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Mardinoglu, Adil
Publications (10 of 39) Show all publications
Benfeitas, R., Bidkhori, G., Mukhopadhyay, B., Klevstig, M., Arif, M., Zhang, C., . . . Mardinoglu, A. (2019). Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis. EBioMedicine
Open this publication in new window or tab >>Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964Article in journal (Refereed) Published
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-248702 (URN)
Note

QC 20190423

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-23Bibliographically approved
Lundgren, S., Fagerström-Vahman, H., Zhang, C., Ben-Dror, L., Mardinoglu, A., Uhlén, M., . . . Jirström, K. (2019). Discovery of KIRREL as a biomarker for prognostic stratification of patients within melanoma [Letter to the editor]. Biomarker Research
Open this publication in new window or tab >>Discovery of KIRREL as a biomarker for prognostic stratification of patients within melanoma
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2019 (English)In: Biomarker Research, ISSN 0961-088X, E-ISSN 1475-925XArticle in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-248690 (URN)000455575200001 ()2-s2.0-85062927349 (Scopus ID)
Note

QC 20190425

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-08-01Bibliographically approved
Turanli, B., Zhang, C., Kim, W., Benfeitas, R., Uhlén, M., Yalcin Arga, K. & Mardinoglu, A. (2019). Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning. EBioMedicine, 42, 386-396
Open this publication in new window or tab >>Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 42, p. 386-396Article in journal (Refereed) Published
Abstract [sv]

Background: Genome-scale metabolic models (GEMs)offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment. Methods: In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions. Findings: We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line. Interpretation: Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Medical and Health Sciences Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-248689 (URN)10.1016/j.ebiom.2019.03.009 (DOI)000466175100052 ()30905848 (PubMedID)2-s2.0-85063114920 (Scopus ID)
Note

QC 20190424

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-05-21Bibliographically approved
Zhang, C., Aldrees, M., Arif, M., Li, X., Mardinoglu, A. & Aziz, M. A. (2019). Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling. Frontiers in Oncology, 9, Article ID 681.
Open this publication in new window or tab >>Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling
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2019 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 681Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer is the third most incidental cancer worldwide, and the response rate of current treatment for colorectal cancer is very low. Genome-scale metabolic models (GEMs) are systems biology platforms, and they had been used to assist researchers in understanding the metabolic alterations in different types of cancer. Here, we reconstructed a generic colorectal cancer GEM by merging 374 personalized GEMs from the Human Pathology Atlas and used it as a platform for systematic investigation of the difference between tumor and normal samples. The reconstructed model revealed the metabolic reprogramming in glutathione as well as the arginine and proline metabolism in response to tumor occurrence. In addition, six genes including ODC1, SMS, SRM, RRM2, SMOX, and SAT1 associated with arginine and proline metabolism were found to be key players in this metabolic alteration. We also investigated these genes in independent colorectal cancer patients and cell lines and found that many of these genes showed elevated level in colorectal cancer and exhibited adverse effect in patients. Therefore, these genes could be promising therapeutic targets for treatment of a specific colon cancer patient group.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
colorectal cancer, genome scale metabolic model, polyamine metabolism, personalized medicine, transcriptomics
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:kth:diva-255737 (URN)10.3389/fonc.2019.00681 (DOI)000477876200001 ()2-s2.0-85072220274 (Scopus ID)
Note

QC 20190814

Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-10-04Bibliographically approved
Svensson, M. C., Borg, D., Zhang, C., Hedner, C., Nodin, B., Uhlén, M., . . . Jirström, K. (2019). Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival. Frontiers in Oncology
Open this publication in new window or tab >>Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival
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2019 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943XArticle in journal (Refereed) Published
Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-248694 (URN)10.3389/fonc.2019.00136 (DOI)000461111200002 ()2-s2.0-85063302688 (Scopus ID)
Note

QC 20190424

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-08-06Bibliographically approved
Cadenas, C., Vosbeck, S., Edlund, K., Grgas, K., Madjar, K., Hellwig, B., . . . Hengstler, J. G. (2019). LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer. International Journal of Cancer, 145(4), 901-915
Open this publication in new window or tab >>LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 4, p. 901-915Article in journal (Refereed) Published
Abstract [en]

Endothelial lipase (LIPG) is a cell surface associated lipase that displays phospholipase A1 activity towards phosphatidylcholine present in high-density lipoproteins (HDL). LIPG was recently reported to be expressed in breast cancer and to support proliferation, tumourigenicity and metastasis. Here we show that severe oxidative stress leading to AMPK activation triggers LIPG upregulation, resulting in intracellular lipid droplet accumulation in breast cancer cells, which supports survival. Neutralizing oxidative stress abrogated LIPG upregulation and the concomitant lipid storage. In human breast cancer, high LIPG expression was observed in a limited subset of tumours and was significantly associated with shorter metastasis-free survival in node-negative, untreated patients. Moreover, expression of PLIN2 and TXNRD1 in these tumours indicated a link to lipid storage and oxidative stress. Altogether, our findings reveal a previously unrecognized role for LIPG in enabling oxidative stress-induced lipid droplet accumulation in tumour cells that protects against oxidative stress, and thus supports tumour progression.

