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Sökning: WFRF:(Levin Max 1969)

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1.
  • Drevinge, Christina, 1983, et al. (författare)
  • Perilipin 5 is protective in the ischemic heart
  • 2016
  • Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 219, s. 446-454
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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2.
  • Andersson, Linda, 1973, et al. (författare)
  • Deficiency in perilipin 5 reduces mitochondrial function and membrane depolarization in mouse hearts.
  • 2017
  • Ingår i: The international journal of biochemistry & cell biology. - : Elsevier BV. - 1878-5875 .- 1357-2725. ; 91:Pt A, s. 9-13
  • Tidskriftsartikel (refereegranskat)abstract
    • Myocardial triglycerides stored in lipid droplets are important in regulating the intracellular delivery of fatty acids for energy generation in mitochondria, for membrane biosynthesis, and as agonists for intracellular signaling. Previously, we showed that deficiency in the lipid droplet protein perilipin 5 (Plin5) markedly reduces triglyceride storage in cardiomyocytes and increases the flux of fatty acids into phospholipids. Here, we investigated whether Plin5 deficiency in cardiomyocytes alters mitochondrial function. We found that Plin5 deficiency reduced mitochondrial oxidative capacity. Furthermore, in mitochondria from Plin5((-/)(-)) hearts, the fatty acyl composition of phospholipids in mitochondrial membranes was altered and mitochondrial membrane depolarization was markedly compromised. These findings suggest that mitochondria isolated from hearts deficient in Plin5, have specific functional defects.
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3.
  • Andersson, Linda, 1973, et al. (författare)
  • Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking
  • 2021
  • Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:43, s. 4481-4492
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.METHODS AND RESULTS: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.CONCLUSIONS: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.
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4.
  • Andersson, Linda, 1973, et al. (författare)
  • Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischemia
  • 2015
  • Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:4, s. 478-486
  • Tidskriftsartikel (refereegranskat)abstract
    • In myocardial ischemia, vascular endothelial growth factor (VEGF) induces permeability by activating a signalling pathway that includes VEGF receptor 2 (VEGFR2), resulting in increased oedema and inflammation and thereby expanding the area of tissue damage. In this study, we investigated the role of receptor-interacting protein 2 (Rip2) in VEGF signalling and myocardial ischemia/reperfusion injury.
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5.
  • Bjursten, Sara, et al. (författare)
  • Early rise in brain damage markers and high ICOS expression in CD4+and CD8+T cells during checkpoint inhibitor-induced encephalomyelitis
  • 2021
  • Ingår i: Journal for Immunotherapy of Cancer. - : BMJ. - 2051-1426. ; 9:7
  • Tidskriftsartikel (refereegranskat)abstract
    • We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient's recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.
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6.
  • Cinato, Mathieu, et al. (författare)
  • Cardiac Plin5 interacts with SERCA2 and promotes calcium handling and cardiomyocyte contractility
  • 2023
  • Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 6:4
  • Tidskriftsartikel (refereegranskat)abstract
    • The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally prog-resses to heart failure, physiological hypertrophy may be car-dioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear whether this response is beneficial. We analyzed RNA -sequencing data from human left ventricle and showed that car-diac PLIN5 expression correlates with up-regulation of cardiac contraction-related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression of Plin5 (MHC-Plin5 mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) as a Plin5-interacting protein. In situ proximity ligation assay further confirmed the Plin5/SERCA2 interaction. Live imaging showed in-creases in intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function in MHC-Plin5 versus WT cardiomyocytes. These results identify a role of Plin5 in improving cardiac contractility through enhanced Ca2+ signaling.
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7.
  • Ekstrand, Matias, et al. (författare)
  • Depletion of ATP and glucose in advanced human atherosclerotic plaques
  • 2017
  • Ingår i: PLoS One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Severe hypoxia develops close to the necrotic core of advanced human atherosclerotic plaques, but the energy metabolic consequences of this hypoxia are not known. In animal models, plaque hypoxia is also associated with depletion of glucose and ATP. ATP depletion may impair healing of plaques and promote necrotic core expansion. To investigate if ATP depletion is present in human plaques, we analyzed the distribution of energy metabolites (ATP, glucose, glycogen and lactate) in intermediate and advanced human plaques.Snap frozen carotid endarterectomies from 6 symptomatic patients were analyzed. Each endarterectomy included a large plaque ranging from the common carotid artery (CCA) to the internal carotid artery (ICA). ATP, glucose, and glycogen concentrations were lower in advanced (ICA) compared to intermediate plaques (CCA), whereas lactate concentrations were higher. The lowest concentrations of ATP, glucose and glycogen were detected in the perinecrotic zone of advanced plaques.Our study demonstrates severe ATP depletion and glucose deficiency in the perinecrotic zone of human advanced atherosclerotic plaques. ATP depletion may impair healing of plaques and promote disease progression.
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8.
  • Glise, Lars, 1988, et al. (författare)
  • pH-Dependent Protonation of Histidine Residues Is Critical for Electrostatic Binding of Low-Density Lipoproteins to Human Coronary Arteries
  • 2022
  • Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 42:8, s. 1037-1047
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The initiating step in atherogenesis is the electrostatic binding of LDL (low-density lipoprotein) to proteoglycan glycosaminoglycans in the arterial intima. However, although proteoglycans are widespread throughout the intima of most coronary artery segments, LDL is not evenly distributed, indicating that LDL retention is not merely dependent on the presence of proteoglycans. We aim to identify factors that promote the interaction between LDL and the vessel wall of human coronary arteries. Methods: We developed an ex vivo model to investigate binding of labeled human LDL to human coronary artery sections without the interference of cellular processes. Results: By staining consecutive sections of human coronary arteries, we found strong staining of sulfated glycosaminoglycans throughout the arterial intima, whereas endogenous LDL deposits were focally distributed. Ex vivo binding of LDL was uniform at all intimal areas with sulfated glycosaminoglycans. However, lowering the pH from 7.4 to 6.5 triggered a 35-fold increase in LDL binding. The pH-dependent binding was abolished by pretreating LDL with diethyl-pyrocarbonate, which blocks the protonation of histidine residues, or cyclohexanedione, which inhibits the positive charge of site B on LDL. Thus, both histidine protonation and site B are required for strong electrostatic LDL binding to the intima. Conclusions: This study identifies histidine protonation as an important component for electrostatic LDL binding to human coronary arteries. Our findings show that the local pH will have a profound impact on LDL's affinity for sulfated glycosaminoglycans, which may influence the retention and accumulation pattern of LDL in the arterial vasculature.
