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  • 7851.
    Alström, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Systematic Zoology.
    Rasmussen, Pamela C.
    Olsson, Urban
    Sundberg, Per
    Species delimitation based on multiple criteria: the Spotted Bush Warbler Bradypterus thoracicus complex (Aves : Megaluridae)2008In: Zoological Journal of the Linnean Society, ISSN 0024-4082, E-ISSN 1096-3642, Vol. 154, no 2, p. 291-307Article in journal (Refereed)
    Abstract [en]

    We demonstrate the importance of using multiple criteria in species delimitations, whatever the conceptual base for species delimitation. We do this by studying plumage, biometrics, egg coloration, song, mitochondrial DNA and habitat/altitudinal distribution in the Spotted Bush Warbler Bradypterus thoracicus (Blyth) complex, and by conducting playback experiments. Taxa that we suggest are best treated as separate species [B. thoracicus (Blyth), B. davidi (La Touche) and B. kashmirensis (Sushkin)] differ in most or all of these aspects, particularly in song and mitochondrial DNA, while those that we treat as subspecies (suschkini) or synonyms (przevalskii) differ slightly and only in morphology.

  • 7852.
    Alström, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Swedish Univ Agr Sci SLU, Swedish Species Informat Ctr, Box 7007, S-75007 Uppsala, Sweden; Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Rasmussen, Pamela C.
    Michigan State Univ, Dept Integrat Biol, E Lansing, MI 48864 USA;Michigan State Univ, MSU Museum, E Lansing, MI 48864 USA;Nat Hist Museum Tring, Bird Grp, Akeman St, Tring HP23 6AP, England.
    Xia, Canwei
    Beijing Normal Univ, Minist Educ, Coll Life Sci, Key Lab Biodivers & Ecol Engn, Beijing 100875, Peoples R China.
    Gelang, Magnus
    Gothenburg Nat Hist Museum, Box 7283, S-40235 Gothenburg, Sweden.
    Liu, Yang
    Sun Yat Sen Univ, Sch Life Sci, Dept Ecol, State Key Lab Biocontrol, Guangzhou 510275, Guangdong, Peoples R China.
    Chen, Guoling
    Sun Yat Sen Univ, Sch Life Sci, Dept Ecol, State Key Lab Biocontrol, Guangzhou 510275, Guangdong, Peoples R China.
    Zhao, Min
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China;Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
    Hao, Yan
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China;Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
    Zhao, Chao
    Cloud Mt Conservat, Dali 671003, Yunnan, Peoples R China.
    Zhao, Jian
    Sun Yat Sen Univ, Sch Life Sci, Dept Ecol, State Key Lab Biocontrol, Guangzhou 510275, Guangdong, Peoples R China.
    Yao, Chengte
    COA, Endem Species Res Inst, High Altitude Expt Stn, Chi Chi 55244, Taiwan.
    Eaton, James A.
    Birdtour Asia, 17 Keats Ave, Derby DE23 4EE, England.
    Hutchinson, Robert
    Birdtour Asia, 17 Keats Ave, Derby DE23 4EE, England.
    Lei, Fumin
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Olsson, Urban
    Univ Gothenburg, Dept Biol & Environm Sci, Systemat & Biodivers, Box 463, S-40530 Gothenburg, Sweden.
    Taxonomy of the White-browed Shortwing (Brachypteryx montana) complex on mainland Asia and Taiwan: an integrative approach supports recognition of three instead of one species2018In: Avian Research, ISSN 0005-2175, E-ISSN 2053-7166, Vol. 9, article id 34Article in journal (Refereed)
    Abstract [en]

    Background: The White-browed Shortwing (Brachypteryx montana) is widespread from the central Himalayas to the southeast Chinese mainland and the island of Taiwan, the Philippines and Indonesia. Multiple subspecies are recognised, and several of these have recently been suggested to be treated as separate species based on differences in morphology and songs.

    Methods: We here analyse plumage, morphometrics, songs, two mitochondrial and two nuclear markers, and geographical distributions of the two mainland Asian taxa B. m. cruralis and B. m. sinensis and the Taiwanese B. m. goodfellowi.

    Results: We conclude that these differ congruently in morphology, songs and DNA. Male B. m. goodfellowi is the most divergent in plumage (sexually monomorphic, unlike the two others; male similar to female), and B. m. cruralis and B. m. sinensis differ in male plumage maturation. The song of B. m. cruralis is strongly divergent from the others, whereas the songs of B. m. sinensis and B. m. goodfellowi are more similar to each other. Brachypteryx m. sinensis and B. m. goodfellowi are sisters, with an estimated divergence time 4.1 million years ago (mya; 95% highest posterior distribution [HPD] 2.8-5.5mya), and B. m. cruralis separated from these two 5.8mya (95% HPD 4.1-7.5mya). We also report notable range extensions of B. m. sinensis as well as sympatry between this taxon and B. m. cruralis in Sichuan Province, China. Brachypteryx m. montana from Java is found to be more closely related to Lesser Shortwing (B. leucophris) and Rusty-bellied Shortwing (B. hyperythra) than to the mainland Asian and Taiwanese taxa.

    Conclusion: Our data support a recent proposal to treat the three mainland Asian and Taiwanese taxa as three species, separate from B. montana sensu stricto: B. cruralis (central Himalayas to south central China and south Vietnam), B. sinensis (north central to southeastern part of mainland China) and B. goodfellowi (Taiwan Island).

  • 7853.
    Alström, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.; Swedish Univ Agr Sci, Swedish Species Informat Ctr, Box 7007, S-75007 Uppsala, Sweden.
    Rasmussen, Pamela C
    Michigan State Univ, Dept Integrat Biol, E Lansing, MI 48864 USA.; Michigan State Univ, MSU Museum, E Lansing, MI 48864 USA.; Nat Hist Museum Tring, Bird Grp, Akeman St, Tring HP23 6AP, England.
    Zhao, Chao
    Cloud Mt Conservat, Dali 671003, Peoples R China.
    Xu, Jingzi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Dalvi, Shashank
    GKVK, Natl Ctr Biol Sci, Researchers Wildlife Conservat, F-21,Bellary Rd, Bengaluru 560065, Karnataka, India.
    Cai, Tianlong
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.; Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China.
    Guan, Yuyan
    Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China.; Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China.
    Zhang, Ruiying
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Kalyakin, Mikhail V.
    Lomonosov Moscow State Univ, Zool Museum, Bolshaya Nikitskaya Str 2, Moscow 125009, Russia.
    Lei, Fumin
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Olsson, Urban
    Univ Gothenburg, Dept Biol & Environm Sci, Systemat & Biodivers, Box 463, S-40530 Gothenburg, Sweden.
    Integrative taxonomy of the Plain-backed Thrush (Zoothera mollissima) complex (Aves, Turdidae) reveals cryptic species, including a new species2016In: Avian Research, ISSN 0005-2175, E-ISSN 2053-7166, Vol. 7, article id 1Article in journal (Refereed)
    Abstract [en]

    Background: The Plain-backed Thrush Zoothera mollissima breeds in the Himalayas and mountains of central China. It was long considered conspecific with the Long-tailed Thrush Zoothera dixoni, until these were shown to be broadly sympatric.

    Methods: We revise the Z. mollissimaZ. dixoni complex by integrating morphological, acoustic, genetic (two mitochondrial and two nuclear markers), ecological and distributional datasets.

    Results: In earlier field observations, we noted two very different song types of “Plain-backed” Thrush segregated by breeding habitat and elevation. Further integrative analyses congruently identify three groups: an alpine breeder in the Himalayas and Sichuan, China (“Alpine Thrush”); a forest breeder in the eastern Himalayas and northwest Yunnan (at least), China (“Himalayan Forest Thrush”); and a forest breeder in central Sichuan (“Sichuan Forest Thrush”). Alpine and Himalayan Forest Thrushes are broadly sympatric, but segregated by habitat and altitude, and the same is probably true also for Alpine and Sichuan Forest Thrushes. These three groups differ markedly in morphology and songs. In addition, DNA sequence data from three non-breeding specimens from Yunnan indicate that yet another lineage exists (“Yunnan Thrush”). However, we find no consistent morphological differences from Alpine Thrush, and its breeding range is unknown. Molecular phylogenetic analyses suggest that all four groups diverged at least a few million years ago, and identify Alpine Thrush and the putative “Yunnan Thrush” as sisters, and the two forest taxa as sisters. Cytochrome b divergences among the four Z. mollissima sensu lato (s.l.) clades are similar to those between any of them and Z. dixoni, and exceed that between the two congeneric outgroup species. We lectotypify the name Oreocincla rostrata Hodgson, 1845 with the Z. mollissima sensu stricto (s.s.) specimen long considered its type. No available name unambiguously pertains to the Himalayan Forest Thrush.

