| 1. |
- Trinks, Cecilia, et al.
(author)
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The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells
- 2011
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier Science B.V., Amsterdam. - 0006-291X .- 1090-2104. ; 410:3, s. 422-427
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Journal article (peer-reviewed)abstract
- Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.
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| 2. |
- Djerf, Emelie, et al.
(author)
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ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells : inhibition by gefitinib (ZD1839)
- 2009
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In: Melanoma research. - 0960-8931 .- 1473-5636. ; 19:3, s. 156-166
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Journal article (peer-reviewed)abstract
- Members of the epidermal growth factor (EGF) family of structurally related tyrosine kinase receptors, known as the ErbB receptors (EGFR/ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) and their respective ligands, have been suggested to be involved in the development and progression of malignant melanoma. Here we investigate the effects of the ErbB1 tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) on human malignant melanoma cells (RaH3 and RaH5) in vitro. ZD1839 inhibited proliferation of exponentially growing RaH3 and RaH5 cells in a dose-dependent manner with a half-maximally effective dose of 3.5 and 2.0 mu mol/l, respectively. Cell growth was inhibited at 0.1 mu mol/l ZD1839 in both cell lines. Maximal inhibition was accomplished at 10 mu mol/l ZD1839; however, the effect was not complete as both cell lines showed a continuous slow growth during the treatment period. Flow cytometry analysis of cell-cycle distribution showed that ZD1839 treatment caused accumulation of RaH3 and RaH5 cells in the G, phase. The growth arrest induced by ZD1839 coincided with upregulation of the cyclin-dependent kinase inhibitor p27(KIP1). There was no increase in apoptosis as determined by analysis of plasma phosphatidyl serine redistribution. Western blot analysis revealed that ZD1839 substantially reduced tyrosine phosphorylation of ErbB1 as well as ErbB2 and ErbB3. This was accompanied by a concomitant decrease in Akt-phosphorylation, Erk1/2-phosphorylation, and Stat3-phosphorylation. Our results show that ZD1839 interferes with the growth of human malignant melanoma cells by cytostatic effects. These findings indicate the possible use of ErbB receptor kinase inhibitors as a novel treatment strategy in malignant melanoma.
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| 3. |
- Djerf, Emelie, et al.
(author)
-
The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
- 2011
-
In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier. - 0006-291X .- 1090-2104. ; 414:3, s. 563-568
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Journal article (peer-reviewed)abstract
- The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses less than= 5 mu M canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.
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| 4. |
- Edvinsson, Joakim, et al.
(author)
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Senior alert: A quality registry to support a standardized, structured, and systematic preventive care process for older adults
- 2015
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In: Quality Management in Health Care. - 1063-8628 .- 1550-5154. ; 24:2, s. 96-101
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Journal article (peer-reviewed)abstract
- The average life expectancy and the proportion of the elderly in the Western countries are increasing. The care processes used for the elderly are known to differ between the care providers in Sweden. Accordingly, the need to develop a system to support the processes in order to attain a standardized, structured, and systematic approach to improve preventive care processes for the elderly has been called for. The County Council of Jönköping developed a national Web-based quality registry, Senior Alert, with a focus on the following areas: falls, pressure ulcers, malnutrition, and oral health. The patients are evaluated using validated risk assessment instruments, and the care is planned, executed, evaluated. The registry supports the users to work with preventive care systematically and in a standardized way and provides feedback to the care providers on their preventive care processes. The registry helps the caregivers fulfill the preventive care according to the best available clinical knowledge and practice. The registry also provides the government and health care politicians with data for setting aims for elderly care. The registry is used in 90% of the municipalities and county councils throughout the country. The total number of risk assessments completed from 2009 to 2014 exceeded 1 000 000.
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| 5. |
- Engström, Karolina, et al.
(author)
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Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection
- 2020
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In: Molecular Genetics & Genomic Medicine. - : John Wiley & Sons. - 2324-9269. ; 8:4
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Journal article (peer-reviewed)abstract
- Background: Pathogenic variants in the SMAD3 gene affecting the TGF-beta/SMAD3 signaling pathway with aortic vessel involvement cause Loeys-Dietz syndrome 3, also known as aneurysms-osteoarthritis syndrome.Methods: Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis.Results: We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co-segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G > C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin-fixed paraffin-embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta.Conclusion: A "variant of uncertain significance" according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.
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| 6. |
- Kissopoulou, Antheia, et al.
(author)
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Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy
- 2018
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In: ESC Heart Failure. - : WILEY PERIODICALS, INC. - 2055-5822. ; 5:4, s. 716-723
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Journal article (peer-reviewed)abstract
- Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation. Genotype analysis revealed a missense MYBPC3 variant NM_000256.3:c.2618Camp;gt;A,p.(Pro873His) that presented in the homozygous form. Conflicting interpretations of pathogenicity have been reported for the Pro873His MYBPC3 variant described here. Our patient, presenting with two copies of the variant and devoid of a normal allele, progressed to end-stage heart failure, which supports the notion of a deleterious effect of this variant in the homozygous form.
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| 7. |
- Trinks, Anna, et al.