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9.
  • Jernås, Margareta, 1961, et al. (författare)
  • Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression
  • 2006
  • Ingår i: The FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 20
  • Tidskriftsartikel (refereegranskat)abstract
    • Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+-3.54 um) and large cells (mean 100.1+-3.94 um). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.
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10.
  • Magnusson, Lisa U., 1975, et al. (författare)
  • Arachidonate 15-Lipoxygenase Type B Knockdown Leads to Reduced Lipid Accumulation and Inflammation in Atherosclerosis
  • 2012
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Inflammation in the vascular wall is important for development of atherosclerosis. We have shown previously that arachidonate 15-lipoxygenase type B (ALOX15B) is more highly expressed in human atherosclerotic lesions than in healthy arteries. This enzyme oxidizes fatty acids to substances that promote local inflammation and is expressed in lipid-loaded macrophages (foam cells) present in the atherosclerotic lesions. Here, we investigated the role of ALOX15B in foam cell formation in human primary macrophages and found that silencing of human ALOX15B decreased cellular lipid accumulation as well as proinflammatory cytokine secretion from macrophages. To investigate the role of ALOX15B in promoting the development of atherosclerosis in vivo, we used lentiviral shRNA silencing and bone marrow transplantation to knockdown mouse Alox15b gene expression in LDL-receptor-deficient (Ldlr(-/-)) mice. Knockdown of mouse Alox15b in vivo decreased plaque lipid content and markers of inflammation. In summary, we have shown that ALOX15B influences progression of atherosclerosis, indicating that this enzyme has an active proatherogenic role.
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11.
  • Mardani, Ismena, et al. (författare)
  • Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart.
  • 2019
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Myocardial dysfunction is commonly associated with accumulation of cardiac lipid droplets (LDs). Perilipin 2 (Plin2) is a LD protein that is involved in LD formation, stability and trafficking events within the cell. Even though Plin2 is highly expressed in the heart, little is known about its role in myocardial lipid storage. A recent report shows that cardiac overexpression of Plin2 result in massive myocardial steatosis suggesting that Plin2 stabilizes LDs. In this study, we hypothesized that deficiency in Plin2 would result in reduced myocardial lipid storage. In contrast to our hypothesis, we found increased accumulation of triglycerides in hearts, and specifically in cardiomyocytes, from Plin2-/- mice. Although Plin2-/- mice had markedly enhanced lipid levels in the heart, they had normal heart function under baseline conditions and under mild stress. However, after an induced myocardial infarction, stroke volume and cardiac output were reduced in Plin2-/- mice compared with Plin2+/+ mice. We further demonstrated that the increased triglyceride accumulation in Plin2-deficient hearts was caused by altered lipophagy. Together, our data show that Plin2 is important for proper hydrolysis of LDs.
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12.
  • Pandita, Ankur, et al. (författare)
  • Intussusceptive angiogenesis in human metastatic malignant melanoma. : Intussusception in human melanoma
  • 2021
  • Ingår i: The American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 191:11, s. 2023-2038
  • Tidskriftsartikel (refereegranskat)abstract
    • Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. The limited effect may be explained by an additional, less vascular endothelial growth factor-driven, form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered BRAF-induced, PTEN-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cell infiltration were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, invitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation invitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.
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13.
  • Perman Sundelin, Jeanna, et al. (författare)
  • Increased Expression of the Very Low-Density Lipoprotein Receptor Mediates Lipid Accumulation in Clear-Cell Renal Cell Carcinoma
  • 2012
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Clear-cell renal cell carcinoma (RCC) is, in most cases, caused by loss of function of the tumor suppressor gene von Hippel-Lindau, resulting in constitutive activation of hypoxia-inducible factor (HIF)-1 alpha and expression of hypoxia-induced genes in normoxic conditions. Clear-cell RCC cells are characterized histologically by accumulation of cholesterol, mainly in its ester form. The origin of the increased cholesterol remains unclear, but it is likely explained by an HIF-1 alpha-driven imbalance between cholesterol uptake and excretion. Here, we showed that expression of the very low-density lipoprotein receptor (VLDL-R) was significantly increased in clear-cell RCC human biopsies compared with normal kidney tissue. Partial knockdown of HIF-1 alpha in clear-cell RCC cells significantly reduced the VLDL-R expression, and knockdown of either HIF-1 alpha or VLDL-R reduced the increased lipid accumulation observed in these cells. We also showed increased uptake of fluorescently labeled lipoproteins in clear-cell RCC cells, which was significantly reduced by knockdown of HIF-1 alpha or VLDL-R. Taken together, our results support the concept that the pathological increase of HIF-1 alpha in clear-cell RCC cells upregulates VLDL-R, which mediates increased uptake and accumulation of lipids. These results explain the morphological characteristics of clear-cell RCC, and open up novel possibilities for detection and treatment of clear-cell RCC.
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14.
  • Pirazzi, Carlo, et al. (författare)
  • Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro
  • 2012
  • Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 57:6, s. 1276-1282
  • Tidskriftsartikel (refereegranskat)abstract
    • Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins. Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 1481 wild type or 148M mutant PNPLA3 protein. Results: In humans, carriers of the PNPLA3 148M allele had increased liver fat compared to 1481 homozygotes, and kinetic analysis showed a relatively lower secretion of the large, triglyceride-rich VLDL (VLDL1) in 148M carriers vs. 1481 homozygotes for the same amount of liver fat. McA-RH 7777 cells overexpressing the 148M mutant protein showed a higher intracellular triglyceride content with a lower apoB secretion and fatty acid efflux, compared to cells overexpressing the 1481 wild type protein. The responses with 148M matched those observed in cells expressing the empty vector, indicating that the mutation results in loss of function. Conclusions: We have shown that PNPLA3 affects the secretion of apoB-containing lipoproteins both in humans and in vitro and that the 148M protein is a loss-of-function mutation. We propose that PNPLA3 148M promotes intracellular lipid accumulation in the liver by reducing the lipidation of VLDL.
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15.
