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BETA
Jangamreddy, Jaganmohan R.ORCID iD iconorcid.org/0000-0001-6105-1213
Alternative names
Publications (10 of 14) Show all publications
Jangamreddy, J. R. (2015). Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Current cancer treatments involving surgery, radiotherapy, and chemotherapy target the vast majority of cancer cells, but they are only partially effective in eliminating the disease. Failure to eliminate cancer with conventional treatments can lead to recurrence, which usually kills patient. This often occurs when cancer cells develop resistance to cancer drugs or when cancer-initiating cells (cancer stem cells), unaffected by existing treatment procedures, are present. Here, we studied two drugs, salinomycin and apoptin, that exhibit great potential in the future of cancer treatment not only for restricting malignancy, but also in preventing tumor recurrence. Salinomycin is an antibiotic that was used in poultry farming that is now used clinically to target cancer stem cells, and apoptin is a chicken anemia virus-derived protein that is capable of detecting and killing transformed cells. In this study, we delved into the molecular mechanism of salinomycin action leading to cancer cell death. We showed that salinomycin induces autophagy in both cancer and normal primary cells. We further demonstrated that salinomycin promotes mitochondrial fission, thus increasing mitochondrial mass and mitochondria-specific autophagy, mitophagy. Salinomycin-induced cell death was both necrotic and apoptotic as determined by increased release of HMGB1 and caspase-3, -8 and -9 activation. We also found that stress responses of normal and cancer cells to salinomycin differ and this difference is aggravated by starvation conditions. We proposed that a combinational treatment with glucose starvation, or glucose analogues such as 2DG or 2FDG, might enhance the effects of salinomycin on cancer cells while protecting normal cells. We previously reported that apoptin interacts with BCRABL1, a protein that is expressed in patients with chronic myeloid leukemia (CML). We located a minimal region on the apoptin protein that triggers inhibition of downstream BCR-ABL1 signaling effects. This deca-peptide region was tested on patient samples and was shown to effectively kill cancer cells derived from patients, similar to the drug Imatinib. We further show that the apoptin decapeptide is cytotoxic to Imatinib-resistant patient-derived cancer cells. Thus, we identified a novel therapeutic targeting agent that can not only overcome drug resistance, but it can also induce cancer cell death without affecting normal cells.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. p. 53
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1436
National Category
Basic Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-113709 (URN)10.3384/diss.diva-113709 (DOI)978-91-7519-153-9 (ISBN)
Public defence
2015-02-26, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2018-01-11Bibliographically approved
Jangamreddy, J. R., Jain, M. V., Hallbeck, A.-L., Roberg, K., Lotfi, K. & Los, M. J. (2015). Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death. OncoTarget, 6(12), 10134-10145
Open this publication in new window or tab >>Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
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2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, p. 10134-10145Article in journal (Refereed) Published
Abstract [en]

Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2015
Keywords
Glucose starvation, 2DG, 2FDG, Normoxia and Hypoxia, Differential Stress Response, autophagy, Akt, Tricirabine, Salinomycin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-113707 (URN)000358874600039 ()
Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2018-01-11Bibliographically approved
Reddy Jangamreddy, J., Panigrahi, S. & Los, M. J. (2015). Monitoring of autophagy is complicated: Salinomycin as an example. Biochimica et Biophysica Acta. Molecular Cell Research, 1853(3), 604-610
Open this publication in new window or tab >>Monitoring of autophagy is complicated: Salinomycin as an example
2015 (English)In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, ISSN 0167-4889, Vol. 1853, no 3, p. 604-610Article in journal (Refereed) Published
Abstract [en]

Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10μM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30μM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Autophagic flux; GFP-LC3; Salinomycin; Vacuolization; mTandem GFP-RFP LC3; p62/SQSTRM1
National Category
Basic Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-113565 (URN)10.1016/j.bbamcr.2014.12.022 (DOI)000349878500007 ()25541282 (PubMedID)
Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2018-01-11Bibliographically approved
Vilas Jain, M., Jangamreddy, J., Grabarek, J., Schweizer, F., Klonisch, T., Cieslar-Pobuda, A. & Los, M. J. (2015). Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21(Waf1/Cip1) and p27(kip1). Cell Cycle, 14(13), 2109-2120
Open this publication in new window or tab >>Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21(Waf1/Cip1) and p27(kip1)
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2015 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 13, p. 2109-2120Article in journal (Refereed) Published
Abstract [en]

Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44(+High)/CD24(-Low) phenotype. This effect was completely reversed in the presence of Akt-specific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21(Waf1/Cip1) and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

Place, publisher, year, edition, pages
Taylor and Francis: STM, Behavioural Science and Public Health Titles, 2015
Keywords
Akt-NLS; cancer stem-like cells; mTOR; PI3K; stemness
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-120274 (URN)10.1080/15384101.2015.1041692 (DOI)000356959800021 ()26030190 (PubMedID)
Note

Funding Agencies|Linkoping University; Integrative Regenerative Medicine Center (IGEN); VR-NanoVision [K2012-99X-22325-01-5]; Cancerfonden [2013/391]; Canadian Breast Cancer Foundation (CBCF); Natural Sciences and Engineering Research Council of Canada (NSERC); [BK/265/RAU1/2014/t.10]

Available from: 2015-07-24 Created: 2015-07-24 Last updated: 2018-01-11
Patra, H. K., Imani, R., Jangamreddy, J., Pazoki, M., Iglic, A., Turner, A. & Tiwari, A. (2015). On/off-switchable anti-neoplastic nanoarchitecture. Scientific Reports, 5(14571), 1-9
Open this publication in new window or tab >>On/off-switchable anti-neoplastic nanoarchitecture
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 14571, p. 1-9Article in journal (Refereed) Published
Abstract [en]

Throughout the world, there are increasing demands for alternate approaches to advanced cancer therapeutics. Numerous potentially chemotherapeutic compounds are developed every year for clinical trial and some of them are considered as potential drug candidates. Nanotechnology-based approaches have accelerated the discovery process, but the key challenge still remains to develop therapeutically viable and physiologically safe materials suitable for cancer therapy. Here, we report a high turnover, on/off-switchable functionally popping reactive oxygen species (ROS) generator using a smart mesoporous titanium dioxide popcorn (TiO2 Pops) nanoarchitecture. The resulting TiO2 Pops, unlike TiO2 nanoparticles (TiO2 NPs), are exceptionally biocompatible with normal cells. Under identical conditions, TiO2 Pops show very high photocatalytic activity compared to TiO2 NPs. Upon on/off-switchable photo activation, the TiO2 Pops can trigger the generation of high-turnover flash ROS and can deliver their potential anticancer effect by enhancing the intracellular ROS level until it crosses the threshold to open the death gate, thus reducing the survival of cancer cells by at least six times in comparison with TiO2 NPs without affecting the normal cells.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2015
National Category
Cancer and Oncology Other Basic Medicine
Identifiers
urn:nbn:se:liu:diva-122109 (URN)10.1038/srep14571 (DOI)000361873500001 ()26415561 (PubMedID)
Note

Funding Agencies|Swedish Research Council [VR-2011-6058357]; IGEN (Post-Doctoral Fellowship); Slovenian Research Agency (ARRS) [J1-6728, P2-0232]

Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2018-01-11
Ghavami, S., Shojaei, S., Yeganeh, B., Ande, S. R., Jangamreddy, J. R., Mehrpour, M., . . . Łos, M. J. (2014). Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders. Progress in Neurobiology, 112, 24-49
Open this publication in new window or tab >>Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders
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2014 (English)In: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 112, p. 24-49Article, review/survey (Refereed) Published
Abstract [en]

Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.