(author)
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Acute Alcohol Consumption and Motivation to Reduce Drinking Among Injured Patients in a Swedish Emergency Department
- 2012
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In: Journal on Addictions Nursing. - 1088-4602 .- 1548-7148. ; 23:3, s. 152-158
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Journal article (peer-reviewed)abstract
- Abstract: Injuries constitute a major public health problem. Millions of people are injured each year, and acute drinking is a well-known risk factor for injuries. Research suggests that acknowledgment of alcohol as a factor in an injury enhances willingness to change drinking behavior, possibly because the patient becomes aware of the negative consequences of their drinking. This study aims to investigate the prevalence of acute alcohol consumption (drinking before the event) among injury patients and to examine the importance of factors potentially associated with motivation to reduce alcohol consumption among these patients. All patients aged 18-69 years were requested to answer alcohol-related questions on a touchscreen computer. Fifteen percent of injured patients were categorized as acute drinkers, and of these, 64% reported that their injury was connected to alcohol. There were significant differences for all sociodemographic and drinking characteristics between acute drinkers and nonacute drinkers. Acute drinkers were categorized as risky drinkers to a much higher extent than nonacute drinkers. Acute drinkers had a considerably higher average weekly alcohol consumption and engaged far more frequently in heavy episodic drinking than nonacute drinkers. Acute drinkers were motivated to reduce their alcohol intake to a greater extent than nonacute drinkers; 51% were in the action, preparation, and contemplation stages, compared with 19% of the nonacute drinkers. Acute drinkers had considerably more detrimental alcohol consumption than nonacute drinkers, and the acute drinkers were more motivated to reduce their drinking than the nonacute drinkers.
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| 8. |
- Trinks, Anna, et al.
(author)
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Alcohol consumption and motivation to reduce drinking among emergency care patients in Sweden.
- 2009
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In: International Journal of Injury Control and Safety Promotion. - : Informa UK Limited. - 1745-7300 .- 1745-7319. ; 16:3, s. 133-41
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Journal article (peer-reviewed)abstract
- This study compares the alcohol consumption and motivation to reduce drinking among injured and non injured patients in a Swedish emergency department (ED). Patients aged 18-69 registered at the ED triage room were requested to answer alcohol-related questions on a touch-screen computer. Injury patients drank alcohol significantly more often than patients without injuries and in a significantly higher typical quantity than non-injury patients, yielding a significantly larger average weekly consumption. However, there were no significant differences between injury and non-injury patients with regard to heavy episodic drinking. As a consequence of injury patients being younger and more often male in comparison with non-injury patients nearly all differences between the two patient groups disappeared when controlling for age and sex. There were no significant differences in motivation to reduce drinking between injury and non-injury patients. There were small differences in the drinking variables and motivation to reduce drinking between injury patients and non-injury patients.
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| 9. |
- Trinks, Anna, 1981-
(author)
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Alcohol prevention in emergency care : Drinking patterns among patients and the impact of a computerized intervention in a Swedish Emergency department
- 2011
-
Doctoral thesis (other academic/artistic)abstract
- The aim of this thesis was to generate knowledge about alcohol consumption among patients in a Swedish ED, the reach and effectiveness of a computerized brief intervention delivered in the ED, and factors that are associated with reduced alcohol consumption 6 months after the ED visit.The results from the studies show that alcohol consumption was higher among patients who were injured than patients who were not injured. Injury patients had a higher weekly consumption, drank more frequently and drank higher typical quantities than non-injury patients. Patients who were categorized as acute drinkers had higher weekly alcohol consumption and were more frequently engaged in heavy episodic drinking (HED) than non-acute drinkers.Among the patients who took part in the computerized test, more than 15% stated that they were at the preparation stage or actively motivated to change their alcohol consumption. Of the patients who were categorized as acute drinkers, 34% were at the action or preparation stage.Among patients who were categorized as risky drinkers, 48% became non-risky drinkers at follow-up. The relative change in average weekly consumption among risky drinkers was 30% and the relative change in HED occasions per month was 37% from baseline to follow-up.Motivated to reduce alcohol consumption at baseline, influenced by just visiting the ED, considering the alcohol-related feedback information and impact from a health care provider are independent predictors for reduced alcohol consumption.
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| 10. |
- Trinks, Anna, et al.
(author)
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Reach and effectiveness of a computer-based alcohol intervention in a Swedish emergency room
- 2010
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In: International emergency nursing. - : Elsevier BV. - 1878-013X .- 1755-599X. ; 18:3, s. 138-146
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Journal article (peer-reviewed)abstract
- OBJECTIVES: This study evaluates a computerized alcohol intervention implemented in a Swedish emergency department (ED) with regard to the effectiveness of two different types of tailored brief feedback on patients drinking patterns and the reach of the intervention. METHODS: The study was a prospective, randomized controlled trial of ED patients. The designated target population was the ED population aged 18-69 years who registered at the triage room before receiving care. Patients who were categorized as risky drinkers and completed the computerized test were randomized to either a long or a short feedback. The feedback was tailored on the basis of the individual patients responses to questions on their drinking patterns. RESULTS: The computerized intervention reached 41% of the target population. Those who completed the computerized test and received the feedback were younger than those who did not receive the intervention. Among those who could be followed up, the feedback was effective in reducing the patients weekly alcohol consumption and the number of heavy episodic drinking occasions. The long feedback was slightly more effective than the short feedback, but the differences were not statistically significant.
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