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Biomedical subjects

M Sprangers

Publications and source records attributed to M Sprangers.

11 recordsLinked to original sources
PubMed2006

SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells.

Perpetual V(D)J recombinase activity involving multiple DNA double-strand break events in B-cell lineage leukemia and lymphoma cells may introduce secondary genetic aberrations leading towards malignant progression. Here, we investigated defective negative feedback signaling through the (pre-) B-cell receptor as a possible reason for deregulated V(D)J recombinase activity in B-cell malignancy. On studying 28 cases of pre-B-lymphoblastic leukemia and 27 B-cell lymphomas, expression of the (pre-) B-cell receptor-related linker molecule SLP65 (SH2 domain-containing lymphocyte protein of 65 kDa) was found to be defective in seven and five cases, respectively. SLP65 deficiency correlates with RAG1/2 expression and unremitting V(H) gene rearrangement activity. Reconstitution of SLP65 expression in SLP65-deficient leukemia and lymphoma cells results in downregulation of RAG1/2 expression and prevents both de novo V(H)-DJ(H) rearrangements and secondary V(H) replacement. We conclude that iterative V(H) gene rearrangement represents a frequent feature in B-lymphoid malignancy, which can be attributed to SLP65 deficiency in many cases.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells.

SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca2+ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca2+-signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca2+-mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation- and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferation-related molecules.

Adaptor Proteins, Signal Transducing↗
PubMed2006

BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells.

Pre-B lymphoblastic leukemia cells carrying a BCR-ABL1 gene rearrangement exhibit an undifferentiated phenotype. Comparing the genome-wide gene expression profiles of normal B-cell subsets and BCR-ABL1+ pre-B lymphoblastic leukemia cells by SAGE, the leukemia cells show loss of B lymphoid identity and aberrant expression of myeloid lineage-specific molecules. Consistent with this, BCR-ABL1+ pre-B lymphoblastic leukemia cells exhibit defective expression of IKAROS, a transcription factor needed for early lymphoid lineage commitment. As shown by inducible expression of BCR-ABL1 in human and murine B-cell precursor cell lines, BCR-ABL1 induces the expression of a dominant-negative IKAROS splice variant, termed IK6. Comparing matched leukemia sample pairs from patients before and during therapy with the BCR-ABL1 kinase inhibitor STI571 (Imatinib), inhibition of BCR-ABL1 partially corrected aberrant expression of IK6 and lineage infidelity of the leukemia cells. To elucidate the contribution of IK6 to lineage infidelity in BCR-ABL1+ cell lines, IK6 expression was silenced by RNA interference. Upon inhibition of IK6, BCR-ABL1+ leukemia cells partially restored B lymphoid lineage commitment. Therefore, we propose that BCR-ABL1 induces aberrant splicing of IKAROS, which interferes with lineage identity and differentiation of pre-B lymphoblastic leukemia cells.

Alternative Splicing↗
PubMed2004

Predictors of patients' choices for breast-conserving therapy or mastectomy: a prospective study.

A study was undertaken to describe the treatment preferences and choices of patients with breast cancer, and to identify predictors of undergoing breast-conserving therapy (BCT) or mastectomy (MT). Consecutive patients with stage I/II breast cancer were eligible. Information about predictor variables, including socio-demographics, quality of life, patients' concerns, decision style, decisional conflict and perceived preference of the surgeon was collected at baseline, before decision making and surgery. Patients received standard information (n=88) or a decision aid (n=92) as a supplement to support decision making. A total of 180 patients participated in the study. In all, 72% decided to have BCT (n=123); 28% chose MT (n=49). Multivariate analysis showed that what patients perceived to be their surgeons' preference and the patients' concerns regarding breast loss and local tumour recurrence were the strongest predictors of treatment preference. Treatment preferences in itself were highly predictive of the treatment decision. The decision aid did not influence treatment choice. The results of this study demonstrate that patients' concerns and their perceptions of the treatment preferences of the physicians are important factors in patients' decision making. Adequate information and communication are essential to base treatment decisions on realistic concerns, and the treatment preferences of patients.

