| 1. |
- Caramuta, S., et al.
(författare)
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Role of microRNAs and microRNA machinery in the pathogenesis of diffuse large B-cell lymphoma
- 2013
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 3, s. e152-
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Tidskriftsartikel (refereegranskat)abstract
- Deregulation of microRNA (miRNA) expression has been documented in diffuse large B-cell lymphoma (DLBCL). However, the impact of miRNAs and their machinery in DLBCL is not fully determined. Here, we assessed the role of miRNA expression and their processing genes in DLBCL development. Using microarray and RT-qPCR approaches, we quantified global miRNAs and core components of miRNA-processing genes expression in 75 DLBCLs (56 de novo and 19 transformed) and 10 lymph nodes (LN). Differential miRNA signatures were identified between DLBCLs and LNs, or between the de novo and transformed DLBCLs. We also identified subsets of miRNAs associated with germinal center B-cell phenotype, BCL6 and IRF4 expression, and clinical staging. In addition, we showed a significant over-expression of TARBP2 in de novo DLBCLs as compared with LNs, and decreased expression of DROSHA, DICER, TARBP2 and PACT in transformed as compared with de novo cases. Interestingly, cases with high TARBP2 and DROSHA expression had a poorer chemotherapy response. We further showed that TARBP2 can regulate miRNA-processing efficiency in DLBCLs, and its expression inhibition decreases cell growth and increases apoptosis in DLBCL cell lines. Our findings provide new insights for the understanding of miRNAs and its machinery in DLBCL.
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| 2. |
- Chen, Rong, et al.
(författare)
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Representing a chemotherapy guideline using openEHR and rules
- 2009
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Ingår i: Medical Informatics in a United and Healthy Europe. - : IOS Press. - 9781607500445 ; , s. 653-657
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Konferensbidrag (refereegranskat)abstract
- Computerized guidelines can provide decision support and facilitate the use of clinical guidelines. Several computerized guideline representation models (GRMs) exist but the poor interoperability between the guideline systems and the Electronic Health Record (EHR) systems limits their clinical usefulness. In this study we analyzed the clinical use of a published lymphoma chemotherapy guideline. We found that existing GRMs have limitations that can make it difficult to meet the clinical requirements. We hypothesized that guidelines could be represented as data and logic using openEHR archetypes, templates and rules. The design was tested by implementing the lymphoma guideline. We conclude that using the openEHR models and rules to represent chemotherapy guidelines is feasible and confers several advantages both from a clinical and from an informatics perspective.
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| 3. |
- Dieterich, Lothar C., et al.
(författare)
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Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization
- 2012
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 228:3, s. 378-390
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.
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| 4. |
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| 5. |
- Georgii-Hemming, Patrik
(författare)
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Life, death ant the role of IGF-I in human multiple myeloma
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is a clonal expansion of malignant cells with a plasmablast- plasma cell morphology in the bone marrow. It is a fatal disease with a median survival of 2-3 years after start of conventional therapy. The aim of the thesis was to study the regulation of growth and survival of MM cell lines and primary, cells to identify potential targets for therapy. The results of the thesis show that MM cells express IGF-I (insulin-like growth factor-I) receptors and IGF-I. Furthermore, IGF-I was shown to stimulate growth and survival of MM cells. When IGF-IR signaling is inhibited by anti-IGF-IR antibodies in MM cells they are growth inhibited and may also undergo apoptosis. The somatostatin analogue octreotide has been demonstrated to interfere with the action of IGF-I. The results of the thesis show that MM cells express sst2, sst3 and sst5 which bind octreotide with a moderate or high affinity. Moreover, octreotide inhibits the growth of all investigated MM clones. In a few cases growth inhibition was also accompanied by the induction of apoptosis.Resistance to apoptosis may be important for cell survival and drug resistance in MM clones. Studies in the thesis demonstrated that interferon (IFN)-α and IFN-γ augment the sensitivity to Fas-induced apoptosis in MM cells independently of their growth inhibitory effect. The sensitivity to apoptosis was also increased by inhibition of IGF-IR signaling. Incubation of MM cells with anti-IGF-IR antibodies increased the sensitivity of the cells to apoptosis induced by Fas ligation and the glucocorticoid dexamethasone. It can be concluded that the IGF-IR may be a potential target for therapy in MM. Furthermore, increasing the sensitivity of MM cells to apoptosis by treatment with IFNs or drugs that interfere with the action of IGF-I may increase the sensitivity of the tumor cells to cytotoxic drugs.
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| 8. |
- Halvardson, Jonatan, et al.
(författare)
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Mutations in HECW2 are associated with intellectual disability and epilepsy
- 2016
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 53:10, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.
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| 9. |
- Lindstrand, Anna, et al.
(författare)
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From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
- 2019
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Ingår i: Genome Medicine. - : BMC. - 1756-994X .- 1756-994X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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