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  • 1. Agborsangaya, Calypse
    et al.
    Toriola, Adetunji T
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Surcel, Heljia-Marja
    Holl, Katsiaryna
    Parkkila, Seppo
    Tuohimaa, Pentti
    Lukanova, Annekatrin
    Lehtinen, Matti
    The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione2010Inngår i: Nutrition and Cancer, ISSN 0163-5581, E-ISSN 1532-7914, Vol. 62, nr 1, s. 51-57Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Knowledge of the stability of serum samples stored in large biobanks is pivotal for reliable assessment of hormone-dependent disease risks. We studied the effects of sample storage time and season of serum sampling on the stability of 25-hydroxy vitamin D (25-OHD) and androstenedione in a stratified random sample of 402 women, using paired sera from the Finnish Maternity Cohort. Serum samples selected were donated between 6 and 24 yr ago. The storage time did not affect serum 25-OHD and androstenedione levels. However, there was a significant mean difference in the 25-OHD levels of sera withdrawn during winter (first sample) vs. during summer (second sample; -18.4 nmol/l, P ≤ 0.001). Also at the individual level, there were significant differences in average 25-OHD levels between individuals with the paired sera taken at winter–winter compared with other alternatives (summer–winter, winter–summer, and summer–summer). The androstenedione levels showed no such differences. Long-term storage does not affect serum 25-OHD and androstenedione levels, but sampling season is an important determinant of 25-OHD levels. Stored serum samples can be used to study disease associations with both hormones. However, sampling season needs to be taken into account for 25-OHD by considering matching and stratification and, if possible, serial sampling.

  • 2.
    Alamdari, Farhood Iranparvar
    et al.
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Rasmuson, Torgny
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi. Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Ljungberg, Börje
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi. Urologi och andrologi.
    Angiogenesis and other markers for prediction of survival in metastatic renal cell carcinoma.2007Inngår i: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, nr 1, s. 5-9Artikkel i tidsskrift (Fagfellevurdert)
  • 3.
    Andersson, Britta
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Behnam Motlagh, Parviz
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi. Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi. Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Pharmacological modulation of lung cancer cells for potassium ion depletion2005Inngår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, nr 4, s. 2609-2616Artikkel i tidsskrift (Fagfellevurdert)
  • 4.
    Andersson, Britta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Janson, Veronica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Behnam Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells.2006Inngår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 20, nr 6, s. 986-994Artikkel i tidsskrift (Fagfellevurdert)
  • 5.
    Andersson, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bergenheim, A. Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Behnam-Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation2002Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 19, nr 1, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

  • 6. Baglietto, Laura
    et al.
    Ponzi, Erica
    Haycock, Philip
    Hodge, Allison
    Bianca Assumma, Manuela
    Jung, Chol-Hee
    Chung, Jessica
    Fasanelli, Francesca
    Guida, Florence
    Campanella, Gianluca
    Chadeau-Hyam, Marc
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Ala, Ugo
    Provero, Paolo
    Wong, Ee Ming
    Joo, Jihoon
    English, Dallas R
    Kazmi, Nabila
    Lund, Eiliv
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    Barrdahl, Myrto
    Sandanger, Torkjel M
    Southey, Melissa C
    Giles, Graham G
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Vineis, Paolo
    Polidoro, Silvia
    Relton, Caroline L
    Severi, Gianluca
    DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk2017Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, nr 1, s. 50-61Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled  = 4 × 10(-17) ), cg03636183 in the F2RL3 gene (p-valuepooled  = 2 × 10 (- 13) ), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled  = 7 × 10(-16) and 1 × 10(-11) respectively), cg06126421 in 6p21.33 (p-valuepooled  = 2 × 10(-15) ) and cg23387569 in 12q14.1 (p-valuepooled  = 5 × 10(-7) ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity  ≤ 1.8 x10 (- 7) ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

  • 7.
    Behnam Motlagh, Parviz
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Tyler, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Brännstrom, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Co-expression of Globotriasosylceramide (Gb3) With MDR1 in Cisplatin-resistant Pleural Mesothelioma and Non-small Cell Lung Cancer Cell May Lead to a New Tumour Resistance Treatment Approach2011Konferansepaper (Fagfellevurdert)
  • 8.
    Behnam-Mothlag, Parviz
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Tyler, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Karlsson, Terese
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Cisplatin Resistance in Malignant Pleural Mesothelioma2012Inngår i: Mesotheliomas: Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis / [ed] Alexander Zubritsky, Zagreb: InTech, 2012, Vol. 11, s. 169-186Kapittel i bok, del av antologi (Fagfellevurdert)
  • 9.
    Behnam-Motlagh, Parviz
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Tyler, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Verotoxin-1 Treatment or Manipulation of its Receptor Globotriaosylceramide (Gb3) for Reversal of Multidrug Resistance to Cancer Chemotherapy2010Inngår i: Toxins, ISSN 2072-6651, Vol. 2, nr 10, s. 2467-2477Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    A major problem with anti-cancer drug treatment is the development of acquired multidrug resistance (MDR) of the tumor cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the globotriaosylceramide membrane receptor (Gb3), a glycolipid associated with multidrug resistance. Gb3 is overexpressed in many human tumors and tumor cell lines with inherent or acquired MDR. Gb3 is co-expressed and interplays with the membrane efflux transporter P-gp encoded by the MDR1 gene. P-gp could act as a lipid flippase and stimulate Gb3 induction when tumor cells are exposed to cancer chemotherapy. Recent work has shown that apoptosis and inherent or acquired multidrug resistance in Gb3-expressing tumors could be affected by VT-1 holotoxin, a sub-toxic concentration of the holotoxin concomitant with chemotherapy or its Gb3-binding B-subunit coupled to cytotoxic or immunomodulatory drug, as well as chemical manipulation of Gb3 expression. The interplay between Gb3 and P-gp thus gives a possible physiological approach to augment the chemotherapeutic effect in multidrug resistant tumors.

  • 10. Berggrund, Malin
    et al.
    Enroth, Stefan
    Lundberg, Martin
    Assarsson, Erika
    Stålberg, Karin
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Olovsson, Matts
    Gyllensten, Ulf
    Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay2019Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, nr 4, s. 735-743, artikkel-id RA118.001208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared to controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared to population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

  • 11. Brenner, Darren R.
    et al.
    Fanidi, Anouar
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Muller, David C.
    Brennan, Paul
    Manjer, Jonas
    Byrnes, Graham
    Hodge, Allison
    Severi, Gianluca
    Giles, Graham G.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Johansson, Mattias
    Inflammatory Cytokines and Lung Cancer Risk in 3 Prospective Studies2017Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 185, nr 2, s. 86-95Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To further investigate the role of inflammation in lung carcinogenesis, we evaluated associations between proinflammatory cytokines and lung cancer risk. We conducted a case-control study nested within 3 prospective cohort studies-the Melbourne Collaborative Cohort Study (1990-1994), the Malm Diet and Cancer Study (1991-1996), and the Northern Sweden Health and Disease Study (initiated in 1985)-involving 807 incident lung cancer cases and 807 smoking-matched controls. Conditional logistic regression models adjusting for serum cotinine concentrations were used to estimate odds ratios for lung cancer risk associated with concentrations of interleukin (IL)-1 beta, IL-2, IL-6, IL-8, IL-10, IL-12, interferon., tumor necrosis factor a, and granulocyte-macrophage colony-stimulating factor. We observed a higher lung cancer risk for participants with elevated concentrations of IL-6 and IL-8. These associations seemed to be stronger among former smokers (for fourth quartile vs. first quartile, odds ratio (OR) = 2.70, 95% confidence interval (CI): 1.55, 4.70) and current smokers (OR = 1.99, 95% CI: 1.15, 3.44) for IL-6 and among former smokers (OR = 2.83, 95% CI: 1.18, 6.75) and current smokers (OR = 1.30, 95% CI: 0.69, 2.44) for IL-8. No notable associations were observed among never smokers. Risk associations with IL-6 and IL-8 were observed for blood samples taken close to diagnosis (< 5 years) as well as more than 15 years postdiagnosis.

