uu.seUppsala University Publications
Change search
Refine search result
1234 151 - 185 of 185
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 151.
    Snellman, Greta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Warensjö-Lemming, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Institutet för miljömedicin, Karolinska Institutet.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Long-term dietary vitamin D intake and risk of fracture and osteoporosis: a longitudinal cohort study of Swedish middle-aged and elderly women2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Suppl 1, p. S65-S65Article in journal (Other academic)
    Abstract [en]

    Context: Vitamin D deficiency may lead to osteoporosis and fracture but the importance of dietary vitamin D intake for skeletal health in adults is uncertain.

    Objective: To investigate associations between long-term dietary intake of vitamin D with risk of fractures and osteoporosis.

    Design: A prospective longitudinal cohort study.

    Setting: The population-based Swedish Mammography Cohort and the subcohort SMC Clinical.

    Participants: 61,433 women (age range 38 to 76 years) were followed for 19 years. Of these, 5,022 participated in the subcohort. Diet was assessed by repeated food frequency questionnaires.   

    Main outcome measures: Incident fractures of any type and hip fractures, which were identified from registry data. Secondary outcome was osteoporosis diagnosed by dual energy x ray absorptiometry in the subcohort.

    Results: 14,738 women experienced any type of first fracture during follow-up, with 3,871 of these being hip fractures. Twenty percent of the women in the subcohort were classified as osteoporotic. A multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for any first fracture was 0.96 (95% CI 0.92-1.01) for the lowest and 1.02 (95% CI 0.96-1.07) for the highest quintile when compared with the third quintile of vitamin D intake. The corresponding HR for a first hip fracture was 1.02 (95% CI, 0.96-1.08) for the lowest and 1.14 (95% CI, 1.03-1.26) for the highest quintile. The odds ratio of osteoporosis by quintiles of vitamin D intake was 1.20 (95% CI, 0.85-1.71) for the lowest and 0.99 (95% CI, 0.78-1.25) for the highest quintile. Bone mineral density, however, were 2% higher at the lumbar spine and 0.3% higher at the total hip in women with highest vs. women with lowest intake of vitamin D (p<0.0001).

    Conclusions: Dietary intake of vitamin D seems to be of minor importance for the occurrence of fractures and osteoporosis in community-dwelling Swedish middle-aged and elderly women.

  • 152.
    Soeria-Atmadja, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lundell, Tomas
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signal Processing.
    Hammerling, Ulf
    Computational detection of allergenic proteins attains a new level of accuracy with in silico variable-length peptide extraction and machine learning2006In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 34, no 13, p. 3779-3793Article in journal (Refereed)
    Abstract [en]

    The placing of novel or new-in-the-context proteins on the market, appearing in genetically modified foods, certain bio-pharmaceuticals and some household products leads to human exposure to proteins that may elicit allergic responses. Accurate methods to detect allergens are therefore necessary to ensure consumer/patient safety. We demonstrate that it is possible to reach a new level of accuracy in computational detection of allergenic proteins by presenting a novel detector, Detection based on Filtered Length-adjusted Allergen Peptides (DFLAP). The DFLAP algorithm extracts variable length allergen sequence fragments and employs modern machine learning techniques in the form of a support vector machine. In particular, this new detector shows hitherto unmatched specificity when challenged to the Swiss-Prot repository without appreciable loss of sensitivity. DFLAP is also the first reported detector that successfully discriminates between allergens and non-allergens occurring in protein families known to hold both categories. Allergenicity assessment for specific protein sequences of interest using DFLAP is possible via ulfh@slv.se.

  • 153.
    Soeria-Atmadja, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallman, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Björklund, Åsa K.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gustafsson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    External cross-validation for unbiased evaluation of protein family detectors: application to allergens2005In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 61, no 4, p. 918-925Article in journal (Refereed)
    Abstract [en]

    Key issues in protein science and computational biology are design and evaluation of algorithms aimed at detection of proteins that belong to a specific family, as defined by structural, evolutionary, or functional criteria. In this context, several validation techniques are often used to compare different parameter settings of the detector, and to subsequently select the setting that yields the smallest error rate estimate. A frequently overlooked problem associated with this approach is that this smallest error rate estimate may have a large optimistic bias. Based on computer simulations, we show that a detector's error rate estimate can be overly optimistic and propose a method to obtain unbiased performance estimates of a detector design procedure. The method is founded on an external 10-fold cross-validation (CV) loop that embeds an internal validation procedure used for parameter selection in detector design. The designed detector generated in each of the 10 iterations are evaluated on held-out examples exclusively available in the external CV iterations. Notably, the average of these 10 performance estimates is not associated with a final detector, but rather with the average performance of the design procedure used. We apply the external CV loop to the particular problem of detecting potentially allergenic proteins, using a previously reported design procedure. Unbiased performance estimates of the allergen detector design procedure are presented together with information about which algorithms and parameter settings that are most frequently selected.

