| 1. |
- Carling, Tobias, et al.
(författare)
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Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor
- 2000
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - 0021-972X .- 1945-7197. ; 85:5, s. 2042-7
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Tidskriftsartikel (refereegranskat)abstract
- Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.
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| 2. |
- Cashin, Peter, et al.
(författare)
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Appendiceal Adenocarcinoids with Peritoneal Carcinomatosis Treated with Cytoreductive Surgery and Intraperitoneal Chemotherapy : a retrospective study of in vitro drug sensitivity and survival
- 2011
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Ingår i: Clinical Colorectal Cancer. - : Elsevier BV. - 1533-0028 .- 1938-0674. ; 10:2, s. 108-112
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The purpose of this study was to present results on cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) of appendiceal adenocarcinoid (MC) with peritoneal carcinomatosis (PC), to assess drug sensitivity of AAC, as compared with colorectal cancer (CRC), and to report any discordant histopathology. Methods: Ten patients were treated with CRS and HIPEC. Treatment, drug sensitivity profiles, histopathology, and survival data were recorded and matched with potential prognostic indicators. Drug sensitivity was assessed with short-term fluorometric microculture cytotoxicity assay and compared with peritoneal metastases from CRC. Results: Patients with completeness of cytoreduction score (CC) 1 (16.4 months). In the CC 1 group. For standard drugs, tumor cells from MC and CRC were equally sensitive; except for docetaxel, to which MC was more sensitive than CRC. Conclusion: The CC-score correlated with overall survival. Candidates for this type of treatment should be referred early for evaluation in order to reach a better CC score. Drugs used for CRC also seem adequate for treatment of MC, although other drugs, eg, docetaxel, might be more active.
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| 3. |
- Daskalakis, Kosmas, et al.
(författare)
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Ex vivo activity of cytotoxic drugs and targeted agents in Small Intestinal NETs
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Small Intestinal Neuroendocrine Tumours (SI-NET) are considered to be generally resistant to systemic treatment. To date predictive markers for drug activity are lacking.Patients and Methods: Tumour samples from 27 patients with SI-NET were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer, and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinico-pathological variables and pre-treatment biomarkers.Results: For standard cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinums, gemcitabine and doxorubicin compared with CRC. For targeted kinase inhibitors, SI-NET was among the most sensitive diagnoses. CLL and ovarian cancer were generally the most sensitive diagnoses to both cytotoxic drugs and protein kinase inhibitors. The mTOR inhibitor sirolimus exhibited modest cytotoxic activity.Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors.Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo.Conclusions: SI-NETs exhibit variable but generally intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinico-pathological factors and currently used biomarkers were not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NETs. The great variability in drug sensitivity calls for individualized selection of therapy.
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| 4. |
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| 5. |
- Daskalakis, Kosmas, et al.
(författare)
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Ex vivo activity of cytotoxic drugs and targeted agents in small intestinal neuroendocrine tumors
- 2018
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 25:4, s. 471-480
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Tidskriftsartikel (refereegranskat)abstract
- Small intestinal neuroendocrine tumors (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumor samples from 27 patients with SI-NETs were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinicopathological variables and pre-treatment biomarkers. For cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinum, gemcitabine and doxorubicin compared with CRC. For several of the targeted kinase inhibitors, SI-NET was among the most sensitive solid tumor types. CLL and ovarian cancer were generally the most sensitive tumor types to both cytotoxic drugs and protein kinase inhibitors. SI-NET was more sensitive to the mTOR inhibitor sirolimus than the other solid tumor types tested. Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors. Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo. SI-NETs exhibit intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinicopathological factors and currently used biomarkers are not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NET. The great variability in drug sensitivity calls for individualized selection of therapy.
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| 6. |
- 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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| 7. |
- 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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| 8. |
- Norlén, Olov
(författare)
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Small Intestinal Neuroendocrine Tumor : A Rare Malignancy with Favorable Outcome
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with computed tomography for easier interpretation, as RFA areas are not clearly distinguishable with 11C-5HTP-PET alone. Paper V studied gallstone complications after somatostatin analog treatment in SI-NET patients, and concluded that there was a rather high risk to be subjected to a cholecystectomy due to biliary colic, cholecystitis, cholangitis or pancreatitis after primary surgery in somatostatin analog treated patients.
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| 9. |
- Abrikosov, Igor A., et al.
