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Hedman, Håkan
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Publications (10 of 62) Show all publications
Stefansson, K., Oda, H., Öfverman, C., Lundin, E., Hedman, H. & Lindquist, D. (2019). LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: association with prognosis in relation to HPV‑DNA and p16INK4a status. Oncology Reports, 42(1), 142-150
Open this publication in new window or tab >>LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: association with prognosis in relation to HPV‑DNA and p16INK4a status
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2019 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 42, no 1, p. 142-150Article in journal (Refereed) Published
Abstract [en]

The present study was conducted to investigate the possible prognostic value of molecular markers LRIG1‑2 and LIM domain 7 protein (LMO7) in vulvar squamous cell carcinoma (VSCC) and their possible correlation to human papilloma virus (HPV)‑ and p16INK4a‑status of the tumors. Patients diagnosed with VSCC at the University Hospital of Umeå, Sweden, during the years 1990‑2013 were selected. Tumor blocks were retrieved from tissue archives and clinical data were collected from the records of patients. HPV‑PCR analysis, HPV genotyping and immunohistochemistry were performed. In total, 112 patients were included. Forty percent of the tumors were HPV‑positive, 27% were p16INK4a‑positive and 23% were positive for both HPV and p16INK4a (considered HPV‑driven). HPV‑positivity and p16INK4a‑positivity were associated with prolonged disease‑free survival (DFS) in Kaplan‑Meier survival analysis. Leucine‑rich repeats and immunoglobulin‑like domains 1 (LRIG1) immunoreactivity was not significantly associated with survival. High leucine‑rich repeats and immunoglobulin‑like domains 2 (LRIG2) immunoreactivity was associated with a prolonged overall survival (OS) (P=0.001). By analyzing HPV‑negative cases only, it was determined that high LRIG2 immunoreactivity was associated with both favorable OS (P=0.008) and DFS (P=0.031). LRIG2 immunoreactivity was also an independent prognostic factor in multivariate analysis of OS (P=0.002, HR=0.41; 95% CI, 0.24‑0.71). High immunoreactivity with LMO7‑1250 antibody was associated with survival benefits in the whole cohort (OS; P=0.011) although DFS was only prolonged in HPV‑negative and not HPV‑driven tumors (P=0.038 and 0.042, respectively). The present study indicated that LRIG2 and LMO7 may be useful prognostic markers in VSCC, particularly for patients without HPV‑driven tumors or with advanced tumors at diagnosis. In contrast to earlier observations regarding other types of squamous cell carcinoma, LRIG1 was not a significant prognostic factor in VSCC.

Place, publisher, year, edition, pages
Spandidos Publications, 2019
Keywords
vulvar squamous cell carcinoma, leucine‑rich repeats and immunoglobulin‑like domains, human papillomavirus, p16INK4a, survival
National Category
Cancer and Oncology
Research subject
health services research
Identifiers
urn:nbn:se:umu:diva-159681 (URN)10.3892/or.2019.7138 (DOI)31059071 (PubMedID)
Available from: 2019-06-03 Created: 2019-06-03 Last updated: 2019-06-05Bibliographically approved
Roberts, N. A., Hilton, E. N., Lopes, F. M., Singh, S., Randles, M. J., Gardiner, N. J., . . . Woolf, A. S. (2019). Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder. Kidney International, 95(5), 1138-1152
Open this publication in new window or tab >>Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder
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2019 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 95, no 5, p. 1138-1152Article in journal (Refereed) Published
Abstract [en]

Mutations in leucine-rich-repeats and immunoglobulin-likedomains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2, including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2019
Keywords
autonomic, ganglia, gene, mouse, urination
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-158940 (URN)10.1016/j.kint.2018.11.040 (DOI)000465213400018 ()30885509 (PubMedID)
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2019-05-27Bibliographically approved
Faraz, M., Herdenberg, C., Holmlund, C., Henriksson, R. & Hedman, H. (2018). A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors. Journal of Biological Chemistry, 293(9), 3421-3435
Open this publication in new window or tab >>A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 9, p. 3421-3435Article in journal (Refereed) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a tumor suppressor and a negative regulator of several receptor tyrosine kinases. The molecular mechanisms by which LRIG1 mediates its tumor suppressor effects and regulates receptor tyrosine kinases remain incompletely understood. Here, we performed a yeast two-hybrid screen to identify novel LRIG1-interacting proteins and mined data from the BioPlex (biophysical interactions of ORFeome-based complexes) protein interaction data repository. The putative LRIG1 interactors identified in the screen were functionally evaluated using a triple co-transfection system in which HEK293 cells were co-transfected with platelet-derived growth factor receptor α, LRIG1, and shRNAs against the identified LRIG1 interactors. The effects of the shRNAs on the ability of LRIG1 to down-regulate platelet-derived growth factor receptor α expression were evaluated. On the basis of these results, we present an LRIG1 protein interaction network with many newly identified components. The network contains the apparently functionally important LRIG1-interacting proteins RAB4A, PON2, GAL3ST1, ZBTB16, LRIG2, CNPY3, HLA-DRA, GML, CNPY4, LRRC40, and LRIG3, together with GLRX3, PTPRK, and other proteins. In silico analyses of The Cancer Genome Atlas data sets revealed consistent correlations between the expression of the transcripts encoding LRIG1 and its interactors ZBTB16 and PTPRK and inverse correlations between the transcripts encoding LRIG1 and GLRX3. We further studied the LRIG1 function–promoting paraoxonase PON2 and found that it co-localized with LRIG1 in LRIG1-transfected cells. The proposed LRIG1 protein interaction network will provide leads for future studies aiming to understand the molecular functions of LRIG1 and the regulation of growth factor signaling.

