| 1. |
- Bränström, Robert, et al.
(författare)
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Electrical short-circuit in β-cells from a patient with non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS) : a case report
- 2010
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Ingår i: Journal of Medical Case Reports. - : Springer Science and Business Media LLC. - 1752-1947. ; 4:1, s. 315-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Non-insulinoma pancreatogenous hypoglycemic syndrome is a rare disorder among adults, and, to our knowledge, only about 40 cases have been reported in the literature. CASE PRESENTATION: The patient is a previously healthy 35-year-old Caucasian man. His symptoms began four years ago when he suddenly felt weakness in his legs and started sweating for unknown reasons. The symptoms worsened, and laboratory tests revealed hypoglycemia and hyperinsulinemia at the time of the symptoms. All diagnostics attempts using magnetic resonance imaging, computed tomography, and endoscopic ultrasound did not reveal any abnormalities. At this stage, surgical intervention was planned, and a distal 80% pancreatectomy was performed. The histopathologic and immunohistochemical investigations of the pancreas showed an increased number of islets of different sizes, more or less evenly distributed in the gland, but no insulinoma. Patch-clamp recordings from isolated pancreatic β-cells showed that, even at a low glucose concentration (3 mmol/L), the β-cell membrane was depolarized, and action potentials were seen. Surprisingly, in patch-clamp experiments, the addition of diazoxide had a marked effect on K-ATP channel activity and membrane potential, but no effect on insulin levels in vivo before surgery. CONCLUSION: This case report adds new information on the pathogenesis of non-insulinoma pancreatogenous hypoglycemic syndrome, as we performed an electrophysiologic characterization of isolated islet cells. We show, for the first time, that β-cells isolated from a non-insulinoma pancreatogenous hypoglycemic syndrome patient are constantly depolarized, even at low glucose levels, but display normal K-ATP channel physiology.
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| 2. |
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| 3. |
- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 4. |
- Hellman, Per, et al.
(författare)
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Ligand surface density is important for efficient capture of immunoglobulin and phosphatidylcholine coated particles by human peripheral dendritic cells
- 2009
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Ingår i: Cellular Immunology. - : Elsevier BV. - 0008-8749 .- 1090-2163. ; 258:2, s. 123-30
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Tidskriftsartikel (refereegranskat)abstract
- A unique property of dealuminated zeolite particles is the exceptional ability to bind both hydrophilic and hydrophobic biomolecules without any covalent linkages. By adsorbing phospholipids onto the particle surface, capture of particles by human peripheral myeloid dendritic cells (mDCs) was observed. Capture of zeolite particles was only seen when a low density of phosphatidylcholine was present on the particles, indicating a specific recognition of the structural features realised by phosphatidylcholine after adsorption on the particle. Adsorbing IgG on the particles revealed capture by mDCs that was dependent upon the density of the IgG molecules. To obtain a smaller particle exposing a high density of IgG molecules, immune complexes (ICs) were formed and both mDCs and pDCs (peripheral plasmacytoid DCs) captured immune complexes, although the mDCs showed a more efficient capture of ICs. As expected, mDCs captured and internalized ICs, whereas pDCs captured ICs but showed no internalization of ICs.
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| 5. |
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| 6. |
- Law, Lucy, et al.
(författare)
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Increased carotid intima-media thickness in patients with radiographic axial spondyloarthritis compared to controls and associations with markers of inflammation
- 2024
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Ingår i: CLINICAL RHEUMATOLOGY. - : Springer Nature. - 0770-3198 .- 1434-9949.
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Tidskriftsartikel (refereegranskat)abstract
- Objective There is an increased risk for cardiovascular disease (CVD) in patients with radiographic axial spondyloarthritis (r-axSpA). In this cross-sectional study, we aimed to, overall and stratified by sex, (i) compare ultrasound derived carotid intima media thickness (cIMT), between patients and controls, and (ii) investigate associations between cIMT, clinical disease activity and inflammation-related laboratory markers in patients with r-axSpA. Method In total, 155 patients diagnosed with r-axSpA using the modified New York criteria and 400 controls were included. Bilateral carotid ultrasound, laboratory testing, and questionaries were acquired. Disease-specific assessments were carried out for patients. Linear regression analysis was used to assess associations. Results Linear regression analyses showed that patients with r-axSpA had increased mean cIMT compared to controls (mean +/- SD, 0.8 +/- 0.1 mm vs 0.7 +/- 0.1 mm, respectively, unstandardized beta (95% CI) -0.076 (-0.10, -0.052), P < 0.001) adjusted for smoking status and age. Linear regression analyses for patients with r-axSpA showed that only males presented significant associations between cIMT and inflammation-related laboratory markers, white blood cell (WBC) count (mean +/- SD, 6.8 +/- 1.6 10(9)/L) and monocytes (0.6 +/- 0.2 10(9)/L); WBC count (unstandardized beta (95% CI) 0.019 (0.0065, 0.031), P = 0.003, R-2 = 0.57) and monocytes (0.13 (0.0047, 0.26), P = 0.041, R-2 = 0.55), adjusted for age, smoking status, body mass index, hypertension, dyslipidemia, diabetes mellitus, ASDAS-CRP, and treatment with DMARDs and glucocorticoids. No significant association was found between cIMT and clinical disease activity assessed by ASDAS-CRP. Conclusion Patients with r-axSpA had significantly increased cIMT compared to controls. In male patients, higher WBC and monocyte count were associated with an increase in cIMT suggesting the role of inflammation in the development of atherosclerosis.
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| 7. |
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| 8. |
- Aad, G., et al.