(författare)
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Finite Temperature, Magnetic, and Many-Body Effects in Ab Initio Simulations of Alloy Thermodynamics
- 2013
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Ingår i: TMS2013 Supplemental Proceedings. - Hoboken, NJ, USA : John Wiley & Sons. - 9781118605813 - 9781118663547 ; , s. 617-626
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Bokkapitel (refereegranskat)abstract
- Ab initio electronic structure theory is known as a useful tool for prediction of materials properties. However, majority of simulations still deal with calculations in the framework of density functional theory with local or semi-local functionals carried out at zero temperature. We present new methodological solution.s, which go beyond this approach and explicitly take finite temperature, magnetic, and many-body effects into account. Considering Ti-based alloys, we discuss !imitations of the quasiharmonic approximation for the treatment of lattice vibrations, and present an accurate and easily extendable method to calculate free ,energies of strongly anharmonic solids. We underline the necessity to going beyond the state-of-the-art techniques for the determination of effective cluster interactions in systems exhibiting mctal-to-insulator transition, and describe a unified cluster expansion approach developed for this class of materials. Finally, we outline a first-principles method, disordered local moments molecular dynamics, for calculations of thermodynamic properties of magnetic alloys, like Cr1-x,.AlxN, in their high-temperature paramagnetic state. Our results unambiguously demonstrate importance of finite temperature effects in theoretical calculations ofthermodynamic properties ofmaterials.
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| 10. |
- Abulaiti, Yiming, et al.
(författare)
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Determination of the strong coupling constant alpha(s) from transverse energy-energy correlations in multijet events at root s=8 TeV using the ATLAS detector
- 2017
-
Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 77:12
-
Tidskriftsartikel (refereegranskat)abstract
- Measurements of transverse energy-energy correlations and their associated asymmetries in multi-jet events using the ATLAS detector at the LHC are presented. The data used correspond to vs = 8 TeV proton-proton collisions with an integrated luminosity of 20.2 fb(-1). The results are presented in bins of the scalar sum of the transverse momenta of the two leading jets, unfolded to the particle level and compared to the predictions from Monte Carlo simulations. A comparison with next-to-leading-order perturbative QCD is also performed, showing excellent agreement within the uncertainties. From this comparison, the value of the strong coupling constant is extracted for different energy regimes, thus testing the running of alpha(s)(mu) predicted in QCD up to scales over 1 TeV. A global fit to the transverse energy-energy correlation distributions yields alpha(s)(m(Z)) = 0.1162 +/- 0.0011 (exp.)(-0.0070)(+0.0084) (theo.), while a global fit to the asymmetry distributions yields a value of alpha(s)(m(Z)) = 0.1196 +/- 0.0013 (exp.)(-0.0045)(+0.0075) (theo.).
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| 11. |
- Abulaiti, Yiming, et al.
(författare)
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Femtoscopy with identified charged pions in proton-lead collisions at root s(NN)=5.02 TeV with ATLAS
- 2017
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Ingår i: Physical Review C. - : American Physical Society. - 2469-9985 .- 2469-9993. ; 96:6
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Tidskriftsartikel (refereegranskat)abstract
- Bose-Einstein correlations between identified charged pions are measured for p+Pb collisions at root s(NN) = 5.02 TeV using data recorded by the ATLAS detector at the CERN Large Hadron Collider corresponding to a total integrated luminosity of 28 nb(-1). Pions are identified using ionization energy loss measured in the pixel detector. Two-particle correlation functions and the extracted source radii are presented as a function of collision centrality as well as the average transverse momentum (k(T)) and rapidity (y*(pi pi)) of the pair. Pairs are selected with a rapidity -2 < y*(pi pi) < 1 and with an average transverse momentum 0.1 < k(T) < 0.8 GeV. The effect of jet fragmentation on the two-particle correlation function is studied, and a method using opposite-charge pair data to constrain its contributions to the measured correlations is described. The measured source sizes are substantially larger in more central collisions and are observed to decrease with increasing pair k(T). A correlation of the radii with the local charged-particle density is demonstrated. The scaling of the extracted radii with the mean number of participating nucleons is also used to compare a selection of initial-geometry models. The cross term R-ol is measured as a function of rapidity, and a nonzero value is observed with 5.1 sigma combined significance for -1 < y*pi pi < 1 in the most central events.
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| 12. |
- Abulaiti, Yiming, et al.
(författare)
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Measurement of jet fragmentation in Pb plus Pb and pp collisions at root s(NN)=2.76 TeV with the ATLAS detector at the LHC
- 2017
-
Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 77:6
-
Tidskriftsartikel (refereegranskat)abstract
- The distributions of transverse momentum and longitudinal momentum fraction of charged particles in jets are measured in Pb+Pb and pp collisions with the ATLAS detector at the LHC. The distributions are measured as a function of jet transverse momentum and rapidity. The analysis utilises an integrated luminosity of 0.14 nb(-1) of Pb+Pb data and 4.0 pb(-1) of pp data collected in 2011 and 2013, respectively, at the same centre-of-mass energy of 2.76 TeV per colliding nucleon pair. The distributions measured in pp collisions are used as a reference for those measured in Pb+Pb collisions in order to evaluate the impact on the internal structure of jets from the jet energy loss of fast partons propagating through the hot, dense medium created in heavy-ion collisions. Modest but significant centrality-dependent modifications of fragmentation functions in Pb+Pb collisions with respect to those in pp collisions are seen. No significant dependence of modifications on jet p(T) and rapidity selections is observed except for the fragments with the highest transverse momenta for which some reduction of yields is observed for more forward jets.
