Biomedical subjects

Anna Andersson

Publications and source records attributed to Anna Andersson.

12 recordsLinked to original sources

PubMed2006

Deregulation of cyclin D2 by juxtaposition with T-cell receptor alpha/delta locus in t(12;14)(p13;q11)-positive childhood T-cell acute lymphoblastic leukemia.

OBJECTIVES: The t(12;14)(p13;q11)--a recurrent translocation in childhood T-cell acute lymphoblastic leukemia (T-ALL)--has very recently been molecularly characterized in one case, which displayed overexpression of the cyclin D2 gene (CCND2). PATIENTS AND METHODS: We have characterized two pediatric t(12;14)-positive T-ALLs using fluorescence in situ hybridization (FISH), cDNA microarray, and real-time polymerase chain reaction (PCR). RESULTS: FISH revealed breakpoints (BPs) in the T-cell receptor alpha/delta locus (14q11) and in the vicinity of the CCND2 gene at 12p13. To investigate the expression of genes in 12p13, cDNA microarray analysis was performed. Expression data for eight genes, including CCND2, surrounding the 12p BP were compared with those in other T-ALLs. The t(12;14)-positive T-ALL displayed an increased expression of CCND2 compared to the controls, whereas the expression of the other genes was similar in all T-ALLs. Expression of CCND2 and two additional genes (PARP11 and FGF23), close to the 12p BP, was investigated with real-time PCR of the two t(12;14)-positive cases and four controls. Neither PARP11 nor FGF23 displayed expression differences among the T-ALLs, whereas CCND2 was clearly overexpressed in both t(12;14)-positive cases as compared to the mean expression level in the controls. CONCLUSION: We have confirmed, in two additional cases, that the recurrent T-ALL-associated t(12;14) results in overexpression of cyclin D2. The t(12;14) is the first neoplasia-associated translocation shown to result in overexpression of cyclin D2. Furthermore, it is the first example of a T-cell neoplasm with a targeted deregulation of a member of a cyclin-encoding gene family.

Adolescent↗

PubMed2006

Tonic GABA(A) receptor-mediated currents in human brain.

GABA(A) receptors can mediate both phasic (synaptic) and tonic (extrasynaptic) forms of inhibition. It has been proposed that tonic inhibition plays a critical part in controlling neuronal and network excitability. Although tonic GABA(A) receptor-mediated currents have been well characterized in rodents, their existence in human tissue has yet to be demonstrated. Here we show that tonic currents can be recorded from human tissue obtained from patients undergoing temporal lobectomies. Tonic GABA(A) receptor-mediated currents were present in pyramidal cells and interneurons in layer V-VI of temporal neocortex and granule cells in the dentate gyrus. These tonic currents have cell type-specific pharmacologies, opening up the possibility of targeted therapeutics.

Animals↗

PubMed2006

Cross-platform classification in microarray-based leukemia diagnostics.

Gene expression profiling is a powerful technique for classifying hematologic malignancies. Its clinical use is, however, currently hindered by the need to collect large sets of expression profiles at each diagnostic facility. To overcome this limitation, we introduced cross-platform classification, allowing classifier construction using pre-existing microarray datasets. As proof-of-principle, we performed cross-platform classification of acute myeloid leukemia and childhood acute lymphoblastic leukemia using expression data from four different facilities. We show that cross-platform classification of these disorders is achievable, and, strikingly, that the diagnostic accuracy can be retained. We conclude that cross-platform classification constitutes an effective and convenient way to implement microarray diagnostics.

Humans↗

PubMed2005

Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations.

Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1, IGH@/MYC, ETV6(TEL)/RUNX1(AML1), 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.

Bone Marrow↗

PubMed2004

Development of an assay using 4-trifluoromethylumbelliferyl as a marker substrate for assessment of drug-drug interactions to multiple isoforms of UDP-glucuronosyltransferases.

Glucuronidation is catalyzed by UDP-glucuronosyltransferases (UGTs) and is one of the most important pathways for elimination of xenobiotics. The aim of the present study was to develop an in vitro assay for assessment of drug-drug interactions related to UGTs applicable to early drug discovery. 4-Trifluoromethylumbelliferyl was tested as a marker substrate for six human recombinant expressed UGT isoforms: 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7. It was shown that 4-trifluoromethylumbelliferyl was glucuronidated by all UGTs tested, except UGT1A4. By using a short HPLC gradient (7 min) and fluorescence detection, the enzyme kinetic parameters for these reactions were obtained. All reactions were found to follow classical Michaelis-Menten kinetics, with K(m) values between 29 microM (UGT1A9) and 80 microM (UGT1A3). The method was validated by using several known competitive inhibitors of UGTs. The most potent inhibition was observed for the reaction between 17alpha-ethynylestradiol and UGT1A1 (K(i) = 10.5 microM), and the weakest interaction was detected for acetaminophen and UGT1A9 (IC(50) > 1 mM). Taken together, we report the development of an assay using 4-trifluoromethylumbelliferyl as a marker substrate for five different human UGT isoforms suitable for the assessment of drug-drug interactions related to UGTs during early drug discovery.

