| 1. |
- Alricsson, Marie, et al.
(author)
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Mobility, muscular strength and endurance in the cervical spine in Swedish air force pilots
- 2001
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In: Aviation, Space and Environmental Medicine. - 0095-6562 .- 1943-4448. ; 72:4, s. 336-342
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Journal article (peer-reviewed)abstract
- PURPOSE: Muscle strength, endurance and range of movement of the cervical spine in a group of Swedish Air Force jet pilots (AF) and in a reference group of conscripts doing their military service (RG) were compared. METHODS: We tested 30 (AF) 24-42 yr and 33 (RG) 19-22 yr. A questionnaire was used to document complaints. Maximum voluntary isometric muscle strength of the flexor and extensor muscles of the cervical spine and sub-maximum isometric endurance in the flexor and extensor muscles were measured. RESULTS: Eleven AF (37%) and four RG (12%) had experienced discomfort in the neck within the previous year. The pilots' flexor and extensor muscle strength (47 Nm and 65 Nm) was superior to that of the conscripts (36 Nm and 59 Nm) (p = 0.0001, p = < 0.05, respectively). However, the RG group had greater isometric endurance in the flexor muscles than AF (p = < 0.05) and greater neck rotation (p = <0.005). There was no difference between the two groups in the other variables. CONCLUSION: Differences between the groups with regard to muscle strength and endurance might depend on variations in work-related physical muscle strain, and/or differences in fiber composition in the muscles, which might be reflected by pilot selection procedures.
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| 2. |
- Blimark, Cecilie, et al.
(author)
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Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry
- 2018
-
In: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 103:3, s. 506-513
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Journal article (peer-reviewed)abstract
- Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent 'real-world' patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients' characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabi-ants per year. Among initially symptomatic patients (n= 3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (P<0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95% CI: 0.77-0.92; P<0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95% CI: 0.87-0.99; P<0.05). We report here on a near complete 'real-world' population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period.
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| 3. |
- D'Arcy, Pádraig, et al.
(author)
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Inhibition of proteasome deubiquitinating activity as a novel cancer therapy
- 2011
-
In: Nature Medicine. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1546-170X .- 1078-8956.
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Journal article (peer-reviewed)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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| 4. |
- Demidova, Marina M., et al.
(author)
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Prognostic value of early sustained ventricular arrhythmias in ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention : A substudy of VALIDATE-SWEDEHEART trial
- 2023
-
In: Heart rhythm O2. - : Elsevier. - 2666-5018. ; 4:3, s. 200-206
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Prognostic assessment of ventricular tachycardia (VT) or ventricular fibrillation (VF) in ST-segment elevation myocardial infarction (STEMI) is based mainly on distinguishing between early (<48 hours) and late arrhythmias, and does not take into account its time distribution with regard to reperfusion, or type of arrhythmia.OBJECTIVE: We analyzed the prognostic value of early ventricular arrhythmias (VAs) in STEMI with regard to their type and timing.METHODS: The prespecified analysis of the multicenter prospective Bivalirudin versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarctionin Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease evaluated according to Recommended Therapies Registry Trial included 2886 STEMI patients undergoing primary percutaneous coronary intervention (PCI). VA episodes were characterized regarding their type and timing. Survival status at 180 days was assessed through the population registry.RESULTS: Nonmonomorphic VT or VF was observed in 97 (3.4%) and monomorphic VT in 16 (0.5%) patients. Only 3 (2.7%) early VA episodes occurred after 24 hours from symptom onset. VA was associated with higher risk of death (hazard ratio 3.59; 95% confidence interval [CI] 2.01-6.42) after adjustment for age, sex, and STEMI localization. VA after PCI was associated with an increased mortality compared with VA before PCI (hazard ratio 6.68; 95% CI 2.90-15.41). Early VA was associated with in-hospital mortality (odds ratio 7.39; 95% CI 3.68-14.83) but not with long-term prognosis in patients discharged alive. The type of VA was not associated with mortality.CONCLUSION: VA after PCI was associated with an increased mortality compared with VA before PCI. Long-term prognosis did not differ between patients with monomorphic VT and nonmonomorphic VT or VF, but events were few. VA incidence during 24 to 48 hours of STEMI is negligibly low, thus precluding assessment of its prognostic importance.