  • Sjöberg, Sara, 1979, et al. (författare)
  • CD44-deficiency on hematopoietic cells limits T-cell number but does not protect against atherogenesis in LDL receptor-deficient mice
  • 2009
  • Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 206:2, s. 369-374
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Vascular and inflammatory cells express adhesion molecule CD44. We demonstrated previously that enhanced CD44 localizes in human atherosclerotic lesions. Apolipoprotein E/cd44 double-deficient mice and apolipoprotein E-deficient mice transplanted with CD44-deficient bone marrow (BM) exhibit reduced atherosclerosis. Since CD44 is a novel factor in atherogenesis, it is imperative that it is investigated in more than one animal model to conclusively determine its role in this particular disease pathology. To test the hypothesis that CD44 expressed by hematopoietic cells plays a critical role in atherogenesis in the low density lipoprotein (LDL) receptor-deficient mouse model, we performed BM reconstitution experiments.METHODS: Lethally irradiated LDL receptor-deficient mice were transplanted with either CD44-deficient or wild-type BM. Beginning 10 weeks after successful reconstitution, mice consumed a cholesterol-enriched atherogenic diet for 6 or 11 weeks.RESULTS: Surprisingly, CD44-deficiency on BM-derived inflammatory cells did not affect lesion size. Additionally, neither group displayed differences in smooth muscle cell, macrophage, collagen, or elastin content as well as lipoprotein levels. However, lesions in CD44-deficient BM-recipient mice contained fewer T-cells compared to wild-type BM mice. Interestingly, CD44-deficient T-cells expressed less chemokine receptor-5 mRNA. Furthermore, in vivo leukocyte adhesion decreased in CD44-deficient mice compared to wild-type mice.CONCLUSION: This study surprisingly revealed that atherogenesis does not require CD44 expression on hematopoietic cells in the LDL receptor-deficient mouse model. However, CD44 promotes T-cell recruitment, downregulates chemokine receptor-5, and participates critically in leukocyte adhesion in vivo. Consequently, the anti-atherogenic role of CD44 may require CD44-deficiency on cell types other than inflammatory cells in the LDL receptor-deficient mouse model.
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16.
  • Alexanderson, Camilla, 1978, et al. (författare)
  • A single early postnatal estradiol injection affects morphology and gene expression of the ovary and parametrial adipose tissue in adult female rats.
  • 2010
  • Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 122:1-3, s. 82-90
  • Tidskriftsartikel (refereegranskat)abstract
    • Events during early life can affect reproductive and metabolic functions in adulthood. We evaluated the programming effects of a single early postnatal estradiol injection (within 3h after birth) in female rats. We assessed ovarian and parametrial adipose tissue morphology, evaluated gene expression related to follicular development and adipose tissue metabolism, and developed a non-invasive volumetric estimation of parametrial adipose tissue by magnetic resonance imaging. Estradiol reduced ovarian weight, increased antral follicle size and number of atretic antral follicles, and decreased theca interna thickness in atretic antral follicles. Adult estradiol-injected rats also had malformed vaginal openings and lacked corpora lutea, confirming anovulation. Estradiol markedly reduced parametrial adipose tissue mass. Adipocyte size was unchanged, suggesting reduced adipocyte number. Parametrial adipose tissue lipoprotein lipase activity was increased. In ovaries, estradiol increased mRNA expression of adiponectin, complement component 3, estrogen receptor alpha, and glucose transporter 3 and 4; in parametrial adipose tissue, expression of complement component 3 was increased, expression of estrogen receptor alpha was decreased, and expression of leptin, lipoprotein lipase, and hormone-sensitive lipase was unaffected. These findings suggest that early postnatal estradiol exposure of female rats result in long-lasting effects on the ovary and parametrial adipose tissue at adult age.
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17.
  • Arheden, A., et al. (författare)
  • Real-world data on PD-1 inhibitor therapy in metastatic melanoma
  • 2019
  • Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 58:7, s. 962-966
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Phase III studies of PD-1 inhibitors have demonstrated remarkable improvements in the survival of patients with metastatic melanoma (MM). If these results are generalizable to an unselected patient population treated in clinical routine is unknown. This study aimed to investigate and describe clinical efficacy and safety of PD-1 inhibitors in patients with MM treated in routine clinical practice. Material and methods: A retrospective descriptive study of patients with metastatic or inoperable cutaneous melanoma treated with PD-1 inhibitors at a single institution (Department of Oncology, Sahlgrenska University Hospital) from 1 September 2015 to 31 August 2017. Data were obtained from medical records. Results: A total of 116 patients were included in the analyses. The overall survival (OS) at 12-month follow-up was 70.2% and the median OS was 27.9 months. Patients with BRAF mutated tumors had increased OS, whereas ECOG PS >= 2, LDH > ULN and presence or history of brain metastases (stage M1d) were associated with impaired survival. Immune-related AEs of any grade occurred in 64 (55.2%) patients and 15 (12.9%) patients experienced immune-related AEs of grades 3 and 4. Notably, rheumatic adverse events occurred at a higher rate (15.5%) than previously reported. The occurrence of immune-related AEs was associated with a benefit in OS, while the severity of immune-related AEs did not affect survival, nor did the use of systemic corticosteroids. Conclusions: The efficacy and safety of PD1 inhibitors in routine clinical practice appear comparable to that described in clinical trials.
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18.
  • Bandaru, Sashidar, et al. (författare)
  • Targeting filamin A reduces macrophage activity and atherosclerosis. : Filamin A in atherogenesis
  • 2019
  • Ingår i: Circulation. - 1524-4539. ; 140:1, s. 67-79
  • Tidskriftsartikel (refereegranskat)abstract
    • The actin-binding protein FLNA (filamin A) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored.We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice ( Flna o/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter ( LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna o/fl/ LC mice to atherogenic low-density lipoprotein receptor-deficient ( Ldlr-/-) mice; and by infecting Flna o/fl and Flna o/fl/ LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage.We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques. Flna o/fl/ LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; exhibited reduced foam cell formation and lipid uptake; and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr-/-BMT: Flnao/fl/LC and AdPCSK9-infected Flna o/fl/ LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient mice than in control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl-terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, interleukin 6 secretion, foam cell formation, and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9.Genetic inactivation of Flna and chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis.
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19.
