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Linder, A., Westbom-Fremer, S., Mateoiu, C., Olsson Widjaja, A., Österlund, T., Veerla, S., . . . Sundfeldt, K. (2024). Genomic alterations in ovarian endometriosis and subsequently diagnosed ovarian carcinoma. Human Reproduction, 39(5), 1141-1154, Article ID deae043.
Åpne denne publikasjonen i ny fane eller vindu >>Genomic alterations in ovarian endometriosis and subsequently diagnosed ovarian carcinoma
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2024 (engelsk)Inngår i: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 39, nr 5, s. 1141-1154, artikkel-id deae043Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

STUDY QUESTION: Can the alleged association between ovarian endometriosis and ovarian carcinoma be substantiated by genetic analysis of endometriosis diagnosed prior to the onset of the carcinoma?

SUMMARY ANSWER: The data suggest that ovarian carcinoma does not originate from ovarian endometriosis with a cancer-like genetic profile; however, a common precursor is probable.

WHAT IS KNOWN ALREADY: Endometriosis has been implicated as a precursor of ovarian carcinoma based on epidemiologic studies and the discovery of common driver mutations in synchronous disease at the time of surgery. Endometrioid ovarian carcinoma and clear cell ovarian carcinoma are the most common endometriosis-associated ovarian carcinomas (EAOCs).

STUDY DESIGN, SIZE, DURATION: The pathology biobanks of two university hospitals in Sweden were scrutinized to identify women with surgically removed endometrioma who subsequently developed ovarian carcinoma (1998-2016). Only 45 archival cases with EAOC and previous endometriosis were identified and after a careful pathology review, 25 cases were excluded due to reclassification into non-EAOC (n = 9) or because ovarian endometriosis could not be confirmed (n = 16). Further cases were excluded due to insufficient endometriosis tissue or poor DNA quality in either the endometriosis, carcinoma, or normal tissue (n = 9). Finally 11 cases had satisfactory DNA from all three locations and were eligible for further analysis.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Epithelial cells were collected from formalin-fixed and paraffin-embedded (FFPE) sections by laser capture microdissection (endometrioma n = 11) or macrodissection (carcinoma n = 11) and DNA was extracted. Normal tissue from FFPE sections (n = 5) or blood samples collected at cancer diagnosis (n = 6) were used as the germline controls for each included patient. Whole-exome sequencing was performed (n = 33 samples). Somatic variants (single-nucleotide variants, indels, and copy number alterations) were characterized, and mutational signatures and kataegis were assessed. Microsatellite instability and mismatch repair status were confirmed with PCR and immunohistochemistry, respectively.

MAIN RESULTS AND THE ROLE OF CHANCE: The median age for endometriosis surgery was 42 years, and 54 years for the subsequent ovarian carcinoma diagnosis. The median time between the endometriosis and ovarian carcinoma was 10 (7-30) years. The data showed that all paired samples harbored one or more shared somatic mutations. Non-silent mutations in cancer-associated genes were frequent in endometriosis; however, the same mutations were never observed in subsequent carcinomas. The degree of clonal dominance, demonstrated by variant allele frequency, showed a positive correlation with the time to cancer diagnosis (Spearman's rho 0.853, P < 0.001). Mutations in genes associated with immune escape were the most conserved between paired samples, and regions harboring these genes were frequently affected by copy number alterations in both sample types. Mutational burdens and mutation signatures suggested faulty DNA repair mechanisms in all cases.

LARGE SCALE DATA: Datasets are available in the supplementary tables.

LIMITATIONS, REASONS FOR CAUTION: Even though we located several thousands of surgically removed endometriomas between 1998 and 2016, only 45 paired samples were identified and even fewer, 11 cases, were eligible for sequencing. The observed high level of intra- and inter-heterogeneity in both groups (endometrioma and carcinoma) argues for further studies of the alleged genetic association.

WIDER IMPLICATIONS OF THE FINDINGS: The observation of shared somatic mutations in all paired samples supports a common cellular origin for ovarian endometriosis and ovarian carcinoma. However, contradicting previous conclusions, our data suggest that cancer-associated mutations in endometriosis years prior to the carcinoma were not directly associated with the malignant transformation. Rather, a resilient ovarian endometriosis may delay tumorigenesis. Furthermore, the data indicate that genetic alterations affecting the immune response are early and significant events.