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| 5. |
- Flanagan, John N., et al.
(author)
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Role of follistatin in promoting adipogenesis in women
- 2009
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:8, s. 3003-9
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Journal article (peer-reviewed)abstract
- CONTEXT: Follistatin is a glycoprotein that binds and neutralizes biological activities of TGFbeta superfamily members including activin and myostatin. We previously identified by expression profiling that follistatin levels in white adipose tissue (WAT) were regulated by obesity. OBJECTIVE: The objective of the study was to elucidate the role of follistatin in human WAT and obesity. DESIGN: We measured secreted follistatin protein from WAT biopsies and fat cells in vitro. We also quantified follistatin mRNA expression in sc and visceral WAT and in WAT-fractionated cells and related it to obesity status, body region, and cellular origin. We investigated the effects of follistatin on adipocyte differentiation of progenitor cells in vitro. PARTICIPANTS: Women (n = 66) with a wide variation in body mass index were recruited by advertisement and from a clinic for weight-reduction therapy. RESULTS: WAT secreted follistatin in vitro. Follistatin mRNA levels in sc but not visceral WAT were decreased in obesity and restored to nonobese levels after weight reduction. Follistatin mRNA levels were high in the stroma-vascular fraction of WAT and low in adipocytes. Recombinant follistatin treatment promoted adipogenic differentiation of progenitor cells and neutralized the inhibitory action of myostatin on differentiation in vitro. Moreover, activin and myostatin signaling receptors were detected in WAT and adipocytes. CONCLUSION: Follistatin is a new adipokine important for adipogenesis. Down-regulated WAT expression of follistatin in obesity may counteract adiposity but could, by inhibiting adipogenesis, contribute to hypertrophic obesity (large fat cells) and insulin resistance.
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| 6. |
- Gimsing, Peter, et al.
(author)
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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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In: LANCET ONCOLOGY. - : Elsevier Science B.V., Amsterdam.. - 1470-2045 .- 1474-5488. ; 11:10, s. 973-982
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Journal article (peer-reviewed)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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| 7. |
- Hillert, Ellin-Kristina, et al.
(author)
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Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation
- 2019
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In: Cancer Letters. - : ELSEVIER IRELAND LTD. - 0304-3835 .- 1872-7980. ; 448, s. 70-83
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Journal article (peer-reviewed)abstract
- Proteasome inhibitors have been shown to induce cell death in cancer cells by triggering an acute proteotoxic stress response characterized by accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species. The aggresome pathway has been described as an escape mechanism from proteotoxicity by sequestering toxic cellular aggregates. Here we show that b-AP15, a small-molecule inhibitor of proteasomal deubiquitinase activity, induces poly-ubiquitin accumulation in absence of aggresome formation. b-AP15 was found to affect organelle transport in treated cells, raising the possibility that microtubule-transport of toxic protein aggregates is inhibited, leading to enhanced cytotoxicity. In contrast to the antiproliferative effects of the clinically used proteasome inhibitor bortezomib, the effects of b-AP15 are not further enhanced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Our results suggest an inhibitory effect of b-AP15 on the transport of misfolded proteins, resulting in a lack of aggresome formation, and a strong proteotoxic stress response.
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| 8. |
- Hjorth, Martin, et al.
(author)
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Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study.
- 2012
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In: European journal of haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 88:6, s. 485-496
-
Journal article (other academic/artistic)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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| 9. |
- Jansen, Gunilla Brodda, et al.
(author)
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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
-
In: Journal of Multidisciplinary Healthcare. - 1178-2390. ; 4, s. 281-292
-
Journal article (peer-reviewed)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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| 10. |
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| 11. |
- Lenhoff, Stig, et al.
