF-15 provided prognostic information in clinically relevant patient subgroups, defined according to age, gender, cardiovascular risk factors, haemodynamic status, and the TIMI risk score. Moreover, GDF-15 added prognostic information to the established biomarkers of adverse prognosis in STEMI, troponin T, and NT-proBNP. Conclusion GDF-15 is a new biomarker in STEMI that provides prognostic information beyond established clinical and biochemical markers.
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| 4. |
- Lind, Lars, et al.
(författare)
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Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly : results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study
- 2009
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:19, s. 2346-2353
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Growth-differentiation factor-15 (GDF-15) is emerging as an independent prognostic biomarker in patients with cardiovascular (CV) disease. Little is known about the pathophysiological basis for the close association of GDF-15 to future CV events. We hypothesized that GDF-15 is related to underlying CV pathologies. METHODS AND RESULTS: To relate the levels of GDF-15 to indices of CV dysfunction and disease in elderly individuals, serum levels of GDF-15 were measured in 1004 subjects aged 70 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Carotid intima-media thickness and plaque burden, and left ventricular (LV) geometry and function were assessed by ultrasound. Endothelial function was evaluated in forearm resistance vessels and in the brachial artery by venous occlusion plethysmography and ultrasound imaging, respectively. Elevated levels of GDF-15 were related to several CV risk factors (male gender, current smoking, body mass index, waist circumference, diabetes, fasting glucose, triglycerides, and low HDL cholesterol). After adjustment for CV risk factors, increased levels of GDF-15 were associated with reduced endothelium-dependent vasodilation in resistance vessels, plaque burden, LV mass and concentric LV hypertrophy, reduced LV ejection fraction, and clinical manifestations of coronary artery disease and heart failure. CONCLUSION: GDF-15 carries information on CV dysfunction and disease that is not captured by traditional CV risk factors in elderly individuals.
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| 5. |
- Lundin, Catarina, et al.
(författare)
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B-cell precursor t(8;14)(q11;q32)-positive acute lymphoblastic leukemia in children is strongly associated with Down syndrome or with a concomitant Philadelphia chromosome.
- 2009
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 82:1, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- We review the clinical and cytogenetic features of 44 acute lymphoblastic leukemias (ALLs) with t(8;14)(q11;q32), including three from our department and 41 ascertained in the literature, focusing on age and gender distribution, peripheral blood values, immunophenotypic data, survival and additional chromosomal changes. Most patients are children or young adults, with a median age of 10 yr for children and 28 for adults. There is a male preponderance, particularly in patients with Down syndrome (DS) or in children with concomitant t(9;22)(q34;q11). The median blood values are hemoglobin 72 g/L, platelets 17 x 10(9)/L and white blood cell count 9 x 10(9)/L, with hyperleukocytosis >50 x 10(9)/L having been reported in only approximately 10%. All reported cases have had a B-cell precursor immunophenotype, typically characterized by CD10+, CD19+, CD20+/-, CD22+, CD24+, CD34+, CD45dim/-, CD66c+/- and CD123+. At the time of reporting, 75% of the patients have been alive. The t(8;14) is the sole acquired change in 30%. The most common additional aberrations are t(9;22)(q34;q11), der(14)t(8;14), +21, +X and +14, the presence of which does not seem to confer a prognostic impact. A substantial proportion of the patients have DS (27%) or t(9;22) (16%). All patients with both t(8;14) and t(9;22) have been children without DS; the frequency of t(9;22) in that cohort is 30%. As t(9;22), or its molecular genetic correlate, may escape detection by conventional banding analysis we would strongly suggest that this aberration is actively looked for in pediatric ALL with t(8;14).
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| 6. |
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| 7. |
- Panagopoulos, Ioannis, et al.
(författare)
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MLL/GAS7 fusion in a pediatric case of t(11;17)(q23;p13)-positive precursor B-cell acute lymphoblastic leukemia
- 2006
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Ingår i: Haematologica. - 1592-8721. ; 91:9, s. 1287-1288
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- AML/GAS7, resulting from t(11;17)(q23;p13), has been reported in one case of treatment-related acute myeloid leukemia (AML). We present a de novo case of t(11;17)-positive pediatric acute lymphoblastic leukemia. Fluorescent in situ hybridization and reverse transcriptase polymerase chain reaction analyses revealed an MLL/GAS7 chimera identical to the one previously described in AML. The molecular genetic features of MLL/GAS7 and the clinical impact of t(11;17) are discussed.
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| 8. |
- Paulsson, Kajsa, et al.
(författare)
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A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42
- 2006
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 20:2, s. 224-229
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Tidskriftsartikel (refereegranskat)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 50 part of USP42 was deleted. USP42 maps to a 7p22 region characterized by segmental duplications. Notably, 17 kb duplicons are present 1Mb proximal to USP42 and 3Mb 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.
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| 9. |
- Paulsson, Kajsa, et al.
(författare)
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Characterisation of genomic translocation breakpoints and identification of an alternative TCF3/PBX1 fusion transcript in t(1;19)(q23;p13)-positive acute lymphoblastic leukaemias.
- 2007
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 138:2, s. 196-201
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Tidskriftsartikel (refereegranskat)abstract
- The t(1;19)(q23; p13), one of the most common translocations in childhoodand adult acute lymphoblastic leukaemias (ALLs), usually results in fusion of exons 1-16 of TCF3 (previously E2A) and exons 3-9 of PBX1. However, some t(1;19)-positive ALLs are negative for this chimaera. We here report an alternative TCF3/PBX1 transcript, fusing exon 17 of TCF3 with exon 5 of PBX1, in a paediatric t(1;19)-positive ALL. The different breakpoints made this hybrid undetectable by reverse transcription polymerase chain reaction using standard TCF3 and PBX1 primers. Hence, ALLs with t(1;19) that test negative for TCF3/PBX1 should be analysed further before excluding this alternative fusion. Furthermore, we have characterised the genomic translocation breakpoints in eight TCF3/PBX1-positive ALLs; four cases with a balanced t(1;19) and four with an unbalanced der(19) t(1;19). It has previously been suggested that the breakpoints are clustered, particularly in TCF3, and that N-nucleotides are frequently present in the fusion junctions. Three of seven investigated TCF3 intron 16 breakpoints were within the previously described 14 base pair-cluster, and all but two junctions harboured N-nucleotides. The PBX1 breakpoints were more dispersed, although still clustered in two regions. This confirms that most t(1;19) rearrangements may arise by a combination of illegitimate V(D)J recombination and nonhomologous end joining.
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| 10. |
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