(författare)
-
- 2015
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Ingår i: Physical Review D. Particles and fields. - : American Physics Society. - 0556-2821 .- 1089-4918. ; 92:11
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Journal of High Energy Physics. - : Springer. - 1029-8479 .- 1126-6708. ; :12
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Aad, G., et al.
(författare)
-
- 2016
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Ingår i: Physical Review D. Particles and fields. - : American Physical Society. - 0556-2821 .- 1089-4918. ; 93:1
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Tidskriftsartikel (refereegranskat)
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| 11. |
- Abulaiti, Yiming, et al.
(författare)
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Measurements of W(+/-)Z production cross sections in pp collisions at root s=8 TeV with the ATLAS detector and limits on anomalous gauge boson self-couplings
- 2016
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Ingår i: Physical Review D. - : American Physical Society. - 2470-0010. ; 93:9
-
Tidskriftsartikel (refereegranskat)abstract
- This paper presents measurements of W(+/-)Z production in pp collisions at a center-of-mass energy of 8 TeV. The gauge bosons are reconstructed using their leptonic decay modes into electrons and muons. The data were collected in 2012 by the ATLAS experiment at the Large Hadron Collider and correspond to an integrated luminosity of 20.3 fb(-1). The measured inclusive cross section in the detector fiducial region is sigma W(+/-)Z -> l'nu ll = 35.1 +/- 0.9(stat) +/- 0.8(sys) +/- 0.8(lumi) fb, for one leptonic decay channel. In comparison, the next-to-leading-order Standard Model expectation is 30.0 +/- 2.1 fb. Cross sections for W(+)Z and W(-)Z production and their ratio are presented as well as differential cross sections for several kinematic observables. Limits on anomalous triple gauge boson couplings are derived from the transverse mass spectrum of the W(+/-)Z system. From the analysis of events with a W and a Z boson associated with two or more forward jets an upper limit at 95% confidence level on the W(+/-)Z scattering cross section of 0.63 fb, for each leptonic decay channel, is established, while the Standard Model prediction at next-to-leading order is 0.13 +/- 0.01 fb. Limits on anomalous quartic gauge boson couplings are also extracted.
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| 12. |
- Abulaiti, Yiming, et al.
(författare)
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Observation of Long-Range Elliptic Azimuthal Anisotropies in root s=13 and 2.76 TeV pp Collisions with the ATLAS Detector
- 2016
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 116:17
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Tidskriftsartikel (refereegranskat)abstract
- ATLAS has measured two-particle correlations as a function of the relative azimuthal angle, Delta phi, and pseudorapidity, Delta eta, in root s = 13 and 2.76 TeV pp collisions at the LHC using charged particles measured in the pseudorapidity interval vertical bar eta vertical bar < 2.5. The correlation functions evaluated in different intervals of measured charged-particle multiplicity show a multiplicity-dependent enhancement at Delta phi similar to 0 that extends over a wide range of Delta eta, which has been referred to as the ridge. Per-trigger-particle yields, Y(Delta phi) are measured over 2 < vertical bar Delta eta vertical bar < 5. For both collision energies, the Y(Delta phi) distribution in all multiplicity intervals is found to be consistent with a linear combination of the per-trigger-particle yields measured in collisions with less than 2 phi reconstructed tracks, and a constant combinatoric contribution modulated by cos (2 Delta phi). The fitted Fourier coefficient, nu(2,2), exhibits factorization, suggesting that the ridge results from per-event cos (2 phi) modulation of the single-particle distribution with Fourier coefficients nu(2). The nu(2) values are presented as a function of multiplicity and transverse momentum. They are found to be approximately constant as a function of multiplicity and to have a p(T) dependence similar to that measured in p + Pb and Pb + Pb collisions. The nu(2) values in the 13 and 2.76 TeV data are consistent within uncertainties. These results suggest that the ridge in pp collisions arises from the same or similar underlying physics as observed in p + Pb collisions, and that the dynamics responsible for the ridge has no strong root s dependence.
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| 13. |
- Abulaiti, Yiming, et al.
(författare)
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Search for a high-mass Higgs boson decaying to a W boson pair in pp collisions at root s=8TeV with the ATLAS detector
- 2016
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Ingår i: Journal of High Energy Physics (JHEP). - 1126-6708 .- 1029-8479. ; :1
-
Tidskriftsartikel (refereegranskat)abstract
- A search for a high-mass Higgs boson H is performed in the H -> WW -> l nu l nu and H -> WW -> l nu qq decay channels using pp collision data corresponding to an integrated luminosity of 20.3 fb(-1) collected at root s = 8TeV by the ATLAS detector at the Large Hadron Collider. No evidence of a high-mass Higgs boson is found. Limits on sigma(H) x BR(H -> WW) as a function of the Higgs boson mass m(H) are determined in three different scenarios: one in which the heavy Higgs boson has a narrow width compared to the experimental resolution, one for a width increasing with the boson mass and modeled by the complex-pole scheme following the same behavior as in the Standard Model, and one for intermediate widths. The upper range of the search is m(H) = 1500 GeV for the narrow-width scenario and m(H) = 1000 GeV for the other two scenarios. The lower edge of the search range is 200{300 GeV and depends on the analysis channel and search scenario. For each signal interpretation, individual and combined limits from the two WW decay channels are presented. At m(H) = 1500 GeV, the highest-mass point tested, sigma(H) x BR(H -> WW) for a narrow-width Higgs boson is constrained to be less than 22 fb and 6.6 fb at 95% CL for the gluon fusion and vector-boson fusion production modes, respectively.
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| 14. |
- Abulaiti, Yiming, et al.
