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Bergh, Anders
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Publications (10 of 167) Show all publications
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
Open this publication in new window or tab >>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 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, no 8, p. 1763-1777Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
bone metastasis, gene expression, gene set enrichment analysis, morphology, survival, unsupervised cluster analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-162668 (URN)10.1002/1878-0261.12526 (DOI)000478600200009 ()31162796 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-05Bibliographically approved
Zang, G., Mu, Y., Gao, L., Bergh, A. & Landström, M. (2019). PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model. Oncogene, 38(22), 4215-4231
Open this publication in new window or tab >>PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model
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2019 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 22, p. 4215-4231Article in journal (Refereed) Published
Abstract [en]

Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C ζ (PKCζ) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKCζ in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKCζ shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKCζ-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKCζ-knockout or knockdown impaired the activation of AKT, ERK, and NF-κB signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKCζ regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKCζ plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-160292 (URN)10.1038/s41388-019-0722-9 (DOI)000469339100002 ()30705401 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research CouncilSwedish Cancer Society, CAN 2017/544Swedish Cancer Society, 2016/387Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-06-17Bibliographically approved
Adamo, H. H., Hammarsten, P., Hägglöf, C., Scherdin, T. D., Egevad, L., Stattin, P., . . . Bergh, A. (2019). Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome. The Prostate, 79(5)
Open this publication in new window or tab >>Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
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2019 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 5Article in journal (Refereed) Published
Abstract [en]

Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
biomarkers, C, EBP, prostate cancer, tumors instruct adjacent tissues
National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-157947 (URN)10.1002/pros.23749 (DOI)000461573200001 ()30536410 (PubMedID)
Available from: 2019-04-17 Created: 2019-04-17 Last updated: 2019-04-17Bibliographically approved
Aripaka, K., Gudey, S. K., Zang, G., Schmidt, A., Åhrling, S. S., Österman, L., . . . Landström, M. (2019). TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer. EBioMedicine, 45, 192-207
Open this publication in new window or tab >>TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed) Published
Abstract [en]

Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
beta-Catenin, LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161915 (URN)10.1016/j.ebiom.2019.06.046 (DOI)000475860000026 ()31262711 (PubMedID)2-s2.0-85067957867 (Scopus ID)
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved
Assel, M., Dahlin, A., Ulmert, D., Bergh, A., Stattin, P., Lilja, H. & Vickers, A. J. (2018). Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening. European Urology, 73(6), 961-967
Open this publication in new window or tab >>Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening
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2018 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 73, no 6, p. 961-967Article in journal (Refereed) Published
Abstract [en]

Background: Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. Objective: To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. Design, setting, and participants: The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3-10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Outcome measurements and statistical analysis: Multivariable logistic regression was used to predict high-grade (Gleason grade group >= 2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. Results and limitations: The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10-1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28-0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Conclusions: Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Patient summary: Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Lead-time, Prostate cancer, Screening, PSA
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-148723 (URN)10.1016/j.eururo.2017.10.004 (DOI)000432495800028 ()29066048 (PubMedID)2-s2.0-85045959048 (Scopus ID)
Funder
Swedish Research Council, 2016-02974Swedish Cancer Society, 14-0722
Available from: 2018-06-21 Created: 2018-06-21 Last updated: 2018-06-21Bibliographically approved
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.
Open this publication in new window or tab >>Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity
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2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 4, article id 1223Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
prostate cancer, bone, metastasis, androgen receptor, osteoblast, osteoclast, BMP
National Category
Orthopaedics
Identifiers
urn:nbn:se:umu:diva-146973 (URN)10.3390/ijms19041223 (DOI)000434978700302 ()29670000 (PubMedID)2-s2.0-85045938451 (Scopus ID)
Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-11-21Bibliographically approved
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
Open this publication in new window or tab >>Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 50-50Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-151399 (URN)000441803800065 ()
Conference
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Note

Supplement: S, Meeting Abstract: A048

Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
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
Open this publication in new window or tab >>Clinically relevant molecular subgroups of prostate cancer bone metastases
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 123-123Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-151398 (URN)000441803800194 ()
Conference
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Note

