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1.
  • Cheng, Qing, et al. (författare)
  • Combining [11C]-AnxA5 PET imaging with serum biomarkers for improved detection in live mice of modest cell death in human solid tumor xenografts.
  • 2012
  • Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1932-6203. ; 7:8, s. e42151-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: In vivo imaging using Annexin A5-based radioligands is a powerful technique for visualizing massive cell death, but has been less successful in monitoring the modest cell death typically seen in solid tumors after chemotherapy. Here we combined dynamic positron emission tomography (PET) imaging using Annexin A5 with a serum-based apoptosis marker, for improved sensitivity and specificity in assessment of chemotherapy-induced cell death in a solid tumor model.METHODOLOGY/PRINCIPAL FINDINGS: Modest cell death was induced by doxorubicin in a mouse xenograft model with human FaDu head and neck cancer cells. PET imaging was based on (11)C-labeled Sel-tagged Annexin A5 ([(11)C]-AnxA5-ST) and a size-matched control. 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]-FDG) was utilized as a tracer of tissue metabolism. Serum biomarkers for cell death were ccK18 and K18 (M30 Apoptosense® and M65). Apoptosis in tissue sections was verified ex vivo for validation. Both PET imaging using [(11)C]-AnxA5-ST and serum ccK18/K18 levels revealed treatment-induced cell death, with ccK18 displaying the highest detection sensitivity. [(18)F]-FDG uptake was not affected by this treatment in this tumor model. [(11)C]-AnxA5-ST gave robust imaging readouts at one hour and its short half-life made it possible to perform paired scans in the same animal in one imaging session.CONCLUSIONS/SIGNIFICANCE: The combined use of dynamic PET with [(11)C]-AnxA5-ST, showing specific increases in tumor binding potential upon therapy, with ccK18/K18 serum measurements, as highly sensitive markers for cell death, enabled effective assessment of modest therapy-induced cell death in this mouse xenograft model of solid human tumors.
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2.
  • Collins, Ruairi, et al. (författare)
  • Biochemical Discrimination between Selenium and Sulfur 1 : A Single Residue Provides Selenium Specificity to Human Selenocysteine Lyase
  • 2012
  • Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1932-6203. ; 7:1, s. e30581-
  • Tidskriftsartikel (refereegranskat)abstract
    • Selenium and sulfur are two closely related basic elements utilized in nature for a vast array of biochemical reactions. While toxic at higher concentrations, selenium is an essential trace element incorporated into selenoproteins as selenocysteine (Sec), the selenium analogue of cysteine (Cys). Sec lyases (SCLs) and Cys desulfurases (CDs) catalyze the removal of selenium or sulfur from Sec or Cys and generally act on both substrates. In contrast, human SCL (hSCL) is specific for Sec although the only difference between Sec and Cys is the identity of a single atom. The chemical basis of this selenium-over-sulfur discrimination is not understood. Here we describe the X-ray crystal structure of hSCL and identify Asp146 as the key residue that provides the Sec specificity. A D146K variant resulted in loss of Sec specificity and appearance of CD activity. A dynamic active site segment also provides the structural prerequisites for direct product delivery of selenide produced by Sec cleavage, thus avoiding release of reactive selenide species into the cell. We thus here define a molecular determinant for enzymatic specificity discrimination between a single selenium versus sulfur atom, elements with very similar chemical properties. Our findings thus provide molecular insights into a key level of control in human selenium and selenoprotein turnover and metabolism.
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3.
  • Gong, Tong, et al. (författare)
  • Parental socioeconomic status, childhood asthma and medication use : a population-based study
  • 2014
  • Ingår i: PLoS One. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1932-6203.