    Conclusions: The Plain-backed Thrush Z. mollissima s.l. comprises at least three species: Alpine Thrush Z. mollissima s.s., with a widespread alpine breeding distribution; Sichuan Forest Thrush Z. griseiceps, breeding in central Sichuan forests; and Himalayan Forest Thrush, breeding in the eastern Himalayas and northwest Yunnan (at least), which is described herein as a new species. “Yunnan Thrush” requires further study.

  • 7854.
    Alström, Per
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Swedish Univ Agr Sci SLU, Swedish Species Informat Ctr, Box 7007, SE-75007 Uppsala, Sweden;Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Rheindt, Frank E.
    Natl Univ Singapore, Dept Biol Sci, 16 Sci Dr 4, Singapore 117558, Singapore.
    Zhang, Ruiying
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Zhao, Min
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Wang, Jing
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Zhu, Xiaojia
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Gwee, Chyi Yin
    Natl Univ Singapore, Dept Biol Sci, 16 Sci Dr 4, Singapore 117558, Singapore.
    Hao, Yan
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Ohlson, Jan
    Swedish Museum Nat Hist, Dept Bioinformat & Genet, Box 50007, SE-10405 Stockholm, Sweden.
    Jia, Chenxi
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Prawiradilaga, Dewi M.
    Indonesian Inst Sci LIPI, Cibinong Sci Ctr, Res Ctr Biol, Jalan Raya Jakarta Bogor KM 46, Bogor 16911, Indonesia.
    Ericson, Per G. P.
    Swedish Museum Nat Hist, Dept Bioinformat & Genet, Box 50007, SE-10405 Stockholm, Sweden.
    Lei, Fumin
    Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing 100101, Peoples R China.
    Olsson, Urban
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, SE-40530 Gothenburg, Sweden.
    Complete species-level phylogeny of the leaf warbler (Aves: Phylloscopidae) radiation2018In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 126, p. 141-152Article in journal (Refereed)
    Abstract [en]

    The leaf warbler radiation (Aves: Phylloscopidae) has undergone a c. 50% increase in the number of recognised species over the last three decades, mainly as a result of analyses of vocalisations and DNA. Using a multilocus dataset for all of the species in this family, and multispecies coalescent-based as well as concatenation methods, we provide the first complete species-level phylogeny for this important group, as well as an estimate of the timing of diversification. The most recent common ancestor for the family was dated at 11.7 million years ago (mya) (95% highest posterior density 9.8-13.7 mya), and divergence times between sister species ranged from 0.5 mya (0.3-0.8 mya) to 6.1 mya (4.8-7.5 mya). Based on our results, we support synonymising Seicercus with Phylloscopus, which results in a monogeneric Phylloscopidae. We discuss the pros and cons of this treatment, and we argue against proliferation of taxonomic names, and conclude that a large monogeneric Phylloscopidae leads to the fewest taxonomic changes compared to traditional classifications. We briefly discuss morphological evolution in the light of the phylogeny. The time calibrated phylogeny is a major improvement compared to previous studies based on a smaller number of species and loci and can provide a basis for future studies of other aspects of phylloscopid evolution.

  • 7855. Alström, Per
    et al.
    Saitoh, Takema
    Williams, Dawn
    Nishiumi, Isao
    Shigeta, Yoshimitsu
    Ueda, Keisuke
    Irestedt, Martin
    Björklund, Mats
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal Ecology.
    Olsson, Urban
    The Arctic Warbler Phylloscopus borealis - three anciently separated cryptic species revealed2011In: Ibis, ISSN 0019-1019, E-ISSN 1474-919X, Vol. 153, no 2, p. 395-410Article in journal (Refereed)
    Abstract [en]

    The Arctic Warbler Phylloscopus borealis breeds across the northern Palaearctic and northwestern-most Nearctic, from northern Scandinavia to Alaska, extending south to southern Japan, and winters in Southeast Asia, the Philippines and Indonesia. Several subspecies have been described based on subtle morphological characteristics, although the taxonomy varies considerably among different authors. A recent study (T. Saitoh et al. (2010) BMC Evol. Biol. 10: 35) identified three main mitochondrial DNA clades, corresponding to: (1) continental Eurasia and Alaska, (2) south Kamchatka, Sakhalin and northeast Hokkaido, and (3) most of Japan (Honshu, Shikoku, Kyushu). These three clades were estimated to have diverged during the late Pliocene to early Pleistocene (border at c. 2.6 million years ago). Differences in morphometrics have also been reported among members of the three clades (T. Saitoh et al. (2008) Ornithol. Sci. 7: 135-142). Here we analyse songs and calls from throughout the range of the Arctic Warbler, and conclude that these differ markedly and consistently among the populations representing the three mitochondrial clades. Kurile populations, for which no sequence data are available, are shown to belong to the second clade. To determine the correct application of available scientific names, mitochondrial DNA was sequenced from three name-bearing type specimens collected on migration or in the winter quarters. Based on the congruent variation in mitochondrial DNA, morphology and vocalizations, we propose that three species be recognized: Arctic Warbler Phylloscopus borealis (sensu stricto) (continental Eurasia and Alaska), Kamchatka Leaf Warbler Phylloscopus examinandus (Kamchatka (at least the southern part), Sakhalin, Hokkaido and Kurile Islands), and Japanese Leaf Warbler Phylloscopus xanthodryas (Japan except Hokkaido).

  • 7856.
    Alström, Ulrica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Platelet Inhibition and Bleeding in Coronary Artery Bypass Surgery2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A substantial number of patients undergoing cardiac surgery are on dual anti-platelet treatment with clopidogrel and aspirin. A disadvantage with this treatment is increased risk of bleeding. Bleeding is a complication of major concern associated with adverse outcome for the patient and increased hospital resource utilization. Great variability in individual response to clopidogrel has been reported. If in vitro measurements of platelet reactivity would correlate with clinical bleeding parameters, potential bleeders could be identified preoperatively.

    The aims of this thesis were: (1) to describe the degree of pre-operative platelet inhibition in patients scheduled for primary isolated coronary artery bypass graft surgery; (2) to prospectively investigate whether the pre-operative platelet inhibition correlated with intra- and postoperative bleeding and transfusion requirements; and (3) to test the ability of clinically relevant risk factors to predict re-exploration for bleeding. (4) In addition, a cost analysis was performed on patients re-explored for bleeding, to analyse the magnitude of added resource utilization and costs. Based on this, a cost model of prophylactic treatment with haemostatic drugs was calculated.

    Platelet function tests investigated were: (1) flow cytometry, (2) VASP, (3) VerifyNowSystem, (4) PlateletMapping (a modified TEG), and (5) PFA-100.

    Clinical risk factors for re-exploration and the influence of antiplatelet and antifibrinolytic therapy were evaluated in a retrospective analysis. Cost analysis at three cardiothoracic centres was performed in a case-control study.

    In conclusion, there was no clinically useful correlation between preoperative assessment of platelet inhibition and blood loss or transfusion requirements during coronary artery bypass surgery. Furthermore, there was only modest agreement between the methods evaluating ADP-receptor blockade.

    Pre-operative treatment with the P2Y12-receptor inhibitor clopidogrel was an essential risk factor for re-exploration due to bleeding. Except for clopidogrel, no strong clinical factor to predict the risk of re-exploration was identified.

    The resource utilisation costs were 47% higher in patients requiring re-exploration due to bleeding than in those not requiring re-exploration. Prolonged stay in the ICU and recovery ward accounted for half of the added cost, a third was due to the costs of surgery, one fifth due to increased cost of transfusions, and <2% was due to haemostatic drug treatment.

     

     

    List of papers
    1. The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment
    Open this publication in new window or tab >>The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment
    Show others...
    2007 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 120, no 3, p. 353-359Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Addition of clopidogrel to patients treated with ASA has been shown to decrease the incidence of in-stent thrombosis after percutaneous coronary interventions. However, it has also been reported that up to 30% of patients do not achieve adequate platelet inhibition from standard dosages of ASA and clopidogrel. There is a demand for reliable methods to measure the individual platelet inhibiting effect of this combination therapy. MATERIALS AND METHODS: The primary aim of the present investigation was to compare three methods for evaluation of the platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment. Thirty patients presenting for coronary angiography/PCI were included. Two patients were excluded due to technical problems. All patients were on 75-100 mg ASA/day for at least 8 days. Blood samples were analysed before and 16 h after a 300 mg clopidogrel bolus dose. The platelet inhibiting effect was measured with (1) Whole blood flow cytometry (17 patients); (2) a bed-side test, Platelet Mapping assay for the thrombelastograph (28 patients); and (3) PFA (Platelet function analyser) -100 (26 patients). RESULTS: With flow cytometry, the percentage of platelets expressing P-selectin (p=0.03) on their surface decreased significantly after the bolus dose of clopidogrel. There was also a reduction of platelets binding fibrinogen when stimulated with ADP. A significantly (p=0.002) increased platelet inhibition could also be demonstrated with Platelet Mapping. PFA-100 could not measure any significant platelet inhibiting effect of clopidogrel. CONCLUSION: A significant platelet inhibition could be demonstrated with flow cytometry and the Platelet Mapping assay, but not with PFA-100. However, levels of response for the individual patient with these three methods were inconsistent. Further studies are needed to evaluate how the results correlate to the clinical risk of thrombosis and bleeding.