Biomarkers↗

PubMed2004

Cloning, expression and characterization of two new IgE-binding proteins from the yeast Malassezia sympodialis with sequence similarities to heat shock proteins and manganese superoxide dismutase.

Malassezia sympodialis is an opportunistic yeast that colonizes human skin and may induce IgE and T cell reactivity in patients with atopic eczema/dermatitis syndrome (AEDS). Previously, we have cloned and expressed six recombinant allergens (rMala s 1 and rMala s 5 to rMala s 9) from this yeast. By combining high throughput screening and phage surface display techniques, 27 complete and partial IgE-binding clones of M. sympodialis have been identified. Here we enlarged the panel of recombinant M. sympodialis allergens by RACE-PCR, cloning and nucleotide sequencing to obtain the coding sequences of two new IgE-binding clones. The coding sequences of one of the clones showed similarity to the heat shock protein (HSP) family and the other to manganese superoxide dismutase (MnSOD), and both had a high degree of homology to human counterparts. The coding sequences were expressed in Escherichia coli as six-histidine tagged recombinant proteins and generated products with molecular masses of 86.1 kDa for HSP and 22.4 kDa for MnSOD. Their IgE-binding frequencies were shown to be 69% and 75%, respectively, to 28 sera from AEDS patients with serum IgE to M. sympodialis extract, indicating that HSP and MnSOD are major M. sympodialis allergens. In inhibition immunoblotting, M. sympodialis extract could inhibit the binding of serum IgE from AEDS patients to rHSP and rMnSOD in a concentration-dependent manner. The high frequency of sera from AEDS patients, showing IgE binding to both HSP and MnSOD, indicates that these allergens, designated Mala s 10 and Mala s 11, could play a role in AEDS.

Adult↗

PubMed2004

Clinical impact of internal tandem duplications and activating point mutations in FLT3 in acute myeloid leukemia in elderly patients.

BACKGROUND: The FLT3 gene is frequently mutated in acute myeloid leukemia (AML), either by an internal tandem duplication (ITD) of the juxtamembrane domain or by activating point mutations in the second tyrosine kinase domain (ATKD). Only a few investigations have focused on the prognostic significance of FLT3 alterations in AML among the elderly, yielding conflicting results. In the present study, the frequency and clinical relevance of FLT3 abnormalities were ascertained in a cohort of elderly AML patients. PATIENTS AND METHODS: A total of 109 AMLs, occurring in patients above the age of 60 yr (median 71.5), were investigated. DNA was extracted from fresh bone marrow cells or from cells in fixative and investigated for the presence of ITD of exons 14 and 15 and the ATKD D835 in exon 20. RESULTS: ITDs and ATKDs were identified in 20 (18%) and 11 (10%) of the cases, respectively. Three cases displayed both an ITD and an ATKD. FLT3 abnormalities were associated with leukocytosis (ITD P < 0.01; ATKD P = 0.069), and the monocytic FAB subtypes M4 and M5 [ITD (P < 0.05), ATKD (P = 0.05)], and ITD and ATKD were significantly (P < 0.05) more common in cases with a normal karyotype. There was no correlation between the presence of FLT3 abnormalities and complete remission rates or overall survival. CONCLUSION: A correlation was observed between FLT3 abnormalities and leukocytosis, a normal karyotype, and the M4/M5 subtypes of leukemia. However, no clear-cut prognostic impact of FLT3 abnormalities was identified in elderly AML patients.

Acute Disease↗

PubMed2004

A management information system model for process-oriented health care.

OBJECTIVE: To develop a conceptual model of a management information system for process-oriented health care organizations. METHODS: Qualitative data was collected from two case studies in process-oriented health care settings. The first study addressed the information requirements of health care managers and the second study focused on organizational activities and clinical practice. From these data, preliminary models were iteratively developed, interpreted, and further revised. SETTING: A county hospital in southern Sweden with 30 clinics and 3,200 employees. RESULTS: A conceptual model of a management information system for process-oriented health care organizations was developed in two parts: one part that describes the organizational interface of the model and the other part that describes the architecture of the model. CONCLUSION: A conceptual model has been developed for local-level integration of management information systems and organizational procedures in process-oriented health care organizations

Delivery of Health Care↗

PubMed2003

Inhibition of C6 glioma cell proliferation by anandamide, 1-arachidonoylglycerol, and by a water soluble phosphate ester of anandamide: variability in response and involvement of arachidonic acid.