STUDY FUNDING/COMPETING INTEREST(S): The present work has been funded by the Sjöberg Foundation (2021-01145 to K.S.; 2022-01-11:4 to A.S.), Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (965552 to K.S.; 40615 to I.H.; 965065 to A.S.), Swedish Cancer Society (21-1848 to K.S.; 21-1684 to I.H.; 22-2080 to A.S.), BioCARE-A Strategic Research Area at Lund University (I.H. and S.W.-F.), Mrs Berta Kamprad's Cancer Foundation (FBKS-2019-28, I.H.), Cancer and Allergy Foundation (10381, I.H.), Region Västra Götaland (A.S.), Sweden's Innovation Agency (2020-04141, A.S.), Swedish Research Council (2021-01008, A.S.), Roche in collaboration with the Swedish Society of Gynecological Oncology (S.W.-F.), Assar Gabrielsson Foundation (FB19-86, C.M.), and the Lena Wäpplings Foundation (C.M.). A.S. declares stock ownership and is also a board member in Tulebovaasta, SiMSen Diagnostics, and Iscaff Pharma. A.S. has also received travel support from EMBL, Precision Medicine Forum, SLAS, and bioMCC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

sted, utgiver, år, opplag, sider
Oxford University Press, 2024
Emneord
clear cell ovarian carcinoma, copy number alteration, endometrioid ovarian carcinoma, exome-sequencing, mutation, ovarian endometriosis
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-23673 (URN)10.1093/humrep/deae043 (DOI)001181452700001 ()38459814 (PubMedID)
Forskningsfinansiär
Sjöberg Foundation, 2021-01145Sjöberg Foundation, 2022-01-11:4Swedish Cancer Society, 21-1848Swedish Cancer Society, 21-1684Swedish Cancer Society, 22-2080Mrs. Berta Kamprad's Cancer Foundation, FBKS-2019-28Cancer and Allergy Foundation, 10381Region Västra GötalandVinnova, 2020-04141Swedish Research Council, 2021- 01008Stiftelsen Assar Gabrielssons fond, FB19-86
Merknad

CC BY-NC 4.0 Deed

Published: 09 March 2024

Correspondence address: Karin Sundfeldt, Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academyat University of Gothenburg, SE-405 30 Gothenburg, Sweden. E-mail: karin.sundfeldt@gu.se (K.S.) https://orcid.org/0000-0002-7135-3132;

Division of Oncology,Department of Clinical Sciences Lund, Lund University, SE-223 81 Lund, Sweden. E-mail: ingrid.hedenfalk@med.lu.se (I.H.) https://orcid.org/0000-0002-6840-3

The present work has been funded by the Sjöberg Foundation (2021-01145 to K.S.; 2022-01-11:4 to A.S.), Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (965552 to K.S.; 40615 to I.H.; 965065 to A.S.), Swedish Cancer Society (21-1848 to K.S.; 21-1684 to I.H.; 22-2080 to A.S.), BioCARE—a strategic research area at Lund University (I.H. and S.W.-F.), Mrs Berta Kamprad’s Cancer Foundation (FBKS-2019-28, I.H.), Cancer and Allergy Foundation (10381, I.H.), Region Västra Götaland (A.S.), Sweden’s Innovation Agency (2020-04141, A.S.), Swedish Research Council (2021- 01008, A.S.), Roche in collaboration with the Swedish Society of Gynecological Oncology (S.W.-F.), Assar Gabrielsson Foundation (FB19-86, C.M.), and the Lena Wäpplings Foundation (C.M.).