  • 12.
    Bölenius, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Brulin, Christine
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lindkvist, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Söderberg, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    A content validated questionnaire for assessment of self reported venous blood sampling practices2012Inngår i: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 5, s. 39-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Venous blood sampling is a common procedure in health care. It is strictly regulated by national and international guidelines. Deviations from guidelines due to human mistakes can cause patient harm. Validated questionnaires for health care personnel can be used to assess preventable "near misses"--i.e. potential errors and nonconformities during venous blood sampling practices that could transform into adverse events. However, no validated questionnaire that assesses nonconformities in venous blood sampling has previously been presented. The aim was to test a recently developed questionnaire in self reported venous blood sampling practices for validity and reliability.

    FINDINGS: We developed a questionnaire to assess deviations from best practices during venous blood sampling. The questionnaire contained questions about patient identification, test request management, test tube labeling, test tube handling, information search procedures and frequencies of error reporting. For content validity, the questionnaire was confirmed by experts on questionnaires and venous blood sampling. For reliability, test-retest statistics were used on the questionnaire answered twice. The final venous blood sampling questionnaire included 19 questions out of which 9 had in total 34 underlying items. It was found to have content validity. The test-retest analysis demonstrated that the items were generally stable. In total, 82% of the items fulfilled the reliability acceptance criteria.

    CONCLUSIONS: The questionnaire could be used for assessment of "near miss" practices that could jeopardize patient safety and gives several benefits instead of assessing rare adverse events only. The higher frequencies of "near miss" practices allows for quantitative analysis of the effect of corrective interventions and to benchmark preanalytical quality not only at the laboratory/hospital level but also at the health care unit/hospital ward.

  • 13.
    Bölenius, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Lindkvist, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa. Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Brulin, Christine
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad. Institutionen för omvårdnad i Örnsköldsvik.
    Söderberg, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Impact of a large-scale educational intervention program on venous blood specimen collection practices2013Inngår i: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 13, artikkel-id 463Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Phlebotomy performed with poor adherence to venous blood specimen collection (VBSC) guidelines jeopardizes patient safety and may lead to patient suffering and adverse events. A first questionnaire study demonstrated low compliance to VBSC guidelines, motivating an educational intervention of all phlebotomists within a county council. The aim was to evaluate the impact of a large-scale educational intervention program (EIP) on primary health care phlebotomists' adherence to VBSC guidelines. We hypothesised that the EIP would improve phlebotomists' VBSC practical performance.

    METHODS: The present study comprise primary health care centres (n = 61) from two county councils in northern Sweden. The final selected study group consisted of phlebotomists divided into an intervention group (n = 84) and a corresponding control group (n = 79). Both groups responded to a validated self-reported VBSC questionnaire twice. The EIP included three parts: guideline studies, an oral presentation, and an examination. Non-parametric statistics were used for comparison within and between the groups.

    RESULTS: Evaluating the EIP, we found significant improvements in the intervention group compared to the control group on self-reported questionnaire responses regarding information search (ES = 0.23-0.33, p < 0.001-0.003), and patient rest prior to phlebotomy (ES = 0.27, p = 0.004). Test request management, patient identity control, release of venous stasis, and test tube labelling had significantly improved in the intervention group but did not significantly differ from the control group (ES = 0.22- 0.49, p = < 0.001- 0.006). The control group showed no significant improvements at all (ES = 0--0.39, p = 0.016-0.961).

    CONCLUSIONS: The present study demonstrated several significant improvements on phlebotomists' adherence to VBSC practices. Still, guideline adherence improvement to several crucial phlebotomy practices is needed. We cannot conclude that the improvements are solely due to the EIP and suggest future efforts to improve VBSC. The program should provide time for reflections and discussions. Furthermore, a modular structure would allow directed educational intervention based on the specific VBSC guideline flaws existing at a specific unit. Such an approach is probably more effective at improving and sustaining adherence to VBSC guidelines than an EIP containing general pre-analytical practices.

  • 14.
    Bölenius, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Söderberg, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lindkvist, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Brulin, Christine
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Minor improvement of venous blood specimen collection practices in primary health care after a large-scale educational intervention2013Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 51, nr 2, s. 303-310Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Venous blood specimen collection is a common health care practice that has to follow strict guidelines, non-compliance among sampling staff may compromise patient safety. We evaluated a large-scale 2 h educational intervention that emphasised guideline adherence to assess possible improvements of venous blood specimen collection practices.

    Methods: Blood specimen haemolysis is usually caused by inadequate venous blood specimen collection and handling, reflecting overall pre-analytical handling. We monitored haemolysis of serum samples with haemolysis index corresponding to ≥150 mg/L of free haemoglobin for specimens sent from 11 primary health care centres and analysed on a Vitros 5,1 clinical chemistry analyser before (2008, n=6652 samples) and after (2010, n=6121 samples) the intervention.

    Results: The total percentage of haemolysed specimens was 11.8% compared to 10.5% (p=0.022) before the intervention. As groups, rural primary health care centres demonstrated a significant reduction [Odds ratios (OR)=0.744] of haemolysed specimens after intervention, whereas urban primary health care centres demonstrated a significant increase (OR=1.451) of haemolysis.

    Conclusions: A large-scale 2 h educational intervention to make venous blood specimen collection staff comply with guideline practices had minor effects on collection practices. Educational interventions may be effective in wards/care centres demonstrating venous blood specimen collection practices with larger deviations from guidelines.

  • 15. Cadamuro, Janne
    et al.
    Lippi, Giuseppe
    von Meyer, Alexander
    Ibarz, Mercedes
    van Dongen-Lases, Edmee
    Cornes, Michael
    Nybo, Mads
    Vermeersch, Pieter
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Guimaraes, Joao Tiago
    Kristensen, Gunn B. B.
    de la Salle, Barbara
    Simundic, Ana-Maria
    European survey on preanalytical sample handling - Part 1: How do European laboratories monitor the preanalytical phase? On behalf of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE)2019Inngår i: Biochemia Medica, ISSN 1330-0962, E-ISSN 1846-7482, Vol. 29, nr 2, artikkel-id 020704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Compared to other activities of the testing process, the preanalytical phase is plagued by a lower degree of standardization, which makes it more vulnerable to errors. With the aim of providing guidelines and recommendations, the EFLM WG-PRE issued a survey across European medical laboratories, to gather information on local preanalytical practices. This is part one of two coherent articles, which covers all practices on monitoring preanalytical quality except haemolysis, icterus and lipemia (HIL).

    Materials and methods: An online survey, containing 39 questions dealing with a broad spectrum of preanalytical issues, was disseminated to EFLM member countries. The survey included questions on willingness of laboratories to engage in preanalytical issues.

    Results: Overall, 1405 valid responses were received from 37 countries. 1265 (94%) responders declared to monitor preanalytical errors. Assessment, documentation and further use of this information varied widely among respondents and partially among countries. Many responders were interested in a preanalytical online platform, holding information on various aspects of the preanalytical phase (N = 1177; 87%), in a guideline for measurement and evaluation of preanalytical variables (N = 1235; 92%), and in preanalytical e-learning programs or webinars (N = 1125; 84%). Fewer responders were interested in, or already participating in, preanalytical EQA programs (N = 951; 71%).