(author)
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Intensive therapy for multiple myeloma in patients younger than 60 years. Long-term results focusing on the effect of the degree of response on survival and relapse pattern after transplantation
- 2006
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In: Haematologica. - 0390-6078 .- 1592-8721. ; 91:9, s. 1228-1233
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Journal article (peer-reviewed)abstract
- Background and Objectives. From 1994 to 1997 we conducted a population-based, prospective study on intensive therapy in newly diagnosed symptomatic myeloma patients younger than 60 years, comparing their survival to that of a conventionally treated historic population. Long-term results are presented, including the impact of the degree of response on survival and relapse pattern after transplantation. Design and Methods. The prospective population was formed of 397 patients and the historic population of 313 patients. Both populations were calculated to comprise more than 75% of the expected number of new cases. Results. After a median follow-up of 7 years survival was longer in the prospective population than in the historic one (median 60 versus 39 months; p=0.0002). When comparing only patients eligible for intensive therapy the median survival was 63 versus 44 months (p < 0.0001). Attaining a complete response was associated with prolonged event-free survival but not overall survival. The pattern of relapse after transplantation was heterogeneous but could be divided into four major groups; insidious, classical, plasmacytoma form and transformed disease. The median survival after relapse was 29 months. The relapse pattern and time to relapse predicted outcome. Patients relapsing with an insidious or classical form of disease with skeletal events only, or after a long lasting first response were likely to respond well to conventional salvage therapy. In contrast, relapse with multiple symptoms, transformed disease or a short duration of first response implied bad prognosis. Interpretation and conclusions. The relapse pattern after autologous transplantation is heterogeneous and response to salvage therapy is variable. The degree of response and event-free survival after transplantation are not reliable surrogate markers for survival.
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| 12. |
- Linder, Astrid, et al.
(author)
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Design and validation of the neck for a rear impact dummy (BioRID I)
- 2002
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In: Traffic Injury Prevention. - : Informa UK Limited. - 1538-9588 .- 1538-957X. ; 3:2, s. 167-174
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Journal article (peer-reviewed)abstract
- To assess the protective performance of seats and head restraints, occupant models able to mimic the motion of a human in a crash are needed. Hence, a new mechanical dummy neck for low-velocity rear collision tests was developed. The dummy neck consists of seven cervical elements connected by pin joints. The stiffness properties of the neck were represented by rubber blocks mounted between each pair of vertebrae, as well as by muscle substitutes between the head and the first thoracic vertebra (T1). The muscle substitutes consist of cables connected to a unit containing springs and a damper. The neck was validated against volunteer test data (Δv of 7 km/h) and compared with the kinematics of the Hybrid III dummy. The new neck was tested as a part of a new dummy (BioRID) that produced a human-like motion of the T1. The kinematics of the new neck was within the corridor of the volunteers, during the major part of the first 250 ms of the crash event, for both displacement of the head relative to T1 and for the acceleration of the head. This applies to both duration and peak values. When compared with the new neck, the Hybrid III showed an earlier decrease of the horizontal acceleration of the head, less maximum horizontal displacement, and an earlier increase of the rearward angular displacement of the head relative to T1.
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| 13. |
- Linder, Astrid, et al.
(author)
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The New Neck Design for the Rear-End Impact Dummy, BioRID I
- 1998
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In: Annual Proceedings. - : Association for the Advancement of Automotive Medicine. ; , s. 172-192
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Conference paper (other academic/artistic)abstract
- A new mechanical neck was developed for a new dummy possessing a complete articulated spine, for low speed rear-end collisions. The new neck consists of seven cervical elements connected by hinge joints. The neck stiffness properties were created by rubber blocks between each pair of vertebrae in combination with simulated muscle elements between the head and T1. The neck was validated against volunteer tests (Δv of 7 km/h) results. Both displacement and acceleration of the head relative to the upper torso for both duration and peak values, were in agreement with the volunteer data.
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| 14. |
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| 15. |
- Linder Ekberg, Kristina
(author)
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Gene expression patterns in human adipose tissue in relation to fat mass and adipose depot
- 2012
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Doctoral thesis (other academic/artistic)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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| 16. |
- Linder, Juergen, et al.