Tilgjengelig fra: 2024-03-22 Laget: 2024-03-22 Sist oppdatert: 2024-06-13bibliografisk kontrollert
Larsson, S., Holmgren, S., Jenndahl, L., Ulfenborg, B., Strehl, R., Synnergren, J. & Ghosheh, N. (2024). Proteome of Personalized Tissue-Engineered Veins. ACS Omega, 9(13), 14805-14817
Åpne denne publikasjonen i ny fane eller vindu >>Proteome of Personalized Tissue-Engineered Veins
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2024 (engelsk)Inngår i: ACS Omega, E-ISSN 2470-1343, Vol. 9, nr 13, s. 14805-14817Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Vascular diseases are the largest cause of death globally and impose a major global burden on healthcare. The gold standard for treating vascular diseases is the transplantation of autologous veins, if applicable. Alternative treatments still suffer from shortcomings, including low patency, lack of growth potential, the need for repeated intervention, and a substantial risk of developing infections. The use of a vascular ECM scaffold reconditioned with the patient's own cells has shown successful results in preclinical and clinical studies. In this study, we have compared the proteomes of personalized tissue-engineered veins of humans and pigs. By applying tandem mass tag (TMT) labeling LC/MS-MS, we have investigated the proteome of decellularized (DC) veins from humans and pigs and reconditioned (RC) DC veins produced through perfusion with the patient's whole blood in STEEN solution, applying the same technology as used in the preclinical studies. The results revealed high similarity between the proteomes of human and pig DC and RC veins, including the ECM texture after decellularization and reconditioning. In addition, functional enrichment analysis showed similarities in signaling pathways and biological processes involved in the immune system response. Furthermore, the classification of proteins involved in immune response activity that were detected in human and pig RC veins revealed proteins that evoke immunogenic responses, which may lead to graft rejection, thrombosis, and inflammation. However, the results from this study imply the initiation of wound healing rather than an immunogenic response, as both systems share the same processes, and no immunogenic response was reported in the preclinical and clinical studies. Finally, our study assessed the application of STEEN solution in tissue engineering and identified proteins that may be useful for the prediction of successful transplantations. 

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2024
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-23682 (URN)10.1021/acsomega.3c07098 (DOI)001189129300001 ()38585136 (PubMedID)2-s2.0-85188351102 (Scopus ID)
Forskningsfinansiär
Knowledge Foundation, 2018/0125
Merknad

CC BY-NC-ND 4.0 DEED

© 2024 The Authors. Published by American Chemical Society.

Correspondence Address: N. Ghosheh; Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, SE-541 28, Sweden; email: nidal.ghosheh@his.se

The study was supported by VERIGRAFT AB (Gothenburg, Sweden), XVIVO Perfusion AB (Gothenburg, Sweden), and the University of Skövde under a grant from the Knowledge Foundation [2018/0125]. The authors appreciate the Proteogenomics unit at SciLifeLab (Solna, Sweden) and Georgios Mermelekas for the proteomics service. The authors also appreciate the scientific advice from Anne-Li Sigvardsson and the laboratory support from Carina Ström.

Tilgjengelig fra: 2024-03-28 Laget: 2024-03-28 Sist oppdatert: 2024-04-30bibliografisk kontrollert
Marzec-Schmidt, K., Ghosheh, N., Stahlschmidt, S. R., Küppers-Munther, B., Synnergren, J. & Ulfenborg, B. (2023). Artificial intelligence supports automated characterization of differentiated human pluripotent stem cells. Stem Cells, 41(9), 850-861, Article ID sxad049.
Åpne denne publikasjonen i ny fane eller vindu >>Artificial intelligence supports automated characterization of differentiated human pluripotent stem cells
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2023 (engelsk)Inngår i: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 41, nr 9, s. 850-861, artikkel-id sxad049Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Revolutionary advances in AI and deep learning in recent years have resulted in an upsurge of papers exploring applications within the biomedical field. Within stem cell research, promising results have been reported from analyses of microscopy images to e.g., distinguish between pluripotent stem cells and differentiated cell types derived from stem cells. In this work, we investigated the possibility of using a deep learning model to predict the differentiation stage of pluripotent stem cells undergoing differentiation towards hepatocytes, based on morphological features of cell cultures. We were able to achieve close to perfect classification of images from early and late time points during differentiation, and this aligned very well with the experimental validation of cell identity and function. Our results suggest that deep learning models can distinguish between different cell morphologies, and provide alternative means of semi-automated functional characterization of stem cell cultures.

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Oxford University Press, 2023
Emneord
artificial intelligence, cell differentiation, computer-assisted, hepatocytes, image analysis, pluripotent stem cells, quality control
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-23064 (URN)10.1093/stmcls/sxad049 (DOI)001025294200001 ()37357747 (PubMedID)2-s2.0-85171393798 (Scopus ID)
Forskningsfinansiär
Knowledge Foundation, 20170302Knowledge Foundation, 20200014University of Skövde
Merknad

CC BY 4.0

Corresponding author: Benjamin Ulfenborg, PhD, Department of Biology and Bioinformatics, School of Bioscience, University of Skövde, SE-541 28, Sweden. Email: benjamin.ulfenborg@his.se

This work was supported by the Swedish Knowledge Foundation (grant numbers 20170302 and 20200014), the Systems Biology Research Center, University of Skövde, Sweden and Takara Bio Europe, Gothenburg, Sweden.