  • 154.
    Soeria-Atmadja, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Statistical evaluation of local alignment features predicting allergenicity using supervised classification algorithms2004In: International archives of allergy and immunology, ISSN 1018-2438, Vol. 133, no 2, p. 101-112Article in journal (Refereed)
  • 155.
    Soeria-Atmadja, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Önell, Annica
    Kober, Anita
    Mattson, Per
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Multivariate statistical analysis of large-scale IgE antibody measurements reveals allergen extract relationships in sensitized individuals2007In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 120, no 6, p. 1433-1440Article in journal (Refereed)
    Abstract [en]

    Background: Many allergenic sources are reportedly cross-reactive because of protein structural similarities. Although several aggregations are well characterized, no holistic mapping of IgE reactivity has hitherto been reported. Objective: The aim of this study was to disclose relevant associations within a large set of allergen preparations, as revealed by specific IgE antibody levels in blood sera of multireactive human donors. Methods: A dataset of recorded IgE antibody serum concentrations of 1011 nonidentifiable multireactive individuals (devoid of clinical records) to 89 allergen extracts was compiled for in silico analysis. Various algorithms were used to identify specific multivariate dependencies between the IgE antibody levels. Results: Exhaustive cluster analysis demonstrates that IgE antibody responses to the 89 extracts can be aggregated into 12 stable formations. These clusters hold both well-known relationships, unexpected patterns, and unknown patterns, the latter categories being exemplified by the coclustering of wasp and certain seafood and a clear differentiation among pollen allergens. Conclusion: Identified relationships within several well-known groups of cross-reactive allergen extracts confirm the applicability of dedicated multivariate data analysis within the allergology field. Moreover, some of the unexpected IgE reactivity associations in sensitized human subjects might help in identifying new relationships with potential importance to allergy. Clinical implications: Although clinical implications from this study should be validated in subsequent investigations with documentation on symptoms included, we believe this seminal approach is a key step toward the development of new analysis tools for interpretation of allergy data generated by using high-throughput recording systems.

  • 156.
    Sooman, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tsakonas, Georgios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Edqvist, Per-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jaiswal, Archita
    The Human Protein Atlas Project, Mumbai Site, Lab Surgpath, 204 Bombay Market, 731/1 Tardeo Main Road, Mumbai 400034, India.
    Navani, Sanjay
    The Human Protein Atlas Project, Mumbai Site, Lab Surgpath, 204 Bombay Market, 731/1 Tardeo Main Road, Mumbai 400034, India.
    Alafuzoff, Irina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Popova, Svetlana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival2013In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, no 3, p. 638-Article in journal (Refereed)
    Abstract [en]

    The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.

  • 157. Sundström, Anders
    et al.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Data mining in pharmacovigilance detecting the unexpected: the role of index of suspicion of the reporter2009In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 32, no 5, p. 419-427Article in journal (Refereed)
    Abstract [en]

    Background: One of the most important aims of pharmacovigilance is to detect signals of adverse drug reactions (ADRs) as early as possible. However, some ADRs are difficult to detect, one example being so called 'type C' reactions. These are effects that present as seemingly 'spontaneous' diseases occurring during treatment with a drug, such as the occurrence of a cardiovascular event while the patient is taking rofecoxib. As this type of ADR is often mistaken for a spontaneous disease, the causative agent may appear as an innocent bystander.

    Objective: The primary aim of this study was to investigate the possibility of using data mining approaches to detect signals of 'type C' reactions. We hypothesized that by including concomitant, and not only suspected medications in the calculations of disproportionality analyses, we would be able to identify such reactions.

    Study design: We used data from the Swedish Drug Information System, SWEDIS, which contains spontaneous reports submitted by Swedish physicians to the Swedish Medical Products Agency, and applied Bayesian confidence propagation neural network (BCPNN) methodology to calculate the information component (IC) value for drug-event combinations for drugs belonging to the Anatomic Therapeutic Chemical (ATC) classes cardiovascular system, musculoskeletal system and nervous system (number of reports = 51 270) where only the suspected drug was considered, and also where both concomitant and suspected drugs were considered. We then classified drug-event combinations that were signalled by a statistically significantly raised IC value as labelled or Unlabelled based on the approved summary of product characteristics (SPC) in Sweden as of November 2007, and further classified them as 'type C' reactions or not 'type C.

    Main outcome measure: The proportion of 'type C' reactions signalled when considering both concomitant and suspected drugs compared with suspected drugs only.

    Results: The proportion of labelled drug-event combinations when considering suspected drugs was 78.6%. Drug-event combinations classified as 'type C' reactions were more likely to be found when considering both concomitant and suspected drugs compared with suspected drugs only; 18/449 versus 0/248 when considering drug-event combinations that were signalled exclusively by one of the approaches. Such drug-event combinations included, for example, sudden death and celecoxib, myocardial infarction and diclofenac, suicide-related events and several antidepressants.

    Conclusion: Including both concomitant and suspected drugs in data mining practices may be a way of detecting 'type C' reactions earlier. This could constitute an advance in data mining for pharmacovigilance practices.

  • 158.
    Svangård, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes2007In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 70, no 4, p. 643-647Article in journal (Refereed)
    Abstract [en]

    In recent years, the cyclotides have emerged as the largest family of naturally cyclized proteins. Cyclotides display potent cytotoxic activity that varies with the structure of the proteins, and combined with their unique structure, they represent novel cytotoxic agents. However, their mechanism of action is yet unknown. In this work we show that disruption of cell membranes plays a crucial role in the cytotoxic effect of the cyclotide cycloviolacin O2 (1), which has been isolated from Viola odorata. Cell viability and morphology studies on the human lymphoma cell line U-937 GTB showed that cells exposed to 1 displayed disintegrated cell membranes within 5 min. Functional studies on calcein-loaded HeLa cells and on liposomes showed rapid concentration-dependent release of their respective internal contents. The present results show that cyclotides have specific membrane-disrupting activity.