    Conclusion: Although substantial heterogeneity was found across European laboratories on preanalytical phase monitoring, the interest in preanalytical issues was high. A large majority of participants indicated an interest in new guidelines regarding preanalytical variables and learning activities. This important data will be used by the WG-PRE for providing recommendations on the most critical issues.

  • 16. Cadamuro, Janne
    et al.
    Lippi, Giuseppe
    von Meyer, Alexander
    Ibarz, Mercedes
    van Dongen-Lases, Edmee
    Cornes, Michael
    Nybo, Mads
    Vermeersch, Pieter
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Guimaraes, Joao Tiago
    Kristensen, Gunn B. B.
    de la Salle, Barbara
    Simundic, Ana-Maria
    European survey on preanalytical sample handling - Part 2: Practices of European laboratories on monitoring and processing haemolytic, icteric and lipemic samples. On behalf of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE)2019Inngår i: Biochemia Medica, ISSN 1330-0962, E-ISSN 1846-7482, Vol. 29, nr 2, artikkel-id 020705Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: No guideline currently exists on how to detect or document haemolysis, icterus or lipemia (HIL) in blood samples, nor on subsequent use of this information. The EFLM WG-PRE has performed a survey for assessing current practices of European laboratories in HIL monitoring. This second part of two coherent articles is focused on HIL.

    Materials and methods: An online survey, containing 39 questions on preanalytical issues, was disseminated among EFLM member countries. Seventeen questions exclusively focused on assessment, management and follow-up actions of HIL in routine blood samples.

    Results: Overall, 1405 valid responses from 37 countries were received. A total of 1160 (86%) of all responders stating to analyse blood samples - monitored HIL. HIL was mostly checked in clinical chemistry samples and less frequently in those received for coagulation, therapeutic drug monitoring and serology/infectious disease testing. HIL detection by automatic HIL indices or visual inspection, along with haemolysis cut-offs definition, varied widely among responders. A quarter of responders performing automated HIL checks used internal quality controls. In haemolytic/icteric/lipemic samples, most responders (70%) only rejected HIL-sensitive parameters, whilst about 20% released all test results with general comments. Other responders did not analysed but rejected the entire sample, while some released all tests, without comments. Overall, 26% responders who monitored HIL were using this information for monitoring phlebotomy or sample transport quality.

    Conclusion: Strategies for monitoring and treating haemolytic, icteric or lipemic samples are quite heterogeneous in Europe. The WG-PRE will use these insights for developing and providing recommendations aimed at harmonizing strategies across Europe.

  • 17. Carreras-Torres, Robert
    et al.
    Johansson, Mattias
    Haycock, Philip C.
    Wade, Kaitlin H.
    Relton, Caroline L.
    Martin, Richard M.
    Smith, George Davey
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline
    Arnold, Susanne M.
    Bickeböller, Heike
    Bojesen, Stig E.
    Brunnström, Hans
    Manjer, Jonas
    Brüske, Irene
    Caporaso, Neil E.
    Chen, Chu
    Christiani, David C.
    Christian, W. Jay
    Doherty, Jennifer A.
    Duell, Eric J.
    Field, John K.
    Davies, Michael P. A.
    Marcus, Michael W.
    Goodman, Gary E.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Haugen, Aage
    Hong, Yun-Chul
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Kraft, Peter
    Johansson, Mikael B.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lam, Stephen
    Landi, Maria Teresa
    Lazarus, Philip
    Le Marchand, Loïc
    Liu, Geoffrey
    Melander, Olle
    Park, Sungshim L.
    Rennert, Gad
    Risch, Angela
    Haura, Eric B.
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Savić, Milan
    Lissowska, Jolanta
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Mates, Dana
    Schabath, Matthew B.
    Shen, Hongbing
    Tardon, Adonina
    Teare, Dawn
    Woll, Penella
    Tsao, Ming-Sound
    Wu, Xifeng
    Yuan, Jian-Min
    Hung, Rayjean J.
    Amos, Christopher I.
    McKay, James
    Brennan, Paul
    Obesity, metabolic factors and risk of different histological types of lung cancer: a Mendelian randomization study2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 6, artikkel-id e0177875Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95% CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m(2)]), but not for adenocarcinoma (OR [95% CI] = 0.93 [0.79-1.08]) (P-heterogeneity = 4.3x10(-3)). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10(-3)), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95% CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95% CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

  • 18. Chen, Tianhui
    et al.
    Lukanova, Annekatrin
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Johansson, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Schock, Helena
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Toniolo, Paolo
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    IGF-I during primiparous pregnancy and maternal risk of breast cancer2010Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 121, nr 1, s. 169-175Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previously, we reported that insulin-like growth factor (IGF)-I during early pregnancy is positively associated with maternal risk of breast cancer. To further explore this association, we designed a new study limited to women who donated a blood sample during their first pregnancy ending with childbirth. A case-control study was nested within the Northern Sweden Maternity Cohort in which repository since 1975, serum specimens remaining after early pregnancy screening for infectious diseases had been preserved. Study subjects were selected among women who donated a blood sample during the full-term pregnancy that led to the birth of their first child. Two hundred and forty-four women with invasive breast cancer were eligible. Two controls, matching the index case for age and date at blood donation were selected (n = 453). IGF-I was measured in serum samples on an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. A significant positive association of breast cancer with IGF-I was observed, with OR of 1.73 (95% CI: 1.14-2.63) for the top tertile, P < 0.009. Subgroup analyses did not indicate statistical heterogeneity of the association by ages at sampling and diagnosis or by lag time to cancer diagnosis, although somewhat stronger associations with risk were observed in women < or = age 25 at index pregnancy and for cases diagnosed within 15 years of blood donation. The results of the study add further evidence for an adverse effect of elevated IGF-I concentrations during early reproductive life on risk of breast cancer.

  • 19. Chen, Tianhui
    et al.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Afanasyeva, Yelena
    Schock, Helena
    Johansson, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Toniolo, Paolo
    Lukanova, Annekatrin
    Maternal hormones during early pregnancy: a cross-sectional study2010Inngår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, nr 5, s. 719-727Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II. METHODS: About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models. RESULTS: In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed. CONCLUSIONS: Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations.

  • 20. Chen, Tianhui
    et al.
    Surcel, Helja-Marja
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kaasila, Marjo
    Lakso, Hans-Ake
    Schock, Helena
    Kaaks, Rudolf
    Koskela, Pentti
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Pukkala, Eero
    Zeleniuch-Jacquotte, Anne
    Toniolo, Paolo
    Lehtinen, Matti
    Lukanova, Annekatrin
    Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer2011Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, nr 2, s. 324-336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. Impact: Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC. Cancer Epidemiol Biomarkers Prev; 20(2); 324-36. ©2010 AACR.