Tilgjengelig fra: 2023-07-31 Laget: 2023-07-31 Sist oppdatert: 2023-12-19bibliografisk kontrollert
Stahlschmidt, S. R., Ulfenborg, B. & Synnergren, J. (2023). Predicting Cancer Stage from Circulating microRNA: A Comparative Analysis of Machine Learning Algorithms. In: Ignacio Rojas; Olga Valenzuela; Fernando Rojas Ruiz; Luis Javier Herrera; Francisco Ortuño (Ed.), Bioinformatics and Biomedical Engineering: 10th International Work-Conference, IWBBIO 2023, Meloneras, Gran Canaria, Spain, July 12–14, 2023, Proceedings, Part I. Paper presented at 10th International Work-Conference on Bioinformatics and Biomedical Engineering, IWBBIO 2023 Meloneras 12 July 2023 through 14 July 2023 Code 297199 (pp. 103-115). Cham: Springer
Åpne denne publikasjonen i ny fane eller vindu >>Predicting Cancer Stage from Circulating microRNA: A Comparative Analysis of Machine Learning Algorithms
2023 (engelsk)Inngår i: Bioinformatics and Biomedical Engineering: 10th International Work-Conference, IWBBIO 2023, Meloneras, Gran Canaria, Spain, July 12–14, 2023, Proceedings, Part I / [ed] Ignacio Rojas; Olga Valenzuela; Fernando Rojas Ruiz; Luis Javier Herrera; Francisco Ortuño, Cham: Springer, 2023, s. 103-115Konferansepaper, Publicerat paper (Fagfellevurdert)
Abstract [en]

In recent years, serum-based tests for early detection and detection of tissue of origin are being developed. Circulating microRNA has been shown to be a potential source of diagnostic information that can be collected non-invasively. In this study, we investigate circulating microRNAs as predictors of cancer stage. Specifically, we predict whether a sample stems from a patient with early stage (0-II) or late stage cancer (III-IV). We trained five machine learning algorithms on a data set of cancers from twelve different primary sites. The results showed that cancer stage can be predicted from circulating microRNA with a sensitivity of 71.73%, specificity of 79.97%, as well as positive and negative predictive value of 54.81% and 89.29%, respectively. Furthermore, we compared the best pan-cancer model with models specialized on individual cancers and found no statistically significant difference. Finally, in the best performing pan-cancer model 185 microRNAs were significant. Comparing the five most relevant circulating microRNAs in the best performing model with the current literature showed some known associations to various cancers. In conclusion, the study showed the potential of circulating microRNA and machine learning algorithms to predict cancer stage and thus suggests that further research into its potential as a non-invasive clinical test is warranted. 

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Cham: Springer, 2023
Serie
Lecture Notes in Computer Science, ISSN 0302-9743, E-ISSN 1611-3349 ; 13919
Emneord
cancer stage, circulating microRNA, liquid biopsy, machine learning, Clinical research, Diseases, Forecasting, Learning algorithms, RNA, Cancer models, Comparative analyzes, Diagnostics informations, Late stage, Machine learning algorithms, Machine-learning, Potential sources
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-23058 (URN)10.1007/978-3-031-34953-9_8 (DOI)2-s2.0-85164958861 (Scopus ID)978-3-031-34952-2 (ISBN)978-3-031-34953-9 (ISBN)
Konferanse
10th International Work-Conference on Bioinformatics and Biomedical Engineering, IWBBIO 2023 Meloneras 12 July 2023 through 14 July 2023 Code 297199
Forskningsfinansiär
Knowledge Foundation, 20170302Knowledge Foundation, 20200014Swedish Research Council, 2022–06725
Merknad

Part of the book sub series: Lecture Notes in Bioinformatics (LNBI) Electronic ISSN 2366-6331 Print ISSN 2366-6323

© 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

This work was supported by the University of Skövde, Swede nunder grants from the Knowledge Foundation (20170302, 20200014). The computations were enabled by resources provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) at Chalmers University of Technology partially funded by the Swedish Research Council through grant agreement no. 2022–06725.