(författare)
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Search for invisible decays of a Higgs boson using vector-boson fusion in pp collisions at root s=8 TeV with the ATLAS detector
- 2016
-
Ingår i: Journal of High Energy Physics (JHEP). - : Springer. - 1126-6708 .- 1029-8479. ; :1
-
Tidskriftsartikel (refereegranskat)abstract
- A search for a Higgs boson produced via vector-boson fusion and decaying into invisible particles is presented, using 20.3 fb(-1) of proton-proton collision data at a centre-of-mass energy of 8TeV recorded by the ATLAS detector at the LHC. For a Higgs boson with a mass of 125 GeV, assuming the Standard Model production cross section, an upper bound of 0.28 is set on the branching fraction of H -> invisible at 95% confidence level, where the expected upper limit is 0.31. The results are interpreted in models of Higgs-portal dark matter where the branching fraction limit is converted into upper bounds on the dark-matter-nucleon scattering cross section as a function of the dark-matter particle mass, and compared to results from the direct dark-matter detection experiments.
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| 15. |
- Adams, Emma Catherine, et al.
(författare)
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The structure-function relationship for alumina supported platinum during the formation of ammonia from nitrogen oxide and hydrogen in the presence of oxygen
- 2016
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 18:16, s. 10850-10855
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Tidskriftsartikel (refereegranskat)abstract
- We study the structure-function relationship of alumina supported platinum during the formation of ammonia from nitrogen oxide and dihydrogen by employing in situ X-ray absorption and Fourier transform infrared spectroscopy. Particular focus has been directed towards the effect of oxygen on the reaction as a model system for emerging technologies for passive selective catalytic reduction of nitrogen oxides. The suppressed formation of ammonia observed as the feed becomes net-oxidizing is accompanied by a considerable increase in the oxidation state of platinum as well as the formation of surface nitrates and the loss of NH-containing surface species. In the presence of (excess) oxygen, the ammonia formation is proposed to be limited by weak interaction between nitrogen oxide and the oxidized platinum surface. This leads to a slow dissociation rate of nitrogen oxide and thus low abundance of the atomic nitrogen surface species that can react with the adsorbed hydrogen species. In this case the consumption of hydrogen through the competing water formation reaction and decomposition/oxidation of ammonia are of less importance for the net ammonia formation.
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| 16. |
- Adams, Emma, 1989, et al.
(författare)
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Structure-function relationship for alumina supported platinum during formation of ammonia from nitrogen oxide and hydrogen in presence of oxygen
- 2016
-
Ingår i: Physical Chemistry Chemical Physics. - 1463-9084 .- 1463-9076. ; 18:16, s. 10850-10855
-
Tidskriftsartikel (refereegranskat)abstract
- We study the structure-function relationship of alumina supported platinum during forma- tion of ammonia from nitrogen oxide and dihydrogen by employing in situ X-ray absorption and Fourier transformed infrared spectroscopy. Particular focus is directed towards the effect of increased levels of oxygen on the reaction as a model system for emerging technologies for passive selective catalytic reduction of nitrogen oxides. The suppressed formation of ammo- nia observed as the feed becomes net-oxidizing is accompanied by a considerable increase in the oxidation state of platinum as well as enhanced formation of surface nitrates and loss of NH-containing surface species. In the presence of (excess) oxygen, the ammonia formation is proposed to be limited by the weak interaction between nitrogen oxide and the oxidized platinum surface. This leads to slow dissociation rate of nitrogen oxide and thus low abun- dance of atomic nitrogen surface species that can react with adsorbed hydrogen atoms. In this case the consumption of hydrogen through the competing water formation reaction and decomposition/oxidation of ammonia are of less importance for the net ammonia formation.
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| 17. |
- Ahlberg, Viktor, et al.
(författare)
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Innate immune responses induced by the saponin adjuvant Matrix-M in specific pathogen free pigs
- 2017
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Ingår i: Veterinary Research. - : Springer Science and Business Media LLC. - 0928-4249 .- 1297-9716. ; 48
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Tidskriftsartikel (refereegranskat)abstract
- Saponin-based adjuvants have been widely used to enhance humoral and cellular immune responses in many species, but their mode of action is not fully understood. A characterization of the porcine transcriptional response to Matrix-M was performed in vitro using lymphocytes, monocytes or monocyte-derived dendritic cells (MoDCs) and in vivo. The effect of Matrix-M was also evaluated in specific pathogen free (SPF) pigs exposed to conventionally reared pigs. The pro-inflammatory cytokine genes IL1B and CXCL8 were up-regulated in monocytes and lymphocytes after Matrix-M exposure. Matrix-M also induced IL12B, IL17A and IFNG in lymphocytes and IFN-a gene expression in MoDCs. Several genes were indicated as up-regulated by Matrix-M in blood 18 h after injection, of which the genes for IFN-a and TLR2 could be statistically confirmed. Respiratory disease developed in all SPF pigs mixed with conventional pigs within 1-3 days. Two out of four SPF pigs injected with saline prior to contact exposure displayed systemic symptoms that was not recorded for the four pigs administered Matrix-M. Granulocyte counts, serum amyloid A levels and transcription of IL18 and TLR2 coincided with disease progression in the pigs. These results support further evaluation of Matrix-M as a possible enhancer of innate immune responses during critical moments in pig management.
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| 18. |
- Ahlström, Tommy, et al.