  • Bjursten, Sara, et al. (författare)
  • Concentrations of S100B and neurofilament light chain in blood as biomarkers for checkpoint inhibitor-induced CNS inflammation
  • 2024
  • Ingår i: EBioMedicine. - 2352-3964. ; 100
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Cancer treatment with immune checkpoint inhibition (ICI) can cause immune -related adverse events in the central nervous system (CNS irAE). There are no blood biomarkers to detect CNS irAE. We investigated if concentrations of S100 -calcium -binding protein B (S100B) and neurofilament light chain (NfL) in blood can be used as biomarkers for CNS irAE and assessed the incidence of CNS irAE in a cohort of ICI -treated patients. Methods In this single -centre, retrospective cohort study, we examined medical records and laboratory data of 197 consecutive patients treated with combined CTLA-4 and PD -1 inhibition (ipilimumab; ipi + nivolumab; nivo) for metastatic melanoma or renal cell carcinoma. CNS irAE was diagnosed using established criteria. Concentrations of S100B and NfL in blood were measured in patients with CNS irAE and in 84 patients without CNS irAE. Findings Nine of 197 patients (4.6%) fulfilled criteria for CNS irAE. S100B and NfL in blood increased during CNS inflammation and normalized during immunosuppression. CNS irAE was detected with a sensitivity of 100% (S100B) and 79% (NfL) and a specificity of 89% (S100B) and 74% (NfL). Patients with CNS irAE had simultaneous increased concentration of C -reactive protein (CRP) (9/9) and alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) in blood (8/9). Interpretation Analysis of S100B, NfL and CRP in blood facilitates the diagnosis of CNS irAE. CNS irAE may be more common than previously reported. There may be shared immune mechanisms between CNS and hepatitis irAE.
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20.
  • Bjursten, Sara, et al. (författare)
  • Response to BRAF/MEK Inhibition in A598_T599insV BRAF Mutated Melanoma
  • 2019
  • Ingår i: Case Reports in Oncology. - : S. Karger AG. - 1662-6575. ; 12:3, s. 872-879
  • Tidskriftsartikel (refereegranskat)abstract
    • Approximately 50% of patients with metastatic melanoma harbor an activating BRAF mutation. Tumors with activating mutation BRAF gene proliferate excessively and can be treated with targeted BRAF-inhibitors in combination with MEK inhibitors. The most common BRAF mutation occurs at amino acid position 600. Other BRAF mutations are rare and their predictive value for treatment response to BRAF/MEK inhibition is low. Here, we report on a patient with a BRAF A598_T599insV mutated melanoma, a mutation that has only been described in one previous melanoma patient in which the treatment response to BRAF/MEK inhibition was transient. Our patient had a large ulcerated metastasis that showed a durable complete response implying that BRAF/MEK inhibition should be considered a treatment option for this mutation. We analyzed circulating cell-free tumor DNA (ctDNA) carrying the BRAF A598_T599insV mutation throughout treatment. The allele frequency of BRAF A598_T599insV decreased during regression of the tumors, indicating that this method has potential to monitor treatment response. Our case demonstrates durable response to BRAF/MEK inhibition in a melanoma patient carrying a BRAF A598_T599insV mutation. In addition, we show that allele frequency analysis of A598_T599insV mutation in blood using ultrasensitive sequencing can be used to monitor treatment response.
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21.
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22.
  • Björnheden, Tom, 1945, et al. (författare)
  • Computerized determination of adipocyte size.
  • 2004
  • Ingår i: Obesity research. - 1071-7323. ; 12:1, s. 95-105
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Fat cell size is a fundamental parameter in the study of adipose tissue metabolism, because it markedly influences the cellular rates of metabolism. Previous techniques for the sizing of adipocytes are often complicated or time-consuming. The aim of this study was to develop a new, computerized method for rapid and accurate determination of adipocyte size in a cell suspension obtained by incubating human or rat adipose tissue biopsies with collagenase. RESEARCH METHODS AND PROCEDURES: The cell suspension was placed between a siliconized glass slide and a cover slip. Using the reference method [designated as (R)], the cell diameters were determined manually using a microscope with a calibrated ocular. The new method presented here [designated as (C)] was based on computerized image analysis. RESULTS: After two well-defined corrective adjustments, measurements with (R) and (C) agreed very well. The small remaining differences seemed, in fact, to depend on inconsistencies in (R). DISCUSSION: We propose that (C) constitutes a valuable tool to study fat cell size, because this method is fast and allows the assessment of a sufficient number of cells to get reliable data on size distribution. Furthermore, images of cell preparations may be stored for future reference.
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23.
  • Bondeson, Lisa, et al. (författare)
  • Clinical outcomes in cancer patients with COVID-19 in Sweden.
  • 2021
  • Ingår i: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; 60:12, s. 1572-1579
  • Tidskriftsartikel (refereegranskat)abstract
    • The results of studies on the relationship between cancer and COVID-19 have been conflicting and therefore further studies are needed. We aimed to examine the incidence of COVID-19 among patients at one of the largest oncology departments in Sweden, and to evaluate and identify risk factors for poor outcomes, hospital care and death, associated with COVID-19 among cancer patients.This retrospective study included cancer patients at a single center who tested positive for SARS-CoV-2 by PCR either in hospital, primary health care center or commercial laboratory between 1 March and 14 August 2020. Clinical and demographic data were collected from the medical records. Logistic regression analysis was used to identify variables that associated the primary outcomes of need for hospital care and death within 30days of positive test.Of 10,774 patients from the Department of Oncology at Sahlgrenska University Hospital, 135 tested positive for SARS-CoV-2 (1.3%). Twenty-eight patients were excluded from further the data collection since they did not meet the inclusion criteria. Altogether, 107 cancer patients were included and the case fatality rate (CFR) was 12% (13) within 30days of confirmed SARS-CoV-2 infection by PCR. Increasing years of age (OR 1.10; CI 95% 1.03-1.18), palliative treatment intent (OR 15.7; CI 95% 1.8-135.8), and transition to end-of-life care (OR 52.0; CI 95% 3.7-735.6) were associated with increased odds of death within 30days. Male sex was associated with needing hospital care (OR 3.7; CI 95% 1.50-9.1).As in the general population, male sex was found to be at greater risk of needing hospital care for COVID-19, with terminal cancer disease, and older age increasing the odds of fatality. Compared to the general population, slightly more cancer patients had COVID-19. The CFR was within the lower range of others reported in cancer patients.
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24.