Tilgjengelig fra: 2023-07-31 Laget: 2023-07-31 Sist oppdatert: 2023-12-19bibliografisk kontrollert
Cruz, M. A., Ulfenborg, B., Blomstrand, P., Faresjö, M., Ståhl, F. & Karlsson, S. (2022). Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden. Scientific Reports, 12(1), Article ID 12670.
Åpne denne publikasjonen i ny fane eller vindu >>Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden
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2022 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 12, nr 1, artikkel-id 12670Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Numerous studies have shown that lifestyle factors, such as regular physical activity and vitamin D intake, may remarkably improve overall health and mental wellbeing. This is especially important in older adults whose vitamin D deficiency occurs with a high prevalence. This study aimed to examine the influence of lifestyle and vitamin D on global DNA methylation patterns in an elderly cohort in Southwest of Sweden. We also sought to examine the methylation levels of specific genes involved in vitamin D's molecular and metabolic activated pathways. We performed a genome wide methylation analysis, using Illumina Infinium DNA Methylation EPIC 850kBeadChip array, on 277 healthy individuals from Southwest Sweden at the age of 70-95. The study participants also answered queries on lifestyle, vitamin intake, heart medication, and estimated health. Vitamin D intake did not in general affect methylation patterns, which is in concert with other studies. However, when comparing the group of individuals taking vitamin supplements, including vitamin D, with those not taking supplements, a difference in methylation in the solute carrier family 25 (SCL25A24) gene was found. This confirms a previous finding, where changes in expression of SLC25A24 were associated with vitamin D treatment in human monocytes. The combination of vitamin D intake and high physical activity increased methylation of genes linked to regulation of vitamin D receptor pathway, the Wnt pathway and general cancer processes. To our knowledge, this is the first study detecting epigenetic markers associated with the combined effects of vitamin D supplementation and high physical activity. These results deserve to be further investigated in an extended, interventional study cohort, where also the levels of 25(OH)D3 can be monitored.

sted, utgiver, år, opplag, sider
Nature Portfolio, 2022
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-21658 (URN)10.1038/s41598-022-15924-x (DOI)000830116000026 ()35879377 (PubMedID)2-s2.0-85134761700 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2018-05973
Merknad

CC BY 4.0

© 2022 Springer Nature Limited

Correspondence and requests for materials should be addressed to S.K. sandra.karlsson@ju.se

We thank the “Aktiva seniorer” association in Sweden for their collaboration in this study. The computations in this study were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX), partially funded by the Swedish Research Council through Grant Agreement No. 2018-05973.

Open access funding provided by Jönköping University. The University of Borås and the University of Skövde provided with funding for the different experiments performed in this study. Jönköping University supplied with the necessary resources to carry out this investigation.

Tilgjengelig fra: 2022-08-08 Laget: 2022-08-08 Sist oppdatert: 2022-10-14bibliografisk kontrollert
Jain, S., Nadeem, N., Ulfenborg, B., Mäkelä, M., Ruma, S. A., Terävä, J., . . . Gidwani, K. (2022). Diagnostic potential of nanoparticle aided assays for MUC16 and MUC1 glycovariants in ovarian cancer. International Journal of Cancer, 151(7), 1175-1184
Åpne denne publikasjonen i ny fane eller vindu >>Diagnostic potential of nanoparticle aided assays for MUC16 and MUC1 glycovariants in ovarian cancer
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2022 (engelsk)Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 151, nr 7, s. 1175-1184Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

This study reports the discovery and evaluation of nanoparticle aided sensitive assays for glycovariants of MUC16 and MUC1 in a unique collection of paired ovarian cyst fluids and serum samples obtained at or prior to surgery for ovarian carcinoma suspicion. Selected glycovariants and the immunoassays for CA125, CA15-3 and HE4 were compared and validated in 347 cyst fluid and serum samples. Whereas CA125 and CA15-3 performed poorly in cyst fluid to separate carcinoma and controls, four glycovariants including MUC16MGL , MUC16STn , MUC1STn and MUC1Tn provided highly improved separations. In serum, the two STn glycovariants outperformed conventional CA125, CA15-3 and HE4 assays in all sub-categories analysed with main benefits obtained at high specificities and at postmenopausal and early-stage disease. Serum MUC16STn performed best at high specificity (90-99%), but sensitivity was also improved by the other glycovariants and CA15-3. The highly improved specificity, excellent analytical sensitivity, and robustness of the nanoparticle assisted glycovariant assays carry great promise for improved identification and early detection of ovarian carcinoma in routine differential diagnostics. This article is protected by copyright. All rights reserved.