(författare)
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Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women
- 2009
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 71:5, s. 673-678
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: In recent years, an association has been noted between several abnormalities that characterize the metabolic syndrome (MetS) and primary hyperparathyroidism (pHPT). These abnormalities include dyslipidaemia, obesity, insulin resistance and hypertension. The correlations between plasma calcium, parathyroid hormone (PTH) and the variables in the MetS in a normal population are still unclear.OBJECTIVE: To describe correlations between plasma calcium and PTH and the various abnormalities present in the MetS in a healthy population.DESIGN: We studied 1016 healthy individuals from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) population of 70 years old, by means of plasma analyses of calcium, PTH, creatinine, lipids, insulin and glucose, as well as by standardized blood pressure measurements. Further, body mass index (BMI) and waist circumference were determined.RESULTS: The more National Cholesterol Education Program (NCEP) criteria for the MetS that were met, the higher the s-PTH and albumin-corrected s-calcium. Further, positive correlations between plasma calcium and BMI (P = 0.0003), waist circumference (P = 0.0009) and insulin resistance (P = 0.079) were found. PTH and BMI (P < 0.0001), waist circumference (P < 0.0001), systolic blood pressure (P = 0.0034), diastolic blood pressure (P = 0.0008), serum triglycerides (P = 0.0003) and insulin resistance (P = 0.0003) were positively correlated, whereas serum high density lipoproteins (HDL) (P = 0.036) and PTH were negatively correlated.CONCLUSIONS: We conclude that PTH correlates with several of the metabolic factors included in the MetS within a normocalcaemic population. In addition, individuals with mild pHPT present significantly more NCEP criteria for MetS. We postulate that increased levels of PTH in pHPT may be associated with the increased cardiovascular morbidity and mortality seen in pHPT.
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| 19. |
- Andersson, Maria, et al.
(författare)
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Interindividual differences in initial DNA repair capacity when evaluating H2O2-induced DNA damage in extended-term cultures of human lymphocytes using the comet assay
- 2007
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Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 23:6, s. 401-411
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that extended-term cultures of human lymphocytes could be used as a complement to cell lines based on transformed cells when testing the genotoxicity of chemicals. To investigate whether the pattern of induced DNA damage and its subsequent repair differs significantly between cultures based on different blood donors, hydrogen peroxide (H2O2)-induced DNA damage was measured in cultures from four different subjects using the comet assay. The DNA damage was significantly increased in all cultures after 10 min exposure to 0.25 mmol/L H2O2, and there was a significant decrease in the H2O2-induced DNA damage in all cultures after 30 min of DNA repair. The level of damage varied between the different donors, especially after the repair. Using PCR and DNA sequencing, exon 5 of the p53 gene was sequenced in the lymphocytes from the donors with the lowest and highest residual damage. No such mutation was found. Mouse lymphoma L5178Y cells carrying the p53 mutation in exon 5 were included as a reference. These cells were found to be less sensitive toward the H2O2-induced DNA damage, and they were also found to have a rather low DNA repair capacity. The demonstrated variation in H2O2-induced DNA damage and DNA repair capacity between the cultures from the different subjects may be important from a risk assessment perspective, but is obviously not of decisive importance when it comes to the development of a routine assay for genotoxicity.
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| 20. |
- Andersson, Mattias K., 1978-
(författare)
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Cleavage Specificity of Mast Cell Chymases
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mast cells (MC) are potent inflammatory cells that are known primarily for their prominent role in IgE mediated allergies. However, they also provide beneficial functions to the host, e.g. in bacterial and parasitic defence. MCs react rapidly upon stimulation by releasing potent granule-stored mediators, and serine proteases of the chymase or tryptase families are such major granule constituents. As a first step towards a better understanding of the biological function of these proteases, we have determined the extended cleavage specificities of four mammalian mast cell chymases, by utilizing a substrate phage display approach. The specificities of these enzymes have then been used to compare their functional characteristics.The major mucosal MC chymase in mice, mMCP-1, was found to possess a strict preference in four amino acid positions of the peptide substrate. Using this sequence to search the mouse proteome for potential in vivo substrates led to the identification of several very interesting potential novel substrates. Some of them may explain the increased epithelial permeability provided by this enzyme.Human MCs, express only one single α-chymase, and the rodent α-chymases have secondarily gained elastase-like primary cleavage specificity. However, rodents express additional chymases, the β-chymases, and rodent β-chymases may have adopted the function of the α-chymases. The cleavage specificities of the human chymase and two rodent β-chymases were therefore determined (rat rMCP-1 and mouse mMCP-4). N-terminal of the cleaved bond the three chymases showed similar preferences, but C-terminal the human chymase and mMCP-4 shared a high preference for acidic amino acids in the P2´ position and therefore seem to be functional homologues. The molecular interactions mediating the preference for acidic amino acids in position P2´ were further investigated. By site-directed mutagenesis of the human chymase, amino acids Arg143 and Lys192 were concluded to synergistically mediate this preference.Our data show that chymases, of different MC subpopulations, display quite different extended cleavage specificities. However mouse do possess a MC chymase with almost identical cleavage specificity as the human MC chymase indicating a strong evolutionary pressure to maintain this enzyme specificity.
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| 21. |
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| 22. |
- Annebäck, Matilda, et al.