  • 159.
    Söderberg, Mao Mao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Haslemo, Tore
    Centre for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
    Molden, Espen
    Centre for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
    Dahl, Marja-Liisa
    Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients2013In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 13, no 6, p. 544-550Article in journal (Refereed)
    Abstract [en]

    The widely used antipsychotic drug, olanzapine (OLA) shows large interindividual variability in metabolic clearance. Although the role of the enzymes CYP1A2, CYP2D6 and UGT1A4 has been extensively explored, little is known about the in vivo role of flavin-containing monooxygenases (FMOs) catalyzing the N-oxidation of OLA in vitro. We investigated the influence of FMO1 and 3 polymorphisms on the steady state serum concentrations of OLA and its N-oxide metabolite in 379 patients. The upstream FMO1*6 was associated with increased dose-adjusted serum OLA concentrations (C/Ds; P=0.008), an effect further enhanced by FMO1rs7877C>T in smokers. The influence of FMO3 polymorphisms was limited to variability in OLA N-oxide. Homozygous carriers of FMO3rs2266780A>G (p.E308G) displayed 50% lower C/D of OLA N-oxide compared with subjects homo- or heterozygous for the A-variant (P<0.003). Our data support the role of FMO3 in the N-oxidation of OLA and implicate for the first time the contribution of FMO1 and its functional *6 variant in OLA disposition.

  • 160. Takeuchi, Fumihiko
    et al.
    McGinnis, Ralph
    Bourgeois, Stephane
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Soranzo, Nicole
    Whittaker, Pamela
    Ranganath, Venkatesh
    Kumanduri, Vasudev
    McLaren, William
    Holm, Lennart
    Lindh, Jonatan
    Rane, Anders
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Deloukas, Panos
    Barnes, Chris
    A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose2009In: PLoS genetics, ISSN 1553-7390, Vol. 5, no 3, p. e1000433-Article in journal (Refereed)
    Abstract [en]

    We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5×10−7) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that ~30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another ~12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10−78) at SNPs clustering near VKORC1 and the second lowest p-values (p<10−31) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3×10−10) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.

    Author Summary

    Recently, geneticists have begun assaying hundreds of thousands of genetic markers covering the entire human genome to systematically search for and identify genes that cause disease. We have extended this “genome-wide association study” (GWAS) method by assaying ~326,000 markers in 1,053 Swedish patients in order to identify genes that alter response to the anticoagulant drug warfarin. Warfarin is widely prescribed to reduce blood clotting in order to protect high-risk patients from stroke, thrombosis, and heart attack. But patients vary widely (20-fold) in the warfarin dose needed for proper blood thinning, which means that initial doses in some patients are too high (risking severe bleeding) or too low (risking serious illness). Our GWAS detected two genes (VKORC1, CYP2C9) already known to cause ~40% of the variability in warfarin dose and discovered a new gene (CYP4F2) contributing 1%–2% of the variability. Since our GWAS searched the entire genome, additional genes having a major influence on warfarin dose might not exist or be found in the near-term. Hence, clinical trials assessing patient benefit from individualized dose forecasting based on a patient's genetic makeup at VKORC1, CYP2C9 and possibly CYP4F2 could provide state-of-the-art clinical benchmarks for warfarin use during the foreseeable future.

  • 161.
    Trulson, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Byström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The functional heterogeneity of eosinophil cationic protein is determined by a gene polymorphism and post-translational modifications2007In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 37, no 2, p. 208-218Article in journal (Refereed)
    Abstract [en]

    Background

    The eosinophil is a cytotoxic cell and takes part in parasite killing and tissue-destructive processes by secretion of proteins such as eosinophil cationic protein (ECP). A polymorphism was demonstrated in the ECP gene, giving rise to a substitution of arginine at position 97 with threonine. This polymorphism is related to disease development.

    Objective

    To investigate the functional and molecular heterogeneity of native ECP and the functional consequences of the replacement of arginine with a threonine.

    Methods

    ECP was purified from healthy blood donors by gel filtration, ion-exchange chromatography and reversed-phase chromatography. Recombinant ECPs i.e. rECP 97arg and rECP 97thr were produced by the pFASTBAC baculovirus expression system. The cytotoxic activity was determined against an erythroleukaemia or a small cell lung cancer cell line.

    Results

    Native ECP was purified to apparent homogeneity and showed a considerable molecular heterogeneity and a corresponding functional heterogeneity with respect to cytotoxic activity. After reduction, the native cytotoxic ECP showed three bands on sodium dodecylsulphate polyacrylamide gel electrophoresis: one major band at 18-20 kDa and two minor bands at about 10 and 5 kDa, respectively. The 5 kDa contained two masses differing with 56.2 Da, which corresponds to the difference in molecular masses of arginine and threonine. rECP 97arg was cytotoxic in contrast to rECP97thr. Deglycosylation with N-glycosidase F did not affect the cytotoxic activity of native ECP to any measurable extent nor the activity of rECP 97arg, whereas rECP 97thr achieved cytotoxic activity. The RNase activities of the recombinant and native ECPs were similar.

    Conclusion

    We conclude that ECP is present in several molecular forms with varying biological activities. Some of this functional heterogeneity is based on the genetic polymorphism of the ECP gene and some on post-translational modifications. In subjects carrying the ECP 97thr variant, the cytotoxic activity may be disguised by N-linked glycosylation of the active site.