  • 21. Chuang, Shu-Chun
    et al.
    Fanidi, Anouar
    Ueland, Per Magne
    Relton, Caroline
    Midttun, Oivind
    Vollset, Stein Emil
    Gunter, Marc J.
    Seckl, Michael J.
    Travis, Ruth C.
    Wareham, Nicholas
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H. M.
    Bueno-de-Mesquita, H. Bas
    Boeing, Heiner
    Wientzek, Angelika
    Kuehn, Tilman
    Kaaks, Rudolf
    Tumino, Rosario
    Agnoli, Claudia
    Palli, Domenico
    Naccarati, Alessio
    Ardanaz Aicua, Eva
    Sanchez, Maria-Jose
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Agudo, Antonio
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Weiderpass, Elisabete
    Riboli, Elio
    Brennan, Paul J.
    Vineis, Paolo
    Johansson, Mattias
    Circulating Biomarkers of Tryptophan and the Kynurenine Pathway and Lung Cancer Risk2014Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 23, nr 3, s. 461-468Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer. Methods: We conducted a nested case-control study within the European Prospective Investigation into Cancer andNutrition (EPIC) that included 893 incident lung cancer cases and 1,748matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk. Results: Tryptophan (P-trend = 2 Chi 10(-5)) and the kynurenine/ tryptophan ratio (KTR; P-trend 4 Chi 10(-5)) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th (vs. 1st)) were 0.52 [ 95% confidence interval (CI), 0.37-0.74] for tryptophan and 1.74 (95% CI, 1.24-2.45) for KTR. After adjusting for plasma methionine (available fromprevious work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted P-trend 0.13) and KTR (P-trend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62-4.94, P-trend -3 Chi 10(-5)) that was only marginally affected by adjusting for methionine. Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology. Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk.

  • 22. Cornes, Michael
    et al.
    Ibarz, Mercedes
    Ivanov, Helene
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Blood sampling guidelines with focus on patient safety and identification: a review2019Inngår i: Diagnosis, ISSN 2194-8011, Vol. 6, nr 1, s. 33-37Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    It has been well documented over recent years that the preanalytical phase is a leading contributor to errors in the total testing process (TTP). There has however been great progress made in recent years due to the exponential growth of working groups specialising in the field. Patient safety is clearly at the forefront of any healthcare system and any reduction in errors at any stage will improve patient safety. Venous blood collection is a key step in the TTP, and here we review the key errors that occur in venous phlebotomy process and summarise the evidence around their significance to patient safety. Recent studies have identified that patient identification and tube labelling are the steps that carry the highest risk with regard to patient safety. Other studies have shown that in 16.1% of cases, patient identification is incorrectly performed and that 56% of patient identification errors are due to poor labelling practice. We recommend that patient identification must be done using open questions and ideally three separate pieces of information. Labelling of the tube or linking the identity of the patient to the tube label electronically must be done in the presence of the patient whether it is before or after sampling. Combined this will minimise any chance of patient misidentification.

  • 23. Cornes, Michael P.
    et al.
    Church, Stephen
    van Dongen-Lases, Edmee
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Guimaraes, Joao T.
    Ibarz, Mercedes
    Kovalevskaya, Svetlana
    Kristensen, Gunn B. B.
    Lippi, Giuseppe
    Nybo, Mads
    Sprongl, Ludek
    Sumarac, Zorica
    Simundic, Ana-Maria
    The role of European Federation of Clinical Chemistry and Laboratory Medicine Working Group for Preanalytical Phase in standardization and harmonization of the preanalytical phase in Europe2016Inngår i: Annals of Clinical Biochemistry, ISSN 0004-5632, E-ISSN 1758-1001, Vol. 53, nr 5, s. 539-547Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Patient safety is a leading challenge in healthcare and from the laboratory perspective it is now well established that preanalytical errors are the major contributor to the overall rate of diagnostic and therapeutic errors. To address this, the European Federation of Clinical Chemistry and Laboratory Medicine Working Group for Preanalytical Phase (EFLM WG-PRE) was established to lead in standardization and harmonization of preanalytical policies and practices at a European level. One of the key activities of the WG-PRE is the organization of the biennial EFLM-BD conference on the preanalytical phase to provide a forum for National Societies (NS) to discuss their issues. Since 2012, a year after the first Preanalytical phase conference, there has been a rapid growth in the number of NS with a working group engaged in preanalytical phase activities and there are now at least 19 countries that have one. As a result of discussions with NS at the third conference held in March 2015 five key areas were identified as requiring harmonisation. These were test ordering, sample transport and storage, patient preparation, sampling procedures and management of unsuitable specimens. The article below summarises the work that has and will be done in these areas. The goal of this initiative is to ensure the EFLM WG-PRE produces work that meets the needs of the European laboratory medicine community. Progress made in the identified areas will be updated at the next preanalytical phase conference and show that we have produced guidance that has enhanced standardisation in the preanalytical phase and improved patient safety throughout Europe.

  • 24. Cornes, Michael
    et al.
    van Dongen-Lases, Edmée
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Ibarz, Mercedes
    Kristensen, Gunn
    Lippi, Giuseppe
    Nybo, Mads
    Simundic, Ana-Maria
    Order of blood draw: Opinion Paper by the European Federation for Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE)2017Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 55, nr 1, s. 27-31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It has been well reported over recent years that most errors within the total testing process occur in the pre-analytical phase (46%-68.2%), an area that is usually outside of the direct control of the laboratory and which includes sample collection (phlebotomy). National and international (WHO, CLSI) guidelines recommend that the order of draw of blood during phlebotomy should be blood culture/sterile tubes, then plain tubes/gel tubes, then tubes containing additives. This prevents contamination of sample tubes with additives from previous tubes that could cause erroneous results. There have been a number of studies recently looking at whether order of draw remains a problem with modern phlebotomy techniques and materials, or it is an outdated practice followed simply because of historical reasons. In the following article, the European Federation of Clinical Chemistry and Laboratory Medicine Working Group for the Preanalytical Phase (EFLM WG-PRE) provides an overview and summary of the literature with regards to order of draw in venous blood collection. Given the evidence presented in this article, the EFLM WG-PRE herein concludes that a significant frequency of sample contamination does occur if order of draw is not followed during blood collection and when performing venipuncture under less than ideal circumstances, thus putting patient safety at risk. Moreover, given that order of draw is not difficult to follow and knowing that ideal phlebotomy conditions and protocols are not always followed or possible, EFLM WG-PRE supports the continued recommendation of ensuring a correct order of draw for venous blood collection.

  • 25. Dai, Juncheng
    et al.
    Li, Zhihua
    Amos, Christopher I.
    Hung, Rayjean J.
    Tardon, Adonina
    Andrew, Angeline S.
    Chen, Chu
    Christiani, David C.
    Albanes, Demetrios
    van der Heijden, Erik H. F. M.
    Duell, Eric J.
    Rennert, Gad
    Mckay, James D.
    Yuan, Jian-Min
    Field, John K.
    Manjer, Jonas
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Le Marchand, Loic
    Teare, M. Dawn
    Schabath, Matthew B.
    Aldrich, Melinda C.
    Tsao, Ming-Sound
    Lazarus, Philip
    Lam, Stephen
    Bojesen, Stig E.
    Arnold, Susanne
    Wu, Xifeng
    Haugen, Aage
    Janout, Vladimir
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Brhane, Yonathan
    Fernandez-Somoano, Ana
    Kiemeney, Lambertus A.
    Davies, Michael P. A.
    Zienolddiny, Shanbeh
    Hu, Zhibin
    Shen, Hongbing
    Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci2019Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 40, nr 3, s. 432-440Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 x 10(-7)) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 x 10(-6)) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 x 10(-4)). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