Aged↗
PubMed2004

Use of item response theory to develop a shortened version of the EORTC QLQ-C30 emotional functioning scale.

BACKGROUND: As part of a larger study whose objective is to develop an abbreviated version of the EORTC QLQ-C30 suitable for research in palliative care, analyses were conducted to determine the feasibility of generating a shorter version of the 4-item emotional functioning (EF) scale that could be scored in the original metric. METHODS: We used data from 24 European cancer studies conducted in 10 different languages (n = 8242). Item selection was based on analyses by item response theory (IRT). Based on the IRT results, a simple scoring algorithm was developed to predict the original 4-item EF sum scale score from a reduced number of items. RESULTS: Both a 3-item and a 2-item version (item 21 'Did you feel tense?' and item 24 'Did you feel depressed?') predicted the total score with excellent agreement and very little bias. In group comparisons, the 2-item scale led to the same conclusions as those based on the original 4-item scale with little or no loss of measurement efficiency. CONCLUSION: Although these results are promising, confirmatory studies are needed based on independent samples. If such additional studies yield comparable results, incorporation of the 2-item EF scale in an abbreviated version of the QLQ-C30 for use in palliative care research settings would be justified. The analyses reported here demonstrate the usefulness of the IRT-based methodology for shortening questionnaire scales.

Adult↗
PubMed2003

Return to work of cancer survivors: a prospective cohort study into the quality of rehabilitation by occupational physicians.

AIMS: To describe and assess the quality of rehabilitation of cancer survivors by occupational physicians and to relate the quality of the process of occupational rehabilitation to the outcome of return to work. METHODS: One hundred occupational physicians of a cohort of cancer survivors were interviewed about return to work management. Quality of rehabilitation was assessed by means of four indicators that related to performance in knowledge of cancer and treatment, continuity of care, patients complaints, and relations at work. The cohort of patients was prospectively followed for 12 months to assess time to return to work and rate of return to work. Patients' and physicians' satisfaction with care was also assessed. The relation between performance and these outcome measures was studied in a multivariate analysis, taking into account the influence of other work and disease related factors that could potentially predict return to work. RESULTS: For knowledge of cancer and treatment, only 3% had optimal performance because occupational physicians did not communicate with treating physicians. For continuity of care, patient complaints, and relations at work, performance was optimal for 55%, 78%, and 60% of the physicians respectively. After adjustment for other prognostic factors, overall physician's performance (hazard ratio (HR) 0.5, 95% CI 0.3 to 0.8) and continuity of care (HR 0.5, 95% CI 0.3 to 0.9) were related to the return to work of patients. Overall optimal performance was also related to a small but significant higher level of satisfaction with care, both for patients and physicians. CONCLUSION: Quality of occupational rehabilitation of cancer survivors can be improved substantially, especially with regard to communication between physicians and continuity of care. There is a need for the development of more effective rehabilitation procedures which should be evaluated in a randomised controlled trial.

Adult↗
PubMed2001

Proteoglycan synthesis is increased in cells with impaired clathrin-dependent endocytosis.

Overexpression of a GTPase deficient dynamin mutant in HeLa dynK44A cells causes a block in clathrin-dependent endocytosis. When endocytosis is inhibited, these cells incorporate higher levels of [(35)S]sulfate into both cellular and secreted macromolecules and larger amounts of proteoglycans such as syndecan and perlecan are immunoprecipitated from [(35)S]sulfate-labelled lysates. Gel filtration and ion-exchange chromatography revealed that the increased [(35)S]sulfate incorporation into proteoglycans was not due to significant differences in size or density of negative charge of glycosaminoglycan chains attached to proteoglycan core proteins. On the other hand, measurements of the syndecan-1 mRNA level and of [(3)H]leucine-labelled perlecan after immunoprecipitation supported the idea that the increased [(35)S]sulfate incorporation into proteoglycans was due to a selective increase in the synthesis of proteoglycan core proteins. Interestingly, the activity of protein kinase C was increased in cells expressing mutant dynamin and inhibition of protein kinase C with BIM reduced the differences in [(35)S]sulfate incorporation between cells with normal and impaired clathrin-dependent endocytosis. Thus, the activation of protein kinase C observed upon inhibition of clathrin-dependent endocytosis may be responsible for the increased synthesis of proteoglycans.