(author)
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Long-term sick-leavers with difficulty in resuming work : comparisons between psychiatric-somatic co-morbidity and monodiagnosis
- 2009
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In: International Journal of Rehabilitation Research. - 0342-5282 .- 1473-5660. ; 32:1, s. 20-35
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Journal article (peer-reviewed)abstract
- The number of patients with difficulty in resuming work after long-term sick leave has increased in several European countries including Sweden. The general aim of this study was a comprehensive description - based on multidisciplinary diagnostics and assessments - of patients with the common feature of marked difficulty in resuming working life after a long absence. A particular aim was to elucidate the possible effect of comorbidity on pain descriptors, disability, quality of life, assessed working ability and rehabilitation needs. Six hundred and thirty-five long-term sick leavers were referred from National Insurance Offices and consecutively accepted for investigation. Several self-report questionnaires were used. All patients were examined by three board-certified specialist physicians in psychiatry, orthopaedic surgery and rehabilitation medicine, respectively. Fifty-five percent of the patients had psychiatric-somatic comorbidity. The three most frequent combinations of diagnoses in the comorbidity group were fibromyalgia/myalgia and depressive episode, fibromyalgia/myalgia and recurrent depression, spinal pain and depressive episode, whereas the three most frequent in those with psychiatric diagnosis only were depressive episode, recurrent depression, phobias/anxiety. Differences in pain descriptors and in difficulties with activities were found among the three groups. All had lower health-related quality of life than references. Only one-sixth had no assessed working capacity and only 3% were assessed as able to resume work without rehabilitation; 80% were multidisciplinarily assessed as needing rehabilitation. Patients with psychiatric diagnoses, with or without concomitant somatic diagnoses, need medical rehabilitation or medical/vocational rehabilitation in combination to a greater extent than patients with somatic diagnoses only. This implies that medical rehabilitation programmes ought to adapt increasingly to the needs of patients with psychiatric-somatic comorbidity.
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| 17. |
- Linder, J, et al.
(author)
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Long-term sick-leavers with fibromyalgia : Comparing their multidisciplinarily assessed characteristics with those of others with chronic pain conditions and depression
- 2009
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In: Journal of Multidisciplinary Healthcare. - 1178-2390. ; 2, s. 23-37
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Journal article (peer-reviewed)abstract
- Objective: The aim was to gain knowledge of fibromyalgia (FM) patients on long-term sick leave and with particular difficulties in resuming work, and to compare them with patients with myalgia, back or joint diagnoses, and depression.Methods: Patients were identified by and referred from social insurance offices and were multidisciplinarily examined by three board-certified specialists in psychiatry, orthopedic surgery and rehabilitation medicine. Ninety-two women were diagnosed with FM only. Three female comparison groups were chosen: depression, back/joint diagnoses, and myalgia.Results and conclusions: Ceaseless pain was reported by 73% of FM patients, 54% of back/joint diagnoses patients, 43% of myalgia patients, and 35% of depression patients. The distribution of pain (>50%) in FM patients was to almost all regions of the body, and in depression patients to the lower dorsal neck, upper shoulders and lumbosacral back but not in the anterior body. Reduced sleep was more evident in FM patients. FM patients did not meet more criteria for personality disorder than patients with the other somatic pain conditions. The most common dimension of “personality traits” of somatic pain conditions was the “obsessive compulsive” but at a level clearly below that indicating a personality disorder. More FM patients experienced disabilities, the most common being in the mobility and domestic-life areas.
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| 18. |
- Linder, Jurgen, et al.
(author)
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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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In: JOURNAL OF REHABILITATION MEDICINE. - : Medical Journals Sweden AB. - 1651-2081 .- 1650-1977. ; 46:8, s. 798-805
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Journal article (peer-reviewed)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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| 19. |
- Lundh Snis, Ulrika, 1970-, et al.
