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Edqvist, Per-Henrik D
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Publications (10 of 49) Show all publications
Aasebö, K. Ö., Dragomir, A., Sundström, M., Mezheyeuski, A., Edqvist, P.-H. D., Eide, G. E., . . . Sorbye, H. (2019). Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients. Cancer Medicine, 8(7), 3623-3635
Open this publication in new window or tab >>Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 7, p. 3623-3635Article in journal (Refereed) Published
Abstract [en]

Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.

Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.

Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).

Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
colorectal neoplasm, microsatellite instability, proto-oncogene proteins, B-raf, prognosis, neoplasm metastasis, KRAS protein
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-391954 (URN)10.1002/cam4.2205 (DOI)000477017100030 ()31070306 (PubMedID)
Funder
Erik, Karin och Gösta Selanders FoundationSwedish Cancer Society
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-08-27Bibliographically approved
Roodakker, K. R., Alhuseinalkhudhur, A., Al-Jaff, M., Georganaki, M., Zetterling, M., Berntsson, S. G., . . . Smits, A. (2019). Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity. European Journal of Nuclear Medicine and Molecular Imaging, 46(3), 569-579
Open this publication in new window or tab >>Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity
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2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 3, p. 569-579Article in journal (Refereed) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-356591 (URN)10.1007/s00259-018-4107-z (DOI)000457151600005 ()30109401 (PubMedID)
Funder
Erik, Karin och Gösta Selanders Foundation
Available from: 2018-08-14 Created: 2018-08-08 Last updated: 2019-04-06Bibliographically approved
Altai, M., Liu, H., Ding, H., Mitran, B., Edqvist, P.-H. D., Tolmachev, V., . . . Gräslund, T. (2018). Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors. Journal of Controlled Release, 288, 84-95
Open this publication in new window or tab >>Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors
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2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 288, p. 84-95Article in journal (Refereed) Published
Abstract [en]

Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, Z(HER2:2891), conjugated with the cytotoxic maytansine derivate MC-DM1, for targeted cancer therapy. Z(HER2:2891) was expressed as a monomer (Z(HER2:2891)), dimer ((Z(HER2:2891)) 2) and dimer with an albumin binding domain (ABD) for half-life extension ((Z(HER2:2891)) 2-ABD). All proteins had a unique C-terminal cysteine that could be used for efficient and site-specific conjugation with MC-DM1. The resulting affibody drug conjugates were potent cytotoxic molecules for human cells over-expressing HER2, with sub-nanomolar IC50-values similar to trastuzumab emtansine, and did not affect cells with low HER2 expression. A biodistribution study of a radiolabeled version of (Z(HER2:2891))(2)-ABD-MC-DM1, showed that it was taken up by the tumor. The major site of off-target uptake was the kidneys and to some extent the liver. (Z(HER2:2891)) 2-ABD-MC-DM1 was found to have a half-life in circulation of 14 h. The compound was tolerated well by mice at 8.5 mg/kg and was shown to extend survival of mice bearing HER2 over-expressing tumors. The findings in this study show that affibody molecules are a promising class of engineered affinity proteins to specifically deliver small molecular drugs to cancer cells and that such conjugates are potential candidates for clinical evaluation on HER2-overexpressing cancers.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
DM1, Maytansine, Affibody molecule, ADC, HER2
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-367025 (URN)10.1016/j.jconrel.2018.08.040 (DOI)000446237700007 ()30172673 (PubMedID)
Funder
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353VINNOVA, 2016-04060Swedish Society for Medical Research (SSMF)Swedish Cancer Society, 14-0298Swedish Cancer Society, 14/474Swedish Cancer Society, 15/350Swedish Cancer Society, 15/746
Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2018-11-28Bibliographically approved
Fonnes, T., Trovik, J., Edqvist, P.-H. D., Fasmer, K. E., Marcickiewicz, J., Tingulstad, S., . . . Krakstad, C. (2018). Asparaginase-like protein 1 expression in curettage independently predicts lymph node metastasis in endometrial carcinoma: a multicentre study. British Journal of Obstetrics and Gynecology, 125(13), 1695-1703
Open this publication in new window or tab >>Asparaginase-like protein 1 expression in curettage independently predicts lymph node metastasis in endometrial carcinoma: a multicentre study
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2018 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 125, no 13, p. 1695-1703Article in journal (Refereed) Published
Abstract [en]