  • 162. Varsaldi, Federica
    et al.
    Miglio, Gianluca
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Villa, Laura Maria
    Biolcati, Aldo
    Lombardi, Grazia
    Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer's disease patients2006In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 62, no 9, p. 721-726Article in journal (Refereed)
    Abstract [en]

    Objective: The aims of this study were to evaluate the impact of the CYP2D6 polymorphism on both the steady-state plasma concentrations (Cp) and the clinical outcome of donepezil, a selective acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease (AD). Methods: Forty-two patients of Caucasian ethnicity affected by probable AD were included in the study. All had been receiving therapy with donepezil for at least 3 months: 31 patients with 5 mg/day and 11 patients with 10 mg/day. The CYP2D6 genotype was analysed, and donepezil Cp was measured by using high-performance liquid chromatography. Results: On the basis of their CYP2D6 genotype, 30 patients could be classified as homozygous extensive metabolizers (EM), 10 as heterozygous EM and 2 as ultrarapid metabolizers (UM). No poor metabolizer was found. The dose and body weight-corrected median donepezil Cp were slightly, though not significantly, lower in homozygous than in heterozygous EM (0.33 vs. 0.41 ng/ml/mg/kg, respectively). The latter group consistently showed a better clinical response to treatment, as measured by change in Mini-Mental State Examination score (median: 1.40 vs. -1.30, respectively). UM patients had lower Cp than EM patients and showed no clinical improvement. Conclusions: Our preliminary data suggest that the CYP2D6 polymorphism influences both donepezil metabolism and therapeutic outcome and that a knowledge of a patient's CYP2D6 genotype together with donepezil concentration measurements might be useful in the context of improving the clinical efficacy of donepezil therapy.

  • 163. Verhoef, Talitha I.
    et al.
    Redekop, William K.
    van Schie, Rianne M. F.
    Bayat, Samira
    Daly, Ann K.
    Geitona, Mary
    Haschke-Becher, Elisabeth
    Hughes, Dyfrig A.
    Kamali, Farhad
    Levin, Lars-Åke
    Manolopoulos, Vangelis G.
    Pirmohamed, Munir
    Siebert, Uwe
    Stingl, Julia C.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    de Boer, Anthonius
    Maitland-van der Zee, Anke-Hilse
    Cost-effectiveness of pharmacogenetics in anticoagulation: international differences in healthcare systems and costs2012In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 13, no 12, p. 1405-1417Article, review/survey (Refereed)
    Abstract [en]

    Genotyping patients for CYP2C9 and VKORC1 polymorphisms can improve the accuracy of dosing during the initiation of anticoagulation with vitamin K antagonists (coumarin derivatives). The anticipated degree of improvement in the safety of anticoagulation with coumarins through genotyping may vary depending on the quality of patient care, which varies both with and among countries. The management and the cost of anticoagulant care can therefore influence the cost effectiveness of genotyping within any given country. In this article, we provide an overview of the cost effectiveness of pharmacogenetics-guided dosing of coumarin derivatives. We describe the organization of anticoagulant care in the UK, Sweden, The Netherlands, Greece, Germany and Austria, where a genotype-guided dosing algorithm is currently being investigated as part of the EU-PACT trial. We also explore the costs of anticoagulant care for the treatment of atrial fibrillation in these countries.

  • 164. Vik, Anders
    et al.
    Hedner, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Charnock, Colin
    Tangen, Linda
    Samuelsen, Ørjan
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Gundersen, Lise-Lotte
    Antimicrobial and cytotoxic activity of agelasine and agelasimine analogs2007In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 12, p. 4016-4037Article in journal (Refereed)
    Abstract [en]

    Agelasine and agelasimine derivatives with substantially less complicated terpenoid side chains compared to the naturally occurring compounds have been synthesized and their ability to inhibit growth of microorganisms and cancer cells has been studied. Compounds with excellent activity against cancer cell lines (MIC ca. 1 μM for the most potent compounds), including a drug resistant renal cell line, have been identified. Most compounds studied also exhibited broad spectrum antimicrobial activity including activity against Mycobacterium tuberculosis.

  • 165.
    von Heideman, A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sandström, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Csoka, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Tholander, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bergh, J
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Evaluation of drug interactions in the established FEC regimen in primary cultures of tumour cells from patients2000In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, no 10, p. 1301-1307Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Chemotherapy using multi-drug regimens is considered more active than single-agent therapy. This may be due to synergistic interactions or, simply, a higher probability of administering an active agent. We investigated in vitro the type of drug interactions in a recognized regimen in relationship to tumour type and drug sensitivity.

    PATIENTS AND METHODS:

    The possibility of synergistic and additive interactions between individual cytotoxic drugs was investigated for the component drugs of the established FEC regimen, i.e., 5-fluorouracil, epirubicin and cyclophosphamide, in 243 patient tumour samples representing various drug sensitivity using the non-clonogenic fluorometric microculture cytotoxicity assay.

    RESULTS:

    Using a cell survival of < or = 50% as a limit for drug activity and sample sensitivity, the overall response rates to the most active single drug (Dmax) and the combination were 56% and 64%, respectively, with a distribution among diagnoses similar to that in the clinic. For 86% of the samples there was concordance with respect to judgement of activity using either Dmax or the combination. For samples being sensitive to at least one single drug, 95% were also sensitive to the combination whereas for samples with insignificant Dmax effect, only 2% were sensitive to the combination. In samples with modest Dmax effects, i.e., cell survival in the range > 50%- < or = 80%, 45% responded to the combination. The effect of the combination was generally well predicted from the Dmax effect.

    CONCLUSIONS:

    The superior antitumour effect of drug combinations compared with single drugs may be due to the higher chance of selecting an active agent. However, for intermediately sensitive tumours, additional interaction effects of a combination may be of clinical significance.

  • 166.
    von Heideman, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data2010In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 65, no 6, p. 1165-1172Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.

    METHODS:

    A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy.

    RESULTS:

    Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials.

    CONCLUSIONS:

    Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.