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| 13. |
- Abulaiti, Yiming, et al.
(författare)
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Measurement of multi-particle azimuthal correlations in pp, p plus Pb and low-multiplicity Pb plus Pb collisions with the ATLAS detector
- 2017
-
Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 77:6
-
Tidskriftsartikel (refereegranskat)abstract
- Multi-particle cumulants and corresponding Fourier harmonics are measured for azimuthal angle distributions of charged particles in pp collisions at root S = 5.02 and 13 TeV and in p + Pb collisions at root S-NN = 5.02 TeV, and compared to the results obtained for low-multiplicity Pb + Pb collisions at root S-NN = 2.76 TeV. These measurements aim to assess the collective nature of particle production. The measurements of multi-particle cumulants confirm the evidence for collective phenomena in p + Pb and low-multiplicity Pb + Pb collisions. On the other hand, the pp results for four-particle cumulants do not demonstrate collective behaviour, indicating that they may be biased by contributions from non-flow correlations. A comparison of multi-particle cumulants and derived Fourier harmonics across different collision systems is presented as a function of the charged-particle multiplicity. For a given multiplicity, the measured Fourier harmonics are largest in Pb + Pb, smaller in p + Pb and smallest in pp collisions. The pp results show no dependence on the collision energy, nor on the multiplicity.
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| 14. |
- Abulaiti, Yiming, et al.
(författare)
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Measurement of the cross-section for electroweak production of dijets in association with a Z boson in pp collisions at root s=13 TeV with the ATLAS detector
- 2017
-
Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 775, s. 206-228
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Tidskriftsartikel (refereegranskat)abstract
- The cross-section for the production of two jets in association with a leptonically decaying Z boson (Zjj) is measured in proton-proton collisions at a centre-of-mass energy of 13 TeV, using data recorded with the ATLAS detector at the Large Hadron Collider, corresponding to an integrated luminosity of 3.2 fb(-1). The electroweak Zjj cross-section is extracted in a fiducial region chosen to enhance the electroweak contribution relative to the dominant Drell-Yan Zjj process, which is constrained using a data-driven approach. The measured fiducial electroweak cross-section is sigma(Zjj)(EW) = 119 +/- 16 (stat.) +/- 20 (syst.) +/- 2 (lumi.) fb for dijet invariant mass greater than 250 GeV, and 34.2 +/- 5.8 (stat.) +/- 5.5 (syst.) +/- 0.7 (lumi.) fb for dijet invariant mass greater than 1 TeV. Standard Model predictions are in agreement with the measurements. The inclusive Zjj cross-section is also measured in six different fiducial regions with varying contributions from electroweak and Drell-Yan Zjj production.
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| 15. |
- Abulaiti, Yiming, et al.
(författare)
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Measurement of the inclusive jet cross-sections in proton-proton collisions at root s=8 TeV with the ATLAS detector
- 2017
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Ingår i: Journal of High Energy Physics (JHEP). - : SPRINGER. - 1126-6708 .- 1029-8479. ; :9
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Tidskriftsartikel (refereegranskat)abstract
- Inclusive jet production cross-sections are measured in proton-proton collisions at a centre-of-mass energy of root s = 8 TeV recorded by the ATLAS experiment at the Large Hadron Collider at CERN. The total integrated luminosity of the analysed data set amounts to 20.2 fb(-1). Double-differential cross-sections are measured for jets defined by the anti-k(t) jet clustering algorithm with radius parameters of R = 0.4 and R = 0.6 and are presented as a function of the jet transverse momentum, in the range between 70 GeV and 2.5 TeV and in six bins of the absolute jet rapidity, between 0 and 3.0. The measured cross-sections are compared to predictions of quantum chromodynamics, calculated at next-to-leading order in perturbation theory, and corrected for non-perturbative and electroweak effects. The level of agreement with predictions, using a selection of different parton distribution functions for the proton, is quantified. Tensions between the data and the theory predictions are observed.
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| 16. |
- Abulaiti, Yiming, et al.
(författare)
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Measurement of the W-boson mass in pp collisions at root s=7 TeV with the ATLAS detector
- 2018
-
Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 78:2
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Tidskriftsartikel (refereegranskat)abstract
- A measurement of the mass of the W boson is presented based on proton-proton collision data recorded in 2011 at a centre-of-mass energy of 7 TeV with the ATLAS detector at the LHC, and corresponding to 4.6 fb(-1) of integrated luminosity. The selected data sample consists of 7.8 x 10(6) candidates in the W -> mu nu channel and 5.9 x 10(6) candidates in the W -> e nu channel. The W-boson mass is obtained from template fits to the reconstructed distributions of the charged lepton transverse momentum and of the W boson transverse mass in the electron and muon decay channels, yielding m(W) = 80370 +/- 7 (stat.) +/- 11(exp. syst.) +/- 14 (mod. syst.) MeV = 80370 +/- 19 MeV, where the first uncertainty is statistical, the second corresponds to the experimental systematic uncertainty, and the third to the physics-modelling systematic uncertainty. A measurement of the mass difference between the W+ and W- bosons yields m(W+) - m(W-) = -29 +/- 28 MeV.