  • 26. Dewi, Nikmah Utami
    et al.
    Boshuizen, Hendriek C.
    Johansson, Mattias
    Vineis, Paolo
    Kampman, Ellen
    Steffen, Annika
    Tjonneland, Anne
    Halkjaer, Jytte
    Overvad, Kim
    Severi, Gianluca
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Li, Kuanrong
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Klinaki, Eleni
    Tumino, Rosario
    Palli, Domenico
    Mattiello, Amalia
    Tagliabue, Giovanna
    Peeters, Petra H.
    Vermeulen, Roel
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Maria Huerta, Jose
    Agudo, Antonio
    Sanchez, Maria-Jose
    Ardanaz, Eva
    Dorronsoro, Miren
    Ramon Quiros, Jose
    Sonestedt, Emily
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Key, Tim
    Khaw, Kay-Tee
    Wareham, Nick
    Cross, Amanda J.
    Norat, Teresa
    Riboli, Elio
    Fanidi, Anouar
    Muller, David
    Bueno-de-Mesquita, H. Bas
    Anthropometry and the Risk of Lung Cancer in EPIC2016Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 184, nr 2, s. 129-139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The associations of body mass index (BMI) and other anthropometric measurements with lung cancer were examined in 348,108 participants in the European Investigation Into Cancer and Nutrition (EPIC) between 1992 and 2010. The study population included 2,400 case patients with incident lung cancer, and the average length of follow-up was 11 years. Hazard ratios were calculated using Cox proportional hazard models in which we modeled smoking variables with cubic splines. Overall, there was a significant inverse association between BMI (weight (kg)/height (m)(2)) and the risk of lung cancer after adjustment for smoking and other confounders (for BMI of 30.0-34.9 versus 18.5-25.0, hazard ratio = 0.72, 95% confidence interval: 0.62, 0.84). The strength of the association declined with increasing follow-up time. Conversely, after adjustment for BMI, waist circumference and waist-to-height ratio were significantly positively associated with lung cancer risk (for the highest category of waist circumference vs. the lowest, hazard ratio = 1.25, 95% confidence interval: 1.05, 1.50). Given the decline of the inverse association between BMI and lung cancer over time, the association is likely at least partly due to weight loss resulting from preclinical lung cancer that was present at baseline. Residual confounding by smoking could also have influenced our findings.

  • 27. Enroth, Stefan
    et al.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Gyllensten, Ulf
    Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations2016Inngår i: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 12, s. 309-314Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The quality of clinical biobank samples is crucial to their value for life sciences research. A number of factors related to the collection and storage of samples may affect the biomolecular composition. We have studied the effect of long-time freezer storage, chronological age at sampling, season and month of the year and on the abundance levels of 108 proteins in 380 plasma samples collected from 106 Swedish women. Storage time affected 18 proteins and explained 4.8–34.9% of the observed variance. Chronological age at sample collection after adjustment for storage-time affected 70 proteins and explained 1.1–33.5% of the variance. Seasonal variation had an effect on 15 proteins and month (number of sun hours) affected 36 proteins and explained up to 4.5% of the variance after adjustment for storage-time and age. The results show that freezer storage time and collection date (month and season) exerted similar effect sizes as age on the protein abundance levels. This implies that information on the sample handling history, in particular storage time, should be regarded as equally prominent covariates as age or gender and need to be included in epidemiological studies involving protein levels.

  • 28. Fanidi, Anouar
    et al.
    Carreras-Torres, Robert
    Larose, Tricia L.
    Yuan, Jian-Min
    Stevens, Victoria L.
    Weinstein, Stephanie J.
    Albanes, Demetrius
    Prentice, Ross
    Pettinger, Mary
    Cai, Qiuyin
    Blot, William J.
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    McCullough, Marjorie L.
    Le Marchand, Loic
    Wilkens, Lynne R.
    Haiman, Christopher A.
    Zhang, Xuehong
    Stampfer, Meir J.
    Smith-Warner, Stephanie A.
    Giovannucci, Edward
    Giles, Graham G.
    Hodge, Allison M.
    Severi, Gianluca
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Langhammer, Arnulf
    Brumpton, Ben M.
    Wang, Renwei
    Gao, Yu-Tang
    Ericson, Ulrika
    Bojesen, Stig E.
    Arnold, Susanne M.
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Li, Honglan
    Zheng, Wei
    Lan, Qing
    Visvanathan, Kala
    Hoffman-Bolton, Judith
    Ueland, Per M.
    Midttun, Oivind
    Caporaso, Neil E.
    Purdue, Mark
    Freedman, Neal D.
    Buring, Julie E.
    Lee, I-Min
    Sesso, Howard D.
    Gaziano, J. Michael
    Manjer, Jonas
    Relton, Caroline L.
    Hung, Rayjean J.
    Amos, Chris, I
    Johansson, Mattias
    Brennan, Paul
    Is high vitamin B12 status a cause of lung cancer?2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 6, s. 1499-1503Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case–control study, complemented with a Mendelian randomization (MR) approach in an independent case–control sample. We used pre‐diagnostic biomarker data from 5183 case–control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case–control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06–1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD] = 1.08, 95%CI = 1.00–1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

  • 29. Fanidi, Anouar
    et al.
    Muller, David C
    Yuan, Jian-Min
    Stevens, Victoria L
    Weinstein, Stephanie J
    Albanes, Demetrius
    Prentice, Ross
    Thomsen, Cynthia A
    Pettinger, Mary
    Cai, Qiuyin
    Blot, William J
    Wu, Jie
    Arslan, Alan A
    Zeleniuch-Jacquotte, Anne
    McCullough, Marjorie L
    Le Marchand, Loic
    Wilkens, Lynne R
    Haiman, Christopher A
    Zhang, Xuehong
    Han, Jiali
    Stampfer, Meir J
    Smith-Warner, Stephanie A
    Giovannucci, Edward
    Giles, Graham G
    Hodge, Allison M
    Severi, Gianluca
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Langhammer, Arnulf
    Krokstad, Steinar
    Næss, Marit
    Wang, Renwei
    Gao, Yu-Tang
    Butler, Lesley M
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Li, Honglan
    Zheng, Wei
    Lan, Qing
    Visvanathan, Kala
    Bolton, Judith Hoffman
    Ueland, Per Magne
    Midttun, Øivind
    Ulvik, Arve
    Caporaso, Neil E
    Purdue, Mark
    Ziegler, Regina G
    Freedman, Neal D
    Buring, Julie E
    Lee, I-Min
    Sesso, Howard D
    Gaziano, J Michael
    Manjer, Jonas
    Ericson, Ulrika
    Relton, Caroline
    Brennan, Paul
    Johansson, Mattias
    Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)2018Inngår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, nr 1, artikkel-id djx119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.

    Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.

    Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.

    Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.

  • 30. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikkel-id 10192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

  • 31. Ferreiro-Iglesias, Aida
    et al.
    Lesseur, Corina
    McKay, James
    Hung, Rayjean J.
    Han, Younghun
    Zong, Xuchen
    Christiani, David
    Johansson, Mattias
    Xiao, Xiangjun
    Li, Yafang
    Qian, David C.
    Ji, Xuemei
    Liu, Geoffrey
    Caporaso, Neil
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Kontic, Milica
    Ognjanovic, Simona
    Lissowska, Jolanta
    Szolkowska, Malgorzata
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Bolca, Ciprian
    Savic, Milan
    Ognjanovic, Miodrag
    Bojesen, Stig Egil
    Wu, Xifeng
    Albanes, Demetrios
    Aldrich, Melinda C.
    Tardon, Adonina
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    Le Marchand, Loic
    Rennert, Gadi
    Chen, Chu
    Doherty, Jennifer
    Goodman, Gary
    Bickeboeller, Heike
    Wichmann, H-Erich
    Risch, Angela
    Rosenberger, Albert
    Shen, Hongbing
    Dai, Juncheng
    Field, John K.
    Davies, Michael
    Woll, Penella
    Teare, M. Dawn
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Yuan, Jian-Min
    Hong, Yun-Chul
    Haugen, Aage
    Zienolddiny, Shanbeh
    Lam, Stephen
    Tsao, Ming-Sound
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Schabath, Matthew B.
    Andrew, Angeline
    Duell, Eric
    Melander, Olle
    Brunnstrom, Hans
    Lazarus, Philip
    Arnold, Susanne
    Slone, Stacey
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Landi, Maria Teresa
    Amos, Christopher, I
    Brennan, Paul
    Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity2018Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikkel-id 3927Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

  • 32. Fortner, Renee T.
    et al.
    Tolockiene, Egle
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Schock, Helena
    Oda, Husam
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lakso, Hans-Åke
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Kaaks, Rudolf
    Toniolo, Paolo
    Zeleniuch-Jacquotte, Anne
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Early pregnancy sex steroids during primiparous pregnancies and maternal breast cancer: a nested case-control study in the Northern Sweden Maternity Cohort2017Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 19, artikkel-id 82Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones.

