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Thysell, E., Vidman, L., Bovinder Ylitalo, E., Jernberg, E., Crnalic, S., Iglesias-Gato, D., . . . Wikström, P. (2019). Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor. Molecular Oncology, 13(8), 1763-1777
Åpne denne publikasjonen i ny fane eller vindu >>Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor
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2019 (engelsk)Inngår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, nr 8, s. 1763-1777Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2019
Emneord
bone metastasis, gene expression, gene set enrichment analysis, morphology, survival, unsupervised cluster analysis
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-162668 (URN)10.1002/1878-0261.12526 (DOI)000478600200009 ()31162796 (PubMedID)
Tilgjengelig fra: 2019-09-05 Laget: 2019-09-05 Sist oppdatert: 2019-09-05bibliografisk kontrollert
Otten, V. T., Mukka, S., Nilsson, K. G., Crnalic, S. & Kärrholm, J. (2019). Uncemented cups with and without screw holes in primary THA: a Swedish Hip Arthroplasty Register study with 22,725 hips. Acta Orthopaedica, 90(3), 258-263
Åpne denne publikasjonen i ny fane eller vindu >>Uncemented cups with and without screw holes in primary THA: a Swedish Hip Arthroplasty Register study with 22,725 hips
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2019 (engelsk)Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 90, nr 3, s. 258-263Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background and purpose — Uncemented cups in total hip arthroplasty (THA) are often augmented with additional screws to enhance their primary stability. We investigated whether there is a difference in the risk for revision between cups with screw holes and cups without screw holes.

Patients and methods — We analyzed the risk for cup revision of uncemented cups registered in the Swedish Hip Arthroplasty Register (SHAR) between 2000 and 2017 with respe ct to the presence of screw holes. Only patients with primary osteoarthritis (OA) were included. 22,725 cups, including 12,354 without screw holes and 10,371 with screw holes, were evaluated. Revision rates at 2 and 10 years after the primary operation were analyzed.

Results — At a median follow-up time of 3.4 years (0–18), 459 cup revisions were reported. The main reasons for cup revision during the whole observation time were infection, 52% of all cup revisions, and dislocation, 26% of all cup revisions. The survival rate with cup revision due to aseptic loosening as endpoint was 99.9% (95% CI 99.8–99.9) at 2 years for both cups with and cups without screw holes, and the survival rates at 10 years were 99.5% (CI 99.3–99.7) and 99.1% (CI 98.6–99.5), respectively. Cups without screw holes showed a decreased risk of revision due to any reason at both 2 years (adjusted hazard ratio [HR] 0.6, CI 0.5–0.8) and 10 years (HR 0.7, CI 0.5–0.9).

Interpretation — We found a very low revision rate for aseptic loosening with modern, uncemented cup designs. Cups with screw holes had an increased risk of revision due to any reason in patients with primary OA

sted, utgiver, år, opplag, sider
Taylor & Francis Group, 2019
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-158054 (URN)10.1080/17453674.2019.1599777 (DOI)000469038600013 ()30955399 (PubMedID)
Tilgjengelig fra: 2019-04-12 Laget: 2019-04-12 Sist oppdatert: 2019-06-17bibliografisk kontrollert
Wojtowicz, R., Henricson, A., Nilsson, K. G. & Crnalic, S. (2019). Uncemented monoblock trabecular metal posterior stabilized high-flex total knee arthroplasty: similar pattern of migration to the cruciate-retaining design - a prospective radiostereometric analysis (RSA) and clinical evaluation of 40 patients (49 knees) 60 years or younger with 9 years' follow-up. Acta Orthopaedica
Åpne denne publikasjonen i ny fane eller vindu >>Uncemented monoblock trabecular metal posterior stabilized high-flex total knee arthroplasty: similar pattern of migration to the cruciate-retaining design - a prospective radiostereometric analysis (RSA) and clinical evaluation of 40 patients (49 knees) 60 years or younger with 9 years' follow-up
2019 (engelsk)Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682Artikkel i tidsskrift (Fagfellevurdert) Epub ahead of print
Abstract [en]

Background and purpose — Uncemented monoblock cruciate retaining (CR) trabecular metal (TM) tibial components in total knee arthroplasty (TKA) work well in the long-term perspective in patients ≤ 60 years. Younger persons expect nearly normal knee flexion after TKA, but CR implants generally achieve less knee flexion compared with posterior stabilized (PS) implants. Cemented PS implants have higher revision rate than CR implants. Can an uncemented monoblock PS TM implant be used safely in younger patients?