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Little is known about how parental socioeconomic status affects offspring asthma risk in the general population, or its relation to healthcare and medication use among diagnosed children. METHODS: This register-based cohort study included 211,520 children born between April 2006 and December 2008 followed until December 2010. Asthma diagnoses were retrieved from the National Patient Register, and dispensed asthma medications from the Prescribed Drug Register. Parental socioeconomic status (income and education) were retrieved from Statistics Sweden. The associations between parental socioeconomic status and outcomes were estimated by Cox proportional hazard regression. RESULTS: Compared to the highest parental income level, children exposed to all other levels had increased risk of asthma during their first year of life (e.g. hazard ratio, HR 1.19, 95% confidence interval, CI 1.09-1.31 for diagnosis and HR 1.17, 95% CI 1.08-1.26 for medications for the lowest quintile) and the risk was decreased after the first year, especially among children from the lowest parental income quintile (HR 0.84, 95% CI 0.77-0.92 for diagnosis, and HR 0.80, 95% CI 0.74-0.86 for medications). Further, compared to children with college-educated parents, those whose parents had lower education had increased risk of childhood asthma regardless of age. Children with the lowest parental education had increased risk of an inpatient (HR 2.07, 95% CI 1.61-2.65) and outpatient (HR 1.32, 95% CI 1.18-1.47) asthma diagnosis. Among diagnosed children, those from families with lower education used fewer controller medications than those whose parents were college graduates. CONCLUSIONS: Our findings indicate an age-varying association between parental income and childhood asthma and consistent inverse association regardless of age between parental education and asthma incidence, dispensed controller medications and inpatient care which should be further investigated and remedied.
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4.
  • Havland, Ida, et al. (författare)
  • The observed association between maternal anxiety and adolescent asthma : children of twin design suggest familial effects
  • 2013
  • Ingår i: PLoS One. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1932-6203. ; 42
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Previous studies indicate that maternal anxiety is associated with asthma in the adolescent child, but mechanisms are unclear. OBJECTIVE: To investigate the association between maternal anxiety and maternal, self- and register-based report of asthma in the adolescent child, and whether the association remains after control of familial confounding (shared environmental and genetic factors). METHOD: From the Twin and Offspring Study of Sweden, 1691 mothers (1058 twins) and their adolescent child were included. The association between maternal self-reported anxiety (Beck Anxiety Inventory (BAI) and Karolinska Scales of Personality (KSP) somatic or psychic anxiety) and asthma based on subjective (maternal or child report) or objective (register-based diagnosis and medication) measures were analysed using logistic regression. The children-of-twins design was used to explore whether genes or environment contribute to the association. RESULTS: Maternal BAI anxiety (OR 2.02, CI 1.15-3.55) was significantly associated with adolescent asthma reported by the mother. Maternal KSP somatic anxiety (OR 1.74, CI 1.04-2.91) and psychic anxiety (OR 1.74, CI 1.05-2.86) was significantly associated with breathlessness reported by the adolescent child. In contrast, maternal anxiety was not associated with increased risk for the register-based outcomes of asthma diagnosis or medication. The results remained also after adjusting for covariates and the children-of-twins analyses which indicate that the association was due to familial confounding. CONCLUSIONS: We found some associations between maternal anxiety and subjectively reported offspring asthma or breathlessness which may be due to familial effects. A likely candidate for explaining this familial confounding is heritable personality traits associated with both anxiety and subjective measures of asthma.
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5.
  • Hojjat-Farsangi, Mohammad, et al. (författare)
  • RETRACTED: Inhibition of the receptor tyrosine kinase ROR1 by anti-ROR1 monoclonal antibodies and siRNA induced apoptosis of melanoma cells
  • 2013
  • Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
  • Tidskriftsartikel (refereegranskat)abstract
    • The receptor tyrosine kinase (RTK) ROR1 is overexpressed and of importance for the survival of various malignancies, including lung adenocarcinoma, breast cancer and chronic lymphocytic leukemia (CLL). There is limited information however on ROR1 in melanoma. In the present study we analysed in seven melanoma cell lines ROR1 expression and phosphorylation as well as the effects of anti-ROR1 monoclonal antibodies (mAbs) and ROR1 suppressing siRNA on cell survival. ROR1 was overexpressed at the protein level to a varying degree and phosphorylated at tyrosine and serine residues. Three of our four self-produced anti-ROR1 mAbs (clones 3H9, 5F1 and 1A8) induced a significant direct apoptosis of the ESTDAB049, ESTDAB112, DFW and A375 cell lines as well as cell death in complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC). The ESTDAB081 and 094 cell lines respectively were resistant to direct apoptosis of the four anti-ROR1 mAbs alone but not in CDC or ADCC. ROR1 siRNA transfection induced downregulation of ROR1 expression both at mRNA and protein levels proceeded by apoptosis of the melanoma cells (ESTDAB049, ESTDAB112, DFW and A375) including ESTDAB081, which was resistant to the direct apoptotic effect of the mAbs. The results indicate that ROR1 may play a role in the survival of melanoma cells. The surface expression of ROR1 on melanoma cells may support the notion that ROR1 might be a suitable target for mAb therapy.