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| 17. |
- Abulaiti, Yiming, et al.
(författare)
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Measurements of integrated and differential cross sections for isolated photon pair production in pp collisions at root s=8 TeV with the ATLAS detector
- 2017
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Ingår i: Physical Review D. - 2470-0010 .- 2470-0029. ; 95:11
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Tidskriftsartikel (refereegranskat)abstract
- A measurement of the production cross section for two isolated photons in proton-proton collisions at a center-of-mass energy of root s = 8 TeV is presented. The results are based on an integrated luminosity of 20.2 fb(-1) recorded by the ATLAS detector at the Large Hadron Collider. The measurement considers photons with pseudorapidities satisfying vertical bar eta(gamma)vertical bar< 1.37 or 1.56 40 GeV and E-T,2(gamma) > 30 GeV for the two leading photons ordered in transverse energy produced in the interaction. The background due to hadronic jets and electrons is subtracted using data-driven techniques. The fiducial cross sections are corrected for detector effects and measured differentially as a function of six kinematic observables. The measured cross section integrated within the fiducial volume is 16.8 +/- 0.8 pb. The data are compared to fixed-order QCD calculations at next-to-leading-order and next-to-next-to-leading-order accuracy as well as next-to-leading-order computations including resummation of initial-state gluon radiation at next-to-next-to-leading logarithm or matched to a parton shower, with relative uncertainties varying from 5% to 20%.
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| 18. |
- Abulaiti, Yiming, et al.
(författare)
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Measurements of top-quark pair to Z-boson cross-section ratios at root s=13, 8, 7 TeV with the ATLAS detector
- 2017
-
Ingår i: Journal of High Energy Physics (JHEP). - : Springer. - 1126-6708 .- 1029-8479. ; :2, s. 1-54
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Tidskriftsartikel (refereegranskat)abstract
- Ratios of top-quark pair to Z-boson cross sections measured from proton-proton-collisions at the LHC centre-of-mass energies of root S = 13 TeV, 8 TeV, and 7 TeV are presented by the ATLAS Collaboration. Single ratios, at a given root S for the two processes and at different root S , for each process, as well as double ratios of the two processes at different root S , are evaluated. The ratios are constructed using previously published ATLAS measurements of the t (t) over bar and Z-boson production cross sections, corrected to a common phase space where required, and a new analysis of Z -> l(+)l(-) where l = e, mu at root S = 13 TeV performed with data collected in 2015 with an integrated luminosity of 3.2 fb(-1). Correlations of systematic uncertainties are taken into account when evaluating the uncertainties in the ratios. The correlation model is also used to evaluate the combined cross section of the Z -> e (+) e (-) and the Z -> mu (+) mu (-) channels for each value. The results are compared to calculations performed at next-to-next-to-leading-order accuracy using recent sets of parton distribution functions. The data demonstrate significant power to constrain the gluon distribution function for the Bjorken-x values near 0.1 and the light-quark sea for x < 0.02.
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| 19. |
- Abulaiti, Yiming, et al.
(författare)
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Search for additional heavy neutral Higgs and gauge bosons in the ditau final state produced in 36 fb(-1) of pp collisions at root s=13 TeV with the ATLAS detector
- 2018
-
Ingår i: Journal of High Energy Physics (JHEP). - : Springer. - 1126-6708 .- 1029-8479. ; :1
-
Tidskriftsartikel (refereegranskat)abstract
- A search for heavy neutral Higgs bosons and Z' bosons is performed using a data sample corresponding to an integrated luminosity of 36.1 fb(-1) from proton-proton collisions at root s = 13 TeV recorded by the ATLAS detector at the LHC during 2015 and 2016. The heavy resonance is assumed to decay to tau(+)tau(-) with at least one tau lepton decaying to final states with hadrons and a neutrino. The search is performed in the mass range of 0.2-2.25 TeV for Higgs bosons and 0.2-4.0 TeV for Z' bosons. The data are in good agreement with the background predicted by the Standard Model. The results are interpreted in benchmark scenarios. In the context of the hMSSM scenario, the data exclude tan beta > 1.0 for m(A) = 0.25 TeV and tan beta > 42 for m(A) = 1.5 TeV at the 95% confidence level. For the Sequential Standard Model, Z'(SSM) with m(Z') < 2.42 TeV is excluded at 95% confidence level, while Z'(NU) with m(Z') < 2.25 TeV is excluded for the non-universal G(221) model that exhibits enhanced couplings to third-generation fermions.