    Methods: We conducted a nested case–control study in the Northern Sweden Maternity Cohort (1975–2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression.

    Results: Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (ORlog2: 0.64 (0.41–1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (ORlog2: 1.57 (1.13–2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11–3.16)). None of the investigated hormones were associated with ER–/PR– disease, or with AR+ or AR+/ER+/PR+ disease.

    Conclusions: Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease.

  • 33. Fortner, Renée T
    et al.
    Schock, Helena
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Zeleniuch-Jacquotte, Anne
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Toniolo, Paolo
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Surcel, Helja-Marja
    Early pregnancy sex steroids and maternal breast cancer: a nested case-control study2014Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 23, s. 6958-6967Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association.

  • 34. Fortner, Renée T
    et al.
    Schock, Helena
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Korpela, Jaana
    Toriola, Adetunji T
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Zeleniuch-Jacquotte, Anne
    Toniolo, Paolo
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Surcel, Heljä-Marja
    Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort2017Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, nr 1, s. 134-141Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1, 1.10; 95% CI, 0.64-1.89; ≥15 years, ORQ4 vs. Q1, 1.36; 95% CI, 0.86-2.13; pheterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. 

  • 35. Geoghegan, Fintan
    et al.
    Buckland, Robert J.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Rogers, Eric T.
    Khalifa, Karima
    O'Connor, Emma B.
    Rooney, Mary F.
    Behnam-Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Porter, Richard K.
    Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 55, s. 94711-94725Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Acquired cisplatin resistance is a common feature of tumours following cancer treatment with cisplatin and also of non-small cell lung cancer (H1299) and mesothelioma (P31) cell lines exposed to cisplatin. To elucidate the cellular basis of acquired cisplatin resistance, a comprehensive bioenergetic analysis was undertaken. We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance. The differential mitochondrial abundance was supported by data showing reduced sirtuin 1 (SIRT1), peroxisome-proliferator activator receptor-gamma co-activator 1-alpha (PGC1 alpha), sirtuin 3 (SIRT3) and mitochondrial transcription factor A (TFAM) protein expression in resistant cells. Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1 alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit alpha 2 (AMPK alpha 2) transcripts and protein expression in resistant H1299 cells. mRNA expression was also reduced for cisplatin resistant H1299 cells in these genes, however the pattern was not consistent in resistant P31 cells. There was very little change in DNA methylation of these genes, suggesting that the cells are not stably reprogrammed epigenetically. Taken together, our data demonstrate reduced oxidative metabolism, reduced mitochondrial abundance, potential for increased glycolytic flux and increased ROS production in acquired cisplatin resistant cells. This suggests that the metabolic changes are a result of reduced SIRT3 expression and increased HIF-1 alpha stabilization.

  • 36.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Mechanisms of alloxan diabetogenicity1981Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Suspensions of pancreatic islet cells from ob/ob-mice were incubated with Trypan Blue. Microscope photometry showed that apparently viable cells excluded the dye completely, whereas the nuclei of non-viable cells accumulated Trypan Blue by a saturable process. Alloxan rapidly increased the permeability of the plasma membrane in mouse 3-cells; the exclusion of Trypan Blue is a valid and useful measure of islet cell viability following alloxan exposure.

    The diabetogenic action of alloxan may be mediated by hydroxyl radicals. In several biological systems hydroxyl radicals are formed by an iron-catalyzed reaction between superoxide anion radicals and hydrogen peroxide. To test whether this applies to alloxan diabetogenicity, the effects of superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators were tested (a) in a cell-free radical-generating system and (b) on islets and islet-cells exposed to alloxan In vitro. The effect of longtime-circulating superoxide dismutase injected prior to alloxan was tested on mice in vivo.

    Luminol chemiluminescence was used to monitor alloxan-dependent radical production. Accumulation of 8^Rb+ and exclusion of Trypan Blue were used as cell viability criteria in isolated mouse islets and islet-cells. Blood glucose was determined to monitor the development of diabetes in living animals.

    Superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators inhibited the alloxan-dependent chemiluminescence and decreased the toxic effects on Rb+ accumulation or Trypan Blue exclusion in islets and islet-cells. Superoxide dismutase, linked to polyethylene glycol and injected 12 hours before alloxan, largely prevented the development of alloxan diabetes.

    Alloxan toxicity _in vitro and in vivo seems to depend on the formation of superoxide radicals and hydrogen peroxide which in turn form the noxious hydroxyl radical via an iron-catalyzed Haber-Weiss reaction.

    As free radicals and hydrogen peroxide can be formed by other chemicals and during inflammation, and inflammation may accompany the outbreak of human diabetes, studies on the beneficiary effects of superoxide dismutase and other scavengers of free radicals in other forms of diabetes seem warranted.

  • 37.
    Grankvist, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Gomez, Ruben
    Nybo, Mads
    Lima-Oliveira, Gabriel
    von Meyer, Alexander
    Preanalytical aspects on short- and long-term storage of serum and plasma2019Inngår i: Diagnosis, ISSN 2194-8011, Vol. 6, nr 1, s. 51-56Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Following an ordered clinical chemistry plasma/serum test, ideally the venous blood specimen is adequately collected at a health care facility, then swiftly transported to and readily handled, analyzed and sometimes interpreted at a clinical chemistry laboratory followed by a report of the test result to the ordering physician to finally handle the result. However, often there are practical as well as sample quality reasons for short-or long-term storage of samples before and after analysis. If there are specific storage needs, the preanalytical handling practices are specified in the laboratory's specimen collection instructions for the ordered test analyte. Biobanking of specimens over a very long time prior to analysis includes an often neglected preanalytical challenge for preserved quality of the blood specimen and also involves administrative and additional practical handling aspects (specified in a standard operating procedure SOP) when demands and considerations from academic, industry, research organizations and authorities are included. This short review highlights some preanalytical aspects of plasma/serum short-and long-term storage that must be considered by clinicians, laboratory staff as well as the researchers.