  • 167.
    von Heideman, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tholander, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Cajander, Stefan
    Gerdin, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Holm, Leif
    Axelsson, Agneta
    Rosenberg, Per
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from PatientsManuscript (preprint) (Other academic)
    Abstract [en]

    Sensitivity of epithelial ovarian cancer to chemotherapeutic drugs relevant in treatment of this cancer type was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to histopathological subtypes, treatment status and clinical tumour response. For cisplatin, doxorubicin, 5-FU, cyclophosphamide and topotecan, seropapillary high grade and clear cell ovarian cancer were the most sensitive subtypes and the mucinous tumours the most resistant subtype, whereas endometrioid tumours and the seropapillary low grade/borderline tumours showed intermediate sensitivity. In contrast, docetaxel showed the opposite pattern of activity. Samples from patients previously treated with chemotherapy tended, for the majority of drugs, to be slightly more resistant than samples from treatment naïve patients. The activity of cisplatin correlated strongly with that of the other drugs with the exception of docetaxel, implicating non-cross resistance between these key drugs in ovarian cancer. Tumour samples from two sites in the same patient at the same occasion showed similar and samples taken at different occasions different cisplatin sensitivity, which may implicate tumour clonal selection over time. At group level, samples from patients clinically responding to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, optimized analyses of drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 90 – 100% and 54 – 83% ranges, respectively. In conclusion, ovarian cancer subtypes exhibit different chemotherapeutic drug sensitivity in vitro, which needs consideration in treatment decisions for this disease. Furthermore, in vitro assessment of ovarian cancer tumour cell chemotherapeutic drug sensitivity provides clinically relevant information that could be useful in efforts to optimize treatment in individual patients with this disease.

  • 168.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Chen, Leslie Y.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bumpstead, Suzannah
    Ghori, Jilur
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bentley, David
    McGinnis, Ralph
    Deloukas, Panos
    Association of warfarin dose with genes involved in its action and metabolism2007In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 121, no 1, p. 23-34Article in journal (Refereed)
    Abstract [en]

    We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C9*2 and/or *3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to approximately 10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin.

  • 169.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Chen, Leslie Y.
    Lindh, Jonatan D.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Ghori, Mohammed J. R.
    Bumpstead, Suzannah
    Holm, Lennart
    McGinnis, Ralph
    Rane, Anders
    Deloukas, Panos
    The largest prospective warfarin-treated cohort supports genetic forecasting2009In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 4, p. 784-792Article in journal (Refereed)
    Abstract [en]

    Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

  • 170.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Chen, L.Y.
    Downes, K.
    Ghori, J.
    Hunt, S.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bentley, D.
    Deloukas, P.
    Common VKORC1 and GGCX polymorphisms associated with warfarin dose2005In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 5, no 4, p. 262-70Article in journal (Refereed)
    Abstract [en]

    We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.The Pharmacogenomics Journal advance online publication, 10 May 2005; doi:10.1038/sj.tpj.6500313.

  • 171.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Darj, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Frenne, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rane, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Induction of CYP2D6 in pregnancy1997In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 62, no 4, p. 400-7Article in journal (Refereed)
    Abstract [en]

    Expression of the drug-metabolizing enzyme cytochrome P4502D6 (CYP2D6) is predominantly under genetic control, and enzyme-inducing drugs have little influence on its activity. We studied the activity of CYP2D6 during pregnancy. One hundred forty pregnant women were genotyped for CYP2D6. Seventeen of them (four poor metabolizers, seven heterozygous extensive metabolizers, and six extensive metabolizers) were phenotyped with dextromethorphan in late pregnancy and 7 to 11 weeks after parturition. During pregnancy the dextromethorphan/dextrorphan metabolic ratio was significantly reduced (p = 0.0015) among homozygous and heterozygous extensive metabolizers, indicating increased CYP2D6 activity. In contrast, poor metabolizers showed an increased metabolic ratio during pregnancy. These results are consistent with previous findings of a marked increase in metabolism of the CYP2D6 substrate metoprolol during pregnancy. Both studies indicate an increase in CYP2D6 activity during pregnancy, which may be caused by an induction of the CYP2D6 enzyme.

  • 172.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Stjernberg, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wiholm, Bengt-Erik
    Rane, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis2000In: Pharmacogenetics, ISSN 0960-314X, E-ISSN 1473-561X, Vol. 10, no 1, p. 35-41Article in journal (Refereed)
    Abstract [en]

    Agranulocytosis is a rare, but serious adverse reaction to sulphasalazine. The polymorphic enzyme N-acetyltransferase 2 (NAT2) plays an important role in the metabolism of sulphasalazine. This study was conducted to analyse whether the risk of sulphasalazine-induced agranulocytosis is increased in slow acetylators. Patients were treated for inflammatory disease, mostly joint disease, with a mean dose of 2 g sulphasalazine daily. Thirty-nine patients reacted with agranulocytosis, while 75 patients had been treated for a minimum of 3 months without haematological side-effects. A population-based control panel of 448 individuals was used for comparison. All subjects were genotyped for NAT2 by polymerase chain reaction followed by restriction enzyme digestion. The six most common allelic variants were analysed: NAT2*4, NAT2*5A, NAT2*5B, NAT2*5C, NAT2*6 and NAT2*7. The proportion of slow acetylators was significantly higher in patients with sulphasalazine-induced agranulocytosis (69%) and population-based controls (64%) compared to patients who tolerated sulphasalazine (45%); odds ratio 2.71 [95% confidence interval (CI) 1.20; 6.15], P = 0.015, and odds ratio 2.17 (95% CI 1.32; 3.56), P = 0.002, respectively. Patients who developed agranulocytosis did not differ from population-based control subjects in the frequency of slow acetylators; odds ratio 1.25 (95% CI 0.62; 2.53), P = 0.535. The risk of agranulocytosis did not appear to be increased in slow acetylators, provided that the difference compared with sulphasalazine-treated control subjects was not due to a predominance of fast acetylators among patients with inflammatory joint disease. Instead, selection bias was suspected since more slow acetylators may have discontinued sulphasalazine therapy because of drug-intolerance.