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6.
  • Hojjat-Farsangi, Mohammad, et al. (författare)
  • Spontaneous immunity against the receptor tyrosine kinase ROR1 in patients with chronic lymphocytic leukemia
  • 2015
  • Ingår i: PLOS One. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL) and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients. Materials and Methods: Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9) and healthy donors (n = 6). IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay. Results: The majority of CLL patients had antibodies against ROR1. Significantly higher titers of antiROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A produc ing T cells could be dete cted in CLL patie nts, preferent ially in non-pro gressive as compared to patients with progr essive dis ease (p < 0.05). Conclusion: ROR1 seemed to spo ntaneousl y induc e a humoral as well as a T cell response in CLL patients. The data suppo rt the notion th at ROR1 might be a specific neo-antige n and may serve as a target for immunotherapy.
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7.
  • Hojjat-Farsangi, Mohammad, et al. (författare)
  • The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL) cells
  • 2013
  • Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
  • Tidskriftsartikel (refereegranskat)abstract
    • Phosphorylation of receptor tyrosine kinases (RTKs) has a key role in cellular functions contributing to the malignant phenotype of tumor cells. We and others have previously demonstrated that RTK ROR1 is overexpressed in chronic lymphocytic leukemia (CLL). Silencing siRNA downregulated ROR1 and induced apoptosis of CLL cells. In the present study we analysed ROR1 isoforms and the phosphorylation pattern in CLL cells (n=38) applying western blot and flow-cytometry using anti-ROR1 antibodies and an anti-phospho-ROR1 antibody against the TK domain. Two major ROR1 bands with the size of 105 and 130 kDa respectively were identified, presumably representing unglycosylated (immature) and glycosylated (mature) ROR1 respectively as well as a 260 kDa band which may represent dimerized ROR1. A ROR1 band of 64 kDa that may correspond to a C-terminal fragment was also noted, present only in the nucleus. The 105 kDa ROR1 isoform was more frequently expressed in non-progressive as compared to progressive CLL patients (p=0.03). The 64, 105, 130 and 260 kDa bands were constitutively phosphorylated both at tyrosine and serine residues. Phosphorylation intensity of the mature (130 kDa) isoform was significantly higher in progressive than in non-progressive disease (p<0.001). Incubation of CLL cells with a mouse anti-ROR1 KNG or an anti-ROR1 CRD mAb respectively induced dephosphorylation of ROR1 before entering apoptosis. In conclusion CLL cells expressed different isoforms of ROR1 which were constitutively phosphorylated. The mature, phosphorylated ROR1 isoform was associated with a progressive disease stage. Targeting ROR1 by mAbs induced specific dephosphorylation and leukemic cell death. ROR1 might be an interesting therapeutic target.
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8.