    Keywords
    Clopidogrel, Flow cytometry, Thrombelastograph, Platelets, PFA-100
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-24441 (URN)10.1016/j.thromres.2006.10.009 (DOI)000247762600005 ()17137616 (PubMedID)
    Available from: 2007-02-15 Created: 2007-02-15 Last updated: 2017-12-07Bibliographically approved
    2. Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery
    Open this publication in new window or tab >>Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery
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    2009 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 124, no 5, p. 572-577Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: A substantial number of patients with coronary artery disease undergo cardiac surgery within five days of discontinuing anti-platelet treatment with aspirin and clopidogrel. The aims of this study were to describe the degree of platelet inhibition in patients with dual anti-platelet treatment scheduled for coronary artery bypass graft (CABG) surgery and to investigate whether the measured platelet inhibition correlated to intra- and postoperative risk for bleeding and transfusion requirements. MATERIAL AND METHODS: Sixty patients were included. Platelet inhibition was analysed with flow cytometry including phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP-assay) and two bed-side analyzers, VerifyNow-System and PlateletMapping, a modified thrombelastograph. All 60 patients were analysed with VerifyNow and PlateletMapping, and 48 were analysed with flow cytometry and VASP-assay. RESULTS: There was a correlation between the ADP-receptor inhibition as measured by VASP-assay and VerifyNowP2Y(12) (r = -0.29, p<0.05), and between VASP-assay and the expression of P-selectin (r = 0.29, p<0.05) as measured by flow cytometry when platelets were stimulated with 5 microM ADP. VerifyNowP2Y(12) was the only measurement of platelet inhibition correlated to total blood loss (Spearman r = 0.29, p=0.03) and red blood cell transfusion (Spearman r = 0.43, p<0.01) requirements, although this might be confounded by aprotinin treatment. CONCLUSION: We found a modest agreement between the methods for preoperative platelet inhibition, though not for PlateletMapping-MA(ADP). There was a correlation between preoperative platelet inhibition measured by VerifyNowP2Y(12) and surgical blood loss or transfusion requirements. However, for the individual patient, preoperative use of VerifyNowP2Y(12) as an instrument to decide bleeding and transfusion risk does not seem helpful.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-120242 (URN)10.1016/j.thromres.2009.06.024 (DOI)000271712800012 ()19631364 (PubMedID)
    Available from: 2010-03-10 Created: 2010-03-10 Last updated: 2017-12-12Bibliographically approved
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  • 7857.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Granath, Fredrik
    Friberg, Orjan
    Ekbom, Anders
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Risk factors for re-exploration due to bleeding after coronary artery bypass grafting2012In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 46, no 1, p. 39-44Article in journal (Refereed)
    Abstract [en]

    Objective. The study aimed to investigate relevant clinical risk factors for re-exploration due to bleeding after primary coronary artery bypass graft (CABG) surgery, and to evaluate the influence of antiplatelet and antifibrinolytic drugs. Design. Three retrospective analyses were performed on patients who underwent CABG: (1) Logistic regression was used to identify clinical risk factors for re-exploration (n = 3000). (2) A case-control study (n = 228) was used to obtain information on exposure of antithrombotic and hemostatic therapy. (3) Based on exposure to antiplatelet and antifibrinolytic therapy, and odds ratios (ORs) in multivariate logistic models, the proportion of re-explorations attributed to these drugs was calculated. Results. A receiver operating characteristic curve was created for clinical risk factors. The C-index was 0.64, indicating limited ability to predict re-exploration for bleeding. Clopidogrel was the only drug influencing the risk of re-exploration (OR 3.2, 95% CI 1.7-5.9). The harmful effect of clopidogrel was confirmed in multivariate model (OR 4.7, 95% CI 2.2-9.9), and aprotinin had a protective effect of the same magnitude (OR 0.2, 95% CI 0.1-0.6). Conclusions. Clopidogrel is an essential risk factor for re-exploration due to bleeding, and attributable to at least one-quarter of surveyed cases. Aside from pharmaceuticals, there are no strong clinical risk factors.

  • 7858.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Granath, Fredrik
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Tydén, Hans
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery2009In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 124, no 5, p. 572-577Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: A substantial number of patients with coronary artery disease undergo cardiac surgery within five days of discontinuing anti-platelet treatment with aspirin and clopidogrel. The aims of this study were to describe the degree of platelet inhibition in patients with dual anti-platelet treatment scheduled for coronary artery bypass graft (CABG) surgery and to investigate whether the measured platelet inhibition correlated to intra- and postoperative risk for bleeding and transfusion requirements. MATERIAL AND METHODS: Sixty patients were included. Platelet inhibition was analysed with flow cytometry including phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP-assay) and two bed-side analyzers, VerifyNow-System and PlateletMapping, a modified thrombelastograph. All 60 patients were analysed with VerifyNow and PlateletMapping, and 48 were analysed with flow cytometry and VASP-assay. RESULTS: There was a correlation between the ADP-receptor inhibition as measured by VASP-assay and VerifyNowP2Y(12) (r = -0.29, p<0.05), and between VASP-assay and the expression of P-selectin (r = 0.29, p<0.05) as measured by flow cytometry when platelets were stimulated with 5 microM ADP. VerifyNowP2Y(12) was the only measurement of platelet inhibition correlated to total blood loss (Spearman r = 0.29, p=0.03) and red blood cell transfusion (Spearman r = 0.43, p<0.01) requirements, although this might be confounded by aprotinin treatment. CONCLUSION: We found a modest agreement between the methods for preoperative platelet inhibition, though not for PlateletMapping-MA(ADP). There was a correlation between preoperative platelet inhibition measured by VerifyNowP2Y(12) and surgical blood loss or transfusion requirements. However, for the individual patient, preoperative use of VerifyNowP2Y(12) as an instrument to decide bleeding and transfusion risk does not seem helpful.

  • 7859.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Levin, L-Å
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Svedjeholm, R
    Friberg, Ö
    Cost analysis of re-exploration for bleeding after coronary artery bypass graft surgery2012In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 108, no 2, p. 216-222Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Re-exploration for bleeding after cardiac surgery is an indicator of substantial haemorrhage and is associated with increased hospital resource utilization. This study aimed to analyse the costs of re-exploration and estimate the costs of haemostatic prophylaxis.

    METHODS:

    A total of 4232 patients underwent isolated, first-time, coronary artery bypass graft (CABG) surgery during 2005-8. Each patient re-explored for bleeding (n=127) was matched with two controls not requiring re-exploration (n=254). Cost analysis was based on resource utilization from completion of CABG until discharge. A mean cost per patient for re-exploration was calculated. Based on this, the net cost of prophylactic treatment with haemostatic drugs for preventing re-exploration was calculated.

    RESULTS:

    Patients undergoing re-exploration had higher exposure to clopidogrel before operation, prolonged stays in the intensive care unit, and more blood transfusions than controls. The mean incremental cost for re-exploration was (sic)6290 [95% confidence interval (CI) (sic)3408-(sic)9173] per patient, of which 48% [(sic)3001 (95% CI (sic)249-(sic)2147)] was due to prolonged stay, 31% [(sic)1928 (95% CI (sic)1710-(sic)2147)] to the cost of surgery/anaesthesia, 20% [(sic)1261 (95% CI (sic)1145-(sic)1378)] to the increased number of blood transfusions, and <2% [(sic)100 (95% CI (sic)39-(sic)161)] to the cost of haemostatic drugs. A cost model, at an estimated 50% efficacy for recombinant activated clotting factor VIIa and a 50% expected risk for re-exploration without prophylaxis, demonstrated that to be cost neutral, prophylaxis of four patients needed to result in one avoided re-exploration.

    CONCLUSIONS:

    The resource utilization costs were substantially higher in patients requiring re-exploration for bleeding. From a strict cost-effectiveness perspective, clinical interventions to prevent haemorrhage might be underutilized.