  • Bratulic, Sinisa, 1981, et al. (författare)
  • Analysis of normal levels of free glycosaminoglycans in urine and plasma in adults
  • 2022
  • Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 298:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Plasma and urine glycosaminoglycans (GAGs) are long, linear sulfated polysaccharides that have been proposed as potential noninvasive biomarkers for several diseases. However, owing to the analytical complexity associated with the measurement of GAG concentration and disaccharide composition (the so-called GAGome), a reference study of the normal healthy GAGome is currently missing. Here, we prospectively enrolled 308 healthy adults and analyzed their free GAGomes in urine and plasma using a standardized ultra-high-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry method together with comprehensive demographic and blood chemistry biomarker data. Of 25 blood chemistry biomarkers, we mainly observed weak correlations between the free GAGome and creatinine in urine and hemoglobin or erythrocyte counts in plasma. We found a higher free GAGome concentration - but not a more diverse composition - in males. Partitioned by gender, we also established reference intervals for all detectable free GAGome features in urine and plasma. Finally, we carried out a transference analysis in healthy individuals from two distinct geographical sites, including data from the Lifelines Cohort Study, which validated the reference intervals in urine. Our study is the first large-scale determination of normal free GAGomes reference intervals in plasma and urine and represents a critical resource for future physiology and biomarker research. © 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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25.
  • Bratulic, Sinisa, 1981, et al. (författare)
  • Noninvasive detection of any-stage cancer using free glycosaminoglycans.
  • 2022
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 119:50
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (Nurine = 220 cancer vs. 360 healthy) and plasma (Nplasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.
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26.
  • Carow, Berit, et al. (författare)
  • Immune mapping of human tuberculosis and sarcoidosis lung granulomas
  • 2024
  • Ingår i: FRONTIERS IN IMMUNOLOGY. - 1664-3224. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Tuberculosis (TB) and sarcoidosis are both granulomatous diseases. Here, we compared the immunological microenvironments of granulomas from TB and sarcoidosis patients using in situ sequencing (ISS) transcriptomic analysis and multiplexed immunolabeling of tissue sections. TB lesions consisted of large necrotic and cellular granulomas, whereas "multifocal" granulomas with macrophages or epitheloid cell core and a T-cell rim were observed in sarcoidosis samples. The necrotic core in TB lesions was surrounded by macrophages and encircled by a dense T-cell layer. Within the T-cell layer, compact B-cell aggregates were observed in most TB samples. These B-cell clusters were vascularized and could contain defined B-/T-cell and macrophage-rich areas. The ISS of 40-60 immune transcripts revealed the enriched expression of transcripts involved in homing or migration to lymph nodes, which formed networks at single-cell distances in lymphoid areas of the TB lesions. Instead, myeloid-annotated regions were enriched in CD68, CD14, ITGAM, ITGAX, and CD4 mRNA. CXCL8 and IL1B mRNA were observed in granulocytic areas in which M. tuberculosis was also detected. In line with ISS data indicating tertiary lymphoid structures, immune labeling of TB sections expressed markers of high endothelial venules, follicular dendritic cells, follicular helper T cells, and lymph-node homing receptors on T cells. Neither ISS nor immunolabeling showed evidence of tertiary lymphoid aggregates in sarcoidosis samples. Together, our finding suggests that despite their heterogeneity, the formation of tertiary immune structures is a common feature in granulomas from TB patients.
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27.
  • Ekstrand, Matias, et al. (författare)
  • Imaging of Intracellular and Extracellular ROS Levels in Atherosclerotic Mouse Aortas Ex Vivo: Effects of Lipid Lowering by Diet or Atorvastatin
  • 2015
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective The first objective was to investigate if intracellular and extracellular levels of reactive oxygen species (ROS) within the mouse aorta increase before or after diet-induced lesion formation. The second objective was to investigate if intracellular and extracellular ROS correlates to cell composition in atherosclerotic lesions. The third objective was to investigate if intracellular and extracellular ROS levels within established atherosclerotic lesions can be reduced by lipid lowering by diet or atorvastatin. To address our objectives, we established a new imaging technique to visualize and quantify intracellular and extracellular ROS levels within intact mouse aortas ex vivo. Using this technique, we found that intracellular, but not extracellular, ROS levels increased prior to lesion formation in mouse aortas. Both intracellular and extracellular ROS levels were increased in advanced lesions. Intracellular ROS correlated with lesion content of macrophages. Extracellular ROS correlated with lesion content of smooth muscle cells. The high levels of ROS in advanced lesions were reduced by 5 days high dose atorvastatin treatment but not by lipid lowering by diet. Atorvastatin treatment did not affect lesion inflammation (aortic arch mRNA levels of CXCL 1, ICAM-1, MCP-1, TNF-alpha, VCAM, IL-6, and IL-1 beta) or cellular composition (smooth muscle cell, macrophage, and T-cell content). Aortic levels of intracellular ROS increase prior to lesion formation and may be important in initiation of atherosclerosis. Our results suggest that within lesions, macrophages produce mainly intracellular ROS whereas smooth muscle cells produce extracellular ROS. Short term atorvastatin treatment, but not lipid lowering by diet, decreases ROS levels within established advanced lesions; this may help explain the lesion stabilizing and anti-inflammatory effects of long term statin treatment.
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28.
  • Friederich-Persson, M., et al. (författare)
  • Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induces Nephropathy Independently of Hyperglycemia and Oxidative Stress
  • 2013
  • Ingår i: Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0194-911X .- 1524-4563. ; 62:5, s. 914-919
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.
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29.
  • Gatto, Mariele, et al. (författare)
  • Early increase of circulating transitional B cells and autoantibodies to joint-related proteins in patients with metastatic melanoma developing checkpoint inhibitor-induced inflammatory arthritis.