  • 173.
    Wadelius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Sörlin, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Karlsson, Jacob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Yue, Q.Y.
    Magnusson, P.K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors2004In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 4, no 1, p. 40-8Article in journal (Refereed)
    Abstract [en]

    The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.

  • 174.
    Wagner, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Pedersen, Nancy L.
    Karolinska institutet, MEB.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Simply ask them about their balance-future fracture risk in a nationwide cohort study of twins2009In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 169, no 2, p. 143-149Article in journal (Refereed)
    Abstract [en]

    The principal causal components of an osteoporotic fracture are a fall and weakened bone strength. While bone quality measures have been frequently studied, the ability of simple measures of impaired balance to predict fracture risk has received less attention. Computer-assisted telephone interviews were conducted between 1998 and 2000 among 24,598 Swedish twins aged 55 years or older. Impaired balance at the time of interview was reported by 2,890 (12%) of the twins. Twin pairs who were discordant with regard to impaired balance were selected for analysis and followed for fractures through 2005. In a pairwise analysis, the odds ratio for hip fracture was 3.13 (95% confidence interval (CI): 1.62, 6.05) among twins with impaired balance as compared with their co-twins with normal balance. When previously recognized clinical risk factors for osteoporotic fracture were considered in the model, the odds ratio for hip fracture with impaired balance was 3.88 (95% CI: 1.40, 10.72). Approximately 40% of all hip fractures were attributable to impaired balance. The odds ratios for any fracture and any osteoporotic fracture for twins with impaired balance were 2.00 (95% CI: 1.29, 3.11) and 2.39 (95% CI: 1.49, 3.82), respectively. These results imply that self-reported impaired balance is a novel and readily assessed risk factor for future fractures in the elderly.

  • 175.
    Wagner, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pedersen, Nancy L
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Genetic influence on bone phenotypes and body composition: a Swedish twin study2013In: Journal of Bone and Mineral Metabolism, ISSN 0914-8779, E-ISSN 1435-5604, Vol. 31, no 6, p. 681-689Article in journal (Refereed)
    Abstract [en]

    Bone mineral density (BMD), bone size and bone turnover are independent determinants of fractures in elderly. Earlier twin studies of these phenotypes have revealed high heritability for BMD and bone area, and more moderate heritability for bone turnover markers. No previous Scandinavian study has evaluated the genetic and environmental contribution to the variance of these phenotypes, despite the fact that Scandinavian countries have the highest incidence of osteoporotic fractures worldwide. Participants were selected from the Swedish Twin Registry. All intact like-sexed twin pairs born in 1965 or earlier and living in the county of Uppsala were invited to participate. A total of 102 twin pairs (45 monozygotic and 57 dizygotic) accepted the invitation to participate. All twins underwent measurement of BMD and bone area using dual-energy X-ray absorptiometry. Hip geometry was also calculated. Markers for bone formation (osteocalcin) and bone resorption (CrossLaps) were measured in serum. We observed a substantial heritability for BMD at the lumbar spine (0.85; 95 % CI 0.54-0.90), the femoral neck (0.75; 95 % CI 0.62-0.83), and the proximal femur (0.84; 95 % CI 0.74-0.90). The values for bone area were approximately similar to those for BMD. Bone turnover markers had a slightly lower genetic influence with a value of 0.69 (0.53-0.80) for osteocalcin and 0.58 (95 % CI 0.33-0.75) for CrossLaps. As a comparison, the heritabilities of body height and weight were 0.95 and 0.82, respectively. The high heritability on bone phenotypes among Swedish middle-aged and older men and women should encourage further work on the identification of specific genetic pathways. Continuing research in this area could reveal the mechanisms behind the strong genetic susceptibility of bone-related phenotypes.

  • 176.
    Walsh, Sarah H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grabowski, Pawel
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thorsélius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tobin, Gerard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Karlsson, Karin
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, Göran
    Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas2007In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 78, no 4, p. 283-289Article in journal (Refereed)
    Abstract [en]

    Telomere length was recently reported to correlate with cellular origin of B-cell malignancies in relation to the germinal center (GC). In this report, we measured telomere length by quantitative-PCR in 223 B-cell lymphomas/leukemias and correlated results with immunoglobulin (Ig) mutation status and immunostainings for GC/non-GC subtypes of diffuse large B-cell lymphoma (DLBCL). Shortest telomeres were found in Ig-unmutated chronic lymphocytic leukemia (CLL) [median telomere to single copy gene value (T/S) 0.33], differing significantly to Ig-mutated CLL (0.63). Contrary to this, mantle cell lymphomas (MCLs) exhibited similar telomere lengths regardless of Ig mutation status (0.47). Telomere length differed significantly between GC-like (0.73) and non-GC-like DLBCLs (0.43), and follicular lymphomas (FLs) had shorter telomeres (0.53) than GC-DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres (0.62) than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. We conclude that although DLBCL and CLL subsets can be clearly distinguished, telomere length reflects many parameters and may not simply correlate with GC-related origin.

  • 177.
    Warensjö, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gedeborg, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study2011In: BMJ (British edition), ISSN 1756-1833, Vol. 342, p. d1473-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis.

    DESIGN:

    A longitudinal and prospective cohort study, based on the Swedish Mammography Cohort, including a subcohort, the Swedish Mammography Cohort Clinical.

    SETTING:

    A population based cohort in Sweden established in 1987.

    PARTICIPANTS:

    61,433 women (born between 1914 and 1948) were followed up for 19 years. 5022 of these women participated in the subcohort.