It has previously been shown that the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) inhibit the proliferation of C6 glioma cells in a manner that can be prevented by a combination of capsazepine (Caps) and cannabinoid (CB) receptor antagonists. It is not clear whether the effect of 2-AG is due to the compound itself, due to the rearrangement to form 1-arachidonoylglycerol (1-AG) or due to a metabolite. Here, it was found that the effects of 2-AG can be mimicked with 1-AG, both in terms of its potency and sensitivity to antagonism by Caps and CB receptor antagonists. In order to determine whether the effect of Caps could be ascribed to actions upon vanilloid receptors, the effect of a more selective vanilloid receptor antagonist, SB366791 was investigated. This compound inhibited capsaicin-induced Ca(2+) influx into rVR1-HEK293 cells with a pK(B) value of 6.8+/-0.3. The combination of SB366791 and CB receptor antagonists reduced the antiproliferative effect of 1-AG, confirming a vanilloid receptor component in its action. 1-AG, however, showed no direct effect on Ca(2+) influx into rVR1-HEK293 cells indicative of an indirect effect upon vanilloid receptors. Identification of the mechanism involved was hampered by a large inter-experimental variation in the sensitivity of the cells to the antiproliferative effects of 1-AG. A variation was also seen with anandamide, which was not a solubility issue, since its water soluble phosphate ester showed the same variability. In contrast, the sensitivity to methanandamide, which was not sensitive to antagonism by the combination of Caps and CB receptor antagonists, but has similar physicochemical properties to anandamide, did not vary between experiments. This variation greatly reduces the utility of these cells as a model system for the study of the antiproliferative effects of anandamide. Nevertheless, it was possible to conclude that the antiproliferative effects of anandamide were not solely mediated by either its hydrolysis to produce arachidonic acid or its CB receptor-mediated activation of phospholipase A(2) since palmitoyltrifluoromethyl ketone did not prevent the response to anandamide. The same result was seen with the fatty acid amide hydrolase inhibitor palmitoylethylamide. Increasing intracellular arachidonic acid by administration of arachidonic acid methyl ester did not affect cell proliferation, and the modest antiproliferative effect of umbelliferyl arachidonate was not prevented by a combination of Caps and CB receptor antagonists.

Anilides↗

PubMed2003

AM404 and VDM 11 non-specifically inhibit C6 glioma cell proliferation at concentrations used to block the cellular accumulation of the endocannabinoid anandamide.

AM404 [ N-(4-hydroxyphenyl)arachidonylamide] and VDM 11 [(5 Z,8 Z,11 Z,14 Z)- N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] are commonly used to prevent the cellular accumulation of the endocannabinoid anandamide, and thereby to potentiate its actions. However, it has been reported that AM404 can produce an influx of calcium into cells, which might be expected to have deleterious effects on cell proliferation. In the present study, AM404 and VDM 11 were found to reduce C6 glioma cell proliferation with IC(50) values of 4.9 and 2.7 microM, respectively. The inhibition of cell proliferation following a 96-h exposure was not accompanied by dramatic caspase activation, and was not prevented by either a combination of cannabinoid and vanilloid receptor antagonists, or by the antioxidant alpha-tocopherol, suggestive of a non-specific mode of action. Similar results were seen with palmitoylisopropylamide, although this compound only produced significant inhibition of cell proliferation at 30 microM concentrations. AM404 (1 microM), VDM 11 (1 microM) and palmitoylisopropylamide (3-30 microM), i.e. concentrations producing relatively modest effects on cell proliferation per se, reduced the vanilloid receptor-mediated antiproliferative effects of anandamide, as would be expected for compounds preventing the cellular accumulation of anandamide (and thereby access to its binding site on the vanilloid receptor). It is concluded that concentrations of AM404 and VDM 11 that are generally used to reduce the cellular accumulation of anandamide have deleterious effects upon cell proliferation, and that lower concentrations of these compounds may be more appropriate to use in vitro.

Animals↗

PubMed2003

A model for interpreting work and information management in process-oriented healthcare organisations.

BACKGROUND: To increase productivity, management in healthcare organisations have introduced different types of process-oriented organisational configurations. Few studies have addressed clinical practice and information management in these settings. METHODS: A case study was performed at a paediatric clinic. Data was collected from archives, through interviews, by participatory observation, and by performing a focus group session. The collected data was analysed using a qualitative and interpretative research strategy. RESULTS: A model was developed of care practitioners' daily work in process-oriented organisations. The model shows that clinical work was deeply integrated; the care activities were dependent on supply activities and tightly connected to management routines. CONCLUSION: The resulting model can be used to support development of health information system (HIS) embedded in process-oriented healthcare work.

Efficiency, Organizational↗

PubMed2002

Management demands on information and communication technology in process-oriented health-care organizations: the importance of understanding managers' expectations during early phases of systems design.

There are numerous challenges to overcome before information and communication technology (ICT) can achieve its full potential in process-oriented health-care organizations. One of these challenges is designing systems that meet users' needs, while reflecting a continuously changing organizational environment. Another challenge is to develop ICT that supports both the internal and the external stakeholders' demands. In this study a qualitative research strategy was used to explore the demands on ICT expressed by managers from functional and process units at a community hospitaL The results reveal a multitude of partially competing goals that can make the ICT development process confusing, poor in quality, inefficient and unnecessarily costly. Therefore, from the perspective of ICT development, the main task appears to be to coordinate the different visions and in particular clarify them, as well as to establish the impact that these visions would have on the forthcoming ICT application.

Attitude of Health Personnel↗