  • 2023
  • Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 75:5, s. 856-863
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate potential associations between B cell-related immunological changes and development of inflammatory arthritis (IA) after treatment with immune checkpoint inhibitors (ICI).Patients who developed IA (ICI-IA) and patients who did not develop immune-related adverse events (non-irAE) after receiving ICI due to metastatic melanoma were consecutively recruited. Blood samples were collected at the time of ICI-IA occurrence and at different timepoints during treatment. Peripheral blood B cell subsets during ICI treatment were analyzed by flow cytometry. Rheumatoid factor, autoantibodies against citrullinated peptides and against joint-related proteins were measured.Proportions of CD19+ B cells were higher in patients with ICI-IA (n=7) vs. non-irAE (n=15; median (interquartile range, IQR), %: 11.7 (9.7-16.2) vs. 8.1 (5.7-11.0), p=0.03). The proportion and absolute numbers of transitional CD19+ CD10+ CD24hi CD38hi B cells were increased in patients with ICI-IA vs. non-irAE (median (IQR); %: 8.1 (4.9-12.1) vs. 3.6 (1.9-4.9); cells/μl: 10.7 (8.9-19.6) vs. 4.4 (2.3-6.6), p<0.01 for both), and higher levels of transitional B cells were associated with development of ICI-IA (OR 95% CI: 2.25 (1.03-4.9), p=0.04). Transitional B cells increased before the onset of overt ICI-IA and decreased from active to quiescent ICI-IA (p=0.02). Autoantibodies to collagen II epitopes were detected in up to 43% of ICI-IA patients compared to none of the non-irAE patients (p=0.02).Development of ICI-IA is accompanied by an increase in transitional B cells and by production of autoantibodies to joint-related proteins. Monitoring of B cell-driven abnormalities upon ICI treatment may help earlier recognition of ICI-IA. This article is protected by copyright. All rights reserved.
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30.
  • Helgadottir, H., et al. (författare)
  • Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations
  • 2020
  • Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 57:5, s. 316-321
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. Methods CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. Results Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). Conclusion Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.
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31.
  • Jespersen, Henrik, et al. (författare)
  • Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study): protocol for a multicenter phase II open label study.
  • 2019
  • Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 19:1
  • Tidskriftsartikel (refereegranskat)abstract
    • While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200mg intravenously every third week in combination with entinostat 5mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24months.The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.
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32.
  • Johansson, I, et al. (författare)
  • PD-1 inhibitor therapy of basal cell carcinoma with pulmonary metastasis. : PD-1 inhibition in basal cell carcinoma
  • 2022
  • Ingår i: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 1468-3083 .- 0926-9959. ; 36:Suppl 1, s. 70-73
  • Tidskriftsartikel (refereegranskat)abstract
    • Basal cell carcinoma (BCC) may be challenging to differentiate from basaloid squamous cell carcinoma (bSCC), both clinically and histologically. BCC constitutes one of the most common tumours and metastatic behaviour is extremely rare. In contrast, bSCC is a rare entity with an increased propensity for distant metastasis. If these conditions develop into inoperable metastatic disease, the therapeutic alternatives are different, but the use of PD-1 inhibitors may be a valid option for both. Here, we report a case with complex histology with a component initially classified as bSCC with lung metastases and treated with the PD-1 inhibitor cemiplimab resulting in radiological and clinical responses. Re-examination of the lung biopsy using routine histomorphology in combination with immunohistochemical staining for cytokeratin 14, cytokeratin17 and BerEp4 has, however, revealed a histopathological pattern of BCC, which is in concordance with a similar analysis of the cutaneous primary tumour in the face that the patient underwent surgery for more than 5years earlier.
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33.
  • Leppanen, Olli, et al. (författare)
  • ATP depletion in macrophages in the core of advanced rabbit atherosclerotic plaques in vivo
  • 2006
  • Ingår i: Atherosclerosis. ; 188:2, s. 323-30
  • Tidskriftsartikel (refereegranskat)abstract
    • The cores of rabbit plaques in vivo are hypoxic, suggesting that ATP depletion due to an insufficient supply of oxygen and nutrients could contribute to macrophage death in atherosclerotic plaques. During hypoxia, however, macrophages maintain ATP levels by anaerobic glycolysis. To directly assess ATP and glucose metabolites in plaques in vivo, we used bioluminescence imaging to map the concentrations of ATP, glucose, glycogen, and lactate in normal and atherosclerotic rabbit aortas in vivo. Hypoxia was assessed with NITP (7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline). Normal aortas and plaques <500 microm thick were not hypoxic and had homogenous concentrations of energy metabolites. In plaques >500 microm thick, however, the cores were characterized by ATP depletion, low concentrations of glucose and glycogen, and a high concentration of lactate. A majority of ATP-depleted macrophages within the core were viable but severely hypoxic and glucose depleted. Hyperoxia in vitro reversed the ATP depletion in macrophages in viable areas of the core. Our findings suggest that ATP depletion contributes to the death of macrophages in atherosclerotic lesions and to the formation of a necrotic core.
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34.
  • Leppänen, Olli, et al. (författare)
  • Bioluminescence imaging of energy depletion in vascular pathology: Patent ductus arteriosus and atherosclerosis
  • 2012
  • Ingår i: Journal of Biophotonics. - : Wiley. - 1864-063X .- 1864-0648. ; 5, s. 336-344
  • Forskningsöversikt (refereegranskat)abstract
    • The artery wall may develop energy depletion due to insufficient nutritional supply. However, until recently it has not been possible to validate this hypothesis because no available technology has allowed assessment of energy metabolism with sufficient spatial resolution. We use high resolution bioluminescence metabolic imaging to study energy metabolism in two mechanistically different vascular pathologies: patent ductus arteriosus and atherosclerosis. Physiological energy depletion in postnatally constricting ductus arteriosus promotes permanent closure. Insufficient ductus energy depletion, common in preterm infants, is associated with persistent patent ductus arteriosus, a condition with significantly increased morbidity and mortality. In contrast, in atherosclerosis, energy depletion in the macrophage-rich lesion core promotes cell death contributing to lesion instability and disease progression. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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35.
  • Levin, Max, 1969, et al. (författare)
  • ATP depletion and cell death in the neonatal lamb ductus arteriosus
  • 2005
  • Ingår i: Pediatr Res. - 0031-3998. ; 57:6, s. 801-805
  • Tidskriftsartikel (refereegranskat)abstract
    • Postnatal constriction of the full-term ductus arteriosus produces cell death and remodeling of the ductus wall. Using a bioluminescence imaging technique, we found that after birth, the lamb ductus develops ATP, glucose, and glycogen depletion in addition to hypoxia. In vitro studies showed that cell death correlates best with ATP depletion and is most marked when both glucose and oxygen are severely depleted; in addition, the degree of ATP depletion found in vivo is sufficient to account for the extensive degree of cell death that occurs after birth. Under hypoxic conditions, the immature ductus is more capable of preserving its ATP supply than the mature ductus as a result of increased glucose availability, glycogen stores, and glucose utilization. However, the immature ductus is just as susceptible as the mature ductus to ATP depletion when glucose supplies are restricted. The extensive degree of cell death that occurs in the newborn ductus after birth is associated primarily with ATP depletion. The increased glycolytic capacity of the immature ductus may enable it to tolerate episodes of hypoxia and nutrient shortage, making it more resistant to developing postnatal cell death and permanent closure.