Place, publisher, year, edition, pages
The American Society for Biochemistry and Molecular Biology, 2018
Keywords
LRIG1, PDGFRA, PON2, PTPRK, ZBTB16, platelet-derived growth factor-C (PDGF-C), protein expression, protein-protein interaction, receptor tyrosine kinase, yeast two-hybrid
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-147386 (URN)10.1074/jbc.M117.807487 (DOI)000426562800032 ()29317492 (PubMedID)
Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-06-09Bibliographically approved
Karlsson, T., Kvarnbrink, S., Holmlund, C., Botling, J., Micke, P., Henriksson, R., . . . Hedman, H. (2018). LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease. Lung Cancer, 125, 174-184
Open this publication in new window or tab >>LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease
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2018 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, p. 174-184Article in journal (Refereed) Published
Abstract [en]

Objectives: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.

Materials and methods: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.

Results: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.

Conclusion: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Non-small cell lung cancer, Lung cancer, Prognosis, LRIG1, LRIG3, LMO7, LIMCH1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-154070 (URN)10.1016/j.lungcan.2018.09.017 (DOI)000450378500025 ()30429017 (PubMedID)
Funder
Swedish Cancer SocietyThe Kempe FoundationsVästerbotten County Council
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved
Mao, F., Holmlund, C., Faraz, M., Wang, W., Bergenheim, T., Kvarnbrink, S., . . . Hedman, H. (2018). Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma. Oncogenesis, 7, Article ID 13.
Open this publication in new window or tab >>Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma
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2018 (English)In: Oncogenesis, E-ISSN 2157-9024, Vol. 7, article id 13Article in journal (Refereed) Published
Abstract [en]

Recently, a genome-wide association study showed that a single nucleotide polymorphism (SNP) —rs11706832—in intron 2 of the human LRIG1 (Leucine-rich repeats and immunoglobulin-like domains 1) gene is associated with susceptibility to glioma. However, the mechanism by which rs11706832 affects glioma risk remains unknown; additionally, it is unknown whether the expression levels of LRIG1 are a relevant determinant of gliomagenesis. Here, we investigated the role of Lrig1 in platelet-derived growth factor (PDGF)-induced experimental glioma in mice by introducing mono-allelic and bi-allelic deletions of Lrig1 followed by inducing gliomagenesis via intracranial retroviral transduction of PDGFB in neural progenitor cells. Lrig1 was expressed in PDGFB-induced gliomas in wild-type mice as assessed using in situ hybridization. Intriguingly, Lrig1-heterozygous mice developed higher grade gliomas than did wild-type mice (grade IV vs. grade II/III, p = 0.002). Reciprocally, the ectopic expression of LRIG1 in the TB107 high-grade human glioma (glioblastoma, grade IV) cell line decreased the invasion of orthotopic tumors in immunocompromised mice in vivo and reduced cell migration in vitro. Concomitantly, the activity of the receptor tyrosine kinase MET was downregulated, which partially explained the reduction in cell migration. In summary, Lrig1 is a haploinsufficient suppressor of PDGFB-driven glioma, possibly in part via negative regulation of MET-driven cell migration and invasion. Thus, for the first time, changes in physiological Lrig1 expression have been linked to gliomagenesis, whereby the SNP rs11706832 may affect glioma risk by regulating LRIG1 expression.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-147385 (URN)10.1038/s41389-017-0012-8 (DOI)000429469500001 ()29391393 (PubMedID)
Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-06-09Bibliographically approved
Lindquist, D., Alsina, F. C., Herdenberg, C., Larsson, C., Höppener, J., Wang, N., . . . Hedman, H. (2018). LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer. International journal of oncology, 52(4), 1189-1197
Open this publication in new window or tab >>LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer
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2018 (English)In: International journal of oncology, ISSN 1791-2423, Vol. 52, no 4, p. 1189-1197Article in journal (Refereed) Published
Abstract [en]

Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a suppressor of various receptor tyrosine kinases, including RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC. LRIG1 was shown to physically interact with both RET2A and RET2B and to restrict their ligand-independent activation. LRIG1 mRNA levels were downregulated in PTC and MTC compared to normal thyroid gland tissue. There was no apparent association between LRIG1 RNA or protein expression levels and patient survival in the studied cohorts. The transgenic RET2B mice developed pre-cancerous medullary thyroid lesions at a high frequency (36%); however, no overt cancers were observed. There was no significant difference in the incidence of pre-cancerous lesions between Lrig1 wild-type and Lrig1-deficient RET2B mice. In conclusion, the findings that LRIG1 is a negative regulator of RET2A and RET2B and is also downregulated in PTC and MTC may suggest that LRIG1 functions as a thyroid tumor suppressor.

Keywords
thyroid cancer, LRIG1, RET, C634R, M918T, MEN2A, MEN2B
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-145641 (URN)10.3892/ijo.2018.4273 (DOI)000427164400013 ()29436694 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-06-09Bibliographically approved
Ranhem, C., Larsson, G. L., Hedman, H., Lindquist, D., Karlsson, M. G., Hellstrom, A.-C., . . . Andersson, S. (2017). Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma. PLoS ONE, 12(8), Article ID e0183816.
Open this publication in new window or tab >>Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0183816Article in journal (Refereed) Published
Abstract [en]

Background: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients.

Methods: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses.

Results: The majority of PVC patients (72%) had >50% LRIG1- and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival.

Conclusion: LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-140970 (URN)10.1371/journal.pone.0183816 (DOI)000408370700059 ()
Funder
Swedish Research Council, 521-2008-2899
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2018-06-09Bibliographically approved
Neirinckx, V., Hedman, H. & Niclou, S. P. (2017). Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy. Biochimica et Biophysica Acta, 1868(1), 109-116
Open this publication in new window or tab >>Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy
2017 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1868, no 1, p. 109-116Article, review/survey (Refereed) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) is an endogenous feedback regulator of receptor tyrosine kinases (RTKs) and was recently shown to inhibit growth of different types of malignancies. Additionally, this multifaceted RTK inhibitor was reported to be a tumor suppressor, a stem cell regulator, and a modulator of different cellular phenotypes. This mini-review provides a concise and up-to-date summary about the known functions of LRIG1 and its related family members, with a special emphasis on underlying molecular mechanisms and the opportunities for harnessing its therapeutic potential against cancer. 

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Leucine-rich repeats and immunoglobulin-like domains containing protein 1, Receptor tyrosine nase, Ectodomain, Nervous system, Cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-139822 (URN)10.1016/j.bbcan.2017.02.007 (DOI)000408783200010 ()28259645 (PubMedID)
Available from: 2017-09-25 Created: 2017-09-25 Last updated: 2018-06-09Bibliographically approved
Lindquist, D., Henriksson, R. & Hedman, H. (2017). LRIG1 Was Down-Regulated in Medullary Thyroid Cancer but No Significant Effect of LRIG1 Was Found in RET2B Transgenic Mice and Human Differentiated Thyroid Cancer. Paper presented at 14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 08-10, 2017, Barcelona, SPAIN. Neuroendocrinology, 105, 152-152
Open this publication in new window or tab >>LRIG1 Was Down-Regulated in Medullary Thyroid Cancer but No Significant Effect of LRIG1 Was Found in RET2B Transgenic Mice and Human Differentiated Thyroid Cancer
2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, p. 152-152Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
S. Karger, 2017
Keywords
lrig1, ret, mtc
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-142006 (URN)000413957900153 ()
Conference
14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 08-10, 2017, Barcelona, SPAIN
Available from: 2018-01-10 Created: 2018-01-10 Last updated: 2018-06-09Bibliographically approved
Hellström, M., Ericsson, M., Johansson, B., Faraz, M., Anderson, F., Henriksson, R., . . . Hedman, H. (2016). Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice. American Journal of Physiology. Regulatory Integrative and Comparative Physiology, 310(11), R1045-R1052
Open this publication in new window or tab >>Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice
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2016 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 310, no 11, p. R1045-R1052Article in journal (Refereed) Published
Abstract [en]

Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wildtype mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans.

National Category
Physiology
Identifiers
urn:nbn:se:umu:diva-122617 (URN)10.1152/ajpregu.00309.2015 (DOI)000377021700004 ()27009049 (PubMedID)
Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2018-06-07Bibliographically approved
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