(author)
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Enhancing Quality through Work Integrated Learning and Collaboration Partnership
- 2022
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In: International Conference on Work Integrated Learning. - Trollhättan : University West. - 9789189325302 ; , s. 90-91
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Conference paper (other academic/artistic)abstract
- For Sweden to be able to compete in the global economy, our students with a degree from higher education must be ready for a career in working life. Today's work life is facing a major ongoing transformation, characterized by increased complexity, higher specialization, and digitalization. This demands competencies beyond traditional theoretical knowledge, such as preparing for uncertainty and unknown outcomes (Barnett, 2000; Vallo Hult & Byström, 2021). Therefore, it is essential to engage students in learning to learn, i.e., lifelong learning so that the tools and methods for learning in higher education can also be developed through future work (Billett, 2014; Islind, Norström, Vallo Hult, & Ramadani Olsson, 2021). For University West, this means that our education programs must be developed in collaboration with industry partners from the surrounding society to provide arelevant and attractive education, which corresponds to the labour market's long-term competence needs. We want our students to develop abilities and skills that enable them to be part of and drive sustainable societal development in practice.Work Integrated Learning (WIL) is University West's overarching profile, based on the concept of advanced knowledge – characterized by complex problem solving – and the mutual acknowledgment of advanced knowledge within the academy and among its partners. What characterizes WIL at University West is that we have developed and refined a combination of different approaches over a long period, including research -based WIL, through fundamental learning concepts such as socio- cultural, critical and action-oriented learning theories. These influences have shaped WIL at University West into a dynamic and academic area of knowledge and subject. In order to achieve a strategic and qualitative development of work-integrated learning, the University West Board decided to WIL-certify all educational programs with a clear sustainability perspective. The quality processis called the WIL certification process. It has now been developed at the university fortwo years.Experience andrefinements are ready to mature into an overall quality framework worth conceptualizing and disseminating to more universities that systematically want to develop WIL as an explicit quality dimension in higher educa tion. The project is still ongoing but have generated some preliminary findings and outcomes from the initial phase. Data collection activities include workshops and focus groups with selected participants from the target groups at the university (managers/prefects and teachers) as well as at the collaborative partner organization (managers and supervisors/mentors). The focus of the workshops was placed on capturing the participants understanding and perspectives on WIL as a concept, and to map the conditions for and experiences of conducting WIL in teaching and learning at work. We aim for identifying good (or less good) examples of WIL, what they are, how they are understood and why they are (or are not) important.The purpose of this paper is to describe the lessons learned so far and present a conceptual quality framework for WIL in higher education with a clear connection to sustainable development. The quality framework may function as a mediating “support object” between higher education institutions, industry partners, and actors in the surrounding society to promote WIL concepts and experiences in collaboration strategies.
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| 20. |
- Lundh Snis, Ulrika, 1970-, et al.
(author)
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Enhancing Work-Integrated Learning (Wil) through Strategic Stakeholder Collaboration
- 2023
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In: ICERI 2023 Proceedings. - : The International Academy of Technology, Education and Development. - 9788409559428 ; , s. 1298-1302
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Conference paper (other academic/artistic)abstract
- For graduates to be able to compete in the global world, study programmes must include knowledge, competences and skills that ensures that students with a higher education degree are ready for both a complex working life and continuous competence development. This demands competencies beyond traditional theoretical knowledge, such as preparing for uncertainty and unknown outcomes. Therefore, it is essential to engage students in learning to learn, i.e., lifelong learning so that the tools and methods for learning in higher education can also be developed through future work.At University West (UW) in Sweden, this means that programmes are developed in collaboration with societal partners to provide a relevant and attractive educational offer. The University West uses the concept of work-integrated learning (WIL) to embrace a sustained/systematic collaboration with strategic partners outside academia. We consider that knowledge is created in the encounter between academia and our strategic partners, through the integration of knowledge, skills and competences acquired both within academia and work life.To achieve a strategic and qualitative development of work-integrated learning (WIL), the Board of University West in 2018 decided to WIL-certify all educational programs including a sustainability perspective and enhance this process by engaging in strategic partnerships with stakeholders from civic society to international companies. The process is a development of existing and future programmes and their pedagogical approach. The WIL certification process has developed into a renewal of the pedagogical approach through a development process based on a lively exchange of experiences from study programme representatives from political science to nursing; and discussions with our strategic partners that benefits both students, staff as well as the strategic partners through competence development and lifelong learning.The purpose of this paper is to describe the lessons learned so far and present a conceptual quality framework for WIL in higher education with a clear connection to sustainable development. Based on the experiences from the development of the institutional WIL project and a Swedish Innovation agency (VINNOVA) research project we aim for a better understanding and insights into how theoretical and practical knowledge can enhance learning both within academia and within strategic partners. Data collection activities include workshops and focus groups with selected participants from the target groups at the university (managers/prefects and teachers) as well as at the collaborative partner organization (managers and supervisors/mentors). Initial findings suggest that the meeting between academia, working life and the surrounding society can ensure that insights, solutions and mutual development are created to meet the challenges society faces. The paper will discuss the methodology of creating work-integrated learning environments that include well-functioning communication and a community of practice (Wenger, 1998) connecting learners, teachers, and other staff with local, regional and national stakeholders.