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36.
  • Levin, Max, 1969 (författare)
  • Energy metabolic failure within the arterial wall in atherosclerosis
  • 2001
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Atherosclerosis is a disease that affects large and medium sized arteries. The majority of deaths in a Western population can be directly attributed to complications of this disease. Although research efforts have been vast, the pathophysiological mechanisms underlying atherosclerosis are not fully understood. According to the anoxemia theory of atherosclerosis, an imbalance between the demand for and supply of oxygen and nutrients at depth of the arterial wall is a key factor in the development of atherosclerotic lesions. In vitro evidence indicates that zones of hypoxia occur at depth of the atherosclerotic plaque. However, the energy metabolic characteristics of the arterial wall in vivo are not fully described.The focus of this study was to study different aspects of arterial wall energy metabolism in vivo. The hypoxia marker 7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline (NITP) was used to study arterial wall hypoxia. The technique of hypoxia markers have been developed in cancer research and have not previously been used on arterial tissue in vivo. In short, hypoxia markers are trapped in hypoxic, but viable, cells and can be detected in tissue sections with immunohistochemistry. NITP was injected in atherosclerotic rabbits in vivo and the aorta was removed after an accumulation period of 4-6.5 hours. In paraffin sections of the aorta, zones of hypoxia were demonstrated at depth of atherosclerotic plaques that were more than 4-500 µm thick. To analyze local concentrations of ATP (adenosine triphosphate), glucose and lactate in arteries a bioluminescence technique, bioluminescence imaging, was used. Bioluminescence imaging is used to study energy metabolic heterogeneities in cryosections of snap frozen tissue and have not previously been used on arteries. In vitro experiments were performed on arterial segments from pigs (normal vessels) and rabbits (normal and atherosclerotic vessels) to test and optimize the methodology. Bioluminescence imaging allowed for quantification of local concentrations of ATP, glucose and lactate at a spatial resolution of 1-200 µm. To study the in vivo situation, a technique to freeze the aorta in situ in anaesthetized rabbits was used. With this technique, the delay between cessation of normal blood flow and freezing was kept at an absolute minimium (3-4 seconds), thus the in vivo situation was reflected. Energy metabolic failure (ATP depletion) was demonstrated at a distance of 3-500 µm from the lumen in rabbit lesions. Glucose concentrations were low, and lactate concentrations were high in lesion, probably reflecting an increase in both aerobic and anaerobic metabolism. Furthermore, ATP concentrations were reduced and lactate concentrations increased in the media underlying lesions compared to the undiseased media.In conclusion, the results presented in this thesis suggest that hypoxia and energy metabolic failure occurs at depth of the atherosclerotic plaque in vivo. Furthermore, energy metabolic predicaments are also seen in the underlying media. We suggest that the strained energy metabolic situation is the result of a local shortage of oxygen and glucose due to increased diffusion distances in combination with an increased metabolic demand and lactate accumulation within the lesions.
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37.
  • Levin, Max, 1969, et al. (författare)
  • Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus
  • 2006
  • Ingår i: Am J Physiol Regul Integr Comp Physiol. - : American Physiological Society. - 0363-6119. ; 290:2
  • Tidskriftsartikel (refereegranskat)abstract
    • After birth, constriction of the full-term ductus arteriosus induces oxygen, glucose and ATP depletion, cell death, and anatomic remodeling of the ductus wall. The immature ductus frequently fails to develop the same degree of constriction or anatomic remodeling after birth. In addition, the immature ductus loses its ability to respond to vasoconstrictive agents, like oxygen or indomethacin, with increasing postnatal age. We examined the effects of premature delivery and postnatal constriction on the immature baboon ductus arteriosus. By 6 days after birth, surrogate markers of hypoxia (HIF1alpha/VEGF mRNA) and cell death [dUTP nick-end labeling (TUNEL)-staining] increased, while glucose and ATP concentrations (bioluminescence imaging) decreased in the immature ductus. TUNEL-staining was significantly related to the degree of glucose and ATP depletion. Glucose and ATP depletion were directly related to the degree of ductus constriction; while TUNEL-staining was logarithmically related to the degree of ductus constriction. Extensive cell death (>15% TUNEL-positive cells) occurred only when there was no Doppler flow through the ductus lumen. In contrast, HIF1alpha/VEGF expression and ATP concentrations were significantly altered even when the immature ductus remained open after birth. Decreased ATP concentrations produced decreased oxygen-induced contractile responses in the immature ductus. We hypothesize that ATP depletion in the persistently patent immature newborn ductus is insufficient to induce cell death and remodeling but sufficient to decrease its ability to constrict after birth. This may explain its decreasing contractile response to oxygen, indomethacin, and other contractile agents with increasing postnatal age.
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38.
  • Limeta, Angelo, 1996, et al. (författare)
  • Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma.
  • 2020
  • Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:23
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUNDIdentifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored.METHODSWe performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI.RESULTSOur analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348-0.899) and was predictive of prognosis (HR = 0.35, P = 0.081).CONCLUSIONThese results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes.FUNDINGThis work was funded by the Knut and Alice Wallenberg Foundation, BioGaia AB, and Cancerfonden.
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39.
  • Mattsson Hultén, Lillemor, 1951, et al. (författare)
  • The role of hypoxia in atherosclerosis
  • 2009
  • Ingår i: Current Opinion in Lipidology. - 0957-9672. ; 20:5, s. 409-414
  • Forskningsöversikt (refereegranskat)
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40.
  • Mobini, Reza, 1965, et al. (författare)
  • Metabolic effects of Lactobacillus reuteri DSM 17938 in people with type 2 diabetes: A randomized controlled trial
  • 2017
  • Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1463-1326 .- 1462-8902. ; 19:4, s. 579-589
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: To investigate the metabolic effects of 12-week oral supplementation with Lactobacillus reuteri DSM 17938 in patients with type 2 diabetes on insulin therapy. Materials and methods: In a double-blind trial, we randomized 46 people with type 2 diabetes to placebo or a low (10(8) CFU/d) or high dose (10(10) CFU/d) of L. reuteri DSM 17938 for 12 weeks. The primary endpoint was the effect of supplementation on glycated haemoglobin (HbA1c). Secondary endpoints were insulin sensitivity (assessed by glucose clamp), liver fat content, body composition, body fat distribution, faecal microbiota composition and serum bile acids. Results: Supplementation with L. reuteri DSM 17938 for 12 weeks did not affect HbA1c, liver steatosis, adiposity or microbiota composition. Participants who received the highest dose of L. reuteri exhibited increases in insulin sensitivity index (ISI) and serum levels of the secondary bile acid deoxycholic acid (DCA) compared with baseline, but these differences were not significant in the between-group analyses. Post hoc analysis showed that participants who responded with increased ISI after L. reuteri supplementation had higher microbial diversity at baseline, and increased serum levels of DCA after supplementation. In addition, increases in DCA levels correlated with improvement in insulin sensitivity in the probiotic recipients. Conclusions: Intake of L. reuteri DSM 17938 for 12 weeks did not affect HbA1c in people with type 2 diabetes on insulin therapy; however, L. reuteri improved insulin sensitivity in a subset of participants and we propose that high diversity of the gut microbiota at baseline may be important.
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41.
  • Ny, Lars, 1967, et al. (författare)
  • The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival. Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.
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42.
  • Parris, Toshima Z, 1978, et al. (författare)
  • Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas
  • 2014
  • Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 3
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic and epigenetic (DNA methylation, histone modifications, microRNA expression) crosstalk promotes inactivation of tumor suppressor genes or activation of oncogenes by gene loss/hypermethylation or duplications/hypomethylation, respectively. The 8p11-p12 chromosomal region is a hotspot for genomic aberrations (chromosomal rearrangements, amplifications and deletions) in several cancer forms, including breast carcinoma where amplification has been associated with increased proliferation rates and reduced patient survival. Here, an integrative genomics screen (DNA copy number, transcriptional and DNA methylation profiling) performed in 229 primary invasive breast carcinomas identified substantial coamplification of the 8p11-p12 genomic region and the MYC oncogene (8q24.21), as well as aberrant methylation and transcriptional patterns for several genes spanning the 8q12.1-q24.22 genomic region (ENPP2, FABP5, IMPAD1, NDRG1, PLEKHF2, RRM2B, SQLE, TAF2, TATDN1, TRPS1, VPS13B). Taken together, our findings suggest that MYC activity and aberrant DNA methylation may also have a pivotal role in the aggressive tumor phenotype frequently observed in breast carcinomas harboring 8p11-p12 regional amplification.
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43.
  • Sah, Vasu R., et al. (författare)
  • Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy
  • 2023
  • Ingår i: Cancer Research Communications. ; 3:5, s. 884-895
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed.Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tu-mor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival.Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of respond-ing patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling ter -tiar y lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival.Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients.Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomark-ers needing validation and become hypothesis generating for experimental research.
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44.
  • Solem, Jens, 1961, et al. (författare)
  • Composition of coronary plaques obtained by directional atherectomy in stable angina: its relation to serum lipids and statin treatment
  • 2006
  • Ingår i: J Intern Med. ; 259:3, s. 267-75
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: The stability and inflammatory activity in atherosclerotic plaques may be modulated by lipids and lipoproteins as well as the pleiotropic effects of statins. The aim of this study was to analyse the effect of statin treatment as well as the relation of plasma lipids and lipoproteins to tissue composition in atherosclerotic plaques. DESIGN: Patients with stable angina and coronary plaques suitable for directional coronary atherectomy (DCA) were randomized to atorvastatin (80 mg once daily) or placebo (29 randomized, 22 underwent DCA, 11/group). After an average treatment of 10 weeks, patients underwent DCA, tissue specimens were obtained, and the tissue composition was determined by immunohistochemistry. RESULTS: Atorvastatin reduced the T-cell content, but did not change lipid, collagen, smooth muscle cell, or macrophage content. Plasma levels of apolipoprotein AI (apoAI) correlated positively with tissue collagen and inversely with metalloproteinase-9 and macrophage content. About half the specimens contained neutrophil granulocytes. CONCLUSIONS: Short-term atorvastatin treatment tended to reduce the T-cell content of atherosclerotic plaques, indicating modulation of cell-mediated immunity. High plasma levels of apoAI correlated with increased collagen content and reduced inflammation, supporting the notion that plasma apoAI stabilizes atherosclerotic plaques. The significance of neutrophils in the lesions merits further study.
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45.
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46.
  • Wasén, Caroline, et al. (författare)
  • Epidermal growth factor receptor function in the human urothelium
  • 2018
  • Ingår i: International Urology and Nephrology. - : Springer Science and Business Media LLC. - 0301-1623 .- 1573-2584. ; 50:4, s. 647-656
  • Tidskriftsartikel (refereegranskat)abstract
    • © 2018, The Author(s). Purpose: Epidermal growth factor receptor (EGFr)-targeted therapy may be used in subgroups of patients with urinary bladder cancer. Here we assessed the role of EGFr in urothelial proliferation and migration in a two- and three-dimensional cell culture system. Methods: UROtsa cells derived from normal urothelium and malignant T24 cells were cultured in a Type I collagengel. Proliferation and migration of urothelial cells, in the absence and presence of the EGFr inhibitor cetuximab, were assessed with a proliferation test (ATCC) and with the Axioplan 2 imaging microscope with a motorized stage (Carl Zeiss), respectively. The expressions of cytokeratin (CK) 17, CK20, EGFr, pEGFr, laminin, occludin and zonula occludens 1 (ZO-1) were assessed with immunohistochemistry and/or western blot. Results: UROtsa spheroids were formed after 7days in culture, while T24 cells did not form spheroids. UROtsa expressed CK20 but not laminin or CK17 and consequently resembled umbrella cells. In UROtsa and T24, cetuximab inhibited urothelial proliferation, induced cleavage of EGFr and/or pEGFR but did not affect urothelial migration. The tight junction protein occludin was cleaved, and the formation of cellular spheroids was inhibited in UROtsa by the presence of cetuximab. Conclusions: EGFr modulates urothelial proliferation and the formation of the three-dimensional structure of the urothelium possibly by interfering with occludin. The present data also show a cell culture technique enabling phenotypically normal urothelial cells to form epithelial structures in contrast to malignant urothelial cells.
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