Patients and methods — 40 patients (49 knees) age ≤ 60 years with primary (20 knees) or posttraumatic osteoarthritis (OA) were operated with a high-flex TKA using an uncemented monoblock PS TM tibial component. Knees were evaluated with radiostereometric analysis (RSA) a mean 3 days (1–5) postoperatively, and thereafter at 6 weeks, 3 months, 1, 2, 5, and 9 years. Clinical outcome was measured with patient-related outcome measures (PROMs).

Results — The implants showed a pattern of migration with initial large migration followed by early stabilization lasting up to 9 years, a pattern known to be compatible with good long-term results. Clinical and radiological outcome was excellent with 38 of the 40 patients being satisfied or very satisfied with the procedure and bone apposition to the entire implant surface in 46 of 49 knees. Mean knee flexion was 130°. 1 knee was revised at 3 months due to medial tibial condyle collapse.

Interpretation — The uncemented monoblock PS TM implant works well in younger persons operated with TKA due to primary or secondary OA.

sted, utgiver, år, opplag, sider
Taylor & Francis, 2019
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-161717 (URN)10.1080/17453674.2019.1626097 (DOI)000473539500001 ()31210081 (PubMedID)
Tilgjengelig fra: 2019-07-26 Laget: 2019-07-26 Sist oppdatert: 2019-07-26
Henricson, A., Wojtowicz, R., Nilsson, K. G. & Crnalic, S. (2019). Uncemented or cemented femoral components work equally well in total knee arthroplasty. Knee Surgery, Sports Traumatology, Arthroscopy, 27(4), 1251-1258
Åpne denne publikasjonen i ny fane eller vindu >>Uncemented or cemented femoral components work equally well in total knee arthroplasty
2019 (engelsk)Inngår i: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 27, nr 4, s. 1251-1258Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

PURPOSE: To study the pattern of migration and clinical results up to 10 years of uncemented versus cemented fixation of the femoral component in total knee arthroplasty.

METHODS: Randomized controlled trial was conducted of 41 patients (23 women, 18 men) under the age of 60 years using radiostereometric analysis.

RESULTS: About two-thirds of the cemented implants and half of the uncemented implants stabilized between 2 and 10 years, while the remainder displayed a small annual increase of maximum total point motion of 0.09-0.10 mm/year. At 10 years there were no statistically significant differences in migration or clinical results between the groups.

CONCLUSION: Uncemented fixation with titanium fiber mesh coating of the femoral component in total knee arthroplasty works equally as well as cemented fixation up to 10 years. An annual migration of 0.1 mm seems compatible with excellent long-term performance.

LEVEL OF EVIDENCE: I.

sted, utgiver, år, opplag, sider
Springer, 2019
Emneord
Femoral component TKA, RSA, Total knee arthroplasty, Uncemented TKA
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-157681 (URN)10.1007/s00167-018-5227-5 (DOI)000462637500030 ()30361757 (PubMedID)
Tilgjengelig fra: 2019-03-29 Laget: 2019-03-29 Sist oppdatert: 2019-04-15bibliografisk kontrollert
Nordstrand, A., Bovinder Ylitalo, E., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity. International Journal of Molecular Sciences, 19(4), Article ID 1223.
Åpne denne publikasjonen i ny fane eller vindu >>Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity
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2018 (engelsk)Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, nr 4, artikkel-id 1223Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naïve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.