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John Wiley & Sons, 2022
Emneord
STn, diagnosis, epithelial ovarian cancer, europium nanoparticle, mucins
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-21135 (URN)10.1002/ijc.34111 (DOI)000799910200001 ()35531590 (PubMedID)2-s2.0-85130972083 (Scopus ID)
Forskningsfinansiär
Swedish Cancer Society, CAN-2018/834Region Västra Götaland, ALFGBG-721051Region Västra Götaland, ALFGBG-932583
Merknad

CC BY-NC 4.0

Attribution-NonCommercial 4.0 International

First published: 09 May 2022

Corresponding author: Kamlesh Gidwani (kamlesh.gidwani@utu.fi), Karin Sundfeldt (karin.sundfeldt@obgyn.gu.se)

Funding:

Swedish Cancer Foundation CAN-2018/834

ALF-VGR Region, Sweden ALFGBG-721051, ALFGBG-932583

Jane and Aatos Erkko Foundation, Finland 2018-2021

Nordic Cancer Union, Denmark 194914

Tilgjengelig fra: 2022-05-12 Laget: 2022-05-12 Sist oppdatert: 2022-08-16bibliografisk kontrollert
Sandstedt, M., Vukusic, K., Ulfenborg, B., Jonsson, M., Mattsson Hultén, L., Dellgren, G., . . . Sandstedt, J. (2022). Human intracardiac SSEA4+CD34 cells show features of cycling, immature cardiomyocytes and are distinct from Side Population and C-kit+CD45- cells. PLOS ONE, 17(6), Article ID e0269985.
Åpne denne publikasjonen i ny fane eller vindu >>Human intracardiac SSEA4+CD34 cells show features of cycling, immature cardiomyocytes and are distinct from Side Population and C-kit+CD45- cells
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2022 (engelsk)Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 17, nr 6, artikkel-id e0269985Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Cardiomyocyte proliferation has emerged as the main source of new cardiomyocytes in the adult. Progenitor cell populations may on the other hand contribute to the renewal of other cell types, including endothelial and smooth muscle cells. The phenotypes of immature cell populations in the adult human heart have not been extensively explored. We therefore investigated whether SSEA4+CD34- cells might constitute immature cycling cardiomyocytes in the adult failing and non-failing human heart. The phenotypes of Side Population (SP) and C-kit+CD45- progenitor cells were also analyzed. Biopsies from the four heart chambers were obtained from patients with end-stage heart failure as well as organ donors without chronic heart failure. Freshly dissociated cells underwent flow cytometric analysis and sorting. SSEA4+CD34- cells expressed high levels of cardiomyocyte, stem cell and proliferation markers. This pattern resembles that of cycling, immature, cardiomyocytes, which may be important in endogenous cardiac regeneration. SSEA4+CD34- cells isolated from failing hearts tended to express lower levels of cardiomyocyte markers as well as higher levels of stem cell markers. C-kit+CD45- and SP CD45- cells expressed high levels of endothelial and stem cell markers-corresponding to endothelial progenitor cells involved in endothelial renewal.

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PLOS, 2022
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-21252 (URN)10.1371/journal.pone.0269985 (DOI)000843613300105 ()35709180 (PubMedID)2-s2.0-85132081811 (Scopus ID)
Merknad