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| 20. |
- Abulaiti, Yiming, et al.
(författare)
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Search for dark matter at root s=13 TeV in final states containing an energetic photon and large missing transverse momentum with the ATLAS detector
- 2017
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 77:6
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Tidskriftsartikel (refereegranskat)abstract
- Results of a search for physics beyond the Standard Model in events containing an energetic photon and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. As the number of events observed in data, corresponding to an integrated luminosity of 36.1 fb(-1) of proton-proton collisions at a centre-of-mass energy of 13 TeV, is in agreement with the Standard Model expectations, model-independent limits are set on the fiducial cross section for the production of events in this final state. Exclusion limits are also placed in models where dark-matter candidates are pair-produced. For dark-matter production via an axial-vector or a vector mediator in the s-channel, this search excludes mediator masses below 750-1200 GeV for dark-matter candidate masses below 230-480 GeV at 95% confidence level, depending on the couplings. In an effective theory of dark-matter production, the limits restrict the value of the suppression scale M-* to be above 790 GeV at 95% confidence level. A limit is also reported on the production of a high-mass scalar resonance by processes beyond the Standard Model, in which the resonance decays to Z gamma and the Z boson subsequently decays into neutrinos.
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| 21. |
- Abulaiti, Yiming, et al.
(författare)
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Search for dark matter produced in association with bottom or top quarks in root s=13 TeV pp collisions with the ATLAS detector
- 2018
-
Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 78:1
-
Tidskriftsartikel (refereegranskat)abstract
- A search for weakly interacting massive dark matter particles produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and missing transverse momentum are considered. The analysis uses 36.1 fb(-1) of proton proton collision data recorded by the ATLAS experiment at root s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are interpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour-neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross-section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour-charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements.
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| 22. |
- Abulaiti, Yiming, et al.
(författare)
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Search for direct top squark pair production in final states with two leptons in root s=13 TeV pp collisions with the ATLAS detector
- 2017
-
Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 77:12
-
Tidskriftsartikel (refereegranskat)abstract
- The results of a search for direct pair production of top squarks in events with two opposite-charge leptons (electrons or muons) are reported, using 36.1 fb(-1) of integrated luminosity from proton-proton collisions at root s = 13 TeV collected by the ATLAS detector at the Large Hadron Collider. To cover a range of mass differences between the top squark (t) over tilde and lighter supersymmetric particles, four possible decay modes of the top squark are targeted with dedicated selections: the decay (t) over tilde -> b (chi) over tilde (+/-)(1) into a b-quark and the lightest chargino with (chi) over tilde (+/-)(1) W (chi) over tilde (0)(1),the decay (t) over tilde -> t (chi) over tilde (0)(1) into an on-shell top quark and the lightest neutralino, the three-body decay (t) over tilde -> bW (chi) over tilde (0)(1) and the four-body decay (t) over tilde -> bl nu(chi) over tilde (0)(1). No significant excess of events is observed above the Standard Model background for any selection, and limits on top squarks are set as a function of the (t) over tilde and (chi) over tilde (0)(1) masses. The results exclude at 95% confidence level (t) over tilde masses up to about 720 GeV, extending the exclusion region of supersymmetric parameter space covered by previous searches.
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| 23. |
- Abulaiti, Yiming, et al.
(författare)
-
Search for heavy resonances decaying to a W or Z boson and a Higgs boson in the q(q)over-bar(('))b(b)over-bar final state in pp collisions at root s =13 TeV with the ATLAS detector
- 2017
-
Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 774, s. 494-515
-
Tidskriftsartikel (refereegranskat)abstract
- A search for heavy resonances decaying to a W or Z boson and a Higgs boson in the q(q)over-bar(('))b(b)over-bar final state is described. The search uses 36.1 fb(-1)of proton-proton collision data at root s = 13 TeV collected by the ATLAS detector at the CERN Large Hadron Collider in 2015 and 2016. The data are in agreement with the Standard Model expectations, with the largest excess found at a resonance mass of 3.0 TeV with a local (global) significance of 3.3 (2.1) sigma. The results are presented in terms of constraints on a simplified model with a heavy vector triplet. Upper limits are set on the production cross-section times branching ratio for resonances decaying to a W (Z) boson and a Higgs boson, itself decaying to b(b)over-bar, in the mass range between 1.1 and 3.8 TeV at 95% confidence level; the limits range between 83 and 1.6 fb (77 and 1.1 fb) at 95% confidence level.
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| 24. |
- Abulaiti, Yiming, et al.