  • 38.
    Grankvist, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Hammarsten, Ola
    Institutionen för Biomedicin, Göteborgs universitet.
    Berggren Söderlund, Maria
    Klinisk kemi och transfusionsmedicin, Kronoberg.
    Theodorsson, Elvar
    Institutionen för klinisk och experimentell medicin, Linköpings universitet.
    Laboratoriernas verksamhet2018Inngår i: Laurells Klinisk kemi i praktisk medicin / [ed] Elvar Theodorsson & Maria Berggren Söderlund, Lund: Studentlitteratur AB, 2018, 10, s. 13-30Kapittel i bok, del av antologi (Fagfellevurdert)
  • 39.
    Grankvist, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Sigthorsson, Gudmundur
    Kristensen, Gunn B.
    Pelanti, Jonna
    Nybo, Mads
    Status on fasting definition for blood sampling in the Nordic countries - time for a harmonized definition2018Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 78, nr 7-8, s. 591-594Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The preanalytical phase contains a vast number of practices whose variation may influence the results of laboratory testing and should, therefore, be standardized. The Working Group on Preanalytical Phase of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM WG-PA) has suggested a standardization of venous blood specimen collection (VBSC) requirements for fasting samples including 12 h fasting time and water ad lib in the morning prior to specimen collection. The Nordic Scientific Preanalytical Working Group investigated the fasting definitions used in the Nordic countries. The Internet was assessed for stated fasting definitions of official organizations, larger laboratories, or laboratory groups. Fasting instructions for VBSC generally demanded patients to abstain from alcohol a day prior to, and to abstain from coffee, tea, smoking, and snuff intake in the morning of VBSC. Norway had a national fasting definition. Required fasting times varied from 8 to 14 h. The amount of water allowed in the morning of VBSC varied from ad lib to half a glass of water. The list of analytes, where fasting was required, held 9-15 analytes except for Finland with 65 analytes. Implementation of the EFLM WG-PRE standardization of VBSC requirements for fasting samples would decrease preanalytical variability and be beneficial for medical decisions and patient data comparison. We suggest the laboratories in the Nordic countries to implement the suggested fasting requirements, which are in line with those used when fasting reference intervals were established in the Nordic reference interval project.

  • 40. Guida, Florence
    et al.
    Sun, Nan
    Bantis, Leonidas E.
    Muller, David C.
    Li, Peng
    Taguchi, Ayumu
    Dhillon, Dilsher
    Kundnani, Deepali L.
    Patel, Nikul J.
    Yan, Qingxiang
    Byrnes, Graham
    Moons, Karel G. M.
    Tjonneland, Anne
    Panico, Salvatore
    Agnoli, Claudia
    Vineis, Paolo
    Palli, Domenico
    Bueno-de-Mesquita, Bas
    Peeters, Petra H.
    Agudo, Antonio
    Huerta, Jose M.
    Dorronsoro, Miren
    Rodriguez Barranco, Miguel
    Ardanaz, Eva
    Travis, Ruth C.
    Byme, Karl Smith
    Boeing, Heiner
    Steffen, Annika
    Kaaks, Rudolf
    Huesing, Anika
    Trichopoulou, Antonia
    Lagiou, Pagona
    La Vecchia, Carlo
    Severi, Gianluca
    Boutron-Ruault, Marie-Christine
    Sandanger, Torkjel M.
    Weiderpass, Elisabete
    Nost, Therese H.
    Tsilidis, Kostas
    Riboli, Elio
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Goodman, Gary E.
    Feng, Ziding
    Brennan, Paul
    Johansson, Mattias
    Hanash, Samir M.
    Assessment of Lung Cancer Risk on the Basis of a Biomarker Panel of Circulating Proteins2018Inngår i: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 4, nr 10, artikkel-id e182078Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Importance  There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases.

    Objective  To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria.

    Design, Setting, and Participants  Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS).

    Main Outcomes and Measures  Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity).

    Results  In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model.

    Conclusions and Relevance  This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening.

  • 41.
    Hammarsten, Ola
    et al.
    Institutionen för Biomedicin, Göteborgs universitet.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Theodorsson, Elvar
    Institutionen för klinisk och experimentell medicin, Linköpings universitet.
    Tolkning av analysresultat2018Inngår i: Laurells Klinisk kemi i praktisk medicin / [ed] Elvar Theodorsson & Maria Berggren Söderlund, Lund: Studentlitteratur AB, 2018, 10, s. 31-53Kapittel i bok, del av antologi (Fagfellevurdert)
  • 42. Holl, Katsiaryna
    et al.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kaasila, Marjo
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Afanasyeva, Yelena
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Lehtinen, Matti
    Pukkala, Eero
    Surcel, Helja-Marja
    Toniolo, Paolo
    Zeleniuch-Jacquotte, Anne
    Koskela, Pentti
    Lukanova, Annekatrin
    Effect of long-term storage on hormone measurements in samples from pregnant women: the experience of the Finnish Maternity Cohort2008Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, nr 3, s. 406-412Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Validity of biobank studies on hormone associated cancers depend on the extent the sample preservation is affecting the hormone measurements. We investigated the effect of long-term storage (up to 22 years) on immunoassay measurements of three groups of hormones and associated proteins: sex-steroids [estradiol, progesterone, testosterone, dihydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG)], pregnancy-specific hormones [human chorionic gonadotropin (hCG), placental growth hormone (pGH), alpha-fetoprotein (AFP)], and insulin-like growth factor (IGF) family hormones exploiting the world largest serum bank, the Finnish Maternity Cohort (FMC). Hormones of interest were analyzed in a random sample of 154 Finnish women in the median age (29.5 years, range 25 to 34 years) of their first pregnancy with serum samples drawn during the first trimester. All hormone measurements were performed using commercial enzyme-linked- or radio-immunoassays. Storage time did not correlate with serum levels of testosterone, DHEAS, hCG, pGH and total IGFBP-1. It had a weak or moderate negative correlation with serum levels of progesterone (Spearman's ranked correlation coefficient (rs)=− 0.36), IGF-I (rs=−0.23) and IGF binding protein (BP)-3 (rs=−0.38), and weak positive correlation with estradiol (rs=0.23), SHBG (rs=0.16), AFP (rs=0.20) and non-phosphorylated IGF binding protein (BP)-1 (rs=0.27). The variation of all hormone levels studied followed the kinetics reported for early pregnancy. Bench-lag time (the time between sample collection and freezing for storage) did not materially affect the serum hormone levels. In conclusion, the stored FMC serum samples can be used to study hormone-disease associations, but close matching for storage time and gestational day are necessary design components of all related biobank studies.

  • 43. Holl, Katsiaryna
    et al.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Surcel, Heljä-Marja
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Koskela, Pentti
    Dillner, Joakim
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Olafsdottir, Gudridur H
    Ogmundsdottir, Helga M
    Pukkala, Eero
    Lehtinen, Matti
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Lukanova, Annekatrin
    Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: A nested case-referent study.2009Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, nr 12, s. 2923-2928Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring. (c) 2009 UICC.