Animals↗
PubMed2001

Adherence over 48 weeks in an antiretroviral clinical trial: variable within patients, affected by toxicities and independently predictive of virological response.

OBJECTIVES: To investigate adherence to antiretroviral therapy over 48 weeks, to investigate the association between adherence and treatment-related symptoms and to investigate the impact of adherence on virological response over 48 weeks among established predictors of treatment success. METHODS: One-hundred-and-sixty HIV-1 infected protease inhibitor- and stavudine-naive patients participating in a trial of ritonavir/saquinavir versus ritonavir/saquinavir/ stavudine completed an adherence questionnaire and a symptom checklist at weeks 12, 24, 36 and 48. We calculated odds ratios between experienced symptoms and non-adherence. Regression models were used to determine predictors of HIV-1 RNA below 400 copies/ml at week 48, and of the area about the change from baseline over 48weeks (ACFB) in serum HIV-1 RNA. RESULTS: The percentage of patients reporting missing medication, deviation from time schedule, and dietary prescriptions at separate time-points ranged from 12 to 15%, 32 to 35% and 17 to 22%, respectively. The percentage that changed their level of adherence during 48 weeks ranged from 29% for skipping medication to 48% for deviation from time-schedule. Experienced side-effects were associated with an increased likelihood of non-adherence. Not skipping medication was an independent predictor of both having a serum HIV-1 RNA below 400 copies/ml at week 48 and the ACFB over 48weeks in serum HIV-1 RNA. CONCLUSIONS: Adherence was an independent predictor of virological response over 48 weeks. The level of adherence is variable within patients over time. This suggests the need for continued adherence monitoring in all patients as part of standard medical practice.

Anti-HIV Agents↗
PubMed2000

Quality of life evaluation in oncological clinical trials - the EORTC model. The EORTC Quality of Life Study Group.

The European Organization for Research and Treatment of Cancer (EORTC) has taken a leading role in the development of the methodology of quality of life (QL) measurement. In the EORTC Quality of Life Study Group (QLSG) valid instruments to assess QL in a general manner and disease-specific modules have been developed to be used in oncological clinical trials. Statistical and methodological aspects of QL research are discussed. The application of QL assessments in clinical trials represents a subsequent challenge. To improve the practice of QL assessment in clinical trials an 'EORTC model' has been developed. This model requires the collaboration of liaison persons, the EORTC Cooperative Tumour Groups and the EORTC Data Centre Quality of Life Unit (QL Unit). Cooperation between these parties, protocol development and advantages and concerns of the model are mentioned in this paper. Finally, suggestions for improvement are proposed.

Clinical Protocols↗
PubMed1997

Modification of the EORTC QLQ-C30 (version 2.0) based on content validity and reliability testing in large samples of patients with cancer. The Study Group on Quality of Life of the EORTC and the Symptom Control and Quality of Life Committees of the NCI of Canada Clinical Trials Group.

A revision of the Quality of Life Questionnaire (QLQ-C30) of the European Organization for Research and Treatment of Cancer (EORTC) was undertaken to improve low internal consistency estimates (Cronbach's alpha) and content validity for the role functioning scale and a conceptual difficulty (undue emphasis on physical functioning) in the global quality of life (QOL) scale. The role functioning items were reworded and a four-category response format was substituted for the previous dichotomous format. A new item asking about 'overall health' was substituted for the 'overall physical condition' item in the global QOL domain. The original and new versions were tested at three time points in a total of 1,181 patients with cancer in Canada (n = 696) and the Netherlands (n = 485). In both samples there was a marked improvement in internal consistency for the role functioning scale (Cronbach's alpha s ranging from 0.78-0.88) in the new version. In the global QOL scale, the substitution of the new item for the previous one did not alter internal consistency (Cronbach's alpha's ranging from 0.81-0.92). The revised versions of the role functioning and global QOL domains have been incorporated into the QLQ-C30 (version 2.0).

Adult↗