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| 21. |
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| 22. |
- Mandic, Aleksandra, et al.
(author)
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Cisplatin induces the proapoptotic conformation of Bak in a deltaMEKK1-dependent manner
- 2001
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In: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 21:11, s. 3684-3691
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Journal article (peer-reviewed)abstract
- In a panel of four human melanoma cell lines, equitoxic doses of cisplatin induced the proapoptotic conformation of the Bcl-2 family protein Bak prior to the execution phase of apoptosis. Because cisplatin-induced modulation of the related Bax protein was seen in only one cell line, a degree of specificity in the signal to Bak is indicated. Little is known about upstream regulation of Bak activity. In this study, we examined whether the apoptosis-specific pathway mediated by a kinase fragment of MEKK1 (DeltaMEKK1) is involved in the observed Bak modulation. We report that expression of a kinase-inactive fragment of MEKK1 (dominant negative MEKK [dnMEKK]) efficiently blocked cisplatin-induced modulation of Bak and cytochrome c release and consequently also reduced DEVDase activation and nuclear fragmentation. Accordingly, expression of a kinase-active MEKK1 fragment (dominant positive MEKK) was sufficient to induce modulation of Bak in three cell lines and to induce apoptosis in two of these. dnMEKK did not block cisplatin-induced c-Jun N-terminal kinase (JNK) activation, in agreement with a specifically proapoptotic role for the DeltaMEKK1 pathway. Finally, we show that reduction of Bak expression by antisense Bak reduced cisplatin-induced loss of mitochondrial integrity and caspase cleavage activity in breast cancer cell lines. In summary, we have identified Bak as a cisplatin-regulated component downstream in a proapoptotic, JNK-independent DeltaMEKK1 pathway.
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| 23. |
- Mazurkiewicz, Magdalena, et al.
(author)
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Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition
- 2017
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:13, s. 21115-21127
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Journal article (peer-reviewed)abstract
- The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability. VLX1570 treatment increased the levels of a number of proteins, including the chaperone HSP70B , the oxidative stress marker heme oxygenase-1 (HO-1) and the cell cycle regulator p21(Cip1). Unexpectedly, polybiquitin accumulation was found to be uncoupled from ER stress in ALL cells. Thus, increased phosphorylation of eIF2a occurred only at supra-pharmacological VLX1570 concentrations and did not correlate with polybiquitin accumulation. Total cellular protein synthesis was found to decrease in the absence of eIF2a phosphorylation. Furthermore, ISRIB (Integrated Stress Response inhibitor) did not overcome the inhibition of protein synthesis. We finally show that VLX1570 can be combined with L-asparaginase for additive or synergistic antiproliferative effects on ALL cells. We conclude that ALL cells are highly sensitive to the proteasome DUB inhibitor VLX1570 suggesting a novel therapeutic option for this disease.
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| 24. |
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| 25. |
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| 26. |
- Nahi, Hareth, et al.
(author)
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Incidence, characteristics, and outcome of solitary plasmacytoma and plasma cell leukemia. Population-based data from the Swedish Myeloma Register
- 2017
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In: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 99:3, s. 216-222
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Journal article (peer-reviewed)abstract
- Solitary plasmacytoma (SP) and plasma cell leukemia (PCL) are uncommon (3-6%) types of plasma cell disease. The risk of progression to symptomatic multiple myeloma (MM) is probably important for the outcome of SP. PCL is rare and has a dismal outcome. In this study, we report on incidence and survival in PCL/SP, and progression to MM in SP, using the prospective observational Swedish Multiple Myeloma Register designed to document all newly diagnosed plasma cell diseases in Sweden since 2008. Both solitary bone plasmacytoma (SBP) (n=124) and extramedullary plasmacytoma (EMP) (n=67) have better overall survival (OS) than MM (n=3549). Progression to MM was higher in SBP than in EMP (35% and 7% at 2 years, respectively), but this did not translate into better survival in EMP. In spite of treatment developments, the OS of primary PCL is still dismal (median of 11 months, 0% at 5 years). Hence, there is a great need for diagnostic and treatment guidelines as well as prospective studies addressing the role for alternative treatment options, such as allogeneic stem cell transplantation and monoclonal antibodies in the treatment of PCL.
