| 1. |
- Wickström, Malin, et al.
(författare)
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The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo
- 2007
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:9, s. 2409-2417
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.
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| 4. |
- Falkenström, Fredrik, et al.
(författare)
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Development and Validation of a 6-item Working Alliance Questionnaire for Repeated Administrations During Psychotherapy
- 2015
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Ingår i: Psychological Assessment. - : American Psychological Association. - 1040-3590 .- 1939-134X. ; 27:1, s. 169-183
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Tidskriftsartikel (refereegranskat)abstract
- Recently, researchers have started to measure the working alliance repeatedly across sessions of psychotherapy, relating the working alliance to symptom change session by session. Responding to questionnaires after each session can become tedious, leading to careless responses and/or increasing levels of missing data. Therefore, assessment with the briefest possible instrument is desirable. Because previous research on the Working Alliance Inventory has found the separation of the Goal and Task factors problematic, the present study examined the psychometric properties of a 2-factor, 6-item working alliance measure, adapted from the Working Alliance Inventory, in 3 patient samples (ns = 1,095, 235, and 234). Results showed that a bifactor model fit the data well across the 3 samples, and the factor structure was stable across 10 sessions of primary care counseling/psychotherapy. Although the bifactor model with 1 general and 2 specific factors outperformed the 1-factor model in terms of model fit, dimensionality analyses based on the bifactor model results indicated that in practice the instrument is best treated as unidimensional. Results support the use of composite scores of all 6 items. The instrument was validated by replicating previous findings of session-by-session prediction of symptom reduction using the Autoregressive Latent Trajectory model. The 6-item working alliance scale, called the Session Alliance Inventory, is a promising alternative for researchers in search for a brief alliance measure to administer after every session.
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| 5. |
- Fryknäs, Mårten, et al.
(författare)
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Iron chelators target both proliferating and quiescent cancer cells
- 2016
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.
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| 6. |
- Hafstað, Völundur, et al.
(författare)
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Regulatory networks and 5 partner usage of miRNA host gene fusions in breast cancer
- 2022
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 151:1, s. 95-106
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Tidskriftsartikel (refereegranskat)abstract
- Genomic rearrangements in cancer cells can create gene fusions where the juxtaposition of two different genes leads to the production of chimeric proteins or altered gene expression through promoter-swapping. We have previously shown that fusion transcripts involving microRNA (miRNA) host genes contribute to deregulation of miRNA expression regardless of the protein-coding potential of these transcripts. Many different genes can also be used as 5 partners by a miRNA host gene in what we named recurrent miRNA-convergent fusions. Here, we have explored the properties of 5 partners in fusion transcripts that involve miRNA hosts in breast tumours from The Cancer Genome Atlas (TCGA). We hypothesised that firstly, 5 partner genes should belong to pathways and transcriptional programmes that reflect the tumour phenotype and secondly, there should be a selection for fusion events that shape miRNA expression to benefit the tumour cell through the known hallmarks of cancer. We found that the set of 5 partners in miRNA host fusions is non-random, with overrepresentation of highly expressed genes in pathways active in cancer including epithelial-to-mesenchymal transition, translational regulation and oestrogen signalling. Furthermore, many miRNAs were upregulated in samples with host gene fusions, including established onco-genic miRNAs such as mir-21 and the mir-106b similar to mir-93 similar to mir-25 cluster. To the list of mechanisms for deregulation of miRNA expression, we have added fusion transcripts that change the promoter region. We propose that this adds material for genetic selection and tumour evolution in cancer cells and that miRNA host fusions can act as tumour drivers.
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| 7. |
- Holmqvist Larsson, Mattias, 1977-, et al.
(författare)
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Alliance ruptures and repairs in psychotherapy in primary care
- 2018
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Ingår i: Psychotherapy Research. - : Routledge. - 1050-3307 .- 1468-4381. ; 28:1, s. 123-136
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The association between alliance level and outcome in psychotherapy has been extensively studied. One way to expand this knowledge is to study alliance patterns. The main aims of this study were to examine how frequent alliance patterns with ruptures or rupture-repair episodes were in a naturalistic sample of psychotherapies in primary care, and if three alliance patterns (a Rupture pattern, a Repair pattern, and a No Rupture pattern) were differentially associated with treatment outcome.METHOD: The psychotherapies (N = 605) included a wide range of different treatment orientations and patient diagnoses. Alliance patterns were studied at session-to-session level, using patient-rated alliance scores. Outcome data were analyzed using longitudinal multilevel modeling with a slopes-as-outcomes model.RESULTS: The Repair pattern accounted for 14.7% (n = 89) of the treatments, 10.7% (n = 65) exhibited a Rupture pattern, and 74.5% (n = 451) contained no ruptures. The Rupture pattern was associated with inferior treatment outcomes. The Repair pattern was, in longer treatments, associated with better outcomes than the No Rupture pattern.CONCLUSIONS: The results support theory about the importance of ruptures in the therapeutic alliance and suggest that identification of alliance ruptures is important in alliance-outcome research, for feedback purposes in clinical practice, and in training of therapists.
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| 8. |
- Holmqvist Larsson, Mattias, 1977-, et al.
(författare)
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The Alliance and Rupture Observation Scale (AROS) : Development and validation of an alliance and rupture measure for repeated observations within psychotherapy sessions
- 2019
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Ingår i: Journal of Clinical Psychology. - : John Wiley & Sons. - 0021-9762 .- 1097-4679. ; 75:3, s. 404-417
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to test a new observer-rated instrument, the Alliance and Rupture Observation Scale (AROS). It was designed for repeated measurements of the alliance within sessions and to detect alliance ruptures.Method: Videotaped therapy sessions with depressed adults were analyzed. Reliability was mainly assessed as inter-rater reliability. Convergent, predictive, and discriminant validity of the AROS was assessed by comparing the instrument with both observer-rated and patient-rated measures.Results: The AROS exhibited excellent inter-rater reliability. Alliance levels measured with the AROS predicted patients’ ratings of the alliance in the same session and were highly correlated with another observer-rated alliance measure. Alliance patterns (rupture; repair; and no-rupture) based on AROS scores were significantly correlated with patients’ ratings of the alliance.Conclusions: Preliminary support for convergent and predictive validity was found. It is yet to be determined whether AROS scores are related to psychotherapy outcomes.
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| 9. |
- Karlsson, Henning, et al.
(författare)
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A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation
- 2019
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Ingår i: Oncotarget. - Orchard Park, NY United States : Impact Journals. - 1949-2553. ; 10:51, s. 5372-5382
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Tidskriftsartikel (refereegranskat)abstract
- There is a need for preclinical models that can enable identification of novel radiosensitizing drugs in clinically relevant high-throughput experiments. We used a new high-throughput compatible total cell kill spheroid assay to study the interaction between drugs and radiation in order to identify compounds with radiosensitizing activity. Experimental drugs were compared to known radiosensitizers and cytotoxic drugs clinically used in combination with radiotherapy. VLX600, a novel iron-chelating inhibitor of oxidative phosphorylation, potentiated the effect of radiation in tumor spheroids in a synergistic manner. This effect was specific to spheroids and not observed in monolayer cell cultures. In conclusion, the total cell kill spheroid assay is a feasible high-throughput method in the search for novel radiosensitizers. VLX600 shows encouraging characteristics for development as a novel radiosensitizer.
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| 10. |
- Larsson, Britt, et al.
(författare)
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Blood supply and oxidative metabolism in muscle biopsies of female cleaners with and without myalgia
- 2004
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Ingår i: The Clinical Journal of Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0749-8047 .- 1536-5409. ; 20:6, s. 440-446
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Pathomechanisms of work-related myalgia are poorly understood. Myalgia is thought to be caused by excitation of nociceptors present in the muscular tissue but not in the muscle fiber itself. Muscle contraction in combination with hypoxia is known to excite nociceptors. Morphologic analysis can contribute to the knowledge of the excitation of nociceptors. This study thoroughly examines the morphology of the trapezius muscle's capillary supply and signs of disturbed oxidative metabolism to understand their role in work-related myalgia. METHODS: Surgical trapezius muscle biopsies were obtained from 25 female cleaners with long-standing work-related myalgia, 25 female cleaners without trapezius myalgia, and 21 healthy teachers. Enzyme and immunohistochemical stainings were performed to highlight fibers with aberrant intermyofibrillar patterns, indicating a disturbed oxidative metabolism (also known as moth-eaten fibers) and a disturbed capillary supply of different fibers. RESULTS: A significantly lower number of capillaries per fiber area in cleaners suffering from myalgia compared with cleaners without trapezius myalgia was found. Moth-eaten fibers were found in the 3 groups, but these fibers were significantly more prevalent in the groups of cleaners than in the healthy teacher group. CONCLUSION: This work indicates that the capillary supply of trapezius is affected in work-related trapezius myalgia. More studies are needed to understand possible mechanisms that would explain the occurrence of moth-eaten fibers.
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