(författare)
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Preoperative prophylactic active vitamin D to streamline total thyroidectomy
- 2022
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Ingår i: BJS Open. - : Oxford University Press (OUP). - 2474-9842. ; 6:3
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundHypocalcaemia is a common complication after total thyroidectomy (TT). Treatment consists of calcium and active vitamin D supplementation. Low levels of vitamin D before surgery have been shown to be a risk factor for postoperative hypocalcaemia, yet studies examining routine preoperative vitamin D supplementation have shown conflicting results. This retrospective cohort study aims to investigate the potential benefit of preoperative active vitamin D supplementation on hypocalcaemia and its symptoms after TT.MethodsThis study included patients undergoing TT at Uppsala University Hospital from January 2013 to December 2020, resulting in a total of 401 patients after exclusion. Routine preoperative alfacalcidol treatment was initiated for all TT patients in January 2017 resulting in two groups for comparison: one group (pre-January 2017) that was prescribed preoperative alfacalcidol and one that was not. Propensity score matching was used to reduce bias. The primary outcome was early postoperative hypocalcaemia (serum calcium, S-Ca less than 2.10 mmol/l); secondary outcomes were symptoms of hypocalcaemia and length of stay.ResultsAfter propensity score matching, there were 108 patients in each group. There were 2 cases with postoperative day one S-Ca less than 2.10 in the treated group and 10 cases in the non-treated group (P < 0.001). No patients in the treated group had a S-Ca below 2.00 mmol/l. Preoperative alfacalcidol was associated with higher mean serum calcium level day one (2.33 versus 2.27, P = 0.022), and reduced duration of hospital stay (P < 0.001). There was also a trend toward fewer symptoms of hypocalcaemia (18.9 per cent versus 30.5 per cent, P = 0.099).ConclusionsProphylactic preoperative alfacalcidol was associated with reduced biochemical hypocalcaemia and duration of hospital stay following TT. Also, with this protocol, it is suggested that routine day 1 postoperative S-Ca measurement is not required.
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| 23. |
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| 24. |
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| 25. |
- Annerbo, Maria, 1967-
(författare)
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Calcium Homeostasis in Patients with Graves' Disease
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with Graves´ Disease (GD) have a higher risk of developing more severe and prolonged hypocalcaemia after total thyroidectomy (TT) than patients who undergo surgery for benign atoxic goitre. Since TT is the most effective treatment for GD, it is crucial to identify mechanisms for postoperative hypocalcaemia. The aim of this thesis was to study the mechanisms of calcium metabolism in patients with GD.It is safe to operate on GD patients with TT. Results in Paper I showed fewer recurrences and equal complication rates compared to patients who underwent subtotal thyroidectomy (ST). The transient lowering of PTH seen in the hypocalcaemic patients was fully restored one month after surgery (Papers II and V).The calcium-sensing receptor (CaSR) is crucial for maintaining plasma calcium, and single nucleotide polymorphisms (SNPs) in the gene may alter the sensing function. Thus, we analysed SNPs in CaSR in GD patients (Paper II) and showed that they had a more left-shifted calcium-PTH set-point compared to controls, implicating higher sensitivity. This is also supported by the results in the group of postoperatively hypocalcaemic patients. They already had lower plasma calcium preoperatively (Papers II, IV and V) and lacked the T/G G/A G/C, a haplotype shown in Paper III to have a close relationship to higher p-calcium levels. Moreover, a lack of the T allele in rs1801725 was seen in the group of patients needing permanent treatment with calcium and vitamin D, i.e. > 12 months, (paper V).Patients who became hypocalcaemic (p-calcium < 2.00 mmol/L) on day one postoperatively, had lower preoperative levels of thyroid stimulating hormone (TSH) and higher levels of T3, this was also applied to the patient groups requiring temporary or permanent postoperative treatment (Papers II and V). In addition, hypocalcaemic patients treated for less than six months with anti-thyroid drugs had higher levels of bone metabolism markers CTX and P1NP than normocalcaemic patients (Paper V).In conclusion, the postoperative period of hypocalcaemia seen in patients with GD is a complex medical condition, caused by a combination of surgical trauma, different SNPs in CaSR, and high bone metabolism related to preoperative thyroid metabolism.
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| 26. |
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| 27. |
- Annerbo, Maria, et al.
(författare)
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Left-shifted relation between calcium and parathyroid hormone in Graves' Disease
- 2014
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 99:2, s. 545-551
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Tidskriftsartikel (refereegranskat)abstract
- Background:Patients with Graves' disease (GD) have disturbances in calcium regulation with manifestations such as postoperative hypocalcemia. We have investigated the thyroid as well as the parathyroid function in detail.Material and Method:A series of patients undergoing total thyroidectomy for GD (n=56) or Multi Nodular Goitre (MNG, n=50) were scrutinized for postoperative hypocalcemia, need for calcium and/or vitamin D substitution. CiCa-clamp was used in 14 patients and 21 controls to quantify the secretion of PTH in relation to the ionized plasma calcium level. The setpoint, equal to the plasma ionized calcium concentration at which 50% of the maximal secretion of PTH is inhibited, as well as other CiCa-related parameters were calculated.Results:Hypocalcemia was present in 48% of GD and 41.2% of patients with MNG postoperatively. Patients with GD had lower calcium levels, 18% had S-Ca< 2.00 mmol/L compared to 4.0% in the MNG group, p=0.02. A higher degree of GD patients were given parenteral calcium-substitution during the hospital stay (3.6% vs 0 %) and oral calcium substitution at discharge (48% vs 10%), although they had normal vitamin D3 levels. The GD group showed a significantly left-shifted setpoint compared to the normal group on CiCa clamp, 1.16 mmol/l vs. 1.20 mmol/L (p<0.001), as well as an increased PTH release to hypocalcemic stimulus. GD patients also show an association between degree of subclinical toxicosis at time of surgery and risk for developing postoperative hypocalcemia.Conclusion:Patients with GD demonstrate dysregulation of the calcium homeostasis by several parameters. GD patients have lower postoperative S-calcium compared to patients with MNG, lower calcium/PTH setpoint and a significantly increased release of PTH to hypocalcemic stimulus compared to controls. The CiCa clamp response in GD patients with normal 25-OH-vitamin D3 levels mimics that of obese patients in which vitamin D insufficiency has been proposed as an underlying cause.
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| 28. |
- Annerbo, Maria, et al.