Objective Design Correct preoperative identification of high-risk patients is important to optimise surgical treatment and improve survival. We wanted to explore if asparaginase-like protein 1 (ASRGL1) expression in curettage could predict lymph node metastases and poor outcome, potentially improving preoperative risk stratification. Multicentre study. Setting Population Ten hospitals in Norway, Sweden and Belgium. Women diagnosed with endometrial carcinoma. Methods Main outcome measures ASRGL1 expression in curettage specimens from 1144 women was determined by immunohistochemistry. ASRGL1 status related to disease-specific survival, lymph node status, preoperative imaging parameters and clinicopathological data. Results Conclusions ASRGL1 expression had independent prognostic value in multivariate survival analyses, both in the whole patient population (hazard ratio (HR) 1.63, 95% CI 1.11-2.37, P = 0.012) and in the low-risk curettage histology subgroup (HR 2.54, 95% CI 1.44-4.47, P = 0.001). Lymph node metastases were more frequent in women with low expression of ASRGL1 compared with women with high ASRGL1 levels (23% versus 10%, P < 0.001), and low ASRGL1 level was found to independently predict lymph node metastases (odds ratio 2.07, 95% CI 1.27-3.38, P = 0.003). Low expression of ASRGL1 in curettage independently predicts lymph node metastases and poor disease-specific survival.

Keywords
Asparaginase-like protein 1, biomarker, curettage, endometrial carcinoma
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-371035 (URN)10.1111/1471-0528.15403 (DOI)000450069000016 ()29989298 (PubMedID)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-08Bibliographically approved
Fonnes, T., Berg, H. F., Bredholt, T., Edqvist, P.-H. D., Sortland, K., Berg, A., . . . Krakstad, C. (2018). Asparaginase-like protein 1 is an independent prognostic marker in primary endometrial cancer, and is frequently lost in metastatic lesions. Gynecologic Oncology, 148(1), 197-203
Open this publication in new window or tab >>Asparaginase-like protein 1 is an independent prognostic marker in primary endometrial cancer, and is frequently lost in metastatic lesions
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2018 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 148, no 1, p. 197-203Article in journal (Refereed) Published
Abstract [en]

Objective

Loss of Asparaginase-like protein 1 (ASRGL1) has been suggested as a prognostic biomarker in endometrial carcinoma. Our objective was to validate this in a prospectively collected, independent patient cohort, and evaluate ASRGL1 expression in endometrial carcinoma precursor lesion and metastases.

Methods

782 primary endometrial carcinomas, 90 precursor lesions (complex atypical hyperplasia), and 179 metastases (from 87 patients) were evaluated for ASRGL1 expression by immunohistochemistry in relation to clinical and histopathological data. ASRGL1 mRNA level was investigated in 237 primary tumors and related to survival and ASRGL1 protein expression.

Results

Low expression of ASRGL1 protein and ASRGL1 mRNA predicted poor disease specific survival (P < 0.001). In multivariate survival analyses ASRGL1 had independent prognostic value both in the whole patient cohort (Hazard ratio (HR): 1.53, 95% confidence interval (CI): 1.04–2.26, P = 0.031) and within the endometrioid subgroup (HR: 2.64, CI: 1.47–4.74, P = 0.001). Low ASRGL1 expression was less frequent in patients with low grade endometrioid primary tumors compared to high grade endometrioid and non-endometrioid primary tumors, and ASRGL1 was lost in the majority of metastatic lesions.

Conclusions

In a prospective setting ASRGL1 validates as a strong prognostic biomarker in endometrial carcinoma. Loss of ASRGL1 is associated with aggressive disease and poor survival, and is demonstrated for the first time to have independent prognostic value in the entire endometrial carcinoma patient population.