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| 27. |
- Rosengren, Sara, et al.
(author)
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Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation in Sweden, long-term results from all patients treated in 1994-2009.
- 2016
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In: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 51:12, s. 1569-1572
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Journal article (peer-reviewed)abstract
- High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) is widely used in immunoglobulin light chain (AL) amyloidosis, but the benefit is debated mainly because of the high treatment-related mortality (24% in a randomised study comparing HDM/ASCT with oral melphalan/dexamethasone). We report here on the long-term outcome of all patients treated with HDM/ASCT for AL amyloidosis in Sweden between 1994 and 2009. Seventy-two patients were treated at eight Swedish centres. Median follow-up was 67.5 months. At least partial response (organ or haematological) was seen in 64% of the patients. Median overall survival was 98 months or 8.2 years, with 5-year survival 63.9% and 10-year survival 43.4%. In patients with cardiac involvement or multiple organ involvement, survival was significantly shorter, median overall survival 49 and 56 months, respectively. All mortality within 100 days from ASCT was 12.5% for all patients and 17.2% in the patients with cardiac involvement. For patients treated in the earlier time period (1994-2001), 100-day mortality was 23.8% compared with 7.8% in the later period (2002-2009). In conclusion, long survival times can be achieved in patients with AL amyloidosis treated with HDM/ASCT, also in smaller centres. Early mortality is high, but with a decreasing trend over time.
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| 28. |
- Selvaraj, Karthik, et al.
(author)
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Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system
- 2019
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In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Journal article (peer-reviewed)abstract
- A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (similar to 20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.
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| 29. |
- Sparv, David, et al.
(author)
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The Analgesic Effect of Oxygen in Suspected Acute Myocardial Infarction : A Substudy of the DETO2X-AMI Trial
- 2018
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In: JACC: Cardiovascular Interventions. - : Elsevier BV. - 1936-8798 .- 1876-7605. ; 39, s. 546-546
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Journal article (peer-reviewed)abstract
- Objectives: In this substudy of the DETO2X-AMI (An Efficacy and Outcome Study of Supplemental Oxygen Treatment in Patients With Suspected Myocardial Infarction) trial, the authors aimed to assess the analgesic effect of moderate-flow oxygen supplementation in patients with suspected acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI) and to study the effect of oxygen supplementation on the use of opiates and sedatives during PCI. Background: Routine oxygen in normoxemic patients with AMI does not provide clinical benefit. However, oxygen may relieve ischemic pain. Methods: Patients were randomly allocated to oxygen or ambient air according to the main study protocol. After PCI, peak level of pain during PCI was measured by the Visual Analogue Scale. The total amount of opiates and sedatives was reported. Results: A total of 622 patients were enrolled: 330 in the oxygen group and 292 in the ambient air group. There was no significant difference in peak level of pain (oxygen 4.0 [1.0 to 6.0] vs. air 3.0 [0.6 to 6.0]; p = 0.37), use of opiates (mg) (oxygen 0.0 [0.0 to 3.0] vs. air 0.0 [0.0 to 3.0]; p = 0.31), or use of sedatives between the groups (median [interquartile range]) (oxygen 2.5 [0.0 to 2.5] vs. air 2.5 [0.0 to 2.5]; p = 0.74). Conclusions: In the present study, the authors did not find any analgesic effect of routine oxygen as compared with ambient air, and no differences in the use of sedatives and opiates during PCI. Our results indicate that moderate-flow oxygen supplementation does not relieve pain in normoxemic patients with suspected AMI undergoing treatment with PCI and should thus not be used for this purpose.
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| 30. |
- Strålin, Kristoffer, et al.
