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1.
  • Nyholm, Tufve, et al. (författare)
  • A national approach for automated collection of standardized and population-based radiation therapy data in Sweden
  • 2016
  • Ingår i: Radiotherapy and Oncology. - Elsevier. - 0167-8140. ; 119:2, s. 344-350
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose To develop an infrastructure for structured and automated collection of interoperable radiation therapy (RT) data into a national clinical quality registry. Materials and methods The present study was initiated in 2012 with the participation of seven of the 15 hospital departments delivering RT in Sweden. A national RT nomenclature and a database for structured unified storage of RT data at each site (Medical Information Quality Archive, MIQA) have been developed. Aggregated data from the MIQA databases are sent to a national RT registry located on the same IT platform (INCA) as the national clinical cancer registries. Results The suggested naming convention has to date been integrated into the clinical workflow at 12 of 15 sites, and MIQA is installed at six of these. Involvement of the remaining 3/15 RT departments is ongoing, and they are expected to be part of the infrastructure by 2016. RT data collection from ARIA®, Mosaiq®, Eclipse™, and Oncentra® is supported. Manual curation of RT-structure information is needed for approximately 10% of target volumes, but rarely for normal tissue structures, demonstrating a good compliance to the RT nomenclature. Aggregated dose/volume descriptors are calculated based on the information in MIQA and sent to INCA using a dedicated service (MIQA2INCA). Correct linkage of data for each patient to the clinical cancer registries on the INCA platform is assured by the unique Swedish personal identity number. Conclusions An infrastructure for structured and automated prospective collection of syntactically interoperable RT data into a national clinical quality registry for RT data is under implementation. Future developments include adapting MIQA to other treatment modalities (e.g. proton therapy and brachytherapy) and finding strategies to harmonize structure delineations. How the RT registry should comply with domain-specific ontologies such as the Radiation Oncology Ontology (ROO) is under discussion.
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2.
  • Sousa-Uva, M, et al. (författare)
  • 2018 ESC/EACTS Guidelines on myocardial revascularization.
  • 2019
  • Ingår i: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. - 1873-734X. ; 55:1, s. 4-90
  • Tidskriftsartikel (refereegranskat)
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3.
  • Bach, Anders, et al. (författare)
  • A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
  • 2012
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 109:9, s. 3317-3322
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.</p>
4.
  • Bach, Anders, et al. (författare)
  • A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
  • 2012
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:9, s. 3317-3322
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.</p>
5.
  • Bach, Anders, et al. (författare)
  • Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction
  • 2009
  • Ingår i: Angewandte Chemie International Edition. - Wiley-VCH. - 1433-7851 .- 1521-3773. ; 48:51, s. 9685-9689
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>On the double</strong>: Dimerization of monomeric peptide ligands towards the PDZ domains of the protein PSD-95 (postsynaptic density 95) leads to potent inhibitors of protein-protein interactions with stability in blood plasma. Optimization of the length of the polyethylene glycol linker results in unprecedented affinity for inhibitors of the PDZ1-2 domain.</p>
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6.
  • Behrens, Anders, et al. (författare)
  • The Computerized General Neuropsychological INPH Test (CoGNIT) revealed improvement in Idiopathic Normal Pressure Hydrocephalus (INPH) after shunt surgery
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • <p>Background</p><p>We have developed the COmputerized General Neuropsychological INPH Test (CoGNIT) dedicated for patients with idiopathic normal pressure hydrocephalus (INPH). Previously, validity and reliability of included tests have been established. The aim was to evaluate the battery’s sensitivity to detect cognitive changes after shunt surgery in INPH patients.</p><p>Methods</p><p>Preoperatively, thirty-one INPH patients were given CoGNIT, which includes tests assessing memory, executive functions, attention, manual dexterity and psychomotor speed. CoGNIT also includes the Geriatric Depression Scale (GDS). Re-examination was done four months after shunt surgery. Scores and test completion were examined and compared to healthy elderly (n=44).</p><p>Results</p><p>Preoperative INPH test results were significantly lower in all tests compared to healthy. Improvements after shunt surgery were seen in all cognitive domains: memory (Ten-word list test, p&lt;0,01), executive functions (Stroop incongruent, (p&lt;0.05), attention (Two choice reaction test, p&lt;0.01), psychomotor speed (Stroop congruent, p&lt;0.05) and manual dexterity (Four- finger tapping, p&lt;0.01). No ceiling effects were observed. Depressive symptoms were more common in INPH versus healthy and did not change postoperatively. Preoperatively 81 % of INPH patients completed at least eight of the nine included test.</p><p>Conclusions</p><p>CoGNIT is sensitive to cognitive impairment and to investigate changes after shunt surgery in INPH. Completion rates are good. CoGNIT has a potential to be useful in the cognitive assessment of INPH. </p>
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7.
