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- Hassan, Saadia, et al.
(författare)
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Novel activity of acriflavine against colorectal cancer tumor cells
- 2011
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Ingår i: Cancer Science. - : Wiley. - 1347-9032 .- 1349-7006. ; 102:12, s. 2206-2213
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Tidskriftsartikel (refereegranskat)abstract
- A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.
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- Linder, Gustav, 1981-
(författare)
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Esophageal- and Gastroesophageal Junctional Cancer : Aspects on Staging, Treatment and Results
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Esophageal- and gastroesophageal junctional (GEJ) cancer is the sixth cause of cancer-related death worldwide. Some improvements in care are attributed to nationwide disease-specific registries, preoperative staging and increased understanding of mechanisms affecting patient selection. Surgery, however, is a cornerstone for treatment where minimally invasive surgery and increased understanding of perioperative physiology may be beneficial. The aims of this thesis were to validate the Swedish national registry for esophageal and gastric cancer (NREV) and to explore mechanisms in patient selection, perioperative physiology, treatment-related outcomes and staging.A validation study with re-abstracted data on 400 patients determined NREV comparable to other similar registries and to have a completeness of 95.5 %. Overall accuracy was 91.1 % throughout the registry and timeliness to reporting was adequate.In a cohort of 4112 patients from NREV, high education level was associated with an increased probability of being allocated to curative treatment, as was the presence of a multidisciplinary treatment conference. High education level was associated with improved survival.By measuring intramucosal pH (pHi) in 32 patients, to describe perfusion in the gastric conduit during esophagectomy, a reduction in perfusion was seen at all surgical steps altering vascular supply to the conduit but foremost after gastric tube construction by linear stapling. Patients with low pHi on the first postoperative day were more prone to anastomotic insufficiency.In 116 patients undergoing esophagectomy (65 open and 51 minimally invasive), a retrospective cohort study regarding surgical oncological results and postoperative complications was conducted. Lymph node yield was increased, peroperative blood loss and in-hospital stay were reduced with minimally invasive esophagectomy. Postoperative complications were unaffected by surgical approach. In a prospective study of nineteen patients, whole-body integrated PET/MRI was compared to PET/CT in preoperative staging. PET/MRI was safe and feasible. Accuracy and correlations between modalities were good regarding tumor characteristics and N- and M-staging. In T-staging there were discrepancies indicating differences between modalities.The thesis presents data on the quality of NREV for future research and elaborates on patient selection, staging, perioperative physiology and treatment-related outcomes for patients with esophageal- and GEJ cancer.
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- Spangler, Douglas, et al.
(författare)
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The Impact of the Swedish Care Coordination Act on Hospital Readmission and Length-of-Stay among Multi-Morbid Elderly Patients : A Controlled Interrupted Time Series Analysis
- 2023
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Ingår i: International Journal of Integrated Care. - : Ubiquity Press. - 1568-4156. ; 23:2
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Tidskriftsartikel (refereegranskat)abstract
- Coordinating follow-up care after discharge from hospital is critical to ensuring good outcomes for patients, but is difficult when multiple care providers are involved. In 2018, Sweden adopted the Care Coordination Act, which modified economic incentives to reduce discharge delays and mandated a discharge planning process for patients requiring post-discharge social-or primary care services. This study evaluates the impact of this reform on hospital length-of-stay and unplanned readmissions among multi-morbid elderly patients. Interrupted time series analysis of all in-patient care episodes involving multi-morbid elderly patients in Sweden from 2015 - 2019 (n = 2 386 039) was performed. Secondary analyses using case-mix adjustment and controlled interrupted time series analysis were employed to assess for bias. Average length of stay decreased during the post-reform period, corresponding to 248 521 saved care days. Unplanned readmissions meanwhile increased, corresponding to 7 572 excess unplanned readmissions. While reductions in length-of-stay were concentrated among patients targeted by the reform, increases in readmission rates were similar in patients not targeted by the reform, indicating potential confounding. The reform thus appears to have achieved its goal of decreasing in-patient length of stay, but a robust effect on readmissions, outpatient visits, or mortality was not found. This may be due to lackluster implementation or an ineffective mandated intervention.
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- Säll, Johanna, et al.
(författare)
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Insulin induces Thr484 phosphorylation and stabilization of SIK2 in adipocytes
- 2019
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Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 55, s. 73-80
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Salt-inducible kinase 2 (SIK2) is downregulated in adipose tissue from obese or insulin-resistant individuals and inhibition of SIK isoforms results in reduced glucose uptake and insulin signalling in adipocytes. However, the regulation of SIK2 itself in response to insulin in adipocytes has not been studied in detail. The aim of our work was to investigate effects of insulin on various aspects of SIK2 function in adipocytes.METHODS: Primary adipocytes were isolated from human subcutaneous and rat epididymal adipose tissue. Insulin-induced phosphorylation of SIK2 and HDAC4 was analyzed using phosphospecific antibodies and changes in the catalytic activity of SIK2 with in vitro kinase assay. SIK2 protein levels were analyzed in primary adipocytes treated with the proteasome inhibitor MG132.RESULTS: We have identified a novel regulatory pathway of SIK2 in adipocytes, which involves insulin-induced phosphorylation at Thr484. This phosphorylation is impaired in individuals with a reduced insulin action. Insulin stimulation does not affect SIK2 catalytic activity or cellular activity towards HDAC4, but is associated with increased SIK2 protein levels in adipocytes.CONCLUSION/INTERPRETATION: Our data suggest that downregulation of SIK2 in the adipose tissue of insulin-resistant individuals can partially be caused by impaired insulin signalling, which might result in defects in SIK2 expression and function.
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- Säll, Johanna, et al.
(författare)
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Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals : implications for insulin signalling and glucose uptake in human adipocytes
- 2017
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 60:2, s. 314-323
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes.METHODS: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables. SIK2 and SIK3 expression and phosphorylation were analysed in adipocytes treated with TNF-α. Glucose uptake, GLUT protein levels and localisation, phosphorylation of protein kinase B (PKB/Akt) and the SIK substrate histone deacetylase 4 (HDAC4) were analysed after the SIKs had been silenced using small interfering RNA (siRNA) or inhibited using a pan-SIK-inhibitor (HG-9-91-01).RESULTS: We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. Moreover, SIK2 protein levels and specific kinase activity display a negative correlation to BMI in human adipocytes. Furthermore, SIK2 and SIK3 are downregulated by TNF-α in adipocytes. Silencing or inhibiting SIK1-3 in adipocytes results in reduced phosphorylation of HDAC4 and PKB/Akt, less GLUT4 at the plasma membrane, and lower basal and insulin-stimulated glucose uptake in adipocytes.CONCLUSION/INTERPRETATION: This is the first study to describe the expression and function of SIKs in human adipocytes. Our data suggest that SIKs might be protective in the development of obesity-induced insulin resistance, with implications for future treatment strategies.
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