(author)
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Design of a national patient-centred clinical pathway for sepsis in Sweden
- 2023
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In: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 55:10, s. 716-724
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Journal article (peer-reviewed)abstract
- BACKGROUND: The World Health Organization has adopted a resolution on sepsis and urged member states to develop national processes to improve sepsis care. In Sweden, sepsis was selected as one of the ten first diagnoses to be addressed, when the Swedish government in 2019 allocated funds for patient-centred clinical pathways in healthcare. A national multidisciplinary working group, including a patient representative, was appointed to develop the patient-centred clinical pathway for sepsis.METHODS: The working group mapped challenges and needs surrounding sepsis care and included a survey sent to all emergency departments (ED) in Sweden, and then designed a patient-centred clinical pathway for sepsis.RESULTS: The working group decided to focus on the following four areas: (1) sepsis alert for early detection and management optimisation for the most severely ill sepsis patients in the ED; (2) accurate sepsis diagnosis coding; (3) structured information to patients at discharge after sepsis care and (4) structured telephone follow-up after sepsis care. A health-economic analysis indicated that the implementation of the clinical pathway for sepsis will most likely not drive costs. An important aspect of the clinical pathway is implementing continuous monitoring of performance and process indicators. A national working group is currently building up such a system for monitoring, focusing on extraction of this information from the electronic health records systems.CONCLUSION: A national patient-centred clinical pathway for sepsis has been developed and is currently being implemented in Swedish healthcare. We believe that the clinical pathway and the accompanying monitoring will provide a more efficient and equal sepsis care and improved possibilities to monitor and further develop sepsis care in Sweden.
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| 31. |
- Waage, Anders, et al.
(author)
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Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma
- 2010
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 116:9, s. 1405-1412
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Journal article (peer-reviewed)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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| 32. |
- Walinder, Göran, et al.
(author)
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Outcome and characteristics of non-measurable myeloma : A cohort study with population-based data from the Swedish Myeloma Registry
- 2020
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In: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 104:5, s. 376-382
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Journal article (peer-reviewed)abstract
- Objective We describe survival in patients with oligo- and non-secretory multiple myeloma (MM). We refer to the whole group as non-measurable MM and compare it with secretory MM. Methods Oligo-secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non-secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio. Results Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008-2016 eligible for the study, 389 patients (9%) had non-measurable MM. Out of these, 253 patients (6%) had oligo-secretory and 136 (3%) had non-secretory MM. Median survival for secretory MM was 42.7 months, non-measurable MM 40.2 months, oligo-secretory MM 38.6 months, and non-secretory MM 44.6 months. Difference in overall observed survival was non-significant for all groups when compared with secretory MM. Within non-secretory MM, stem cell transplantation (SCT), 95% being auto-SCT, was significant for superior survival in multivariate analysis (HR 0.048. P = .0015). Conclusion In this population-based study, we found no difference in survival between oligo- or non-secretory MM when compared with secretory MM. SCT appears to be important also for patients with non-secretory disease.
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| 33. |
- Wang, Xin, et al.
(author)
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The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells
- 2016
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In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6, s. 1-14
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Journal article (peer-reviewed)abstract
- Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.
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| 34. |
- Zhang, Xiaonan, et al.
(author)
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The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and Check for mitochondrial damage
- 2018
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In: Biochemical Pharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 156, s. 291-301
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Journal article (peer-reviewed)abstract
- Human cancers are characterized by intrinsic or acquired resistance to apoptosis and evasion of apoptosis has been proposed to contribute to treatment resistance. Bis-benzylidine piperidone compounds, containing alpha,beta-unsaturated carbonyl functionalities, have been extensively documented as being effective in killing apoptosis-resistant cells and to display promising antineoplastic activities in a number of tumor models. We here explored the phenotypic response of colon cancer cells to b-AP15, a bis-benzylidine piperidone previously shown to inhibit the proteasome deubiquitinases (DUBs) USP14 and UCHL5. Whereas similar overall mRNA and protein expression profiles were induced by b-AP15 and the clinically available proteasome inhibitor bortezomib, b-APIS induced stronger increases of chaperone expression. b-AP15 also induced a stronger accumulation of polyubiquitinated proteins in exposed cells. These proteins were found to partially colocalize with organelle structures, including mitochondria. Mitochondrial oxidative phosphorylation decreased in cells exposed to b-APIS, a phenomenon enhanced under conditions of severe proteotoxic stress caused by inhibition of the VCP/p97 ATPase and inhibition of protein translocation over the ER. We propose that mitochondrial damage caused by the association of misfolded proteins with mitochondrial membranes may contribute to the atypical cell death mode induced by b-AP15 and related compounds. The robust mode of cell death induction by this class of drugs holds promise for treatment of tumor cells characterized by apoptosis resistance.
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