  • 7860.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tydén, Hans
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment2007In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 120, no 3, p. 353-359Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Addition of clopidogrel to patients treated with ASA has been shown to decrease the incidence of in-stent thrombosis after percutaneous coronary interventions. However, it has also been reported that up to 30% of patients do not achieve adequate platelet inhibition from standard dosages of ASA and clopidogrel. There is a demand for reliable methods to measure the individual platelet inhibiting effect of this combination therapy. MATERIALS AND METHODS: The primary aim of the present investigation was to compare three methods for evaluation of the platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment. Thirty patients presenting for coronary angiography/PCI were included. Two patients were excluded due to technical problems. All patients were on 75-100 mg ASA/day for at least 8 days. Blood samples were analysed before and 16 h after a 300 mg clopidogrel bolus dose. The platelet inhibiting effect was measured with (1) Whole blood flow cytometry (17 patients); (2) a bed-side test, Platelet Mapping assay for the thrombelastograph (28 patients); and (3) PFA (Platelet function analyser) -100 (26 patients). RESULTS: With flow cytometry, the percentage of platelets expressing P-selectin (p=0.03) on their surface decreased significantly after the bolus dose of clopidogrel. There was also a reduction of platelets binding fibrinogen when stimulated with ADP. A significantly (p=0.002) increased platelet inhibition could also be demonstrated with Platelet Mapping. PFA-100 could not measure any significant platelet inhibiting effect of clopidogrel. CONCLUSION: A significant platelet inhibition could be demonstrated with flow cytometry and the Platelet Mapping assay, but not with PFA-100. However, levels of response for the individual patient with these three methods were inconsistent. Further studies are needed to evaluate how the results correlate to the clinical risk of thrombosis and bleeding.

  • 7861.
    Alström-Rapaport, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Functional Genomics.
    Leskinen, Elina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Functional Genomics.
    Parnilo, Pekka
    Seasonal variation in the mode of reproduction of Ulva intestinalis in a brackish water environment2010In: Aquatic Botany, ISSN 0304-3770, E-ISSN 1879-1522, Vol. 93, no 4, p. 244-249Article in journal (Refereed)
    Abstract [en]

    We explored the reproductive modes of Viva intestinalis in the inner part of the Baltic Sea during three consecutive years by using five microsatellite loci to estimate the relative abundance of diploid sporophytes and haploid gametophytes. Our results suggest that both diploid sporophytes and haploid gametophytes occur regularly in the Baltic Sea. The ratio of haploid to diploid individuals changes with seasons. Sporophytes are more abundant than gametophytes throughout the year, but the proportion of haploids increases from 10% in early summer to 35% in September. The over-wintering takes primarily place as diploid spores released by sporophytes. The sporophytes appear to reproduce both sexually and asexually in the Baltic Sea, since clones were found for this life phase. The fraction of individuals which belonged to an apparent diploid clone was higher in spring (62%) than in autumn (33%). We also found evidence for asexual clones in haploid gametophytes. The presence of both diploid and haploid individuals and the pattern of genetic and genotypic diversity provide evidence of sexual reproduction in the Baltic Sea. Thus the sporophytes and gametophytes do not function as two reproductively separate units. Compared with many other algal species with a reduced reproductive cycle in low salinity, U. intestinalis differs by having a multitude of reproductive modes also in the brackish water Baltic Sea, which can in part explain the dynamic propagation and high adaptability of the species.

  • 7862. Alström-Rapaport, Cecilia
    et al.
    Sjödin, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Functional Genomics.
    Wallén, Johan
    Lascoux, Martin
    Phylogeographic structure in Brassica nigra, a signal of early agricultural spread in Europe?Manuscript (Other (popular science, discussion, etc.))
  • 7863.
    Alswait, Aloush
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Lejon, Viktoria
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Förändrade bosättningslagen fördelningen av nyanlända i Sveriges kommuner?2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Fler människor än någonsin är på flykt från krig och förföljelse. I Sverige såväl som i Europa diskuteras det nu hur strömmen av människor skall hanteras trots bostadsbrist, arbetslöshet och integrationsproblematik. Den första mars 2016 trädde den nya bosättningslagen (SFS 2016:38) i kraft i Sverige. Detta gjorde landets kommuner skyldiga att ta emot och bosätta personer som fått uppehållstillstånd. I den här uppsatsen undersöker vi huruvida det går att utläsa en skillnad i hur nyanlända blir fördelade mellan landets kommuner före och efter det att lagen trätt i kraft. Vi använder oss av en regressionsanalys för att se eventuella samband mellan fördelningen av mottagandet av nyanlända mellan landets kommuner och införandet av bosättningslagen. Studien visar på att det är de befolkningsmässigt mindre kommunerna med en hög arbetslöshet som tar emot flest nyanlända i förhållande till folkmängd. Vi finner ingen indikation på att det positiva samband som finns mellan tidigare mottagande av nyanlända, ensamkommande barn och asylsökande och andelen mottagna nyanlända i förhållande till folkmängd har minskat efter införandet av lagen. 

  • 7864.
    Al-Sálehi, Robin Rushdi
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Social and Economic Geography. 199401246138.
    Att skapa social hållbarhet: Fastighetsägaren Hemsös möjligheter och restriktioner för att skapa ett mer levande och självförsörjande stadsrum2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Att skapa hållbara städer är ett av de viktigaste målen idag för att tackla problem som rör ekologiska, ekonomiska och sociala frågor i vår värld. Syftet med denna uppsats är att visa hur ägare av det fysiska rummet i städer, nämligen fastighetsägare, har möjligheter men också restriktioner för att påverka. Genom att lösa sociala problem i städer, med cirkulärt ekonomiska verksamheter i fastigheterna, kan vi komma närmare att uppnå Jane Jacobs bild av en levande och demokratisk stad där människor själva bidrar till en hållbar stadsutveckling. För att kunna förstå fastighetsägarnas möjligheter och restriktioner, i detta fall Hemsö fastighets AB, har intervjuer genomförts med Vd:n som fastställer riktlinjerna i företaget, men även andra medarbetare, för att få en bild av deras handlingsutrymme. Dessa möjligheter och restriktioner diskuteras sedan utifrån Jacobs teorier för en stadsutveckling som i denna uppsats anses vara ett socialt hållbar sätt och exemplifieras med cirkulärt ekonomiska verksamheter för att visa hur detta även leder till en hållbar stadsutveckling. Resultatet visade att restriktionerna är detaljplaner, hyresavtal, bygglov och företagets lönsamhetskrav. Den visade också på många möjligheter och en vilja att vara hållbara. Problemet som visat sig är bristen på kunskapen om hur det kan ske.

  • 7865.
    Alsén, Ellen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Genusperspektiv på sjuksköterskeutbildningen i Uppsala: En kvalitativ studie2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Syfte: Att utforska studenters upplevelse av sjuksköterskeutbildningen i Uppsala ur ett genuspesrpektiv.

    METOD: Vald forskningsmetod var en kvalitativ metod med fokusgruppsintervju samt semistrukturerade enskilda intervjuer.

     Resultat: Deltagarna i studien ansåg att sjuksköterskeutbildningen är könsstereotyp. Sjuksköterskan var en kvinna med stereotypt kvinnliga egenskaper. Informanterna upplevde att bilden av sjuksköterskan var svår att leva upp till, då de inte kunde relatera och känna igen sig själva i bilden som målats upp. Sjuksköterskestudenter som bryter mot könsnormen på utbildningen upplevde detta som mycket påtagligt och frustrerande. Andra vårdyrken upplevdes inte lika tydligt könspräglade som sjuksköterskan även om hierarkin ansågs vara mycket tydlig och frustrerande. Det framkom i studien att studenterna upplevde att bilden av patienten i kurslitteratur och undervisningsmaterial var en heterosexuell man. Studenterna saknade ett norm- och könskritiskt perspektiv i undervisningen. Kvinnors symtom och sjukdomar tenderade att hamna inom parentes.

    Slutsats: Sjuksköterskeutbildningen i Uppsala liksom hälso- och sjukvården i stort är grundad på föreställningar om tydliga könsroller. Detta gäller såväl patienter som vårdpersonal. Studien visar att hälso- och sjukvården är könssegregerad och bygger på könsnormer samt föreställningar om kvinnor och mäns olikheter.  Detta stöds av en rad studier i ämnet. Studiens design, det stora bortfallet samt det låga intresset för att delta i studien gör att ingen generaliserbarhet föreligger.

    Resultaten tyder på att ett könsbias föreligger och att mer forskning kring ämnet genusmedicin, utbildningens påverkan på yrkesverksamheten och genusvetenskap krävs.