 Supplement: S, Meeting Abstract: B081

Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
Sandgren, K., Jonsson, J., Nyholm, T., Strandberg, S., Ögren, M., Axelsson, J., . . . Windmark, A. (2018). Histology correlation of in vivo [68Ga]PSMA-PET/MRI data of the prostate. Paper presented at 37th Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), APR 20-24, 2018, Barcelona, SPAIN. Radiotherapy and Oncology, 127, S541-S541
Open this publication in new window or tab >>Histology correlation of in vivo [68Ga]PSMA-PET/MRI data of the prostate
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2018 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, p. S541-S541Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-150494 (URN)10.1016/S0167-8140(18)31288-X (DOI)000437723402226 ()
Conference
37th Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), APR 20-24, 2018, Barcelona, SPAIN
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-11-01Bibliographically approved
Lindahl, O. A., Ramser, K., Bäcklund, T., Ljungberg, B. & Bergh, A. (2018). Prostate cancer detection ex vivo combining Raman spectroscopy and tactile resonance technology. In: Eskola, H Vaisanen, O Viik, J Hyttinen, J (Ed.), EMBEC & NBC 2017: . Paper presented at Joint Conference of the European Medical and Biological Engineering Conference (EMBEC) / Nordic-Baltic Conference on Biomedical Engineering and Medical Physics (NBC), JUN, 2017, Tampere, FINLAND (pp. 193-196). SPRINGER-VERLAG SINGAPORE PTE LTD
Open this publication in new window or tab >>Prostate cancer detection ex vivo combining Raman spectroscopy and tactile resonance technology
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2018 (English)In: EMBEC & NBC 2017 / [ed] Eskola, H Vaisanen, O Viik, J Hyttinen, J, SPRINGER-VERLAG SINGAPORE PTE LTD , 2018, p. 193-196Conference paper, Published paper (Refereed)
Abstract [en]

Prostate cancer is the most common cancer for men in the western world. The most prevalent curative treatment is radical prostatectomy. However, prostate surgery can give unwanted side effects and there is a need for an instrument that can provide decision support to the surgeon during surgery on the presence of cancer cells in the surgical margin. A dual modality probe, combining Raman spectroscopy and tactile resonance technology, has been used for detecting cancer in fresh human prostate tissue. The tactile resonance modality measures the tissue stiffness and Raman spectroscopy depicts the molecular content in tissue, both related to cancer. After ethical approval, the study investigated the potential of the dual-modality probe by testing its ability to differentiate between normal and cancerous prostate tissue ex vivo. It also investigated the minimal amount of measurement points needed to securely detect cancer on the surface of prostate tissue. Measurements on three prostate tissue slices show that the tactile resonance modality measuring stiffness was able to detect differences between normal and cancerous tissue on a significant level of 90%, but the sample size was too low to draw any firm conclusions. It was also suggested from the study results that the high wavenumber region in the Raman spectrum can give valuable information about cancer in prostate tissue. A number of 24 measurement points were enough for detecting cancer in prostate slices in this study. It can be suggested from this study that combining these two sensor modalities is promising for accurate detection of prostate cancer that is needed during prostate surgery, but more measurements including more prostates must be performed before the full value of the study result can be established.

Place, publisher, year, edition, pages
SPRINGER-VERLAG SINGAPORE PTE LTD, 2018
Series
IFMBE Proceedings, ISSN 1680-0737 ; 65
Keywords
Raman spectroscopy, tactile resonance technology, prostate cancer, radical prostatectomy, surgical margin
National Category
Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:umu:diva-155049 (URN)10.1007/978-981-10-5122-7_49 (DOI)000449778900049 ()978-981-10-5121-0 (ISBN)978-981-10-5122-7 (ISBN)
Conference
Joint Conference of the European Medical and Biological Engineering Conference (EMBEC) / Nordic-Baltic Conference on Biomedical Engineering and Medical Physics (NBC), JUN, 2017, Tampere, FINLAND
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
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