Place, publisher, year, edition, pages
Wiley-Liss Inc, 2019
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-248699 (URN)10.1002/ijc.32138 (DOI)000472571300005 ()30653260 (PubMedID)2-s2.0-85061234180 (Scopus ID)
Note

QC 20190423

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-08-07Bibliographically approved
Harms, M. J., Li, Q., Lee, S., Zhang, C., Kull, B., Hallen, S., . . . Boucher, J. (2019). Mature Human White Adipocytes Cultured under Membranes Maintain Identity, Function, and Can Transdifferentiate into Brown-like Adipocytes. Cell reports
Open this publication in new window or tab >>Mature Human White Adipocytes Cultured under Membranes Maintain Identity, Function, and Can Transdifferentiate into Brown-like Adipocytes
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-248688 (URN)10.1016/j.celrep.2019.03.026 (DOI)000463187700018 ()2-s2.0-85063422988 (Scopus ID)
Note

QC 20190423

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-05-16Bibliographically approved
Turanli, B., Karagoz, K., Bidkhori, G., Sinha, R., Gatza, M. L., Uhlén, M., . . . Arga, K. Y. (2019). Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer. Frontiers in Genetics, 10, Article ID 420.
Open this publication in new window or tab >>Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer
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2019 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, article id 420Article in journal (Refereed) Published
Abstract [en]

Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype, is the 5th leading cause of cancer deaths for women in the United States. The overall prognosis for TNBC patients remains poor given that few treatment options exist; including targeted therapies (not FDA approved), and multi-agent chemotherapy as standard-of-care treatment. TNBC like other complex diseases is governed by the perturbations of the complex interaction networks thereby elucidating the underlying molecular mechanisms of this disease in the context of network principles, which have the potential to identify targets for drug development. Here, we present an integrated "omics" approach based on the use of transcriptome and interactome data to identify dynamic/active protein-protein interaction networks (PPINs) in TNBC patients. We have identified three highly connected modules, EED, DHX9, and AURKA, which are extremely activated in TNBC tumors compared to both normal tissues and other breast cancer subtypes. Based on the functional analyses, we propose that these modules are potential drivers of proliferation and, as such, should be considered candidate molecular targets for drug development or drug repositioning in TNBC. Consistent with this argument, we repurposed steroids, anti-inflammatory agents, anti-infective agents, cardiovascular agents for patients with basal-like breast cancer. Finally, we have performed essential metabolite analysis on personalized genome-scale metabolic models and found that metabolites such as sphingosine-1-phosphate and cholesterol-sulfate have utmost importance in TNBC tumor growth.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
breast cancer, drug repositioning, non-cancer therapeutics, repurposing, basal subtype, personalized metabolic models
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-252378 (URN)10.3389/fgene.2019.00420 (DOI)000467463700001 ()2-s2.0-85067884608 (Scopus ID)
Note

QC 20190718

Available from: 2019-07-18 Created: 2019-07-18 Last updated: 2019-07-18Bibliographically approved
Sahebekhtiari, N., Saraswat, M., Joenvaara, S., Jokinen, R., Lovric, A., Kaye, S., . . . Pietilainen, K. H. (2019). Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity-A Study on Rare BMI-Discordant Monozygotic Twin Pairs. PROTEOMICS - Clinical Applications, 13(4), Article ID 1800173.
Open this publication in new window or tab >>Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity-A Study on Rare BMI-Discordant Monozygotic Twin Pairs
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2019 (English)In: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 13, no 4, article id 1800173Article in journal (Refereed) Published
Abstract [en]

Purpose: The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation. Experimental Design: The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m−2, n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy. Results: Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids. Conclusions and Clinical Relevance: The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2019
Keywords
acquired obesity, complement cascade, monozygotic twins, label-free proteomics, plasma proteomics
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-255773 (URN)10.1002/prca.201800173 (DOI)000475990600007 ()30688043 (PubMedID)2-s2.0-85061063771 (Scopus ID)
Note

QC 20190813

Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Liu, Z., Zhang, C., Lee, S., Kim, W., Klevstig, M., Harzandi, A. M., . . . Mardinoglu, A. (2019). Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function. Metabolic engineering
Open this publication in new window or tab >>Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function
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2019 (English)In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184Article in journal (Refereed) Published
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-248703 (URN)
Note

QC 20190425

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-25Bibliographically approved
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