| 1. |
- Bouyoucef, S E, et al.
(författare)
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Poster Session 2 : Monday 4 May 2015, 08
- 2015
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Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 16 Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Ferraro, Gino B., et al.
(författare)
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Fatty acid synthesis is required for breast cancer brain metastasis
- 2021
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Ingår i: Nature Cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 2:4, s. 414-428
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Tidskriftsartikel (refereegranskat)abstract
- Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2-positive breast cancer and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, resulting in site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase reduces human epidermal growth factor receptor 2-positive breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.
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| 3. |
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| 4. |
- Ankarcrona, M., et al.
(författare)
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Current and future treatment of amyloid diseases
- 2016
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 280:2, s. 177-202
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Forskningsöversikt (refereegranskat)abstract
- There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross--sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid -peptide (A) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit A formation and aggregation or to enhance A clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent A aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.
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| 6. |
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| 7. |
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| 8. |
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| 9. |
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| 10. |
- Jurgens, Catherine A., et al.
(författare)
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beta-Cell Loss and beta-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition
- 2011
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 178:6, s. 2632-2640
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid deposition and reduced beta-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased beta-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased beta-cell area quantified on histological sections is correlated with increased beta-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 +/- 2 and 70 +/- 4 islets/subject, respectively). Amyloid and beta cells were visualized by thioflavin S and insulin inununolabeling. Apoptotic beta cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased beta-cell area, and increased beta-cell apoptosis, as expected. There was a strong inverse correlation between beta-cell area and amyloid deposition (r = -0.42, P < 0.001). beta-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had beta-cell area equivalent to islets from control subjects. Increased amyloid 'deposition was associated with beta-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased beta-cell area and increased beta-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased beta-cell mass that characterizes type 2 diabetes.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Nordeman, Patrik, et al.
(författare)
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C-11 and F-18 Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates
- 2016
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 7:4, s. 368-373
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Tidskriftsartikel (refereegranskat)abstract
- Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Sander, B., et al.
(författare)
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Cutaneous malignant melanoma in Swedish children and teenagers 1973–1992 clinicopathological : study of 130 cases
- 1999
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Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 80:5, s. 646-651
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Tidskriftsartikel (refereegranskat)abstract
- To assess whether there has been a change in histological features and prognostic factors of primary cutaneous malignant melanoma (CMM) in young individuals in Sweden, an unselected, population-based study was undertaken; 177 cases of primary CMM in persons below 20 years of age were reported to the Swedish National Cancer Registry between 1973 and 1992. In 87% of the cases, original tumor tissue was available for histo-pathological review. The original diagnosis was verified in 88% (n = 126) of these cases. All tumors had histological features similar to adult CMM; 17% had an associated precursor lesion. Superficial spreading melanoma (SSM) was the most common sub-type, constituting 20/36 cases in the first decade and 59/90 in the second. Corresponding figures for nodular melanoma (NM) were 11/36 and 23/90. Only 5 melanomas in situ were diagnosed. In girls, the mean thickness of SSM decreased from 1.5 to 0.6 mm (p < 0.001). Overall mortality was 10%, 22% in the group with CMM diagnosed 0-15 years of age and 8% in individuals 15-19 years. Fatal CMM cases diagnosed below 15 years of age (n = 4) were NM >1.6 mm thick and in subjects 15-19 years (n = 9) 44% of fatal tumors were NM with a mean thickness of 2.2 mm. Breslow index was the single most important prognostic factor. However, when known prognostic factors were adjusted for in a Cox regression analysis, young age remained an independent risk factor, with a relative death rate of 0.21 for individuals aged 15-19 compared with children <15 years of age.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Arvidsson, Sandra, 1986-, et al.
(författare)
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Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.MATERIAL AND METHODS: Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.RESULTS: There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.CONCLUSION: This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.
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| 25. |
- Canetti, Diana, et al.