Keywords
Endometrial carcinoma, Hysterectomy, Prognostic, Biomarker, ASRGLI
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-343878 (URN)10.1016/j.ygyno.2017.10.025 (DOI)000423139400031 ()29096882 (PubMedID)
Available from: 2018-03-09 Created: 2018-03-09 Last updated: 2018-03-09Bibliographically approved
Huvila, J., Laajala, T. D., Edqvist, P.-H. D., Mardinoglu, A., Talve, L., Pontén, F., . . . Auranen, A. (2018). Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma. Gynecologic Oncology, 149(1), 173-180
Open this publication in new window or tab >>Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma
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2018 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 149, no 1, p. 173-180Article in journal (Refereed) Published
Abstract [en]

Objective. In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. Methods. A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. Results. A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (295%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P < 0.001) of dying of EEC compared to the low-risk group. Conclusions. P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2018
Keywords
Endometrial cancer, Risk stratification, Prognostic, Modelling, ASRGL1, p53
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-352701 (URN)10.1016/j.ygyno.2018.02.016 (DOI)000430152400026 ()29486992 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2018-06-08Bibliographically approved
Sjöstedt, E., Sivertsson, Å., Noraddin, F. H., Katona, B., Näsström, Å., Vuu, J., . . . Lindskog, C. (2018). Integration of Transcriptomics and Antibody-Based Proteomics for Exploration of Proteins Expressed in Specialized Tissues. Journal of Proteome Research, 17(12), 4127-4137
Open this publication in new window or tab >>Integration of Transcriptomics and Antibody-Based Proteomics for Exploration of Proteins Expressed in Specialized Tissues
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2018 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, no 12, p. 4127-4137Article in journal (Refereed) Published
Abstract [en]

A large portion of human proteins are referred to as missing proteins, defined as protein-coding genes that lack experimental data on the protein level due to factors such as temporal expression, expression in tissues that are difficult to sample, or they actually do not encode functional proteins. In the present investigation, an integrated omics approach was used for identification and exploration of missing proteins. Transcriptomics data from three different sources-the Human Protein Atlas (HPA), the GTEx consortium, and the FANTOM5 consortium-were used as a starting point to identify genes selectively expressed in specialized tissues. Complementing the analysis with profiling on more specific tissues based on immunohistochemistry allowed for further exploration of cell-type-specific expression patterns. More detailed tissue profiling was performed for >300 genes on complementing tissues. The analysis identified tissue-specific expression of nine proteins previously listed as missing proteins (POU4F1, FRMD1, ARHGEF33, GABRG1, KRTAP2-1, BHLHE22, SPRR4, AVPR1B, and DCLK3), as well as numerous proteins with evidence of existence on the protein level that previously lacked information on spatial resolution and cell-type-specific expression pattern. We here present a comprehensive strategy for identification of missing proteins by combining transcriptomics with antibody-based proteomics. The analyzed proteins provide interesting targets for organ-specific research in health and disease.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
Keywords
missing proteins, transcriptomics, proteomics, protein localization, immunohistochemistry, antibodies, tissue profiling
National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-373020 (URN)10.1021/acs.jproteome.8b00406 (DOI)000452930000010 ()30272454 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A. H., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
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2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

National Category
Cancer and Oncology Urology and Nephrology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-325565 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2019-03-29Bibliographically approved
Carreras-Puigvert, J., Zitnik, M., Jemth, A.-S., Carter, M., Unterlass, J. E., Hallström, B., . . . Helleday, T. (2017). A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family. Nature Communications, 8(1), Article ID 1541.
Open this publication in new window or tab >>A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1, article id 1541Article in journal (Refereed) Published
Abstract [en]

The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-333888 (URN)10.1038/s41467-017-01642-w (DOI)000415323000014 ()29142246 (PubMedID)
Funder
EU, Horizon 2020Swedish Research CouncilTorsten Söderbergs stiftelseKnut and Alice Wallenberg FoundationAFA InsuranceSwedish Cancer SocietySwedish Childhood Cancer FoundationEU, FP7, Seventh Framework Programme, 332428
Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2019-01-22Bibliographically approved
Uhlen, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., . . . Ponten, F. (2017). A pathology atlas of the human cancer transcriptome. Science, 357(6352), Article ID eaan2507.
Open this publication in new window or tab >>A pathology atlas of the human cancer transcriptome
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2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6352, article id eaan2507Article in journal (Refereed) Published
Abstract [en]

Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2017
National Category
Medical and Health Sciences Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-334302 (URN)10.1126/science.aan2507 (DOI)000407793600028 ()
Funder
Swedish Cancer SocietyScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2019-03-29Bibliographically approved
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