CC BY 4.0

Copyright:  © 2022 Sandstedt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was funded by grants from the Swedish Society of Medicine (JS, https://www.sls.se/); The Gothenburg Society of Medicine (MS,JS, https://goteborgslakaresallskap.se/); the Emelle Foundation (MS); the Heart-Lung Foundation (LMH, https://www.hjart-lungfonden.se/); ALF research grant from the Sahlgrenska University Hospital (JS, LMH, https://www.sahlgrenska.se/); grants from the foundations of the Sahlgrenska University Hospital (MS, JS, https://www.sahlgrenska.se/) and University of Skövde (JSy, https://www.his.se), by grants from the Swedish Knowledge Foundation (https://www.kks.se).There was no additional external fundingreceived for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Tilgjengelig fra: 2022-06-17 Laget: 2022-06-17 Sist oppdatert: 2023-08-23bibliografisk kontrollert
Stahlschmidt, S. R., Ulfenborg, B. & Synnergren, J. (2022). Multimodal deep learning for biomedical data fusion: a review. Briefings in Bioinformatics, 23(2), Article ID bbab569.
Åpne denne publikasjonen i ny fane eller vindu >>Multimodal deep learning for biomedical data fusion: a review
2022 (engelsk)Inngår i: Briefings in Bioinformatics, ISSN 1467-5463, E-ISSN 1477-4054, Vol. 23, nr 2, artikkel-id bbab569Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

Biomedical data are becoming increasingly multimodal and thereby capture the underlying complex relationships among biological processes. Deep learning (DL)-based data fusion strategies are a popular approach for modeling these nonlinear relationships. Therefore, we review the current state-of-the-art of such methods and propose a detailed taxonomy that facilitates more informed choices of fusion strategies for biomedical applications, as well as research on novel methods. By doing so, we find that deep fusion strategies often outperform unimodal and shallow approaches. Additionally, the proposed subcategories of fusion strategies show different advantages and drawbacks. The review of current methods has shown that, especially for intermediate fusion strategies, joint representation learning is the preferred approach as it effectively models the complex interactions of different levels of biological organization. Finally, we note that gradual fusion, based on prior biological knowledge or on search strategies, is a promising future research path. Similarly, utilizing transfer learning might overcome sample size limitations of multimodal data sets. As these data sets become increasingly available, multimodal DL approaches present the opportunity to train holistic models that can learn the complex regulatory dynamics behind health and disease.

sted, utgiver, år, opplag, sider
Oxford University Press, 2022
Emneord
data integration, deep neural networks, fusion strategies, multi-omics, multimodal machine learning, representation learning
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-20873 (URN)10.1093/bib/bbab569 (DOI)000804196500091 ()35089332 (PubMedID)2-s2.0-85127534700 (Scopus ID)
Forskningsfinansiär
Knowledge Foundation, 20170302Knowledge Foundation, 20200014
Merknad

CC BY-NC 4.0

Corresponding author: Sören Richard Stahlschmidt. Systems Biology Research Center, University of Skövde, Skövde, Sweden. E-mail: soren.richard.stahlschmidt@his.se

Published: 28 January 2022

This work was supported by the University of Skövde, Sweden under grants from the Knowledge Foundation (20170302, 20200014).

Tilgjengelig fra: 2022-01-31 Laget: 2022-01-31 Sist oppdatert: 2022-06-23bibliografisk kontrollert
Johansson, M., Ulfenborg, B., Andersson, C. X., Heydarkhan-Hagvall, S., Jeppsson, A., Sartipy, P. & Synnergren, J. (2022). Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy. Life, 12(2), Article ID 293.
Åpne denne publikasjonen i ny fane eller vindu >>Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy
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2022 (engelsk)Inngår i: Life, E-ISSN 2075-1729, Vol. 12, nr 2, artikkel-id 293Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Cardiac hypertrophy is an important and independent risk factor for the development of cardiac myopathy that may lead to heart failure. The mechanisms underlying the development of cardiac hypertrophy are yet not well understood. To increase the knowledge about mechanisms and regulatory pathways involved in the progression of cardiac hypertrophy, we have developed a human induced pluripotent stem cell (hiPSC)-based in vitro model of cardiac hypertrophy and performed extensive characterization using a multi-omics approach. In a series of experiments, hiPSC-derived cardiomyocytes were stimulated with Endothelin-1 for 8, 24, 48, and 72 h, and their transcriptome and secreted proteome were analyzed. The transcriptomic data show many enriched canonical pathways related to cardiac hypertrophy already at the earliest time point, e.g., cardiac hypertrophy signaling. An integrated transcriptome–secretome analysis enabled the identification of multimodal biomarkers that may prove highly relevant for monitoring early cardiac hypertrophy progression. Taken together, the results from this study demonstrate that our in vitro model displays a hypertrophic response on both transcriptomic- and secreted-proteomic levels. The results also shed novel insights into the underlying mechanisms of cardiac hypertrophy, and novel putative early cardiac hypertrophy biomarkers have been identified that warrant further investigation to assess their potential clinical relevance.