(författare)
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Management of Grave's Disease Is Improved by Total Thyroidectomy
- 2012
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 36:8, s. 1943-1946
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Tidskriftsartikel (refereegranskat)abstract
- A retrospective analysis was performed on 267 consecutive patients with Graves' disease (GD). The principal aim of this study was to evaluate the risk for recurrence and complications when changing the surgical method from subtotal (ST) to total thyroidectomy (TT). Information from 267 consecutive patients operated on for GD between 2000 and 2006 was collected at Uppsala University Hospital (143) and Falun County Hospital (128). There were 229 women and 38 men. Four patients were operated on twice. A total of 40 STs and 229 TTs were performed. Results were compared to those of a previous cohort from the same hospital, with a majority of STs (157/176) performed from 1980 to 1992. The risk for relapse of GD was reduced from 20 to 3.3 % after the shift from ST to TT. In terms of surgical complications, 2.2 % demonstrated permanent vocal cord paralysis and 4.5 % had persistent hypocalcemia, not significant when compared to the previous cohort. In spite of TT, there were four recurrences, all due to remnant thyroid tissue high up at the hyoid bone. Changing the surgical method did not affect postoperative progression of dysthyroid ophthalmopathy (DO, 7.0 vs. 7.5 %). There were no differences in outcome with respect to which hospital the patients had their operation. Change from ST to TT dramatically reduced the risk for recurrence of GD without increasing the rate of complications. TT is not more effective than ST in hampering progression of DO as has been advocated by some. Careful surgical dissection up to the hyoid bone is necessary to avoid recurrence.
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| 29. |
- Arvidsson, Adam, 1990, et al.
(författare)
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Metal dimer sites in ZSM-5 zeolite for methane-to-methanol conversion from first-principles kinetic modelling: is the [Cu-O-Cu]2+ motif relevant for Ni, Co, Fe, Ag, and Au?
- 2017
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Ingår i: Catalysis Science and Technology. - : Royal Society of Chemistry (RSC). - 2044-4753 .- 2044-4761. ; 7:7, s. 1470-1477
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Tidskriftsartikel (refereegranskat)abstract
- Direct methane-to-methanol conversion is a desired process whereby natural gas is transformed into an energy-rich liquid. It has been realised at ambient pressure and temperature in metal ion-exchanged zeolites, where especially copper-exchanged ZSM-5 has shown promising results. The nature of the active sites in these systems is, however, still under debate. The activity has been assigned to a [Cu-O-Cu]2+ motif. One remaining question is whether this motif is general and also active in other metal-exchanged zeolites. Herein, we use first-principles microkinetic modelling to analyse the methane-to-methanol reaction on the [Cu-O-Cu]2+ motif, for Cu and other metals. First, we identify the cluster model size needed to accurately describe the dimer motif. Starting from the [Cu-O-Cu]2+ site, the metal ions are then systematically substituted with Ni, Co, Fe, Ag and Au. The results show that activation of Ag and Au dimer sites with oxygen is endothermic and therefore unlikely, whereas for Cu, Ni, Co and Fe, the activation is possible under realistic conditions. According to the kinetic simulations, however, the dimer motif is a plausible candidate for the active site for Cu only. For Ni, Co and Fe, close-to-infinite reaction times or unreasonably high temperatures are required for sufficient methane conversion. As Ni-, Co- and Fe-exchanged ZSM-5 are known to convert methane to methanol, these results indicate that the Cu-based dimer motif is not an appropriate model system for these metals.
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| 30. |
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| 31. |
- Backlin, Carin, et al.
(författare)
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Immunohistochemical expression of insulin-like growth factor 1 and its receptor in normal and neoplastic human adrenal cortex
- 1995
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 15:6B, s. 2453-2459
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Insulin-like growth factor 1 (IGF-1) may influence cellular growth, differentiation and secretion.MATERIAL AND METHODS:Cryosectioned normal human adrenal glands (n = 6), cortical adenoma (n = 21), and carcinoma (n = 17) were stained immunohistochemically for IGF-1 and its receptor, and human adrenocortical cancer cells expressing the receptor were analysed for influences on proliferation.RESULTS:Normal cortical parenchyma generally displayed faint IGF-1 reactivity and intracellular receptor staining. Similar labelling encompassed the adenomas, but only 6 of them were receptor reactive. IGF-1 expression was conspicuous in 11 carcinomas, and 6 of them displayed cell surface receptor reactivity. All aldosterone producing lesions were receptor antibody unreactive. Recombinant IGF-1 dose-dependently stimulated the cell proliferation, and this effect was reversed by the receptor antibody.CONCLUSION:IGF-1 may interact with function and proliferation of the human adrenal cortex with particular reference to cortical carcinomas lacking discernible aldosterone excess.
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| 32. |
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| 33. |
- Backman, Samuel, et al.
(författare)
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Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.