(författare)
-
Search for new high-mass phenomena in the dilepton final state using 36 fb(-1) of proton-proton collision data at root s=13 TeV with the ATLAS detector
- 2017
-
Ingår i: Journal of High Energy Physics (JHEP). - : Springer-Verlag New York. - 1126-6708 .- 1029-8479. ; :10
-
Tidskriftsartikel (refereegranskat)abstract
- A search is conducted for new resonant and non-resonant high-mass phenomena in dielectron and dimuon fi nal states. The search uses 36 : 1 fb(-1) of proton-proton collision data, collected at root s = 13TeV by the ATLAS experiment at the LHC in 2015 and 2016. No signi fi cant deviation from the Standard Model prediction is observed. Upper limits at 95% credibility level are set on the cross-section times branching ratio for resonances decaying into dileptons, which are converted to lower limits on the resonance mass, up to 4.1 TeV for the E-6 -motivated Z(X)'. Lower limits on the qqll contact interaction scale are set between 2.4 TeV and 40 TeV, depending on the model.
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| 25. |
- Abulaiti, Yiming, et al.
(författare)
-
Search for pair production of heavy vector-like quarks decaying to high-p(T) W bosons and b quarks in the lepton-plus-jets final state in pp collisions at root s=13 TeV with the ATLAS detector
- 2017
-
Ingår i: Journal of High Energy Physics (JHEP). - : SPRINGER. - 1126-6708 .- 1029-8479. ; :10
-
Tidskriftsartikel (refereegranskat)abstract
- A search is presented for the pair production of heavy vector-like T quarks, primarily targeting the T quark decays to a W boson and a b-quark. The search is based on 36: 1 fb(-1) of pp collisions at root s = 13TeV recorded in 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. Data are analysed in the lepton-plus-jets final state, including at least one b-tagged jet and a large-radius jet identified as originating from the hadronic decay of a high-momentum W boson. No significant deviation from the Standard Model expectation is observed in the reconstructed T mass distribution. The observed 95% confidence level lower limit on the T mass are 1350 GeV assuming 100% branching ratio to Wb. In the SU(2) singlet scenario, the lower mass limit is 1170 GeV. This search is also sensitive to a heavy vector-like B quark decaying to Wt and other final states. The results are thus reinterpreted to provide a 95% con fidence level lower limit on the B quark mass at 1250 GeV assuming 100% branching ratio to Wt; in the SU(2) singlet scenario, the limit is 1080 GeV. Mass limits on both T and B production are also set as a function of the decay branching ratios. The 100% branching ratio limits are found to be applicable to heavy vector-like Y and X production that decay to Wb and Wt, respectively.
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| 26. |
- Abulaiti, Yiming, et al.
(författare)
-
Search for super symmetry inevents with b-tagged jets and missing transverse momentum in pp collisions at root s=13 TeV with the ATLAS detector
- 2017
-
Ingår i: Journal of High Energy Physics (JHEP). - : Springer. - 1126-6708 .- 1029-8479. ; :11
-
Tidskriftsartikel (refereegranskat)abstract
- A search for the supersymmetric partners of the Standard Model bottom and top quarks is presented. The search uses 36.1 fb(-1) of pp collision data at root s = 13 TeV collected by the ATLAS experiment at the Large Hadron Collider. Direct production of pairs of bottom and top squarks ((b) over bar (1) and (t) over bar (1)) is searched for in final states with b-tagged jets and missing transverse momentum. Distinctive selections are de fi ned with either no charged leptons (electrons or muons) in the fi nal state, or one charged lepton. The zero-lepton selection targets models in which the (b) over bar (1) is the lightest squark and decays via (b) over bar (1) -> b((chi) over bar1)(0), where (chi) over bar (0)(1) is the lightest neutralino. The one-lepton fi nal state targets models where bottom or top squarks are produced and can decay into multiple channels, (b) over bar (1) -> b((chi) over bar1)(0) and (b) over bar (1) -> b((chi) over bar1)(+/-), or (t) over bar (1) -> t((chi) over bar1)(0) and (t) over bar (1) -> b((chi) over bar1)(+/-), where (X) over bar (+/-)(1) is the lightest chargino and the mass difference m((chi) over bar1)(+/-) - m((chi) over bar1)(0) is set to 1 GeV. No excess above the expected Standard Model background is observed. Exclusion limits at 95% con fi dence level on the mass of third-generation squarks are derived in various supersymmetry-inspired simpli fi ed models.
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| 27. |
- Abulaiti, Yiming, et al.
(författare)
-
Searches for the Z gamma decay mode of the Higgs boson and for new high-mass resonances in pp collisions at root s=13 TeV with the ATLAS detector
- 2017
-
Ingår i: Journal of High Energy Physics (JHEP). - : Springer. - 1126-6708 .- 1029-8479. ; :10
-
Tidskriftsartikel (refereegranskat)abstract
- This article presents searches for the Z gamma decay of the Higgs boson and for narrow high-mass resonances decaying to Z gamma, exploiting Z boson decays to pairs of electrons or muons. The data analysis uses 36.1 fb(-1) of pp collisions at root s = 13 recorded by the ATLAS detector at the CERN Large Hadron Collider. The data are found to be consistent with the expected Standard Model background. The observed (expected - assuming Standard Model pp -> H -> Z gamma production and decay) upper limit on the production cross section times the branching ratio for pp -> H -> Z gamma is 6.6. (5.2) times the Standard Model prediction at the 95% confidence level for a Higgs boson mass of 125.09 GeV. In addition, upper limits are set on the production cross section times the branching ratio as a function of the mass of a narrow resonance between 250 GeV and 2.4 TeV, assuming spin-0 resonances produced via gluon-gluon fusion, and spin-2 resonances produced via gluon-gluon or quark-antiquark initial states. For high-mass spin-0 resonances, the observed (expected) limits vary between 88 fb (61 fb) and 2.8 fb (2.7 fb) for the mass range from 250 GeV to 2.4 TeV at the 95% confidence level.