  • 7866. Alsén, Martin
    et al.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Eggers, Kai
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    »HEART score« – lösningen på säker handläggning av patienter med misstänkt akut kranskärlsjukdom på akutmottagningen?: ["HEART score"--the solution for secure management of patients with suspected acute coronary syndrome in the emergency department?]2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 27-28, p. 1297-Article in journal (Other academic)
  • 7867.
    Alsén, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Immunohistochemical evaluation of antibodies for staining of mouse spinal cord and mouse neuronal cells2013Independent thesis Basic level (university diploma), 10 credits / 15 HE creditsStudent thesis
  • 7868.
    Al-tai, Milad
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economic History.
    Biståndsdebatten. En studie av kritiken mot och argumenten för utvecklingsbiståndet.2012Student paper second term, 5 credits / 7,5 HE creditsStudent thesis
  • 7869.
    Al-Tai, Milad
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    The Macroeconomic Effects of Monetary Policy in Sweden2017Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In this paper, the identification strategy introduced by Romer and Romer (2004) is used to derive more accurate estimates of the effects of monetary policy in Sweden. By constructing a new real-time data set and then matching this data to each of the Riksbank’s repo rate decisions between 1999 and 2016, an exogenous monetary policy shock measure is obtained from the estimated residuals of the first-stage regression. The results from the VAR model show that a one percentage point innovation in the shock reduces output by 8 per cent and inflation by more than 1.4 percentage points. The results also indicate that the macroeconomic effects are protracted and that using the new measure for monetary policy shocks solves the ”price puzzle”.

  • 7870.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tumour Targeting using Radiolabelled Affibody Molecules: Influence of Labelling Chemistry2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Affibody molecules are promising candidates for targeted radionuclide-based imaging and therapy applications. Optimisation of targeting properties would permit the in vivo visualization of cancer-specific surface receptors with high contrast. In therapy, this may increase the ratio of radioactivity uptake between tumour and normal tissues.  This thesis work is based on 5 original research articles (papers I-V) and focuses on optimisation of targeting properties of anti-HER2 affibody molecules by optimising the labelling chemistry.

    Paper I and II report the comparative evaluation of the anti-HER2 ZHER2:2395 affibody molecule site specifically labelled with 111In (suitable for SPECT imaging) and 68Ga (suitable for PET imaging) using the thiol reactive derivatives of DOTA and NODAGA as chelators. The incorporation of different macrocyclic chelators and labelling with different radionuclides modified the biodistribution properties of affibody molecules. This indicates that the labelling strategy may have a profound effect on the targeting properties of radiotracers and must be carefully optimized.

    Paper III reports the study of the mechanism of renal reabsorption of anti-HER2 ZHER2:2395 affibody molecule. An unknown receptor (not HER2) is suspected to be responsible for the high reabsorption of ZHER2:2395 molecules in the kidneys.

    Paper IV reports the optimization and development of in vivo targeting properties of 188Re-labelled anti-HER2 affibody molecules. By using an array of peptide based chelators, it was found that substitution of one amino acid by another or changing its position can have a dramatic effect on the biodistribution properties of 188Re-labelled affibody molecules. This permitted the selection of –GGGC chelator whichdemonstrated the lowest retention of radioactivity in kidneys compared to other variants and showed excellent tumour targeting properties.

    Paper V reports the preclinical evaluation of 188Re-ZHER2:V2 as a potential candidate for targeted radionuclide therapy of HER2-expressing tumours. In vivo experiments in mice along with dosimetry assessment in both murine and human models revealed that future human radiotherapy studies using 188Re-ZHER2:V2 may be feasible.

    It would be reasonable to believe that the results of optimisation of anti-HER2 affibody molecules summarized in this thesis can be of importance for the development of other scaffold protein-based targeting agents.

    List of papers
    1. Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with 111In using a maleimido derivative of NODAGA
    Open this publication in new window or tab >>Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with 111In using a maleimido derivative of NODAGA
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    2012 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 4, p. 518-529Article in journal (Refereed) Published
    Abstract [en]

    Introduction

    Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule.

    Methods

    The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to ZHER2:2395 Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 were studied. Biodistribution of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 and [111In-MMA-DOTA-Cys61]-ZHER2:2395 was compared in mice.

    Results

    The affinity of [MMA-NODAGA-Cys61]-ZHER2:2395 binding to HER2 was 67 pM. The 111In-labeling yield was 99.6%±0.5% after 30 min at 60°C. [111In-MMA-NODAGA-Cys61]-ZHER2:2395 bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 in mice bearing DU-145 xenografts (4.7%±0.8% ID/g) was lower than uptake of [111In-MMA-DOTA-Cys61]-ZHER2:2395 (7.5%±1.6% ID/g). However, tumor-to-organ ratios were higher for [111In-MMA-NODAGA-Cys61]-ZHER2:2395 due to higher clearance rate from normal tissues.

    Conclusions

    MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-164424 (URN)10.1016/j.nucmedbio.2011.10.013 (DOI)000303790600008 ()22172396 (PubMedID)
    Available from: 2012-05-04 Created: 2011-12-20 Last updated: 2017-12-07Bibliographically approved
    2. Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with 68Ga and 111In via Maleimido Derivatives of DOTA and NODAGA
    Open this publication in new window or tab >>Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with 68Ga and 111In via Maleimido Derivatives of DOTA and NODAGA
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    2013 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 24, no 6, p. 1102-1109Article in journal (Refereed) Published
    Abstract [en]

    Accurate detection of cancer-associated molecular abnormalities in tumors could make cancer treatment more personalized. Affibody molecules enable high contrast imaging of tumor-associated protein expression shortly after injection. The use of the generator-produced positron-emitting radionuclide 68Ga should increase sensitivity of HER2 imaging. The chemical nature of radionuclides and chelators influences the biodistribution of Affibody molecules, providing an opportunity to further increase the imaging contrast. The aim of the study was to compare maleimido derivatives of DOTA and NODAGA for site-specific labeling of a recombinant ZHER2:2395 HER2-binding Affibody molecule with 68Ga. DOTA and NODAGA were site-specifically conjugated to the ZHER2:2395 Affibody molecule having a C-terminal cysteine and labeled with 68Ga and 111In. All labeled conjugates retained specificity to HER2 in vitro. Most of the cell-associated activity was membrane-bound with a minor difference in internalization rate. All variants demonstrated specific targeting of xenografts and a high tumor uptake. The xenografts were clearly visualized using all conjugates. The influence of chelator on the biodistribution and targeting properties was much less pronounced for 68Ga than for 111In. The tumor uptake of 68Ga-NODAGA-ZHER2:2395 and 68Ga-DOTA-ZHER2:2395 and tumor-to-blood ratios at 2 h p.i. did not differ significantly. However, the tumor-to-liver ratio was significantly higher for 68Ga-NODAGA- ZHER2:2395 (8 ± 2 vs 5.0 ± 0.3) offering the advantage of better liver metastases visualization. In conclusion, influence of chelators on biodistribution of Affibody molecules depends on the radionuclides and reoptimization of labeling chemistry is required when a radionuclide label is changed.

    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-203054 (URN)10.1021/bc300678y (DOI)000320898900030 ()23705574 (PubMedID)
    Note

    De två (2) första författarna delar förstaförfattarskapet.

    Available from: 2013-07-02 Created: 2013-07-02 Last updated: 2018-01-11Bibliographically approved
    3. In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors
    Open this publication in new window or tab >>In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors
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    2013 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 28, no 3, p. 187-195Article in journal (Refereed) Published
    Abstract [en]

    Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody Z(HER2:342) was developed for imaging of HER2 expression in tumors, and a clinical study has demonstrated that the In-111- and Ga-68-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, a significant renal accumulation of radioactivity after systemic injection of a radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in a murine model and in vitro using opossum-derived proximal tubule (OK) cells. It was found that kidney reabsorption of affibody molecule was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody molecule were involved in binding to OK cells. On OK cells, two types of receptors for anti-HER2 affibody molecule were found: K-D1 = 0.8 nM, B-max1 = 71,500 and K-D2 = 9.2 nM, B-max2 = 367,000. The results of the present study indicate that affibody molecule and other scaffold-based targeting proteins with a relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.

    Keywords
    affibody molecules, HER2, OK cells, megalin, renal reabsorption
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-200076 (URN)10.1089/cbr.2012.1304 (DOI)000317478200002 ()
    Note

    De två (2) första författarna delar förstaförfattarskapet.