Place, publisher, year, edition, pages
Kidlington, Oxford, United Kingdom: Pergamon Press, 2014
National Category
Biological Sciences
Identifiers
urn:nbn:se:liu:diva-99887 (URN)10.1016/j.pneurobio.2013.10.004 (DOI)000330911300002 ()
Available from: 2013-10-22 Created: 2013-10-22 Last updated: 2019-01-22
Farahani, E., Patra, H. K., Jangamreddy, J. R., Rashedi, I., Kawalec, M., Rao Pariti, R. K., . . . Wiechec, E. (2014). Cell adhesion molecules and their relation to (cancer) cell stemness. Carcinogenesis, 35(4), 747-759
Open this publication in new window or tab >>Cell adhesion molecules and their relation to (cancer) cell stemness
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2014 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, no 4, p. 747-759Article, review/survey (Refereed) Published
Abstract [en]

Despite decades of search for anticancer drugs targeting solid tumors, this group of diseases remains largely incurable, especially if in advanced, metastatic stage. In this review, we draw comparison between reprogramming and carcinogenesis, as well as between stem cells (SCs) and cancer stem cells (CSCs), focusing on changing garniture of adhesion molecules. Furthermore, we elaborate on the role of adhesion molecules in the regulation of (cancer) SCs division (symmetric or asymmetric), and in evolving interactions between CSCs and extracellular matrix. Among other aspects, we analyze the role and changes of expression of key adhesion molecules as cancer progresses and metastases develop. Here, the role of cadherins, integrins, as well as selected transcription factors like Twist and Snail is highlighted, not only in the regulation of epithelial-to-mesenchymal transition but also in the avoidance of anoikis. Finally, we briefly discuss recent developments and new strategies targeting CSCs, which focus on adhesion molecules or targeting tumor vasculature.

Place, publisher, year, edition, pages
Oxford University Press, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105306 (URN)10.1093/carcin/bgu045 (DOI)000335001800002 ()
Available from: 2014-03-17 Created: 2014-03-17 Last updated: 2019-02-11Bibliographically approved
Jangamreddy, J. R., Panigrahi, S., Lotfi, K., Yadav, M., Maddika, S., Tripathi, A. K., . . . Los, M. J. (2014). Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy. OncoTarget, 5(16), 7198-7211
Open this publication in new window or tab >>Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy
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2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 16, p. 7198-7211Article in journal (Refereed) Published
Abstract [en]

Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.

Keywords
apoptin, BCR-ABL1, CML, imatinib, STAT5
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-111667 (URN)000347920100055 ()25216532 (PubMedID)
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2018-01-11Bibliographically approved
Wark, L., Novak, D., Sabbaghian, N., Amrein, L., Jangamreddy, J. R., Cheang, M., . . . Tischkowitz, M. (2013). Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three-dimensional nuclear organization of patient-derived cell lines. Genes, Chromosomes and Cancer, 52(5), 480-494
Open this publication in new window or tab >>Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three-dimensional nuclear organization of patient-derived cell lines
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2013 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 52, no 5, p. 480-494Article in journal (Refereed) Published
Abstract [en]

PALB2/FANCN is a BRCA1- and BRCA2-interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in PALB2 predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of PALB2 heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient-derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating PALB2 mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q-FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST-1. The PALB2 c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild-type FCLs generated from first-degree relatives (P =1.04E-10 and P =9.68E-15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three PALB2 heterozygous FCLs analyzed when compared with PALB2 wild-type, BRCA1 and BRCA2 heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of PALB2-related cancers.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-87853 (URN)10.1002/gcc.22045 (DOI)000316325700004 ()23341105 (PubMedID)2-s2.0-84875075153 (Scopus ID)
Available from: 2013-01-24 Created: 2013-01-24 Last updated: 2018-01-11Bibliographically approved
Jangamreddy, J., Ghavami, S., Grabarek, J., Kratz, G., Wiechec, E., Fredriksson, B.-A., . . . Łos, M. (2013). Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells. Biochimica et Biophysica Acta. Molecular Cell Research, 1833(9), 2057-2069
Open this publication in new window or tab >>Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells
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2013 (English)In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1833, no 9, p. 2057-2069Article in journal (Refereed) Published
Abstract [en]

The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca2 +, cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/β-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (∆Ψ) in a subpopulation of cells. Salinomycin strongly, and in time-dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect.

Keywords
cancer stem cells; mitofusin; mitophagy; mTOR; PGC1α; salinomycin
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-91756 (URN)10.1016/j.bbamcr.2013.04.011 (DOI)000321173900004 ()23639289 (PubMedID)
Available from: 2013-05-01 Created: 2013-05-01 Last updated: 2017-12-06
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6105-1213

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