  • 44. Huang, Joyce Y.
    et al.
    Larose, Tricia L.
    Luu, Hung N.
    Wang, Renwei
    Fanidi, Anouar
    Alcala, Karine
    Stevens, Victoria L.
    Weinstein, Stephanie J.
    Albanes, Demetrius
    Caporaso, Neil E.
    Purdue, Mark P.
    Ziegler, Regina G.
    Freedman, Neal D.
    Lan, Qing
    Prentice, Ross L.
    Pettinger, Mary
    Thomson, Cynthia A.
    Cai, Qiuyin
    Wu, Jie
    Blot, William J.
    Shu, Xiao-Ou
    Zheng, Wei
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    Le Marchand, Loic
    Wilkens, Lynn R.
    Haiman, Christopher A.
    Zhang, Xuehong
    Stampfer, Meir J.
    Giles, Graham G.
    Hodge, Allison M.
    Severi, Gianluca
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Langhammer, Arnulf
    Hveem, Kristian
    Xiang, Yong-Bing
    Li, Hong-Lan
    Gao, Yu-Tang
    Visvanathan, Kala
    Ueland, Per M.
    Midttun, Oivind
    Ulvi, Arve
    Buring, Julie E.
    Lee, I-Min
    SeSS, Howard D.
    Gaziano, J. Michael
    Manjer, Jonas
    Relton, Caroline
    Koh, Woon-Puay
    Brennan, Paul
    Johansson, Mattias
    Yuan, Jian-Min
    Han, Jiali
    Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p(trend) < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

  • 45. Hung, Rayjean J.
    et al.
    Spitz, Margaret R.
    Houlston, Richard S.
    Schwartz, Ann G.
    Field, John K.
    Ying, Jun
    Li, Yafang
    Han, Younghun
    Ji, Xuemei
    Chen, Wei
    Wu, Xifeng
    Gorlov, Ivan P.
    Na, Jie
    de Andrade, Mariza
    Liu, Geoffrey
    Brhane, Yonathan
    Diao, Nancy
    Wenzlaff, Angela
    Davies, Michael P. A.
    Liloglou, Triantafillos
    Timofeeva, Maria
    Muley, Thomas
    Rennert, Hedy
    Saliba, Walid
    Ryan, Brid M.
    Bowman, Elise
    Barros-Dios, Juan-Miguel
    Perez-Rios, Monica
    Morgenstern, Hal
    Zienolddiny, Shanbeh
    Skaug, Vidar
    Ugolini, Donatella
    Bonassi, Stefano
    van der Heijden, Erik H. F. M.
    Tardon, Adonina
    Bojesen, Stig E.
    Landi, Maria Teresa
    Johansson, Mattias
    Bickeboeller, Heike
    Arnold, Susanne
    Le Marchand, Loic
    Melander, Olle
    Andrew, Angeline
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Caporaso, Neil
    Teare, M. Dawn
    Schabath, Matthew B.
    Aldrich, Melinda C.
    Kiemeney, Lambertus A.
    Wichmann, H-Erich
    Lazarus, Philip
    Mayordomo, Jose
    Neri, Monica
    Haugen, Aage
    Zhang, Zuo-Feng
    Ruano-Ravina, Alberto
    Brenner, Hermann
    Harris, Curtis C.
    Orlow, Irene
    Rennert, Gadi
    Risch, Angela
    Brennan, Paul
    Christiani, David C.
    Amos, Christopher I.
    Yang, Ping
    Gorlova, Olga Y.
    Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region2019Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 14, nr 8, s. 1360-1369Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  • 46.
    Jacobsen, Jan
    et al.
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Grankvist, Kjell
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Rasmuson, Torgny
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Landberg, G
    Ljungberg, Börje
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Expression of vascular endothelial growth factor protein in human renal cell carcinoma2004Inngår i: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 93, nr 3, s. 297-302Artikkel i tidsskrift (Fagfellevurdert)
  • 47.
    Jacobsen, Jan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Rasmuson, Torgny
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Prognostic importance of serum vascular endothelial growth factor in relation to platelet and leukocyte counts in human renal cell carcinoma2002Inngår i: European Journal of Cancer Prevention, ISSN 0959-8278, E-ISSN 1473-5709, Vol. 11, nr 3, s. 245-252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It has been shown that both serum vascular endothelial growth factor (VEGF) and also platelet counts are associated with survival in renal cell carcinoma (RCC). It is not known, however, whether VEGF in serum relates to the angiogenic activity of the tumour or is derived from circulating blood components. Therefore, the interrelation between serum VEGF, platelet and leukocyte counts compared with health history, clinicopathological findings and outcome was evaluated in patients with RCC. Blood samples were collected before nephrectomy in 161 patients. Serum VEGF165 was assessed by a quantitative ELISA method. Platelet and leukocyte counts were analysed routinely and obtained from medical records. The variables were compared using univariate and multivariate analysis. There were significant correlations between VEGF levels, and platelet (P < 0.001) and leukocyte counts (P < 0.001). Serum VEGF levels, platelet counts, as well as leukocyte counts correlated significantly to stage and grade. Platelet counts were significantly lower in men with medication (P = 0.042), and decreased with age particularly in women (P = 0.001). Age or medication did not affect VEGF levels or leukocyte counts. Both VEGF and platelets gave significant prognostic information in univariate analysis. Using Cox multivariate analysis, VEGF was the last variable to be excluded. Only stage and grade remained as independent prognostic factors. Both VEGF levels and platelet counts gave prognostic information but VEGF was more reliable as predictor of survival in patients with RCC.

  • 48.
    Janson, Veronica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Andersson, Britta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Behnam-Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Engström, Karl-Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na,K(+),2Cl(-;)-cotransport Activity and Cisplatin-induced Early Membrane Blebbing.2008Inngår i: Cell Physiol Biochem, ISSN 1421-9778, Vol. 22, nr 1-4, s. 45-56Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS:

    Resistance mechanisms are important limiting factors in the treatment of solid malignancies with cis-diamminedichloroplatinum(II) (cisplatin). To gain further understanding of the effects of acquired cisplatin-resistance, we compared a human malignant pleural mesothelioma cell line (p31) to a sub-line (p31res1.2) with acquired cisplatin-resistance.

    METHODS AND RESULTS:

    The role of Na(+),K(+),2Cl(-)-cotransport (NKCC1) activity in cisplatin-induced morphological changes and acquired cisplatin-resistance was investigated in a time-resolved manner. Acquisition of cisplatin-resistance resulted in markedly reduced NKCC1 activity, absence of cisplatin-induced early membrane blebbing, and increased basal caspase-3 activity. At equitoxic cisplatin concentrations, P31res1.2 cells had a faster activation of caspase-3 than P31 cells, but the end-stage cytotoxicity and number of cells with DNA fragmentation was similar. Bumetanide inhibition of NKCC1 activity in P31 cells repressed cisplatin-induced early-phase membrane blebbing but did not increase P31 cell resistance to cisplatin.

    CONCLUSIONS:

    Together, these results suggest that active NKCC1 was necessary for cisplatin-induced early membrane blebbing of P31 cells, but not for cisplatin-resistance. Thus, acquisition of cisplatin-resistance can affect mechanisms that have profound effects on cisplatin-induced morphological changes but are not necessary for the subsequent progression to apoptosis.

  • 49.
    Janson, Veronica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Behnam-Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hörstedt, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Engström, Karl Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Phase-contrast microscopy studies of early Cisplatin-induced morphological changes of malignant mesothelioma cells and the correspondence to induced apoptosis2008Inngår i: Experimental Lung Research, ISSN 0190-2148, E-ISSN 1521-0499, Vol. 34, nr 2, s. 49-67Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cisplatin treatment efficacy of malignant pleural mesothelioma (MPM) is aggravated by resistance and adverse effects. In P31 MPM cells, cisplatin induces morphological changes and apoptosis. To determine if very early (10 minutes) morphological responses corresponded to apoptosis-induction, cisplatin effects on P31 morphology were examined with phase-contrast microscopy (PCM), scanning electron microscopy (SEM), and flow cytometry (fluorescence-activated cell sorting [FACS]), and compared to apoptosis-induction over time. Increased membrane protrusions were identified with PCM and SEM, but these were not consistent with the induction of apoptosis. The authors concluded that very early morphological changes can be determined with PCM in MPM, but they did not convincingly correspond to apoptosis induction.

  • 50.
    Janson, Veronica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance.2010Inngår i: Cell death & disease, ISSN 2041-4889, Vol. 1, nr 9, s. e78-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Apoptotic cysteine-aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction.

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