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| 34. |
- Backman, Samuel, 1994-
(författare)
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Molecular studies of endocrine tumors : Insights from genetics and epigenetics
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endocrine tumors may be benign or malignant and may occur in any of the hormone producing tissues. They share several biological characteristics, including a low mutation-burden, and may co-occur in several hereditary tumor syndromes. The aim of this thesis was to identify genetic and epigenetic aberrations in endocrine tumors.In paper I we performed a comprehensive DNA methylation analysis of 39 pheochromocytomas/paragangliomas as well as 4 normal adrenal medullae on the HumanMethylation27 BeadChip array. We validated two previously described clusters based on DNA methylation with distinct genetic associations.In Paper II we performed a transcriptomic analysis of 15 aldosterone producing adenomas. CTNNB1-mutated tumors were found to form a distinct subgroup based on gene expression and to share gene expression similarities with non-aldosterone producing adrenocortical tumors with CTNNB1 mutations, including overexpression of AFF3 and ISM1.In paper III we used whole genome sequencing to identify germline genetic variants in 14 patients with Multiple Endocrine Neoplasia type 1 previously found to be wildtype for the MEN1 gene on routine clinical testing. Three patients were found to carry previously undetected MEN1 mutations. Two patients were confirmed to have phenocopies caused by variants affecting CASR or CDC73. In total 9/14 patients were not found to have a disease-causing germline variant, suggesting that the syndrome may in some cases be due to chance co-occurrence of several sporadic tumors.In paper IV RNA-Seq and whole genome sequencing of a cohort of SI-NETs selected on the basis of unusually short or long survival was performed in order to identify disease causing genes and potential prognostic factors. We confirmed known genetic aberrations and found rare variants in known cancer driver genes. Based on gene expression two clusters that differ in prognosis were detected. Moreover, through integration of copy number variation data and gene expression, we identied novel potential disease causing genes.
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| 35. |
- Backman, Samuel, et al.
(författare)
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Potential prognostic markers and candidate genetic drivers in small intestine neuroendocrine tumours
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundSmall intestinal neuroendocrine tumours (SI-NETs) are the most common tumour of the small intestine. The disease often has a favourable outcome with long survival even in the context of metastatic disease. However, some patients fare worse and succumb to the disease soon after diagnosis despite similar stage and grade. Molecular prognostic markers are lacking. The most common genetic aberration is loss of chromosome 18q, although the oncogenic mechanism of this is unknown. The only recurrently mutated gene is CDKN1B, which is mutated in 9% of cases.AimsTo identify molecular derangements in SI-NETs and identify potential prognostic markers.MethodsForty tumour samples from thirty patients with unusually long or unusually short survival after diagnosis were subjected to whole genome sequencing. Twenty of the samples were also included for RNA Sequencing.ResultsIn addition to mutations in CDKN1B we find rare variants in known cancer genes including NF1, MAX and SPEN. Unsupervised clustering based on gene expression resulted in two clusters with prognostic significance. We identify potential prognostic markers based on gene expression. Finally, we identify genes whose expression is affected by the most common copy number variations in these tumours, including SOCS6 on chromosome 18 and ATM on chromosome 11.
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| 36. |
- Backman, Samuel, et al.
(författare)
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RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs.
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| 37. |
- Backman, Samuel, et al.
(författare)
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The Evolutionary History of Metastatic Pancreatic Neuroendocrine Tumours Reveals a Therapy Driven Route to High-Grade Transformation.
- 2024
-
Ingår i: medRxiv : the preprint server for health sciences.
-
Tidskriftsartikel (refereegranskat)abstract
- Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular, show frequent progression from a low/intermediate to a high-grade disease. To understand the molecular mechanisms underlying this phenomenon, we performed multi-omics analysis of 32 longitudinal samples from six metastatic PanNET patients. Following MEN1 inactivation, PanNETs exhibit genetic heterogeneity on both spatial and temporal dimensions with parallel and convergent tumuor evolution involving the ATRX/DAXX and mTOR pathways. Following alkylating chemotherapy treatment, some PanNETs develop mismatch repair deficiency and acquire a hypermutator phenotype. This DNA hypermutation phenotype was only found in cases that also showed transformation into a high-grade PanNET. Overall, our findings contribute to broaden the understanding of metastatic PanNET, and suggests that therapy driven disease evolution is an important hallmark of this disease.
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| 38. |
- Backman, Samuel, et al.
(författare)
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Whole genome sequencing of apparently mutation-negative MEN1 patients
- 2020
-
Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 182:1, s. 35-45
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.
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| 39. |
- Barazeghi, Elham, et al.
(författare)
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5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
- 2016
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.
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| 40. |
- Barazeghi, Elham, et al.
(författare)
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A role for TET2 in parathyroid carcinoma
- 2017
-
Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 24:7, s. 329-338
-
Tidskriftsartikel (refereegranskat)abstract
- Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.
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| 41. |
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| 42. |
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| 43. |
- Barazeghi, Elham, et al.
(författare)
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Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors.
- 2018
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs.METHODS: The analysis was conducted using 40 primary tumors and corresponding 47 metastases. The level of 5hmC, TET1 and TET2 was analyzed by DNA immune-dot blot assay and immunohistochemistry. Other methods included a colony forming assay, western blotting analysis, and quantitative bisulfite pyrosequencing analysis. The effect of the exportin-1 nuclear transport machinery inhibitors on cell proliferation and apoptosis was also explored using two SI-NET cell lines.RESULTS: Variable levels of 5hmC and a mosaic staining appearance with a mixture of positive and negative cell nuclei, regardless of cell number and staining strength, was observed overall both in primary tumors and metastases. Similarly aberrant staining pattern was observed for TET1 and TET2. In a number of tumors (15/32) mosaic pattern together with areas of negative staining was also observed for TET1. Abolished expression of TET1 in the tumors did not seem to involve hypermethylation of the TET1 promoter region. Overexpression of TET1 in a colony forming assay supported a function as cell growth regulator. In contrast to 5hmC and TET1, TET2 was also observed in the cytoplasm of all the analyzed SI-NETs regardless of nuclear localization. Treatment of CNDT2.5 and KRJ-I cells with the exportin-1 (XPO1/CRM1) inhibitor, leptomycin B, induced reduction in the cytoplasm and nuclear retention of TET2. Aberrant partitioning of TET2 from the nucleus to the cytoplasm seemed therefore to involve the exportin-1 nuclear transport machinery. Reduced cell proliferation and induction of apoptosis were observed after treatment of CNDT2.5 and KRJ-I cells with leptomycin B or KPT-330 (selinexor).CONCLUSIONS: SI-NETs are epigenetically dysregulated at the level of 5-hydroxymethylcytosine/ TET1/TET2. We suggest that KPT-330/selinexor or future developments should be considered and evaluated for single treatment of patients with SI-NET disease and also in combinations with somatostatin analogues, peptide receptor radiotherapy, or everolimus.