  • Johansson, Ann-Louise, et al. (författare)
  • Biochemical Discrimination between Selenium and Sulfur 2 : Mechanistic Investigation of the Selenium Specificity of Human Selenocysteine Lyase
  • 2012
  • Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1932-6203. ; 7:1, s. e30528-
  • Tidskriftsartikel (refereegranskat)abstract
    • Selenium is an essential trace element incorporated into selenoproteins as selenocysteine. Selenocysteine (Sec) lyases (SCLs) and cysteine (Cys) desulfurases (CDs) catalyze the removal of selenium or sulfur from Sec or Cys, respectively, and generally accept both substrates. Intriguingly, human SCL (hSCL) is specific for Sec even though the only difference between Sec and Cys is a single chalcogen atom. The crystal structure of hSCL was recently determined and gain-of-function protein variants that also could accept Cys as substrate were identified. To obtain mechanistic insight into the chemical basis for its substrate discrimination, we here report time-resolved spectroscopic studies comparing the reactions of the Sec-specific wild-type hSCL and the gain-of-function D146K/H389T variant, when given Cys as a substrate. The data are interpreted in light of other studies of SCL/CD enzymes and offer mechanistic insight into the function of the wild-type enzyme. Based on these results and previously available data we propose a reaction mechanism whereby the Sec over Cys specificity is achieved using a combination of chemical and physico-mechanical control mechanisms.
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9.
  • Rantalainen, Mattias, et al. (författare)
  • Robust linear models for cis-eQTL analysis
  • 2015
  • Ingår i: PLoS One. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1932-6203.
  • Tidskriftsartikel (refereegranskat)abstract
    • Expression Quantitative Trait Loci (eQTL) analysis enables characterisation of functional genetic variation influencing expression levels of individual genes. In outbread populations, including humans, eQTLs are commonly analysed using the conventional linear model, adjusting for relevant covariates, assuming an allelic dosage model and a Gaussian error term. However, gene expression data generally have noise that induces heavy-tailed errors relative to the Gaussian distribution and often include atypical observations, or outliers. Such departures from modelling assumptions can lead to an increased rate of type II errors (false negatives), and to some extent also type I errors (false positives). Careful model checking can reduce the risk of type-I errors but often not type II errors, since it is generally too time-consuming to carefully check all models with a non-significant effect in large-scale and genome-wide studies. Here we propose the application of a robust linear model for eQTL analysis to reduce adverse effects of deviations from the assumption of Gaussian residuals. We present results from a simulation study as well as results from the analysis of real eQTL data sets. Our findings suggest that in many situations robust models have the potential to provide more reliable eQTL results compared to conventional linear models, particularly in respect to reducing type II errors due to non-Gaussian noise. Post-genomic data, such as that generated in genome-wide eQTL studies, are often noisy and frequently contain atypical observations. Robust statistical models have the potential to provide more reliable results and increased statistical power under non-Gaussian conditions. The results presented here suggest that robust models should be considered routinely alongside other commonly used methodologies for eQTL analysis.
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10.
  • Rejnö, Gustaf, et al. (författare)
  • Asthma during pregnancy in a population-based study : pregnancy complications and adverse perinatal outcomes
  • 2014
  • Ingår i: PLoS One. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1932-6203.
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Asthma is one of the most common chronic diseases, and prevalence, severity and medication may have an effect on pregnancy. We examined maternal asthma, asthma severity and control in relation to pregnancy complications, labour characteristics and perinatal outcomes. METHODS: We retrieved data on all singleton births from July 1, 2006 to December 31, 2009, and prescribed drugs and physician-diagnosed asthma on the same women from multiple Swedish registers. The associations were estimated with logistic regression. RESULTS: In total, 266 045 women gave birth to 284 214 singletons during the study period. Maternal asthma was noted in 26 586 (9.4%) pregnancies. There was an association between maternal asthma and increased risks of pregnancy complications including preeclampsia or eclampsia (adjusted OR 1.15; 95% CI 1.06-1.24) and premature contractions (adj OR 1.52; 95% CI 1.29-1.80). There was also a significant association between maternal asthma and emergency caesarean section (adj OR 1.29; 95% CI 1.23-1.34), low birth weight, and small for gestational age (adj OR 1.23; 95% CI 1.13-1.33). The risk of adverse outcomes such as low birth weight increased with increasing asthma severity. For women with uncontrolled compared to those with controlled asthma the results for adverse outcomes were inconsistent displaying both increased and decreased OR for some outcomes. CONCLUSION: Maternal asthma is associated with a number of serious pregnancy complications and adverse perinatal outcomes. Some complications are even more likely with increased asthma severity. With greater awareness and proper management, outcomes would most likely improve.
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