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- Bieghs, Liesbeth, et al.
(författare)
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The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic
- 2014
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:22, s. 11193-11208
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Tidskriftsartikel (refereegranskat)abstract
- The ABT-analogous 737, 263 and 199 are BH3 mimetics showing potent anti-myeloma (MM) activity, but only on defined molecular subgroups of MM patients presenting a Bcl-2high/Mcl-1low profile. IGF-1 is a major survival factor in MM regulating the expression of Bcl-2 proteins and might therefore be a resistance factor to these ABT-analogous. We first show that IGF-1 protected human MM cell lines (HMCLs) against ABT-737. Concurrently, the IGF-1 receptor inhibitor picropodophyllin (PPP) synergistically sensitized HMCL, primary human MM and murine 5T33MM cells to ABT-737 and ABT-199 by further decreasing cell viability and enhancing apoptosis. Knockdown of Bcl-2 by shRNA protected MM cells to ABT-737, while Mcl-1 shRNA sensitized the cells. PPP overcame the Bcl-2 dependency of ABT-737, but failed to completely overcome the protective effect of Mcl-1. In vivo, co-treatment of 5T33MM bearing mice significantly decreased tumor burden and prolonged overall survival both in a prophylactic and therapeutic setting. Interestingly, proteasome inhibitor resistant CD138- 5T33MM cells were more sensitive to ABT-737, whereas PPP alone targeted the CD138+ cells more effectively. After co-treatment, both subpopulations were targeted equally. Together, the combination of an IGF-1R inhibitor and an ABT-analogue displays synergistic anti-myeloma activity providing the rational for further (pre)clinical testing.
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| 3. |
- Valentini, Vincenzo, et al.
(författare)
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Multidisciplinary Rectal Cancer Management : 2nd European Rectal Cancer Consensus Conference (EURECA-CC2)
- 2009
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 92:2, s. 148-163
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND AND PURPOSE: During the first decade of the 21st century a number of important European randomized studies were published. In order to help shape clinical practice based on best scientific evidence from the literature, the International Conference on 'Multidisciplinary Rectal Cancer Treatment: Looking for an European Consensus' (EURECA-CC2) was organized in Italy under the endorsement of European Society of Medical Oncology (ESMO), European Society of Surgical Oncology (ESSO), and European Society of Therapeutic Radiation Oncology (ESTRO). METHODS: Consensus was achieved using the Delphi method. The document was available to all Committee members as a web-based document customized for the consensus process. Eight chapters were identified: epidemiology, diagnostics, pathology, surgery, radiotherapy and chemotherapy, treatment toxicity and quality of life, follow-up, and research questions. Each chapter was subdivided by a topic, and a series of statements were developed. Each member commented and voted, sentence by sentence thrice. Sentences upon which an agreement was not reached after voting round # 2 were openly debated during a Consensus Conference in Perugia (Italy) from 11 December to 13 December 2008. A hand-held televoting system collected the opinions of both the Committee members and the audience after each debate. The Executive Committee scored percentage consensus based on three categories: "large consensus", "moderate consensus", and "minimum consensus". RESULTS: The total number of the voted sentences was 207. Of the 207, 86% achieved large consensus, 13% achieved moderate consensus, and only 3 (1%) resulted in minimum consensus. No statement was disagreed by more than 50% of the members. All chapters were voted on by at least 75% of the members, and the majority was voted on by >85%. CONCLUSIONS: This Consensus Conference represents an expertise opinion process that may help shape future programs, investigational protocols, and guidelines for staging and treatment of rectal cancer throughout Europe.
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| 4. |
- Welinder, Karen Gjesing, et al.
(författare)
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Biochemical Foundations of Health and Energy Conservation in Hibernating Free-Ranging Subadult Brown Bear Ursus arctos
- 2016
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Ingår i: Journal of Biological Chemistry. - Rockville, USA : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 291:43, s. 22509-22523
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Tidskriftsartikel (refereegranskat)abstract
- Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating and defecating at a metabolic rate of only 25% of the summer activity rate. Nonetheless, they emerge healthy and alert in spring. We quantified the biochemical adaptations for hibernation by comparing the proteome, metabolome, and hematologic features of blood from hibernating and active free-ranging subadult brown bears with a focus on conservation of health and energy. We found that total plasma protein concentration increased during hibernation, even though the concentrations of most individual plasma proteins decreased, as did the white blood cell types. Strikingly, antimicrobial defense proteins increased in concentration. Central functions in hibernation involving the coagulation response and protease inhibition, as well as lipid transport and metabolism, were upheld by increased levels of very few key or broad-specificity proteins. The changes in coagulation factor levels matched the changes in activity measurements. A dramatic 45-fold increase in sex-hormone-binding-globulin SHBG levels during hibernation draws, for the first time, attention to its significant but unknown role in maintaining hibernation physiology. We propose that energy for the costly protein synthesis is reduced by three mechanisms, (i) dehydration, which increases protein concentration without de novo synthesis; (ii) reduced protein degradation rates due to a 6 °C reduction in body temperature, and decreased protease activity; and (iii) a marked redistribution of energy resources only increasing de novo synthesis of few key proteins. This comprehensive global data identified novel biochemical strategies for bear adaptations to the extreme condition of hibernation, and have implications for our understanding of physiology in general.
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| 5. |
- Westman, Jeanette, et al.
(författare)
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Outcome of a psychosocial health promotion intervention aimed at improving physical health and reducing alcohol use in patients with schizophrenia and psychotic disorders (MINT)
- 2019
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 208, s. 138-144
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Tidskriftsartikel (refereegranskat)abstract
- Background: Life expectancy is reduced by 19 years in men and 17 in women with psychosis in Sweden, largely due to cardiovascular disease. Aim: Assess whether a psychosocial health promotion intervention improves cardiometabolic risk factors, quality of life, and severity of illness in patients with psychotic disorders more than treatment as usual. Methods: A pragmatic intervention trial testing a manual-based multi-component health promotion intervention targeting patients with psychosis. The Swedish intervention was adapted from IMPaCT therapy, a health-promotion program based on motivational interviewing and cognitive behavioral therapy, designed to be incorporated into routine care. The intervention group consisted of 119 patients and the control group of 570 patients from specialized psychosis departments. Outcome variables were assessed 6 months before intervention during the run-in period, again at the start of intervention, and 12 months after the intervention began. The control group received treatment as usual. Results: The intervention had no significant effect on any of the outcome variables. However, BMI, waist circumference, systolic BP, heart rate, HbA1c, general health, and Clinical Global Impressions Scale score improved significantly during the run-in period before the start of the active intervention (observer effect). The multi-component design meant that treatment effects could only be calculated for the intervention as a whole. Conclusion: The results of the intervention are similar to those of the U.K. IMPaCT study, in which the modular health-promotion intervention had little effect on cardiovascular risk indicators. However, in the current study, the run-in period had a positive effect on cardiometabolic risk factors.
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