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| 44. |
- Barazeghi, Elham, et al.
(författare)
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EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine
- 2021
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically dysregulated. In contrast to the undetectable expression of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase in the enterochromaffin cells of the small intestine, we found high and differential expression of EZH2 in primary SI-NETs and corresponding metastases. Silencing EZH2 in the SI-NET cell line CNDT2.5 reduced cell proliferation and induced apoptosis. Furthermore, EZH2 knockout inhibited tumor progression in a CNDT2.5 SI-NET xenograft mouse model, and treatment of SI-NET cell lines CNDT2.5 and GOT1 with the EZH2-specific inhibitor CPI-1205 decreased cell viability and promoted apoptosis. Moreover, CPI-1205 treatment reduced migration capacity of CNDT2.5 cells. The EZH2 inhibitor GSK126 also repressed proliferation of CNDT2.5 cells. Recently, metformin has received wide attention as a therapeutic option in diverse cancers. In CNDT2.5 and GOT1 cells, metformin suppressed EZH2 expression, and inhibited cell proliferation. Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs.
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| 45. |
- Barazeghi, Elham, et al.
(författare)
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PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors
- 2019
-
Ingår i: Endocrine Connections. - : BIOSCIENTIFICA LTD. - 2049-3614. ; 8:8, s. 1126-1135
-
Tidskriftsartikel (refereegranskat)abstract
- Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTP mu (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2'deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.
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| 46. |
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| 47. |
- Barazeghi, Elham
(författare)
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Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Deregulation of the epigenome is associated with the initiation and progression of various types of human cancers. Here we investigated the level of 5-hydroxymethylcytosine (5hmC), expression and function of TET1 and TET2, and DNA methylation in parathyroid tumors and small intestinal neuroendocrine tumors (SI-NETs).In Paper I, an undetectable/very low level of 5hmC in parathyroid carcinomas (PCs) compared to parathyroid adenomas with positive staining, suggested that 5hmC may represent a novel biomarker for parathyroid malignancy. Immunohistochemistry revealed that increased tumor weight in adenomas was associated with a more aberrant staining pattern of 5hmC and TET1. A growth regulatory role of TET1 was demonstrated in parathyroid tumor cells.Paper II revealed that the expression of TET2 was also deregulated in PCs, and promoter hypermethylation was detected in PCs when compared to normal parathyroid tissues. 5-aza-2′-deoxycytidine treatment of a primary PC cell culture induced TET2 expression and further supported involvement of promoter hypermethylation in TET2 gene repression. TET2 knockout demonstrated a role for TET2 in cell growth and migration, and as a candidate tumor suppressor gene.In Paper III, variable levels of 5hmC, and aberrant expression of TET1 and TET2 were observed in SI-NETs. We demonstrated a growth regulatory role for TET1, and cytoplasmic expression with absent nuclear localization for TET2 in SI-NETs. In vitro experiments supported the involvement of exportin-1 in TET2 mislocalization, and suggested that KPT-330/selinexor, an orally bioavailable selective inhibitor of exportin-1 and nuclear export, with anti-cancer effects, could be further investigated as a therapeutic option in patients with SI-NETs.In Paper IV, DNA methylation was compared between SI-NET primary tumors and metastases by reduced representation bisulfite sequencing. Three differentially methylated regions (DMR) on chromosome 18 were detected and chosen for further analyses. The PTPRM gene, at 18p11, displayed low expression in SI-NETs with high levels of methylation in the presumed CpG island shores, and in the DMR rather than the promoter region or exon 1/intron 1 boundary. PTPRM overexpression resulted in inhibition of cell growth, proliferation, and induction of apoptosis in SI-NET cells, suggesting a role for PTPRM as an epigenetically deregulated candidate tumor suppressor gene in SI-NETs.
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| 48. |
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| 49. |
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| 50. |
- Bergström, Joakim, et al.
(författare)
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Two different types of amyloid deposits - apolipoprotein A-IV and transthyretin - in a patient with systemic amyloidosis
- 2004
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Ingår i: Lab. Invest.. ; 84, s. 981-988
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Tidskriftsartikel (refereegranskat)abstract
- Certain forms of systemic amyloidosis have been associated with the pathologic deposition as fibrils of three different apolipoprotein-related proteins--apolipoprotein A-I, apolipoprotein A-II, and serum amyloid A. We have previously reported (Bergstrom et al, Biochem Biophys Res Commun 2001;285:903-908) that amyloid fibrils extracted from the heart of an elderly male with senile systemic amyloidosis contained, in addition to wild-type transthyretin-related molecules, an N-terminal fragment of yet a fourth apolipoprotein--apolipoprotein A-IV (apoA-IV). We now provide the results of our studies that have established the complete amino-acid sequence of this approximately 70-residue component and, additionally, have shown this protein to be the product of an unmutated apoA-IV gene. Notably, the apoA-IV and transthyretin fibrils were not codeposited but, rather, had anatomically distinct patterns of distribution within the heart and other organs, as evidenced immunohistochemically, by variation in the ultra structural morphology and by differences in the intensity of Congo red birefringence. These findings provide the first conclusive evidence that two separate forms of amyloid, each derived from a wild-type amyloidogenic precursor protein, were present in a patient with systemic amyloidosis.
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