    MAIN OUTCOME MEASURES:

    Primary outcome measures were incident fractures of any type and hip fractures, which were identified from registry data. Secondary outcome was osteoporosis diagnosed by dual energy x ray absorptiometry in the subcohort. Diet was assessed by repeated food frequency questionnaires.

    RESULTS:

    During follow-up, 14,738 women (24%) experienced a first fracture of any type and among them 3871 (6%) a first hip fracture. Of the 5022 women in the subcohort, 1012 (20%) were measured as osteoporotic. The risk patterns with dietary calcium were non-linear. The crude rate of a first fracture of any type was 17.2/1000 person years at risk in the lowest quintile of calcium intake, and 14.0/1000 person years at risk in the third quintile, corresponding to a multivariable adjusted hazard ratio of 1.18 (95% confidence interval 1.12 to 1.25). The hazard ratio for a first hip fracture was 1.29 (1.17 to 1.43) and the odds ratio for osteoporosis was 1.47 (1.09 to 2.00). With a low vitamin D intake, the rate of fracture in the first calcium quintile was more pronounced. The highest quintile of calcium intake did not further reduce the risk of fractures of any type, or of osteoporosis, but was associated with a higher rate of hip fracture, hazard ratio 1.19 (1.06 to 1.32).

    CONCLUSION:

    Gradual increases in dietary calcium intake above the first quintile in our female population were not associated with further reductions in fracture risk or osteoporosis.

  • 178.
    Wiberg, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    In vitro activity of bortezomib in cultures of patient tumour cells-potential utility in haematological malignancies2009In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 26, no 2, p. 193-201Article in journal (Refereed)
    Abstract [en]

    Bortezomib represents a new class of anti-cancer drugs, the proteasome inhibitors. We evaluated the in vitro activity of bortezomib with regard to tumour-type specificity and possible mechanisms of drug resistance in 115 samples of tumour cells from patients and in a cell-line panel, using the short-term fluorometric microculture cytotoxicity assay. Bortezomib generally showed dose-response curves with a steep slope. In patient cells, bortezomib was more active in haematological than in solid tumour samples. Myeloma and chronic myeloid leukaemia were the most sensitive tumour types although with great variability in drug response between the individual samples. Colorectal and kidney cancer samples were the least sensitive. In the cell-line panel, only small differences in response were seen between the different cell lines, and the proteasome inhibitors, lactacystin and MG 262, showed an activity pattern similar to that of bortezomib. The cell-line data suggest that resistance to bortezomib was not mediated by MRP-, PgP, GSH-; tubulin and topo II-associated MDR. Combination experiments indicated synergy between bortezomib and arsenic trioxide or irinotecan. The data support the current use of bortezomib but also points to its potential utility in other tumour types and in combination with cytotoxic drugs.

  • 179.
    Wickström, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Danielsson, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients2007In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 73, no 1, p. 25-33Article in journal (Refereed)
    Abstract [en]

    The thiocarbamate drug disulfiram has been used for decades in the treatment of alcohol abuse. Disulfiram induces apoptosis in a number of tumor cell lines and was recently by us proposed to act as a 26S proteasome inhibitor. In this work we characterized disulfiram in vitro with regard to tumor-type specificity, possible mechanisms of action and drug resistance and cell death in human tumor cell lines and in 78 samples of tumor cells from patients using the fluorometric microculture cytotoxicity assay and the automated fluorescence-imaging microscope ArrayScan®. Disulfiram induced cytotoxicity in a biphasic pattern in both cell lines and patient tumor cells. Disulfiram induced apoptosis as measured by cell membrane permeability, nuclear fragmentation/condensation and caspase-3/7 activation using high content screening assays. For many of the cell lines tested disulfiram was active in sub-micromolar concentrations. When comparing the log IC50 patterns with other cytotoxic agents, disulfiram showed low correlation (R < 0.5) with all drugs except lactacystin (R = 0.69), a known proteasome inhibitor, indicating that the two substances may share mechanistic pathways. Disulfiram was more active in hematological than in solid tumor samples, but substantial activity was observed in carcinomas of the ovary and the breast and in non-small cell lung cancer. Disulfiram also displayed higher cytotoxic effect in cells from chronic lymphocytic leukemia than in normal lymphocytes (p < 0.05), which may indicate some tumor selectivity. These results together with large clinical experience and relatively mild side effects encourage clinical studies of disulfiram as an anti-cancer agent.

  • 180.
    Wickström, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Johnsen, John Inge
    Ponthan, Frida
    Segerström, Lova
    Sveinbjörnsson, Baldur
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Viktorsson, Kristina
    Lewensohn, Rolf
    Kogner, Per
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo2007In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 6, no 9, p. 2409-2417Article in journal (Refereed)
    Abstract [en]

    Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.

  • 181.
    Wickström, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Aminopeptidase N (CD13) as a target for cancer chemotherapy2011In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 102, no 3, p. 501-508Article, review/survey (Refereed)
    Abstract [en]

    The enzyme aminopeptidase N (APN, also known as CD13) is a Zn2+ dependent membrane-bound ectopeptidase that degrades preferentially proteins and peptides with a N-terminal neutral amino acid. Aminopeptidase N has been associated with the growth of different human cancers and suggested as a suitable target for anti-cancerous therapy. Different approaches have been used to develop new drugs directed to this target, including enzyme inhibitors as well as APN-targeted carrier constructs. This review discusses the prevalence and possible function of APN in malignant diseases, mainly solid tumors, as well as its “drugability” evaluated in preclinical in vivo models, and also provides a brief overview of current clinical trials focused on APN.