  • Behrens, Anders, et al. (författare)
  • The Computerized General Neuropsychological INPH Test revealed improvement in idiopathic normal pressure hydrocephalus after shunt surgery
  • 2020
  • Ingår i: Journal of Neurosurgery. - AMER ASSOC NEUROLOGICAL SURGEONS. - 0022-3085 .- 1933-0693. ; 132:3, s. 733-740
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>OBJECTIVE The Computerized General Neuropsychological INPH Test (CoGNIT) provides the clinician and the researcher with standardized and accessible cognitive assessments in patients with idiopathic normal pressure hydrocephalus (INPH). CoGNIT includes tests of memory, executive functions, attention, manual dexterity, and psychomotor speed. Investigations of the validity and reliability of CoGNIT have been published previously. The aim of this study was to evaluate CoGNITs sensitivity to cognitive change after shunt surgery in patients with INPH. METHODS Forty-one patients with INPH (median Mini-Mental State Examination score 26) were given CoGNIT preoperatively and at a postoperative follow-up 4 months after shunt surgery. Scores were compared to those of 44 healthy elderly control volunteers. CoGNIT was administered by either a nurse or an occupational therapist. RESULTS Improvement after shunt surgery was seen in all cognitive domains: memory (10-word list test, p amp;lt; 0.01); executive functions (Stroop incongruent color and word test, p amp;lt; 0.01); attention (2-choice reaction test, p amp;lt; 0.01); psychomotor speed (Stroop congruent color and word test, p amp;lt; 0.01); and manual dexterity (4-finger tapping, p amp;lt; 0.01). No improvement was seen in the Mini-Mental State Examination score. Preoperative INPH test scores were significantly impaired compared to healthy control subjects (p amp;lt; 0.001 for all tests). CONCLUSIONS In this study the feasibility for CoGNIT to detect a preoperative impairment and postoperative improvement in INPH was demonstrated. CoGNIT has the potential to become a valuable tool in clinical and research work.</p>
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8.
  • Behrens, Anders, et al. (författare)
  • The Computerized General Neuropsychological INPH Test revealed improvement in idiopathic normal pressure hydrocephalus after shunt surgery
  • 2020
  • Ingår i: Journal of Neurosurgery. - AMER ASSOC NEUROLOGICAL SURGEONS. - 0022-3085 .- 1933-0693. ; 132:3, s. 733-740
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>OBJECTIVE The Computerized General Neuropsychological INPH Test (CoGNIT) provides the clinician and the researcher with standardized and accessible cognitive assessments in patients with idiopathic normal pressure hydrocephalus (INPH). CoGNIT includes tests of memory, executive functions, attention, manual dexterity, and psychomotor speed. Investigations of the validity and reliability of CoGNIT have been published previously. The aim of this study was to evaluate CoGNIT's sensitivity to cognitive change after shunt surgery in patients with INPH.</p><p>METHODS Forty-one patients with INPH (median Mini-Mental State Examination score 26) were given CoGNIT preoperatively and at a postoperative follow-up 4 months after shunt surgery. Scores were compared to those of 44 healthy elderly control volunteers. CoGNIT was administered by either a nurse or an occupational therapist.</p><p>RESULTS Improvement after shunt surgery was seen in all cognitive domains: memory (10-word list test, p &lt; 0.01); executive functions (Stroop incongruent color and word test, p &lt; 0.01); attention (2-choice reaction test, p &lt; 0.01); psychomotor speed (Stroop congruent color and word test, p &lt; 0.01); and manual dexterity (4-finger tapping, p &lt; 0.01). No improvement was seen in the Mini-Mental State Examination score. Preoperative INPH test scores were significantly impaired compared to healthy control subjects (p &lt; 0.001 for all tests).</p><p>CONCLUSIONS In this study the feasibility for CoGNIT to detect a preoperative impairment and postoperative improvement in INPH was demonstrated. CoGNIT has the potential to become a valuable tool in clinical and research work.</p>
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9.
  • Binzer-Panchal, Amrei, et al. (författare)
  • Integrated molecular analysis of undifferentiated uterine sarcomas reveals clinically relevant molecular subtypes
  • 2019
  • Ingår i: Clinical Cancer Research. - American Association for Cancer Research. - 1078-0432. ; 25:7, s. 2155-2165
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort. Experimental Design: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n ¼ 50), copy-number variation (CNV, n ¼ 40), cell morphometry (n ¼ 39), and protein expression (n ¼ 22). Gene ontology and network enrichment analysis were used to relate over- and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings. Results: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multi-variable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm 2 could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.
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10.
  • Chi, Celestine N., et al. (författare)
  • Deciphering the kinetic binding mechanism of dimeric ligands, using a potent plasma-stable dimeric inhibitor of postsynaptic density protein-95 as an example
  • 2010
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:36, s. 28252-28260
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Dimeric ligands can be potent inhibitors of protein-protein or enzyme-substrate interactions. They have increased affinity and specificity towards their targets due to their ability to bind simultaneously to two binding sites and are therefore very attractive in drug design. However, few studies have addressed the kinetic mechanism of interaction of such bivalent ligands. We have investigated the binding interaction of a recently identified potent plasma-stable dimeric pentapeptide of PDZ1-2 of PSD-95 using protein engineering in combination with fluorescence polarisation, isothermal titration calorimetry and stopped-flow fluorimetry. Our experiments demonstrate that binding occurs via a two-step process, where an initial binding to either one of the two PDZ domains is followed by an intramolecular step, which produces the bidentate complex. We have determined all rate constants involved in the binding reaction and we also find evidence for a conformational transition of the complex. Our data demonstrate the importance of a slow dissociation for a successful dimeric ligand, but also highlight the possibility of optimizing the intramolecular association rate. The results may therefore aid the design of dimeric inhibitors in general.</p>
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