    Available from: 2013-05-23 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
    4. Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re
    Open this publication in new window or tab >>Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re
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    2013 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no Suppl. 2, p. S219-S220Article in journal, Meeting abstract (Other academic) Published
    Abstract [en]

    Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1±0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172±32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-211592 (URN)10.1007/s00259-013-2535-3 (DOI)000325853400417 ()
    Conference
    Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Lyon 19-23 oktober 2013.
    Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
    5. 188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment
    Open this publication in new window or tab >>188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment
    Show others...
    2014 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 11, p. 1842-1848Article in journal (Refereed) Published
    Abstract [en]

    Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of 99mTc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide–based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate 188Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)–expressing tumors.

    Methods:

    ZHER2:V2 was labeled with 188Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.

    Results:

    Binding of 188Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that 188Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.

    Conclusion:

    188Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-211593 (URN)10.2967/jnumed.114.140194 (DOI)000344209200015 ()25278516 (PubMedID)
    Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
  • 7871.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Wållberg, Helena
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Dunås, Finn
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Löfblom, John
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Ståhl, Stefan
    Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no Suppl. 2, p. S219-S220Article in journal (Other academic)
    Abstract [en]

    Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1±0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172±32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

  • 7872.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Wållberg, Helena
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Dunås, Finn
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Medical Radiation Sciences.
    Löfblom, John
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Ståhl, Stefan
    Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with 188Re2014In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 87, p. 519-528Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

  • 7873.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Leitao, Charles Dahlsson
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Atterby, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ståhl, Stefan
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs2018In: CELLS, ISSN 2073-4409, Vol. 7, no 10, article id 164Article in journal (Refereed)
    Abstract [en]

    Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD 035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.

  • 7874.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, H.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, T.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Improving of molecular design of a novel Affibody-fused HER2-recognising anticancer toxin using radionuclide-based techniques2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S178-S178Article in journal (Refereed)
  • 7875.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Ding, Haozhong
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Edqvist, Per-Henrik D
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjorn
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 288, p. 84-95Article in journal (Refereed)
    Abstract [en]

    Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, Z(HER2:2891), conjugated with the cytotoxic maytansine derivate MC-DM1, for targeted cancer therapy. Z(HER2:2891) was expressed as a monomer (Z(HER2:2891)), dimer ((Z(HER2:2891)) 2) and dimer with an albumin binding domain (ABD) for half-life extension ((Z(HER2:2891)) 2-ABD). All proteins had a unique C-terminal cysteine that could be used for efficient and site-specific conjugation with MC-DM1. The resulting affibody drug conjugates were potent cytotoxic molecules for human cells over-expressing HER2, with sub-nanomolar IC50-values similar to trastuzumab emtansine, and did not affect cells with low HER2 expression. A biodistribution study of a radiolabeled version of (Z(HER2:2891))(2)-ABD-MC-DM1, showed that it was taken up by the tumor. The major site of off-target uptake was the kidneys and to some extent the liver. (Z(HER2:2891)) 2-ABD-MC-DM1 was found to have a half-life in circulation of 14 h. The compound was tolerated well by mice at 8.5 mg/kg and was shown to extend survival of mice bearing HER2 over-expressing tumors. The findings in this study show that affibody molecules are a promising class of engineered affinity proteins to specifically deliver small molecular drugs to cancer cells and that such conjugates are potential candidates for clinical evaluation on HER2-overexpressing cancers.

  • 7876.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 3, p. 1185-1194Article in journal (Refereed)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 7877.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Membreno, Rosemery
    CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA.;CUNY, Grad Ctr, PhD Program Chem, New York, NY USA.;Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Cook, Brendon
    CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA.;CUNY, Grad Ctr, PhD Program Chem, New York, NY USA.;Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Zeglis, Brian M.
    CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA.;CUNY, Grad Ctr, PhD Program Chem, New York, NY USA.;Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA..
    Pretargeted Imaging and Therapy2017In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no 10, p. 1553-1559Article in journal (Refereed)
    Abstract [en]

    In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.

  • 7878.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Radiolabeled Probes Targeting Tyrosine-Kinase Receptors For Personalized Medicine2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 14, p. 2275-2292Article in journal (Refereed)
    Abstract [en]

    Receptor tyrosine kinases (RTK) are transmembrane receptors regulating cellular proliferation, differentiation, apoptosis, motility and recruitment of the vasculature. Aberrant expression and/or function of RTK have been detected in many malignant tumors and are considered to be a part of the transformed phenotype. The action of several classes of anti-cancer drugs is based on specific recognition of RTK. Monoclonal antibodies target extracellular binding domains, while tyrosine kinase inhibitors (TKI) bind to intracellular kinase domains to suppress RTK signaling. The issues regarding the efficient use of RTK targeting are the inter- and intra-patient heterogeneity of RTK expression and the changes of expression levels during the course of disease and in response to therapy. Radionuclide molecular imaging of RTK expression may aid in selecting patients who would benefit from RTK-targeting therapy and in identifying non-responders. Therefore, the therapy would be more personalized. Currently, radiolabeled proteins (monoclonal antibodies and their fragments, natural peptides ligands to RTK and de novo selected affinity proteins) and TKI and their analogues are under development for the visualization of RTK. In this review, we discuss the advantages and disadvantages of these approaches.

  • 7879.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Perols, Anna
    Eriksson Karlström, Amelie
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Boschetti, Frederic
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with 111In using a maleimido derivative of NODAGA2012In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 4, p. 518-529Article in journal (Refereed)
    Abstract [en]

    Introduction

    Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule.

    Methods

    The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to ZHER2:2395 Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 were studied. Biodistribution of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 and [111In-MMA-DOTA-Cys61]-ZHER2:2395 was compared in mice.

    Results

    The affinity of [MMA-NODAGA-Cys61]-ZHER2:2395 binding to HER2 was 67 pM. The 111In-labeling yield was 99.6%±0.5% after 30 min at 60°C. [111In-MMA-NODAGA-Cys61]-ZHER2:2395 bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 in mice bearing DU-145 xenografts (4.7%±0.8% ID/g) was lower than uptake of [111In-MMA-DOTA-Cys61]-ZHER2:2395 (7.5%±1.6% ID/g). However, tumor-to-organ ratios were higher for [111In-MMA-NODAGA-Cys61]-ZHER2:2395 due to higher clearance rate from normal tissues.

    Conclusions

    MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated.

  • 7880.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Perols, Anna
    Tsourma, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Robillard, Marc
    Rossin, Raffaella
    Ten Hoeve, Wolter
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Feasibility of affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting2016In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 3, p. 431-436Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal re-absorption of affibody molecules prevents the use of residualizing radiometals, including a number of promising low energy beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys.

    Methods:

    TCO was conjugated to the anti-HER2 affibody molecule Z2395. DOTA-tetrazine was labeled with indium-111 and lutetium-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts.

    Results:

    125I-Z2395-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45±16 pM. 111In-tetrazine bound specifically and selectively to Z2395-TCO pre-treated cells. In vivo studies demonstrated HER2-specific 125I-Z2395-TCO accumulation in xenografts. TCO-mediated 111In-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z2395-TCO. At 1 h post injection, the tumor uptake of 111In-tetrazine and 177Lu-tetrazine was ca. 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of 111In in comparison with direct targeting.

    Conclusion:

    The feasibility of affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pretargeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.

  • 7881.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Rosik, D.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Karlstrom, A. Eriksson
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Comparative evaluation of anti-HER2 affibody molecules labeled with 68Ga and 111In using maleimido derivatives of DOTA and NODAGA2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no S2, p. S299-S299Article in journal (Other academic)
  • 7882.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Rosik, Daniel
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson Karlström, Amelie
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with 68Ga and 111In via Maleimido Derivatives of DOTA and NODAGA2013In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 24, no 6, p. 1102-1109Article in journal (Refereed)
    Abstract [en]

    Accurate detection of cancer-associated molecular abnormalities in tumors could make cancer treatment more personalized. Affibody molecules enable high contrast imaging of tumor-associated protein expression shortly after injection. The use of the generator-produced positron-emitting radionuclide 68Ga should increase sensitivity of HER2 imaging. The chemical nature of radionuclides and chelators influences the biodistribution of Affibody molecules, providing an opportunity to further increase the imaging contrast. The aim of the study was to compare maleimido derivatives of DOTA and NODAGA for site-specific labeling of a recombinant ZHER2:2395 HER2-binding Affibody molecule with 68Ga. DOTA and NODAGA were site-specifically conjugated to the ZHER2:2395 Affibody molecule having a C-terminal cysteine and labeled with 68Ga and 111In. All labeled conjugates retained specificity to HER2 in vitro. Most of the cell-associated activity was membrane-bound with a minor difference in internalization rate. All variants demonstrated specific targeting of xenografts and a high tumor uptake. The xenografts were clearly visualized using all conjugates. The influence of chelator on the biodistribution and targeting properties was much less pronounced for 68Ga than for 111In. The tumor uptake of 68Ga-NODAGA-ZHER2:2395 and 68Ga-DOTA-ZHER2:2395 and tumor-to-blood ratios at 2 h p.i. did not differ significantly. However, the tumor-to-liver ratio was significantly higher for 68Ga-NODAGA- ZHER2:2395 (8 ± 2 vs 5.0 ± 0.3) offering the advantage of better liver metastases visualization. In conclusion, influence of chelators on biodistribution of Affibody molecules depends on the radionuclides and reoptimization of labeling chemistry is required when a radionuclide label is changed.