  • 182.
    Wickström, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Viktorsson, Kristina
    Lundholm, Lovisa
    Aesoy, Reidun
    Nygren, Helen
    Sooman, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Vogel, Lotte Katrine
    Lewensohn, Rolf
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan2010In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 79, no 9, p. 1281-1290Article in journal (Refereed)
    Abstract [en]

    The alkylating prodrug of melphalan, J1 (melphalanyl-l-p-fluorophenylalanyl ethyl ester) is currently in early clinical trials. Preclinical studies have shown that J1-mediated cytotoxicity is dependent on hydrolytic activity of tumor cells. In this report we have analyzed potential peptidases and esterases of importance for release of free melphalan from J1. Exposure of tumor cell lines to J1 resulted in a significant increased level of free intracellular melphalan, at least tenfold at Cmax, compared to exposure to melphalan at the same molar concentration. This efficient intracellular delivery could be inhibited in both magnitude and in time by bestatin, a broad spectrum inhibitor of the aminopeptidases, including the metalloproteinase aminopeptidase N (APN, EC 3.4.11.2.), and ebelactone A, an esterase inhibitor. These effects resulted, as expected, in decreased cytotoxic effects of J1. A specific role of APN in hydrolyzing J1 releasing free melphalan was demonstrated in vitro with pure APN enzyme. By using plasmid-based overexpression of APN or down regulation of endogenous APN with siRNA in different tumor cell lines we here confirm the involvement of APN in J1-mediated cytotoxic and apoptotic signaling. In conclusion, this study demonstrates a role of APN in the activation of the melphalan prodrug J1 and subsequently, its cytotoxicity. Given that APN is shown to be overexpressed in several solid tumors our data suggest that J1 may be activated in a tumor selective manner.

  • 183.
    Wu, Xuping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hedman, Håkan
    Department of Radiation Sciences and Oncology, Umeå University.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Henriksson, Roger
    Department of Radiation Sciences and Oncology, Umeå University.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hesselius, Patrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 69-76Article in journal (Refereed)
    Abstract [en]

    Background. Leucine-rich and immunoglobulin-like domains 1-3 (LRIG1-3) proteins have been implicated in the regulation of EGFR signalling. In the present study, we investigated the clinical implications of the expression of EGFR and LRIG1-3 in oesophageal carcinoma, as well as the correlation between their expression levels and the chemosensitivity of oesophageal carcinoma cell lines.

    Patients and methods. Tumours from 80 patients with oesophageal carcinoma were investigated for the expression of EGFR and LRIG proteins by immunohistochemistry. Oesophageal carcinoma cell lines were investigated for their expression of EGFR and LRIG1, 2, and 3 by quantitative real time RT-PCR and for their sensitivity to commonly used chemotherapeutics by a cytotoxicity assay.

    Results and discussion: Based on a total score of intensity and expression rates, a trend towards survival difference was found for EGFR (p = 0.09) and LRIG2 (p = 0.18) whereas for LRIG1 and -3 there was no trend towards any association with survival. Correlation analysis revealed a correlation with the clinical expression of EGFR and LRIG3 (p = 0.0007). Significant correlations were found between LRIG1 expression levels and sensitivity to cisplatin (r = -0.74), docetaxel (r = -0.69), and vinorelbine (r = -0.82) in oesophageal carcinoma cell lines. EGFR and the LRIG proteins may be functionally involved in oesophageal carcinoma, but larger materials are needed to fully elucidate the clinical implication.

  • 184.
    Wu, Xuping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology. The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China .
    Sooman, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dyrager, Christine
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro2013In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 12, no 8, p. 1526-1536Article in journal (Refereed)
    Abstract [en]

    The insulin-like growth factor-1 (IGF-I) and its receptors play an important role in transformation and progression of several malignancies. Inhibitors of this pathway have been developed and evaluated but generally performed poorly in clinical trials, and several drug candidates have been abandoned. The cyclolignan picropodophyllin (PPP) has been described as a potent and selective IGF-IR inhibitor and is currently undergoing clinical trials. We investigated PPP's activity in panels of human cancer cell lines (e.g., esophageal squamous carcinoma cell lines) but found no effects on the phosphorylation or expression of IGF-IR. Nor was the cytotoxic activity of PPP related to the presence or spontaneous phosphorylation of IGF-IR. However, its activity correlated with that of known tubulin inhibitors, and it destabilized microtubule assembly at cytotoxic concentrations also achievable in patients. PPP is a stereoisomer of podophyllotoxin (PPT), a potent tubulin inhibitor, and an equilibrium between the two has previously been described. PPP could thus potentially act as a reservoir for the continuous generation of low doses of PPT. Interestingly, PPP also inhibited downstream signaling from tyrosine kinase receptors, including the serine/threonine kinase Akt. This effect is associated with microtubule-related downregulation of the EGF receptor, rather than the IGF-IR. These results suggest that the cytotoxicity and pAkt inhibition observed following treatment with the cyclolignan PPP in vitro result from microtubule inhibition (directly or indirectly by spontaneous PPT formation), rather than any effect on IGF-IR. It is also suggested that PPT should be used as a reference compound in all future studies on PPP.

  • 185. Åleskog, Anna
    et al.
    Hassan, Sadia
    Hovstadius, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Kristensen, Jörgen
    Höglund, Martin
    Tholander, Bengt
    Binderup, Lise
    Larsson, Rolf
    Jonsson, Elin
    Activity of CHS 828 in primary cultures of human hematological and solid tumors in vitro2001In: Anti-Cancer Drugs, Vol. 12, no 10, p. 821-827Article in journal (Refereed)
1234 151 - 185 of 185
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf