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Gréen, Henrik
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Publications (10 of 77) Show all publications
Vikingsson, S. & Green, H. (2016). Editorial Material: Putting Designer Drugs Back in Pandoras Box: Analytical Challenges and Metabolite Identification in CLINICAL CHEMISTRY, vol 62, issue 1, pp. Clinical Chemistry, 62(1).
Open this publication in new window or tab >>Editorial Material: Putting Designer Drugs Back in Pandoras Box: Analytical Challenges and Metabolite Identification in CLINICAL CHEMISTRY, vol 62, issue 1, pp
2016 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 62, no 1Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
AMER ASSOC CLINICAL CHEMISTRY, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124473 (URN)10.1373/clinchem.2015.248096 (DOI)000367703400002 ()26546634 (PubMedID)
Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2017-11-30
Vikingsson, S., Gréen, H., Brinkhagen, L., Mukhtar, S. & Josefsson, M. (2016). Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.. Drug Testing and Analysis, 8(9), 950-956.
Open this publication in new window or tab >>Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.
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2016 (English)In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 8, no 9, 950-956 p.Article in journal (Refereed) Published
Abstract [en]

Synthetic cannabinoids are a group of psychoactive drugs presently widespread among drug users in Europe. Analytical methods to measure these compounds in urine are in demand as urine is a preferred matrix for drug testing. For most synthetic cannabinoids, the parent compounds are rarely detected in urine. Therefore urinary metabolites are needed as markers of drug intake. AB-FUBINACA was one of the top three synthetic cannabinoids most frequently found in seizures and toxicological drug screening in Sweden (2013-2014). Drug abuse is also reported from several other countries such as the USA and Japan. In this study, 28 authentic case samples were used to identify urinary markers of AB-FUBINACA intake using liquid chromatography quadrupole tandem time of flight mass spectrometry and human liver microsomes. Three metabolites suitable as markers of drug intake were identified and at least two of them were detected in all but one case. In total, 15 urinary metabolites of AB-FUBINACA were reported, including hydrolxylations on the indazole ring and the amino-oxobutane moiety, dealkylations and hydrolysis of the primary amide. No modifications on the fluorobenzyl side-chain were observed. The parent compound was detected in 54% of the case samples. Also, after three hours of incubation with human liver microsomes, 77% of the signal from the parent compound remained. Copyright © 2015 John Wiley & Sons, Ltd.

Keyword
LC-MS/MS; Spice; drugs of abuse; human liver microsomes; metabolites; new psychoactive substances; synthetic cannabinoids; urine
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-125343 (URN)10.1002/dta.1896 (DOI)000384805600007 ()26560240 (PubMedID)
Note

Funding agencies: National Board of Forensic Medicine; Linkoping University; Linkoping physician society; Swedish Civil Contingencies Agency

Available from: 2016-02-19 Created: 2016-02-19 Last updated: 2018-01-10
Skoglund, K., Richter, J., Olsson-Stromberg, U., Bergquist, J., Aluthgedara, W., Ubhayasekera, S. J., . . . Green, H. (2016). In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia. Therapeutic Drug Monitoring, 38(2), 230-238.
Open this publication in new window or tab >>In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia
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2016 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, 230-238 p.Article in journal (Refereed) Published
Abstract [en]

Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2016
Keyword
pharmacokinetics; chronic myeloid leukemia; imatinib; CGP74588; CYP3A
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-129678 (URN)10.1097/FTD.0000000000000268 (DOI)000376938000006 ()26693810 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Society; Medical Research Council of Southeast Sweden; Novartis

Available from: 2016-06-27 Created: 2016-06-23 Last updated: 2018-01-10
Vikingsson, S., Strömqvist, M., Svedberg, A., Hansson, J., Höiom, V. & Gréen, H. (2016). Novel rapid liquid chromatography tandem masspectrometry method for vemurafenib and metabolites in human plasma, including metabolite concentrations at steady-state.. BMC Biomedical chromotography, 30(8), 1234-1239.
Open this publication in new window or tab >>Novel rapid liquid chromatography tandem masspectrometry method for vemurafenib and metabolites in human plasma, including metabolite concentrations at steady-state.
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2016 (English)In: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 30, no 8, 1234-1239 p.Article in journal (Refereed) Published
Abstract [en]

A novel, rapid and sensitive liquid chromatography tandem-mass spectrometry method for quantification of vemurafenib in human plasma, that also for the first time allows for metabolite semi-quantification, was developed and validated to support clinical trials and therapeutic drug monitoring. Vemurafenib was analysed by precipitation with methanol followed by a 1.9 min isocratic liquid chromatography tandem masspectrometry analysis using an Acquity BEH C18 column with methanol and formic acid using isotope labelled internal standards. Analytes were detected in multi reaction monitoring mode on a Xevo TQ. Semi-quantification of vemurafenib metabolites was performed using the same analytical system and sample preparation with gradient elution. The vemurafenib method was successfully validated in the range 0.5-100 µg/mL according to international guidelines. The metabolite method was partially validated due to the lack of commercially available reference materials. For the first time concentration levels at steady-state for melanoma patients treated with vemurafenib is presented. The low abundance of vemurafenib metabolites suggests that they lack clinical significance. This article is protected by copyright. All rights reserved.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keyword
BRAFV600E; LC-MS/MS; melanoma; metabolites;validation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-126098 (URN)10.1002/bmc.3672 (DOI)000379971200010 ()26683023 (PubMedID)
Note

Funding agencies: Swedish Research Council [C0592901, A0671101]; Swedish Cancer Society [130335]; County Council of Ostergotland; County Council of Stockholm-Gotland; Medical Research Council of Southeast Sweden [388611]; Swedish Medical Research Council; Radiumhemmet Rese

Available from: 2016-03-14 Created: 2016-03-14 Last updated: 2017-11-30Bibliographically approved
Green, H., Hasmats, J., Kupershmidt, I., Edsgard, D., de Petris, L., Lewensohn, R., . . . Lundeberg, J. (2016). Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities. Clinical Cancer Research, 22(2), 366-373.
Open this publication in new window or tab >>Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 2, 366-373 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2016
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-125314 (URN)10.1158/1078-0432.CCR-15-0964 (DOI)000369076500013 ()26378035 (PubMedID)
Note

Funding Agencies|European Commission [CHEMORES LSHC-CT-2007-037665]; Swedish Cancer Society; Swedish Research Council; Fondkistan; Stiftelsen Sigurd och Elsa Goljes Minne; Marcus Borgstroms stiftelse

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2018-01-10
Svedberg, A., Green, H., Vikström, A., Lundeberg, J. & Vikingsson, S. (2015). A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma. Journal of Pharmaceutical and Biomedical Analysis, 107, 186-195.
Open this publication in new window or tab >>A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma
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2015 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 107, 186-195 p.Article in journal (Refereed) Published
Abstract [en]

A liquid chromatography tandem mass spectrometry method was developed and validated for quantification of erlotinib and its metabolites in human plasma. The method is suitable for therapeutic drug monitoring and pharmacokinetic studies. The substances were extracted using protein precipitation, separated on a BEH XBridge C18 column (100 x 2.1 mm, 1.7 mu m) by gradient elution at 0.7 mL/min of acetonitrile and 5 mM ammonium acetate. The concentration was determined using a Waters Xevo triple quadrupole mass spectrometer in a multi reaction monitoring mode. The total run time was 7 min. Deuterated erlotinib and OSI-597 were used as internal standard for erlotinib and its metabolites, respectively. Erlotinib, OSI-420 and didesmethyl erlotinib were quantified in the concentration range 25-5000 ng/mL, 0.5-500 ng/mL and 0.15-10 ng/mL, respectively. Precision and accuracy was less than14% except for OSI-420 at LLOQ (17%). Extraction recovery was above 89%, 99% and 89% for erlotinib, OSI-420 and didesmethyl erlotinib, respectively. The human liver microsomes generated 14 metabolites, three of them not previously reported. Twelve metabolites were measured semi-quantitatively and validated with respect to selectivity, precision and stability. (C) 2014 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
LC-MS/MS; Human liver microsomes; Non-small cell lung cancer; EGFR; Tyrosine kinase inhibitor
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117227 (URN)10.1016/j.jpba.2014.12.022 (DOI)000351116900024 ()25594896 (PubMedID)
Note

Funding Agencies|Swedish Research Council [C0592901, A0671101]; Swedish Cancer Society [130335]; Medical Research Council of Southeast Sweden [388611]

Available from: 2015-04-23 Created: 2015-04-21 Last updated: 2017-12-04
Gréen, A., Green, H., Rehnberg, M., Svensson, A., Gunnarsson, C. & Jonasson, J. (2015). Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes. Journal of Molecular Diagnostics, 17(1), 31-42.
Open this publication in new window or tab >>Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes
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2015 (English)In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 1, 31-42 p.Article in journal (Refereed) Published
Abstract [en]

The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TIN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with greater than99% of targeted nucleotides covered by greater than20x. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error causing motif Located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.90/0 to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to Loss of coverage.

Place, publisher, year, edition, pages
Elsevier, 2015
National Category
Basic Medicine Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-113731 (URN)10.1016/j.jmoldx.2014.09.006 (DOI)000347143100006 ()25445213 (PubMedID)
Available from: 2015-01-30 Created: 2015-01-29 Last updated: 2018-01-11
Vikingsson, S., Josefsson, M. & Green, H. (2015). Identification of AKB-48 and 5F-AKB-48 Metabolites in Authentic Human Urine Samples Using Human Liver Microsomes and Time of Flight Mass Spectrometry. Journal of Analytical Toxicology, 39(6), 426-435.
Open this publication in new window or tab >>Identification of AKB-48 and 5F-AKB-48 Metabolites in Authentic Human Urine Samples Using Human Liver Microsomes and Time of Flight Mass Spectrometry
2015 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 39, no 6, 426-435 p.Article in journal (Refereed) Published
Abstract [en]

The occurrence of structurally related synthetic cannabinoids makes the identification of unique markers of drug intake particularly challenging. The aim of this study was to identify unique and abundant metabolites of AKB-48 and 5F-AKB-48 for toxicological screening in urine. Investigations of authentic urine samples from forensic cases in combination with human liver microsome (HLM) experiments were used for identification of metabolites. HLM incubations of AKB-48 and 5F-AKB-48 along with 35 urine samples from authentic cases were analyzed with liquid chromatography quadrupole tandem time of flight mass spectrometry. Using HLMs 41 metabolites of AKB-48 and 37 metabolites of 5F-AKB-48 were identified, principally represented by hydroxylation but also ketone formation and dealkylation. Monohydroxylated metabolites were replaced by di- and trihydroxylated metabolites within 30 min. The metabolites from the HLM incubations accounted for on average 84% (range, 67-100) and 91% (range, 71-100) of the combined area in the case samples for AKB-48 and 5F-AKB-48, respectively. While defluorinated metabolites accounted for on average 74% of the combined area after a 5F-AKB-48 intake only a few identified metabolites were shared between AKB-48 and 5F-AKB-48, illustrating the need for a systematic approach to identify unique metabolites. HLMs in combination with case samples seem suitable for this purpose.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy F, 2015
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121141 (URN)10.1093/jat/bkv045 (DOI)000359730100002 ()25957385 (PubMedID)
Note

Funding Agencies|National Board of Forensic Medicine; Linkoping University; Swedish Civil Contingencies Agency

Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2017-12-04
Lopez-Contreras, A. J., Specks, J., Barlow, J. H., Ambrogio, C., Desler, C., Vikingsson, S., . . . Fernandez-Capetillo, O. (2015). Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. Genes & Development, 29(7), 690-695.
Open this publication in new window or tab >>Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice
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2015 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 29, no 7, 690-695 p.Article in journal (Refereed) Published
Abstract [en]

In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity. Supplemental material is available for this article.

Place, publisher, year, edition, pages
Cold Spring Harbor Laboratory Press, 2015
Keyword
ATR; fragile site; mouse models; RNR; replication stress
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-118056 (URN)10.1101/gad.256958.114 (DOI)000352161600002 ()25838540 (PubMedID)
Note

Funding Agencies|Spanish Association for Cancer Research (AECC); Spanish government [BES-2012-05 2030]; Swedish Research Council; Swedish Cancer Society; Fundacion Botin; Banco Santander through its Santander Universities Global Division; Ministerio de Economia y Competitividad (MINECO) [SAF2011-23753]; Worldwide Cancer Research [12-0229]; Fundacio La Marato de TV3; Howard Hughes Medical Institute; European Research Council [ERC-617840]; Danish Council for Independent Research (DFF); Danish National Research Foundation

Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2017-12-04
Karlsson, L., Zackrisson, A. L., Josefsson, M., Carlsson, B., Green, H. & Kugelberg, F. . (2015). Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.. The Pharmacogenomics Journal, 15(2), 165-71.
Open this publication in new window or tab >>Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.
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2015 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, no 2, 165-71 p.Article in journal (Refereed) Published
Abstract [en]

We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases. In all, 94 postmortem cases found positive for VEN during toxicological screening were included. The CYP2D6 genotype was shown to significantly influence the ODV/VEN (P=0.003), DDV/NDV (P=0.010) and DDV/ODV (P=0.034) ratios. The DDV/ODV (P=0.013) and DDV/VEN (P=0.021) ratios were significantly influenced by the CYP2C19 genotype. The S/R ratios of VEN were significantly influenced by both CYP2D6 and CYP2C19 genotypes. CYP2D6 poor metabolizers (PMs) had lower S/R VEN ratios and CYP2C19 PMs had high S/R ratios of VEN in comparison. Our results show that the CYP2D6 genotype influences the O-demethylation whereas CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favours the R-enantiomer whereas CYP2C19 favours the S-enantiomer.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-116540 (URN)10.1038/tpj.2014.50 (DOI)000351780200008 ()25245581 (PubMedID)
Available from: 2015-03-27 Created: 2015-03-27 Last updated: 2018-01-11
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