  • 7883.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tsourma, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Preclin PET Platform, Uppsala, Sweden..
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Perols, A.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Robillard, M.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    Rossin, R.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    ten Hoeve, W.
    Syncom BV, Groningen, Netherlands..
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Karlstrom, A. Eriksson
    KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting: proof-of-principle2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, no S1, p. S246-S246Article in journal (Other academic)
  • 7884.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Eek, Annemarie
    Boerman, Otto
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors2013In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 28, no 3, p. 187-195Article in journal (Refereed)
    Abstract [en]

    Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody Z(HER2:342) was developed for imaging of HER2 expression in tumors, and a clinical study has demonstrated that the In-111- and Ga-68-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, a significant renal accumulation of radioactivity after systemic injection of a radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in a murine model and in vitro using opossum-derived proximal tubule (OK) cells. It was found that kidney reabsorption of affibody molecule was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody molecule were involved in binding to OK cells. On OK cells, two types of receptors for anti-HER2 affibody molecule were found: K-D1 = 0.8 nM, B-max1 = 71,500 and K-D2 = 9.2 nM, B-max2 = 367,000. The results of the present study indicate that affibody molecule and other scaffold-based targeting proteins with a relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.

  • 7885.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Westerlund, K.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Velletta, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Eriksson-Karlström, A.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Comparative evaluation of Lu-177-HP2 and In-111-HP2, secondary agents for affibody-based PNA-mediated radionuclide pretargeting2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S237-S237Article in journal (Refereed)
  • 7886.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Westerlund, Kristina
    KTH Royal Inst Technol, Div Prot Technol, Sch Biotechnol, Stockholm, Sweden..
    Velletta, Justin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Eriksson Karlström, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting: Development of an optimized conjugation protocol and 177Lu labeling2017In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 54, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Introduction: We have previously developed a pretargeting approach for affibody-mediated cancer therapy based on PNA-PNA hybridization. In this article we have further developed this approach by optimizing the production of the primary agent, Z(HER2.342)-SR-HP1, and labeling the secondary agent, HP2, with the therapeutic radionuclide Lu-177. We also studied the biodistribution profile of Lu-177-HP2 in mice, and evaluated pretargeting with Lu-177-HP2 in vitro and in vivo.

    Methods: The biodistribution profile of Lu-177-HP2 was evaluated in NMRI mice and compared to the previously studied In-111-HP2. Pretargeting using Lu-177-HP2 was studied in vitro using the HER2-expressing cell lines BT-474 and SKOV-3, and in vivo in mice bearing SKOV-3 xenografts.

    Results and conclusion: Using an optimized production protocol for Z(HER2:342)-SR-HP1 the ligation time was reduced from 15 h to 30 min, and the yield increased from 45% to 70%. Lu-177-labeled HP2 binds specifically in vitro to BT474 and SKOV-3 cells pre-treated with Z(HER2:342)-SR-HP1.Lu-177-HP2 was shown to have a more rapid blood clearance compared to In-111-HP2 in NMRI mice, and the measured radioactivity in blood was 0.22 +/- 0.1 and 0.68 +/- 0.07%ID/g for Lu-177- and In-111-HP2, respectively, at 1 h p.i. In contrast, no significant difference in kidney uptake was observed (4.47 +/- 1.17 and 3.94 +/- 0.58%ID/g for Lu-177- and In-111-HP2, respectively, at I h p.i.). Co-injection with either Gelofusine or lysine significantly reduced the kidney uptake for Lu-177-HP2 (1.0 +/- 0.1 and 1.6 +/- 0.2, respectively, vs. 2.97 +/- 0.87%ID/g in controls at 4 h p.i.). Lu-177-HP2 accumulated in SKOV-3 xenografts in BALB/C nu/nu mice when administered after injection of Z(HER2:342)-SR-HP1. Without pre-injection of Z(HER2:342)-SR-HP1, the uptake of Lu-177-HP2 was about 90-fold lower in tumor (0.23 +/- 0.08 vs. 20.7 +/- 3.5%ID/g). The tumor-to-kidney radioactivity accumulation ratio was almost 5-fold higher in the group of mice pre-injected with Z(HER2:342)-SR-HP1. In conclusion, (177)LuHP2 was shown to be a promising secondary agent for affibody-mediated tumor pretargeting in vivo.

  • 7887.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Wållberg, Helena
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Medical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Löfblom, John
    Larsson, Erik
    Strand, Sven-Erik
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Ståhl, Stefan
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 11, p. 1842-1848Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of 99mTc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide–based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate 188Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)–expressing tumors.

    Methods:

    ZHER2:V2 was labeled with 188Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.

    Results:

    Binding of 188Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that 188Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.

    Conclusion:

    188Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

  • 7888.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Wållberg, Helena
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Hosseinimehr, Seyed Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Ståhl, Stefan
    Order of amino acids in C-terminal cysteine-containing peptide-based chelators influences cellular processing and biodistribution of (99m)Tc-labeled recombinant Affibody molecules2012In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 42, no 5, p. 1975-1985Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a novel class of molecular display selected affinity proteins based on non-immunoglobulin scaffold. Preclinical investigations and pilot clinical data have demonstrated that Affibody molecules provide high contrast imaging of tumor-associated molecular targets shortly after injection. The use of cysteine-containing peptide-based chelators at the C-terminus of recombinant Affibody molecules enabled site-specific labeling with the radionuclide (99m)Tc. Earlier studies have demonstrated that position, composition and the order of amino acids in peptide-based chelators influence labeling stability, cellular processing and biodistribution of Affibody molecules. To investigate the influence of the amino acid order, a series of anti-HER2 Affibody molecules, containing GSGC, GEGC and GKGC chelators have been prepared and characterized. The affinity to HER2, cellular processing of (99m)Tc-labeled Affibody molecules and their biodistribution were investigated. These properties were compared with that of the previously studied (99m)Tc-labeled Affibody molecules containing GGSC, GGEC and GGKC chelators. All variants displayed picomolar affinities to HER2. The substitution of a single amino acid in the chelator had an appreciable influence on the cellular processing of (99m)Tc. The biodistribution of all (99m)Tc-labeled Affibody molecules was in general comparable, with the main difference in uptake and retention of radioactivity in excretory organs. The hepatic accumulation of radioactivity was higher for the lysine-containing chelators and the renal retention of (99m)Tc was significantly affected by the amino acid composition of chelators. The order of amino acids influenced renal uptake of some conjugates at 1 h after injection, but the difference decreased at later time points. Such information can be helpful for the development of other scaffold protein-based imaging and therapeutic radiolabeled conjugates.

  • 7889. Altaib, Mohamed S.
    et al.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Govender, Thavendran
    Maguire, Glenn E. M.
    Makatini, Maya
    Onajole, Oluseye K.
    Kruger, Hendrik G.
    Synthesis and NMR elucidation of novel pentacycloundecane-based peptides2010In: Magnetic Resonance in Chemistry, ISSN 0749-1581, E-ISSN 1097-458X, Vol. 48, no 6, p. 435-442Article in journal (Refereed)
    Abstract [en]

    The synthesis and NMR elucidation of two novel pentacycloundecane (PCU)-based peptides are reported. The PCU cage amino acids were synthesised as racemates and the incorporation of the cage amino acid with (S)-natural amino acids produced diastereomeric peptides. The diastereomeric 'cage' peptides were separated using preparative HPLC and the NMR elucidation of these PCU containing peptides are reported for the first time. The H-1 and C-13 NMR spectra showed series of overlapping signals of the cage skeleton and that of the peptide, making it extremely difficult to resolve the structure using one-dimensional NMR techniques only. The use of two-dimensional NMR techniques proved to be a highly effective tool in overcoming this problem.