sted, utgiver, år, opplag, sider
MDPI, 2018
Emneord
prostate cancer, bone, metastasis, androgen receptor, osteoblast, osteoclast, BMP
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-146973 (URN)10.3390/ijms19041223 (DOI)000434978700302 ()29670000 (PubMedID)2-s2.0-85045938451 (Scopus ID)
Tilgjengelig fra: 2018-04-24 Laget: 2018-04-24 Sist oppdatert: 2018-11-21bibliografisk kontrollert
Bovinder Ylitalo, E., Nordstrand, A., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 50-50
Åpne denne publikasjonen i ny fane eller vindu >>Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
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2018 (engelsk)Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 50-50Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
American Association for Cancer Research, 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-151399 (URN)000441803800065 ()
Konferanse
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Merknad

Supplement: S, Meeting Abstract: A048

Tilgjengelig fra: 2018-09-05 Laget: 2018-09-05 Sist oppdatert: 2018-09-05bibliografisk kontrollert
Thysell, E., Bovinder Ylitalo, E., Jernberg, E., Crnalic, S., Widmark, A., Bergh, A. & Wikström, P. (2018). Clinically relevant molecular subgroups of prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 123-123
Åpne denne publikasjonen i ny fane eller vindu >>Clinically relevant molecular subgroups of prostate cancer bone metastases
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2018 (engelsk)Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 123-123Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
American Association for Cancer Research, 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-151398 (URN)000441803800194 ()
Konferanse
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Merknad

 Supplement: S, Meeting Abstract: B081

Tilgjengelig fra: 2018-09-05 Laget: 2018-09-05 Sist oppdatert: 2018-09-05bibliografisk kontrollert
Iglesias-Gato, D., Thysell, E., Crnalic, S., Mann, M., Widmark, A., Bergh, A., . . . Wikström, P. (2018). The proteome of prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 91-92
Åpne denne publikasjonen i ny fane eller vindu >>The proteome of prostate cancer bone metastases
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2018 (engelsk)Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 91-92Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
American Association for Cancer Research, 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-151400 (URN)000441803800138 ()
Konferanse
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Merknad

Supplement: S, Meeting Abstract: B025

Tilgjengelig fra: 2018-09-05 Laget: 2018-09-05 Sist oppdatert: 2018-09-05bibliografisk kontrollert
Iglesias-Gato, D., Thysell, E., Tyanova, S., Crnalic, S., Santos, A., Lima, T. S., . . . Wikström, P. (2018). The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications. Clinical Cancer Research, 24(21), 5433-5444
Åpne denne publikasjonen i ny fane eller vindu >>The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
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2018 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, nr 21, s. 5433-5444Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.

Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.

Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid b-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.

Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. (C) 2018 AACR.

sted, utgiver, år, opplag, sider
American Association for Cancer Research, 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-153547 (URN)10.1158/1078-0432.CCR-18-1229 (DOI)000448895100025 ()30042207 (PubMedID)
Forskningsfinansiär
Swedish Research Council, K2013-64X-20407-04-3Swedish Cancer Society, CAN 2015/732Swedish Cancer Society, CAN 2016/824Swedish Cancer Society, CAN 2013/1324Swedish Cancer Society, 130293Swedish Foundation for Strategic Research , RB13-0119Novo Nordisk, NNF14CC0001
Tilgjengelig fra: 2018-11-22 Laget: 2018-11-22 Sist oppdatert: 2018-11-22bibliografisk kontrollert
Djusberg, E., Jernberg, E., Thysell, E., Golovleva, I., Lundberg, P., Crnalic, S., . . . Wikström, P. (2017). High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases. The Prostate, 77(6), 625-638
Åpne denne publikasjonen i ny fane eller vindu >>High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases
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2017 (engelsk)Inngår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, nr 6, s. 625-638Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

sted, utgiver, år, opplag, sider
Wiley-Blackwell Publishing Inc., 2017
Emneord
androgen receptor variant 7, AKR1C3, extracellular vesicles, exosomes, blood coagulation
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-131817 (URN)10.1002/pros.23307 (DOI)000397496300007 ()28144969 (PubMedID)
Tilgjengelig fra: 2017-02-22 Laget: 2017-02-22 Sist oppdatert: 2018-06-09bibliografisk kontrollert
Organisasjoner