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| 28. |
- Abulaiti, Yiming, et al.
(författare)
-
Study of ordered hadron chains with the ATLAS detector
- 2017
-
Ingår i: Physical Review D. - : AMER PHYSICAL SOC. - 2470-0010 .- 2470-0029. ; 96
-
Tidskriftsartikel (refereegranskat)abstract
- The analysis of the momentum difference between charged hadrons in high-energy proton-proton collisions is performed in order to study coherent particle production. The observed correlation pattern agrees with a model of a helical QCD string fragmenting into a chain of ground-state hadrons. A threshold momentum difference in the production of adjacent pairs of charged hadrons is observed, in agreement with model predictions. The presence of low-mass hadron chains also explains the emergence of charge-combination-dependent two-particle correlations commonly attributed to Bose-Einstein interference. The data sample consists of 190 mu b(-1) of minimum-bias events collected with proton-proton collisions at a center-of-mass energy root s = 7 TeV in the early low-luminosity data taking with the ATLAS detector at the LHC.
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| 29. |
- Adolfsson, Peter, 1963, et al.
(författare)
-
Increased Time in Range and Fewer Missed Bolus Injections After Introduction of a Smart Connected Insulin Pen
- 2020
-
Ingår i: Diabetes Technology & Therapeutics. - : Mary Ann Liebert Inc. - 1520-9156 .- 1557-8593. ; 22:10
-
Tidskriftsartikel (refereegranskat)abstract
- Background: This observational study investigated whether the connected NovoPen(R) 6 could influence insulin regimen management and glycemic control in people with type 1 diabetes (T1D) using a basal-bolus insulin regimen and continuous glucose monitoring in a real-world setting. Methods: Participants from 12 Swedish diabetes clinics downloaded pen data at each visit (final cohort: n = 94). Outcomes included time in range (TIR; sensor glucose 3.9-10.0 mmol/L), time in hyperglycemia (>10 mmol/L), and hypoglycemia (L1: 3.0- <3.9 mmol/L; L2: <3.0 mmol/L). Missed bolus dose (MBD) injections were meals without bolus injection within -15 and +60 min from the start of a meal. Outcomes were compared between the baseline and follow-up periods (>= 5 health care professional visits). Data were analyzed from the first 14 days following each visit. For the TIR and total insulin dose analyses (n = 94), a linear mixed model was used, and for the MBD analysis (n = 81), a mixed Poisson model was used. Results: TIR significantly increased (+1.9 [0.8; 3.0](95% CI) h/day; P < 0.001) from baseline to follow-up period, with a corresponding reduction in time in hyperglycemia (-1.8 [-3.0; -0.6](95% CI) h/day; P = 0.003) and L2 hypoglycemia (-0.3 [-0.6; -0.1](95% CI) h/day; P = 0.005), and no change in time in L1 hypoglycemia. MBD injections decreased by 43% over the study (P = 0.002). Change in MBD injections corresponded to a decrease from 25% to 14% based on the assumption that participants had three main meals per day. Conclusions: Our study highlights the potential benefit on glycemic control and dosing behavior when reliable insulin dose data from a connected pen contribute to insulin management in people with T1D.
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| 30. |
- Al Shemaili, Jasem, et al.
(författare)
-
Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer
- 2016
-
Ingår i: Marine Drugs. - : MDPI AG. - 1660-3397. ; 14:6
-
Tidskriftsartikel (refereegranskat)abstract
- The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.
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| 31. |
- Anderson, Helén, et al.
(författare)
-
Skapa kundnärvaro i innovationsprocessen
- 2008
-
Ingår i: Innovationsförmåga. - Malmö : Holmbergs i Malmö AB. - 9789197785204 ; , s. 40-59
-
Bokkapitel (populärvet., debatt m.m.)
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| 32. |
- Andersson, Linda, et al.
(författare)
-
Myeloid blood dendritic cells and monocyte-derived dendritic cells differ in their endocytosing capability
- 2012
-
Ingår i: Human Immunology. - : Elsevier. - 0198-8859 .- 1879-1166. ; 73:11, s. 1073-1081
-
Tidskriftsartikel (refereegranskat)abstract
- Human dendritic cells (DCs) constitute a heterogeneous population of antigen-presenting cells characterized by a unique capacity to stimulate naive T cells. The functions of DCs depend on the particular subset and in this study we compare two types of myeloid DCs: freshly isolated blood mDCs and in vitro generated monocyte-derived DCs (MoDCs), in their ability to accomplish endocytosis. In our hands, these two DC subtypes showed similarities in the expression of surface markers, but displayed clear differences in endocytic capacity. Freshly isolated blood mDCs showed a high propensity to capture and endocytose particles compared to in vitro generated MoDCs. The blood mDCs also showed a clear receptor-enhanced endocytosis when zeolite particles were co-adsorbed with IgG. On the other hand, the MoDCs differed remarkably compared to blood mDCs in the capture of ovalbumin and immune complexes. Interestingly, the MoDCs showed low endocytosis of IgG-coated particles but an efficient capture of immune complexes. The MoDCs also showed a high capacity to capture ovalbumin although with a relatively low degree of internalization. These data indicate distinct differences in the early process of endocytosis featured by mDCs and MoDCs, which is important to consider when choosing DC populations for future functional or clinical applications.
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| 33. |
- Andersson, Linda, et al.
(författare)
-
Receptor-mediated endocytosis of particles by peripheral dendritic cells
- 2008
-
Ingår i: Human Immunology. - : Elsevier BV. - 0198-8859 .- 1879-1166. ; :69, 625-633, 2008
-
Tidskriftsartikel (refereegranskat)abstract
- Human peripheral dendritic cells (DCs) are antigen-presenting cells with the ability to internalize antigen and present antigen-derived peptides to T cells. Human DCs express several receptors on the surface for endocytosis and other recognition receptors that bind to microbes or microbial products, which are internalized and processed. Here, we report the use of nanometer-size zeolite particles as a tool to study receptor-mediated endocytosis by the two subsets of immature DCs, myeloid (mDC) and plasmacytoid (pDC) dendritic cells. A major difference in receptor-mediated endocytosis was observed between the two populations of peripheral DCs. The pDC population demonstrated an almost complete lack of receptor-mediated endocytosis of zeolite particles, whereas the mDC population demonstrated a clear receptor-mediated endocytosis. Fc receptors are expressed by both peripheral DC populations and lipoteichoic acid (LTA) and lipopolysaccharide (LPS) are known ligands of the Toll-like receptor (TLR)-2 and TLR4, respectively, both TLRs expressed by human mDCs. An efficient receptormediated endocytosis of immunoglobulin G-, LTA-, and LPS-coated zeolite particles was observed by the mDC population and their endocytosing capacity depended strongly on the density of the ligand adsorbed onto the zeolite particles. In conclusion, an efficient receptor-mediated endocytosis was observed from the mDC population, whereas the pDCs demonstrated an almost complete lack of receptor-mediated endocytosis and nanometer-size dealuminated zeolite particles were a useful tool for studying receptor-mediated endocytosis in human peripheral DCs.
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| 34. |
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| 35. |
- Annebäck, Matilda, et al.
(författare)
-
Preoperative prophylactic active vitamin D to streamline total thyroidectomy
- 2022
-
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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| 36. |
- Annerbo, Maria, 1967-
(författare)
-
Calcium Homeostasis in Patients with Graves' Disease
- 2016
-
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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| 37. |
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| 38. |
- Annerbo, Maria, et al.
(författare)
-
Left-shifted relation between calcium and parathyroid hormone in Graves' Disease
- 2014
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 99:2, s. 545-551
-
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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| 39. |
- Annerbo, Maria, et al.
(författare)
-
Management of Grave's Disease Is Improved by Total Thyroidectomy
- 2012
-
Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 36:8, s. 1943-1946
-
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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| 40. |
- Backman, Samuel, et al.
(författare)
-
Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
- 2017
-
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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| 41. |
- Backman, Samuel, 1994-
(författare)
-
Molecular studies of endocrine tumors : Insights from genetics and epigenetics
- 2020
-
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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| 42. |
- Backman, Samuel, et al.
(författare)
-
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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| 43. |
- Backman, Samuel, et al.
(författare)
-
The Evolutionary History of Metastatic Pancreatic Neuroendocrine Tumours Reveals a Therapy Driven Route to High-Grade Transformation.
- 2024
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Ingår i: medRxiv : the preprint server for health sciences.
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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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| 44. |
- Backman, Samuel, et al.
(författare)
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Whole genome sequencing of apparently mutation-negative MEN1 patients
- 2020
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 182:1, s. 35-45
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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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| 45. |
- 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
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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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| 46. |
- Barazeghi, Elham, et al.
(författare)
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A role for TET2 in parathyroid carcinoma
- 2017
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 24:7, s. 329-338
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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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| 47. |
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| 48. |
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| 49. |
- 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
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
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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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| 50. |
- Barazeghi, Elham, et al.
(författare)
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EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11
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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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