sted, utgiver, år, opplag, sider
MDPI, 2022
Emneord
cardiac hypertrophy, cardiomyocytes, disease model, endothelin-1, stem cells, transcriptomics, proteomics
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-20931 (URN)10.3390/life12020293 (DOI)000763058200001 ()35207580 (PubMedID)2-s2.0-85125071986 (Scopus ID)
Forskningsfinansiär
Knowledge Foundation, 20160294Knowledge Foundation, 20160330AstraZeneca
Merknad

CC BY 4.0

Correspondence: markus.johansson@his.se

This article belongs to the Special Issue The Molecular Mechanism of Cardiovascular Disease

This research was funded by the Systems Biology Research Centre at the University of Skövde under grants from the Knowledge Foundation (20160294, 20160330), Takara Bio Europe, Gothenburg, Sweden, and AstraZeneca R&D, Gothenburg.

Tilgjengelig fra: 2022-02-22 Laget: 2022-02-22 Sist oppdatert: 2023-02-21bibliografisk kontrollert
Lycke, M., Ulfenborg, B., Malchau Lauesgaard, J., Kristjansdottir, B. & Sundfeldt, K. (2021). Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics. Clinical Chemistry and Laboratory Medicine, 59(12), 1954-1962
Åpne denne publikasjonen i ny fane eller vindu >>Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics
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2021 (engelsk)Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 59, nr 12, s. 1954-1962Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

To evaluate the impact of different biologic, histopathologic and lifestyle factors on serum levels of human epididymis protein 4 (HE4) and Cancer antigen 125 (CA125) in the diagnostic work up of women with an ovarian cyst or pelvic tumor. The statistical evaluation was performed on a population of 445 women diagnosed with a benign ovarian disease, included in a large Swedish multicenter trial (ClinicalTrials.gov NCT03193671). Multivariable logistic regression analyses were performed to distinguish between the true negatives and false positives through adjusting for biologic, histopathologic and lifestyle factors on serum samples of CA125 and HE4 separately. The likelihood ratio test was used to determine statistical significance and Benjamini-Hochberg correction to adjust for multiple testing. A total of 31% of the women had false positive CA125 but only 9% had false positive results of HE4. Smoking (OR 6.62 95% CI 2.93-15.12) and impaired renal function, measured by eGFR (OR 0.18 95% CI 0.08-0.39), were independently predictive of falsely elevated serum levels of HE4. Endometriosis was the only variable predictive of falsely elevated serum levels of CA125 (OR 7.96 95% CI 4.53-14.39). Age correlated with increased serum levels of HE4. Smoking, renal failure, age and endometriosis are factors that independently should be considered when assessing serum levels of HE4 and CA125 in women with an ovarian cyst or pelvic mass to avoid false indications of malignant disease. 

sted, utgiver, år, opplag, sider
Walter de Gruyter, 2021
Emneord
benign ovarian tumor, cancer antigen 125, diagnostics, endometriosis, human epididymis 4, renal failure, smoking
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-20540 (URN)10.1515/cclm-2021-0510 (DOI)000724219800019 ()34388324 (PubMedID)2-s2.0-85113721277 (Scopus ID)
Forskningsfinansiär
Swedish Cancer Society
Merknad

CC BY 4.0

© 2021

Pre-published online by De Gruyter August 12, 2021

The study was funded by the Swedish Cancer Foundation (KS), LUA-ALF (KS), the Assar Gabrielsson Foundation (ML, BK, CM), the Hjalmar Svensson Foundation (ML), and the Gothenburg Medical Society (ML). Roche Diagnostics Scandinavia covered the cost of running biomarker assays at the accredited laboratory at Sahlgrenska University Hospital, Gothenburg, Sweden. The funding organizations played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Tilgjengelig fra: 2021-09-09 Laget: 2021-09-09 Sist oppdatert: 2022-04-20bibliografisk kontrollert
Organisasjoner
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ORCID-id: ORCID iD iconorcid.org/0000-0001-9242-4852