(författare)
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Clinical ApoA-IV amyloid is associated with fibrillogenic signal sequence
- 2021
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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 311-318
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-IV amyloidosis is an uncommon form of the disease normally resulting in renal and cardiac dysfunction. ApoA-IV amyloidosis was identified in 16 patients attending the National Amyloidosis Centre and in eight clinical samples received for histology review. Unexpectedly, proteomics identified the presence of ApoA-IV signal sequence residues (p.18-43 to p.20-43) in 16/24 trypsin-digested amyloid deposits but in only 1/266 non-ApoA-IV amyloid samples examined. These additional signal residues were also detected in the cardiac sample from the Swedish patient in which ApoA-IV amyloid was first described, and in plasma from a single cardiac ApoA-IV amyloidosis patient. The most common signal-containing peptide observed in ApoA-IV amyloid, p.20-43, and to a far lesser extent the N-terminal peptide, p.21-43, were fibrillogenic in vitro at physiological pH, generating Congo red-positive fibrils. The addition of a single signal-derived alanine residue to the N-terminus has resulted in markedly increased fibrillogenesis. If this effect translates to the mature circulating protein in vivo, then the presence of signal may result in preferential deposition as amyloid, perhaps acting as seed for the main circulating native form of the protein; it may also influence other ApoA-IV-associated pathologies. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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| 26. |
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| 27. |
- Eldhagen, P., et al.
(författare)
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Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis
- 2021
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 289:6, s. 895-905
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Tidskriftsartikel (refereegranskat)abstract
- Background: Wild‐type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy.Objective: To study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis.Materials and methods: A total of 250 patients, aged 50–89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0‐4. All patients with grade 3‐4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT‐proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization.Results: Amyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3‐4; all had fibril type A (mixture of full‐length TTR and fragmented TTR). Twenty‐nine of 42 patients with grade 3‐4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome.Conclusions: The prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.
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| 28. |
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| 29. |
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| 30. |
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| 31. |
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| 32. |
- Giacobini, MaiBritt M J, et al.
(författare)
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Differential effects of platelet-derived growth factors on fetal hippocampal and cortical grafts : evidence from intraocular transplantation in rats
- 1992
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Ingår i: Neuroscience Letters. - 0304-3940 .- 1872-7972. ; 136:2, s. 227-231
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Tidskriftsartikel (refereegranskat)abstract
- Effects of platelet-derived growth factor-AA (PDGF-AA) and platelet-derived growth factor-BB (PDGF-BB) on developing parietal cortex (E16) and hippocampal (E18-E19) grafts were studied using the in vivo method of intraocular transplantation. Survival and growth of grafts in the anterior eye chamber of adult host rats under the influence of regular treatments with 0.5 ng (in a 100 ng/ml concentration) PDGF-AA or PDGF-BB was followed and compared to those receiving vehicle solution alone (0.5 mg HSA/ml Hanks). Both PDGF-AA and PDGF-BB increased the volume of transplanted cortical grafts. PDGF-BB also exerted trophic effects on grafted hippocampal tissue whereas PDGF-AA seemed to inhibit hippocampal growth. Histological and immunohistochemical studies revealed an increase in the density of astroglial elements in PDGF-AA- and PDGF-BB-treated cortical grafts whereas the PDGF-AA- and PDGF-BB-treated hippocampal grafts maintained a cytoarchitecture closely resembling that of control grafts. These findings support in vitro experiments showing that developing glial cells are stimulated by PDGFs and we further propose regional differences of action of PDGFs in the developing central nervous system.
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| 33. |
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| 34. |
- Gustafsson, Sandra, et al.
(författare)
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Amyloid Fibril Composition as a Predictor of Development of Cardiomyopathy After Liver Transplantation for Hereditary Transthyretin Amyloidosis
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:10, s. 1017-1023
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Tidskriftsartikel (refereegranskat)abstract
- Background. Liver transplantation (LTx) is an accepted treatment for hereditary transthyretin (TTR) amyloidosis (ATTR). However, unforeseen heart complications, especially a rapid development of cardiomyopathy after LTx has affected mortality and morbidity. Recently, a relationship between ATTR-fibril composition and cardiomyopathy has been noted. The aim of this study was to investigate whether development of cardiomyopathy and heart failure in LTx ATTR amyloid patients is related to amyloid fibril composition.Methods. Twenty-four patients with hereditary ATTR amyloidosis who had undergone LTx and have had their amyloid fibril type tested were available for the study. They had been examined by echocardiography including tissue Doppler and speckle tracking echocardiography before and after LTx. Patients were divided into two groups according to fibril composition, 10 patients with type A fibrils (a mixture of truncated and full-length TTR) and 14 patients with type B fibrils (full-length TTR fibrils only). There was no difference in time to the follow-up echocardiography between the two groups.Results. After LTx, the group consisting of type A patients developed symptoms of heart failure and with reduced systolic and diastolic ventricular function as shown by echocardiography, whereas no similar deterioration was noted for the group of patients with type B fibrils.Conclusion. Patients with type A fibrils deteriorate an already existing cardiomyopathy and heart failure after LTx, in contrast to patients with type B fibrils. These results might have significant clinical implications in optimizing best patients selection criteria for LTx.
