| 1. |
- Capobianco, Ivan, et al.
(författare)
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Development and internal validation of the Comprehensive ALPPS Preoperative Risk Assessment (CAPRA) score : is the patient suitable for Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS)?
- 2022
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Ingår i: Hepatobiliary surgery and nutrition. - Hong Kong : AME Publishing Company. - 2304-3881 .- 2304-389X. ; 11:1, s. 52-66
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preoperative patient selection in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is not always reliable with currently available scores, particularly in patients with primary liver tumor. This study aims to (I) to determine whether comorbidities and patients characteristics are a risk factor in ALPPS and (II) to create a score predicting 90-day mortality preoperatively. Methods: Thirteen high-volume centers participated in this retrospective multicentric study. A risk analysis based on patient characteristics, underlying disease and procedure type was performed to identify risk factors and model the CAPRA score. A nonparametric receiver operating characteristic analysis was performed to estimate the predictive ability of our score against the Charlson Comorbidity Index (CCI), the age-adjusted CCI (aCCI), the ALPPS risk score before Stage 1 (ALPPS-RS I) and Stage 2 (ALPPS-RS2). The model was internally validated applying bootstrapping. Results: A total of 451 patients were included. Mortality was 14.4%. The CAPRA score is calculated based on the following formula: (0.1*age) - (2*BSA) +1 (in the presence of primary liver tumor) +1 (in the presence of severe cardiovascular disease) +2 (in the presence of moderate or severe diabetes) +2 (in the presence of renal disease) +2 (if classic ALPPS is planned). The predictive ability was 0.837 for the CAPRA score, 0.443 for CCI, 0.519 for aCCI, 0.693 for ALPPS-RS I and 0.807 for ALPPS-RS2. After 1,000 cycles of bootstrapping the C statistic was 0.793. The accuracy plot revealed a cut-off for optimal prediction of postoperative mortality of 4.70. Conclusions: Comorbidities play an important role in ALPPS and should be carefully considered when planning the procedure. By assessing the patients preoperative condition in relation to ALPPS, the CAPRA score has a very good ability to predict postoperative mortality.
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| 2. |
- Efanov, Alexander
(författare)
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Stimulation of insulin secretion independently from changes in cytosolic free Ca²+-concentration : studies with imidazolines and inositol polyphosphates
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Insulin secretion from the islets of Langerhans is regulated by changes in glucose concentration. Glucose stimulates secretion by two mechanisms. First, it increases cytosolic free Ca2+ concentration ([Ca2+]i) by inhibition of ATP-dependent K+-channels (KATP) and induction of membrane depolarization. Second, glucose directly promotes insulin exocytosis. A number of other physiological and pharmacological stimuli, which modulate insulin secretion, can also influence either one or both of the two mentioned pathways. This study concentrates on mechanisms by which insulinotropic agents stimulate insulin exocytosis. For this purpose, we have used two groups of compounds, imidazoline derivatives and inositol polyphosphates. The imidazoline compound, RX871024, stimulated insulin secretion through interaction with several molecular targets. First, the compound inhibited activity of KATP-channels as well as voltage-gated K+-channels, which in turn led to membrane depolarization and increase in [Ca2+]i, Elevated levels of [Ca2+]i stimulated insulin exocytosis. Second, RX871024 induced an increase in insulin secretion in cells with clamped [Ca2+]i, This effect required high both ATP and Ca2+ concentrations inside the cell. Third, the compound increased diacylglycerol (DAG) concentration in the islets. Finally, inhibition of protein kinase C (PKC) and cytochrome P-450 abolished the insulinotropic effect of RX871024. We interpreted these findings as indicating that the direct effect of RX871024 on insulin exocytosis was at least in part mediated by rise in DAG concentration, by the PKC inhibitor, and InsP6 also stimulated PKC activity in HIT T15 cell homogenate which then activated PKC and increased generation of arachidonic acid (AA) metabolites. Both PKC and AA pathway activation resulted in potentiation of insulin secretion. Comparison of the effects of RX871024 and the classical antidiabetic agent glibenclamide on insulin secretion demonstrated that the imidazoline exerted stronger stimulation of insulin secretion than glibenclamide. RX871024 also produced a potent increase in insulin secretion in islets from diabetic GK rats. In non-diabetic and diabetic rats, as well as non-diabetic humans, insulinotropic activity of RX871024 was highly dependent on glucose concentration and was stronger than that of glibenclamide. Inositol polyphosphates: myo-inositol 1,3,4,5,6-pentakisphosphate (InsP5) and myoinositol 1,2,3,4,5,6-hexakisphosphate (InsP6) stimulated basal (Ca2+-independent) insulin exocytosis in permeabilized insulin secreting HIT T15 cells. The effect of inositol polyphosphates was observed only in the presence of low free Ca2+ concentrations (30 nM) as InsP6 did not potentiate Ca2+-induced insulin exocytosis. However, when added before the concentration of Ca2+ was increased, InsP6 exerted a potent priming effect on Ca2+-induced insulin exocytosis. The effects of InsP6 on insulin exocytosis have been blocked. Thus, stimulation of Ca2+-independent insulin exocytosis and priming of Ca2+-dependent insulin exocytosis by inositol polyphosphates are mediated through activation of PKC. In addition to its effects on exocytosis, InsP6 increased rates of endocytosis in HIT T15 cells at both basal and elevated free Ca2+ concentrations. It is concluded that stimulation of protein kinases with subsequent phosphorylation of cellular proteins is responsible for the effects of imidazolines and inositol polyphosphates on insulin secretion. Compounds with effects on transport and fusion of insulin containing granules are therefore potential candidates for treatment of type 2 diabetes.
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| 3. |
- Gromada, Jesper, et al.
(författare)
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Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta
- 2005
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 102:29, s. 10303-8
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Tidskriftsartikel (refereegranskat)abstract
- Cytosolic free Ca2+ plays an important role in the molecular mechanisms leading to regulated insulin secretion by the pancreatic beta cell. A number of Ca2+-binding proteins have been implicated in this process. Here, we define the role of the Ca2+-binding protein neuronal Ca2+ sensor-1 (NCS-1) in insulin secretion. In pancreatic beta cells, NCS-1 increases exocytosis by promoting the priming of secretory granules for release and increasing the number of granules residing in the readily releasable pool. The effect of NCS-1 on exocytosis is mediated through an increase in phosphatidylinositol (PI) 4-kinase beta activity and the generation of phosphoinositides, specifically PI 4-phosphate and PI 4,5-bisphosphate. In turn, PI 4,5-bisphosphate controls exocytosis through the Ca2+-dependent activator protein for secretion present in beta cells. Our results provide evidence for an essential role of phosphoinositide synthesis in the regulation of glucose-induced insulin secretion by the pancreatic beta cell. We also demonstrate that NCS-1 and its downstream target, PI 4-kinase beta, are critical players in this process by virtue of their capacity to regulate the release competence of the secretory granules.
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| 4. |
- Slieker, Roderick C, et al.
(författare)
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Identification of biomarkers for glycaemic deterioration in type 2 diabetes
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-18
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Tidskriftsartikel (refereegranskat)abstract
- We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
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