  • 7890.
    Al-Tamimi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Läkemedelsbehandling vid kronisk hjärtsvikt_ en tvärsnittsstudie baserad på Vårdanalysdatabasen i Stockholms läns landsting2014Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Kronisk hjärtsvikt (CHF) utvecklas ofta gradvis under en längre tid. Det drabbar vanligen äldre, som ofta har andra sjukdomar som hypertoni och ischemisk hjärtsjukdom. Enligt läkemedelsrekommendationer och riktlinjer ska patienter med CHF behandlas med kombinationer av angiotensinkonverterande enzymblockare (ACEI) eller angiotensinreceptorblockerare (ARB) och betablockerande läkemedel (BB) och vid NYHA funktionsklass III och IV ska patienter behandlas ytterligare med mineralkortikoidantagonister (MRA). Syfte: Syftet med studien är att analysera läkemedelsbehandlingen vid CHF, som ett underlag för att förbättra vården och till nytta för patienter med CHF och vårdgivare. Material och metoder: Denna studie var en deskriptiv tvärsnittsstudie ur den individbaserade, administrativa Vårdanalysdatabasen (VAL) vid Stockholms läns landsting (SLL). Studien inkluderade alla patienter som var ≥40 år och levde i SLL någon gång mellan juli-augusti 2012. Resultat: VAL-databasen innehöll totalt 32754 patienter med CHF. Andel patienter med CHF som behandlades med ACEI/ARB var 64 % och BB var 69 % samt MRA var 18 %. Andel patienter med CHF som behandlades med kombinationer av ACEI/ARB och BB var 40 % och med kombinationer av ACEI/ARB och BB samt MRA var 11 %. Andel män som behandlades med dessa läkemedel var högre än andel kvinnor, förutom behandling med MRA som var lika hos män och kvinnor. Behandling med dessa läkemedel minskade med stigande ålder. Konklusion: Tydliga ålders- och könsskillnader i behandling vid CHF observerades. Endast 40 % av patienter med CHF behandlades med rekommenderade kombinationer av ACEI/ARB och BB. Den rekommenderade läkemedelsbehandlingen hos patienter med CHF kan förbättras. 

  • 7891.
    Altamura, C. Edoardo
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economic History.
    World Insurance: The Evolution of a Global Risk Network2014In: Business history review, ISSN 0007-6805, E-ISSN 2044-768X, Vol. 88, no 2, p. 412-414Article, book review (Other academic)
  • 7892.
    Altamura, Carlo Edoardo
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economic History. University of Geneva.
    European Banks and the Rise of International Finance after Bretton Woods (1973–1982)2015Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The 1970s is a crucial decade for understanding the modern financial landscape but it is still relatively unexplored in financial history. It was marked by the end of the Bretton Woods regime, the gradual liberalisation of finance, the return of banking crises and two massive energy crises. As archives are now providing new archival evidence, this thesis seeks to analyse a neglected aspect of the 1970s which touches on all of the above-mentioned phenomena: the progressive privatisation of international financial flows to Less Developed Countries (LDCs), especially in Latin America and South-East Asia, and its impact on the European banking sector.

    After the collapse of the Bretton Woods’ system in 1973 and until the debt crisis of 1982, Western commercial banks assumed an increasing role in transferring huge amounts of dollars accumulated by oil-exporting countries to LDCs through the so-called ‘recycling’ mechanism of the Euromarket. The trend marked a clear break with the past since, until the late 1960s, development finance had mostly been provided by public institutions. This gave commercial banks a new central role in international financial matters.

    In the short term, the privatisation of credit proved to be a profitable bet and it allowed a renaissance of the banking sector after the regime of Bretton Woods. Besides, these international flows of money provided the basis for the financial globalisation to come. In the longer term, many LDCs became subject to the imperatives of private institutions and prisoners of a ‘debt trap’ throughout the 1980s.

    We still know little about the attitude of international organisations towards the progressive privatisation of finance and the recycling mechanism and the impact of the oil crisis on the European banking. This thesis will analyse these topics by relying on new archival evidence from the International Monetary Fund (IMF), the Bank for International Settlements (BIS), the Organisation for Economic Cooperation and Development (OECD), the Bank of England, the Banque de France and the archives of several major European commercial banks in France and United Kingdom, notably Société Générale, Crédit Agricole, Barclays Bank, Midland Bank and Lloyds Bank.

  • 7893.
    Altback, Hanna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Fastställelsetalan om skiljenämnds behörighet: En analys av processuella problemsituationer2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 7894.
    Altebo, Petra
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Peace and Conflict Research.
    Political Ideas and Behaviour of Armed Groups: A comparative analysis of armed groups’ ideology and repertoires of sexual violence during the conflict in Darfur 2003-20062017Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The purpose of this thesis is to study under what conditions armed groups practice different repertoires of sexual violence, by studying ideology’s influence on behaviour. This will be explored through a structured focused comparison of three armed groups active in the conflict in Darfur 2003-2006, the Janjaweed, Sudan’s Liberation Army/Movement and the Justice and Equality Movement. The theory suggest that a strong implemented ideology will lead to control over behaviour and values, hence sexual violence will be practice in line with organizational objectives and ideas, either instrumental or not practiced at all. Consequently, a weak ideological framework will lead to variation in socialization processes and an opportunistic repertoire.  The findings correlate as expected by the hypothesis, while data constraints call for caution. The results suggests a broadening of the theoretical framework as well as further studies on the suggested causal mechanism, combatant socialization, to examine how, and under what circumstances, behaviours are spread as a social practice among combatants.

  • 7895.
    Alteby, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Hylén, Emelie
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Läromedelsanalys inom matematik: En granskning av genus i fyra matematikläromedel2018Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 7896.
    Alteby, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Sjögren, Petra
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Kognitiv matematikträning i förskoleklass: På vinst eller förlust?2016Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 7897. Altekar, G
    et al.
    Dwarkadas, S
    Huelsenbeck, John
    Ronquist, Fredrik
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Systematic Zoology. systematisk zoologi.
    Parallel Metropolis-coupled Markov chain Monte Carlo for Bayesian phylogenetic inference2004In: Bioinformatics, Vol. 20, p. 407-415Article in journal (Refereed)
  • 7898.
    Altenbernd, P
    et al.
    Uppsala University.
    Hansson, H
    Uppsala University.
    The slack method: A new method for static allocation of hard real-time tasks1998In: REAL-TIME SYSTEMS, ISSN 0922-6443, Vol. 15, no 2, p. 103-130Article in journal (Other scientific)
    Abstract [en]

    This article presents and evaluates the Slack Method, a new constructive heuristic for the allocation (mapping) of periodic hard real-time tasks to multiprocessor or distributed systems. The Slack Method is based on task deadlines, in contrast with other

  • 7899.
    Altenburger, Andreas
    et al.
    Section for Evolutionary Genomics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.
    Martinez, Pedro
    Department of Genetics, University of Barcelona, Barcelona, Spain; Institut Català de Recerca i EstudisAvancats, Barcelona, Spain.
    Budd, Graham E.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Holmer, Lars E.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Gene Expression Patterns in Brachiopod Larvae Refute the "€œBrachiopod-Fold"€ Hypothesis2017In: Frontiers in Cell and Developmental Biology, Vol. 5, p. 1-3, article id 74Article in journal (Refereed)
  • 7900. Altenburger, Andreas
    et al.
    Wanninger, Andreas
    Holmer, Lars E.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Metamorphosis in Craniiformea revisited: Novocrania anomala shows delayed development of the ventral valve2013In: Zoomorphology, ISSN 0720-213X, E-ISSN 1432-234X, Vol. 132, no 4, p. 379-387Article in journal (Refereed)
    Abstract [en]

    We revisited the brachiopod fold hypothesis and investigated metamorphosis in the craniiform brachiopod Novocrania anomala. Larval development is lecithotrophic and the dorsal (brachial) valve is secreted by dorsal epithelia. We found that the juvenile ventral valve, which consists only of a thin layer that was previously described as periostracal, is not a valve and is not secreted by the same epithelia as the dorsal valve. It is secreted by the attachment area of the larva at the posterior-most tip of the posterior larval lobe. The same attachment area is used by larvae of rhynchonelliform brachiopods during metamorphosis to cement their pedicle to the substrate. N. anomala is therefore not initially attached by a valve but by material corresponding to pedicle cuticle. This is different to previous descriptions, which had led to speculations about a folding event in the evolution of Brachiopoda. We show that the “brachiopod fold hypothesis,” which argues that brachiopods are transversely “folded” across the ontogenetic anterior–posterior axis, should be rejected at least with respect to the craniiforms. The data now suggest that the Craniiformea may be a derived group within the Rhynchonelliformea. This interpretation suggests that the last common ancestor of the Craniiformea has lost the pedicle and the ventral valve in early juvenile development. Characters that have previously been considered to be shared between the Craniiformea and the Linguliformea (clade Inarticulata), such as a through-gut and missing hinge articulation, may thus be secondarily derived characters of the Craniiformea within the Rhynchonelliformea.

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