| 1. |
- D'Arcy, Pádraig, et al.
(författare)
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Inhibition of proteasome deubiquitinating activity as a novel cancer therapy
- 2011
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Ingår i: Nature Medicine. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1546-170X .- 1078-8956.
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Tidskriftsartikel (refereegranskat)abstract
- Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.
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| 2. |
- Gimsing, Peter, et al.
(författare)
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Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial
- 2010
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Ingår i: LANCET ONCOLOGY. - : Elsevier Science B.V., Amsterdam.. - 1470-2045 .- 1474-5488. ; 11:10, s. 973-982
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Tidskriftsartikel (refereegranskat)abstract
- Background Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. Methods This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials. gov, number NCT00376883. Findings From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62.9-70.0) in the 90 mg group and 68 points (64.6-71.4) in the 30 mg group (95% CI of difference -6.6 to 3.3; p=0.52). Median time to first skeletal-related event in patients who had such an event was 9.2 months (8.1-10.7) in the 90 mg group and 10-2 months (7.3-14.0) in the 30 mg group (p=0.63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. Interpretation Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma.
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| 3. |
- Hjorth, Martin, et al.
(författare)
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Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study.
- 2012
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Ingår i: European journal of haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 88:6, s. 485-496
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives. Methods: Thalidomide- and bortezomib-naïve patients with melphalan refractory myeloma were randomly assigned to low-dose thalidomide + dexamethasone (Thal-Dex) or bortezomib + dexamethasone (Bort-Dex). At progression on either therapy, the patients were offered crossover to the alternative drug combination. An estimated 300 patients would be needed for the trial to detect a 50% difference in median PFS between the treatment arms. Results: After inclusion of 131 patients, the trial was prematurely closed because of low accrual. Sixty-seven patients were randomized to Thal-Dex and 64 to Bort-Dex. Progression-free survival was similar (median, 9.0 months for Thal-Dex and 7.2 for Bort-Dex). Response rate was similar (55% for Thal-Dex and 63% for Bort-Dex), but time to response was shorter (P < 0.05) and the VGPR rate higher (P < 0.01) for Bort-Dex. Time-to-other treatment after crossover was similar (median, 13.2 months for Thal-Dex and 11.2 months for Bort-Dex), as was overall survival (22.8 months for Thal-Dex and 19.0 for Bort-Dex). Venous thromboembolism was seen in seven patients and cerebrovascular events in four patients in the Thal-Dex group. Severe neuropathy, reactivation of herpes virus infections, and mental depression were more frequently observed in the Bort-Dex group. In the quality-of-life analysis, no difference was noted for physical function, pain, and global quality of life. Fatigue and sleep disturbances were significantly more prevalent in the Bort-Dex group. Conclusions: Thalidomide (50–100 mg daily) in combination with dexamethasone seems to have an efficacy comparable with that of bortezomib and dexamethasone in melphalan refractory myeloma. However, the statistical strength of the results in this study is limited by the low number of included patients.
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| 4. |
- Jansen, Gunilla Brodda, et al.
(författare)
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Differences in symptoms, functioning, and quality of life between women on long-term sick-leave with musculoskeletal pain with and without concomitant depression.
- 2011
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Ingår i: Journal of Multidisciplinary Healthcare. - 1178-2390. ; 4, s. 281-292
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim was to describe the differences in symptoms, functioning and quality of life between women on long-term sick-leave due to protracted musculoskeletal pain with and without concomitant depression.DESIGN: Descriptive and comparisons with/without comorbid depression.METHODS: 332 female patients were examined by three specialist physicians in psychiatry, orthopedic surgery, and rehabilitation medicine and assigned to four groups according to the ICD-10 diagnoses: low back/joint disorders (LBJ, n = 150), myalgia (M, n = 43), fibromyalgia (FM, n = 87), or depression without somatic pain diagnosis (DE, n = 52).RESULTS: Patients with somatic pain conditions LBJ, M, or FM showed more activity-related difficulties if concomitant depression was present during the activities 'focusing attention', 'making decisions', and 'undertaking a single task'; and in the domains 'energy level', 'memory functions', 'emotional functions', and 'optimism/pessimism'. Patients with FM and concomitant depression perceived higher pain intensity than patients in group DE. No statistically significant differences in physically related activities were noted between each of the somatic pain conditions with and without coexisting depression. FM patients with coexisting depression reported fewer painful sites on their pain drawings compared with FM-patients without depression. Patients with LBJ or FM and concomitant depression reported lower quality of life in the dimensions vitality, social functioning, emotional role, and mental health. Comorbid depression affected disability and restricted working capacity by reducing mental activity and functioning but not by affecting physical activity problems.CONCLUSION: Women on long-term sick-leave, who have concomitant depression with LBJ or FM, also have more difficulties in focusing attention, making decisions, and carrying out tasks, and with memory functions and optimism/pessimism, as well as reduced quality of life in the dimensions of vitality, social functioning, emotional role, and mental health, than female patients without comorbid depression. As a consequence we suggest further efforts to integrate somatic and psychiatric interventions in the same rehabilitation program.
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| 5. |
- Linder Ekberg, Kristina
(författare)
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Gene expression patterns in human adipose tissue in relation to fat mass and adipose depot
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity, especially excess amount of abdominal fat, predisposes to a high risk for cardiovascular disease. Cancer cachexia is characterized by a specific loss of white adipose tissue (WAT) and skeletal muscle mass, and is associated with decreased survival and poor response to chemotherapy. We hypothesize that alterations in WAT function contribute to the negative metabolic consequences and disease outcome, respectively, of these two disorders. In this thesis we apply global transcriptome profiling on patient abdominal WAT biopsies to identify new genes and pathways of relevance for WAT function. In particular we explore gene expression in relation to (i) WAT depot, (ii) a dietary intervention study, and (iv) cancer with or without cachexia. In addition, we select one gene from microarray, Follistatin, for detailed expression profiling and functional evaluation in human fat cells. In the first study, we successfully set up Representational difference analysis to identify a handful of genes differentially expressed between subcutaneous and visceral WAT, e.g. Adipsin, a component in the complement system, and Phospholipids transfer protein (PLPT), which is involved in transfer of phospholipids between lipoproteins. Our second study was part of a large consortium which compared the effects of a ten week intervention with a low-fat, high-carbohydrate hypoenergetic diet versus a moderate-fat, moderate-carbohydrate hypoenergetic diet. Both diets produced similar weight loss and beneficial changes in blood chemistry parameters. We performed abdominal subcutaneous WAT global transcriptome profiling on a subgroup of patients before and after the dietary intervention. The expression of 96 genes was significantly influenced by hypocaloric diet. Expression of genes involved in the synthesis of polyunsaturated fatty acids was downregulated, and CIDEA was up-regulated by hypocaloric diet. The pattern of gene expression response was almost identical between the two diets. In the third study we report that subcutaneous WAT Follistatin mRNA decreases with increasing weight, and that weight loss restores Follistatin levels. Furthermore, Follistatin is primarily produced by cells of the stroma vascular fraction in WAT. We show that WAT secretes Follistatin in vitro. Treating precursor cells with Follistatin in vitro stimulates adipogeneisis. We cotreated precursor cells with Follistatin and Myostatin under adipogenic conditions, and found that cotreatment reversed the inhibitory effect of Myostatin on adipogenesis. The fourth study compared cancer patients with or without cachexia. Global transcriptome profiling revealed that genes downregulated by cachexia were overrepresented in pathways related to extracellular matrix, actin cytoskeleton and focal adhesion. By contrast, genes upregulated in cachexia were overrepresented in pathways related to energy turnover, e.g. fatty acid degradation, and oxidative phosphorylation. In conclusion, variation in WAT size is associated with changes in tissue morphology, fat cell number and metabolism, as well as adipokine secretion. We provide support that the dietary energy intake, and not the macronutrient composition, is associated with changes in WAT gene expression, and highlight the role of CIDEA, which subsequently has been shown to be an important regulator of metabolic switch in fat cells. We identify Follistatin as a new adipokine. Insufficient Follistatin in obesity could possibly contribute to a hypertrophic WAT with large insulin resistant fat cells. We provide support that cachexia is associated with changes in WAT remodeling, which could be involved in WAT loss in this clinical condition.
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| 6. |
- Linder, Jurgen, et al.
(författare)
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RELATIONSHIP BETWEEN SLEEP DISTURBANCE, PAIN, DEPRESSION AND FUNCTIONING IN LONG-TERM SICK-LISTED PATIENTS EXPERIENCING DIFFICULTY IN RESUMING WORK
- 2014
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Ingår i: JOURNAL OF REHABILITATION MEDICINE. - : Medical Journals Sweden AB. - 1651-2081 .- 1650-1977. ; 46:8, s. 798-805
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe the frequency of reported sleeping, depression and pain problems, the severity of these problems and the degree of self-estimated difficulties in mental functions and activities in relation to the sleep disturbance and pain category group in patients on long-term sick-leave. Design: Cross-sectional study. Patients: A total of 1206 patients experiencing difficulty in resuming work. Methods: Patient examinations by specialists in psychiatry, orthopaedic surgery and rehabilitation medicine. Validated questionnaires, including status regarding depression, sleep, pain and functioning were used. Results: The prevalence of sleep disturbance was 83%; 74% of the patients with moderate/severe sleep disturbance also had moderate/severe pain problems and 26% had no/mild pain problems. Fifty-seven percent of the patients with no/mild sleep disturbance and 83% of the patients with moderate/severe sleep disturbance also had depression. The degree of difficulty in performing the 6 selected International Classification of Functioning, Disability and Health activities and mental functions was higher for the category with moderate/severe sleep problems, compared with those with no/mild sleep problems. Conclusion: To optimize rehabilitation for patients on long-term sick-leave experiencing difficulties in returning to work, the results indicate a need also to focus attention on sleep problems and not only on pain and depression. This may entail the planning of measures to improve decision-making and concentration and alleviate lassitude, fatigability, sadness and pessimistic thoughts.
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| 7. |
- Waage, Anders, et al.
(författare)
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Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 116:9, s. 1405-1412
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Tidskriftsartikel (refereegranskat)abstract
- In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, non-neuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.
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