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| 35. |
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| 36. |
- Hede, Sanna-Maria, et al.
(författare)
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GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background
- 2009
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Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 57:11, s. 1143-1153
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic process.
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| 37. |
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| 38. |
- Hellman, Urban, et al.
(författare)
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A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family
- 2015
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Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 58:4, s. 211-215
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Tidskriftsartikel (refereegranskat)abstract
- In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (similar to 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. In conclusion: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.
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| 39. |
- Henein, Michael Y., et al.
(författare)
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Reduced left atrial myocardial deformation irrespective of cavity size : a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis
- 2018
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Ingår i: Amyloid. - : TAYLOR & FRANCIS LTD. - 1350-6129 .- 1744-2818. ; 25:1, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cardiac amyloidosis (CA) is a myocardial disease and commonly under-diagnosed condition. In CA patients, atrial fibrillation might occur in the absence of left atrial (LA) enlargement.Objectives: The aim of this study is to assess LA size and function, and its relationship with atrial arrhythmia in patients with hereditary transthyretin amyloidosis (ATTR).Methods: Forty-six patients with confirmed ATTR amyloidosis on abdominal biopsy were studied. Assessment with 2D echocardiography and 2D strain showed 31 patients had increased LV wall thickness (LVWT) (septal thickness >12mm), and 15 had normal LVWT. In addition to conventional measurements, LV and LA global longitudinal strain (GLS%) and strain rate (SR) were obtained. Western blot analysis was done to assess fibril type. ATTR patients with increased LVWT were compared with 23 patients with hypertrophic cardiomyopathy (HCM) and 31 healthy controls. ATTR amyloidosis patients also underwent 24hour Holter monitoring to determine the presence of atrial arrhythmia.Results: Atrial deformation during atrial systole was reduced in ATTR amyloidosis patients with increased LVWT independent of LA size and in contrast to HCM. Twenty of the ATTR amyloidosis patients (54%) had ECG evidence of significant atrial arrhythmic events. LA strain rate, during atrial systole, was the only independent predictor of atrial arrhythmia (=3.28, p=.012).Conclusion: In ATTR cardiomyopathy with increased LVWT, LA myocardial function is abnormal, irrespective of atrial cavity size. Reduced LA myocardial SR during atrial systole, irrespective of cavity volume, E/e and LV deformation, is also a strong predictor for atrial arrhythmic events.
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| 40. |
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| 41. |
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| 43. |
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| 44. |
- Ihse, E, et al.
(författare)
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Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
- 2008
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 216:2, s. 253-61
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Tidskriftsartikel (refereegranskat)abstract
- Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.
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| 45. |
- Ihse, Elisabet, et al.
(författare)
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Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis
- 2013
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Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 20:3, s. 142-150
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Tidskriftsartikel (refereegranskat)abstract
- The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.
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| 46. |
- Ihse, Elisabet, 1977-, et al.
(författare)
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Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one composed of only intact ATTR (type B). Patients with type A fibrils have a late age of onset and signs of cardiomyopathy, while patients with type B fibrils have an early onset and much less myocardial involvement. The present study aimed to determine if the correlation between fibril type and clinical phenotype is true for familial amyloidosis in general. Cardiac and/or adipose tissue from 48 patients carrying 21 different non-TTRV30M mutations were examined, as well as 7 non-Swedish ATTRV30M patients. Fibril type was determined with western blotting and compared to the patients´ age of onset and degree of cardiomyopathy. Non-Swedish V30M patients showed the same correlation as described for Swedish V30M patients, with fibrils of only full-length ATTR (type B) linked to less myocardial involvement. In contrast, all patients with non-V30M mutations had a fibril composition with ATTR fragments (type A). Some of these patients had onset of disease at young age. The vast majority had increased thickness of left cardiac ventricle, but a few individuals had values within normal limits. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis. It also suggests that fibrils composed of only full-length ATTR is an exception, perhaps only found among young ATTRV30M amyloidosis patients.
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| 47. |
- Ihse, Elisabet, et al.
(författare)
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Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
- 2011
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 89:2, s. 171-180
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Tidskriftsartikel (refereegranskat)abstract
- Familial transthyretin (TTR) amyloidosis is caused by a mutation in the TTR gene, although wild-type (wt) TTR is also incorporated into the amyloid fibrils. Liver transplantation (LT) is the prevailing treatment of the disease and is performed in order to eliminate the mutant TTR from plasma. The outcome of the procedure is varied; especially problematic is a progressive cardiomyopathy seen in some patients, presumably caused by continued incorporation of wtTTR. What determines the discrepancy in outcome is not clear. We have previously shown that two structurally distinct amyloid fibrils (with or without fragmented ATTR) are found among ATTRV30M patients. In this study, we investigated the proportion of wtATTR in cardiac and adipose amyloid from patients having either fibril type. It was found that cardiac amyloid more easily incorporates wtTTR than adipose amyloid, offering a potential explanation for the vulnerability of cardiac tissue for continued amyloidosis after LT. In cardiac tissue, fibrils with fragmented ATTR contained a higher wt proportion than fibrils without, suggesting that continued incorporation of wtTTR after LT, perhaps, can take place more easily in these patients. In adipose tissue, a rapid increase in wt proportion after LT indicates that a rather fast turnover of the deposits must occur. A difference in wt proportion between the fibril types was seen post-LT but not pre-LT, possibly caused by differences in turnover rate. Conclusively, this study further establishes the basic dissimilarities between the two fibril types and demonstrates that their role in LT outcome needs to be further investigated.
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| 48. |
- Kanatani, Sachie, et al.
(författare)
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Voltage-dependent calcium channel signaling mediates GABA(A) receptor-induced migratory activation of dendritic cells infected by Toxoplasma gondii
- 2017
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- The obligate intracellular parasite Toxoplasma gondii exploits cells of the immune system to disseminate. Upon T. gondii-infection,. Upsilon-aminobutyric acid (GABA)/GABAA receptor signaling triggers a hypermigratory phenotype in dendritic cells (DCs) by unknown signal transduction pathways. Here, we demonstrate that calcium (Ca2+) signaling in DCs is indispensable for T. gondii-induced DC hypermotility and transmigration in vitro. We report that activation of GABAA receptors by GABA induces transient Ca2+ entry in DCs. Murine bone marrow-derived DCs preferentially expressed the L-type voltage-dependent Ca2+ channel (VDCC) subtype Cav1.3. Silencing of Cav1.3 by short hairpin RNA or selective pharmacological antagonism of VDCCs abolished the Toxoplasma-induced hypermigratory phenotype. In a mouse model of toxoplasmosis, VDCC inhibition of adoptively transferred Toxoplasma-infected DCs delayed the appearance of cell-associated parasites in the blood circulation and reduced parasite dissemination to target organs. The present data establish that T. gondii-induced hypermigration of DCs requires signaling via VDCCs and that Ca2+ acts as a second messenger to GABAergic signaling via the VDCC Cav1.3. The findings define a novel motility-related signaling axis in DCs and unveil that interneurons and DCs share common GABAergic motogenic pathways. T. gondii employs GABAergic non-canonical pathways to induce host cell migration and facilitate dissemination.
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- Karlsson, Olov, et al.
(författare)
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Linkages between residual lignin and carbohydrates in bisulphite (magnefite) pulps
- 2001
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Ingår i: Journal of Pulp and Paper Science (JPPS). - 0826-6220. ; 27:9, s. 310-316
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Tidskriftsartikel (refereegranskat)abstract
- The presence of bonds between residual lignin and carbohydrates in bisulphite pulps from hardwoods and softwoods was studied. Results showed that a fraction of the residual lignin was bonded to cellulose in bisulphite pulps of softwood. The treatment with xylanase indicated the existence of alkali-stable lignin-xylan bonds in softwood bisulphite pulps.
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