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  1. Article ; Online: CUP-Syndrom – Diagnostik aus Sicht der Pathologie.

    Pauli, Chantal

    Radiologie (Heidelberg, Germany)

    2023  Volume 63, Issue 5, Page(s) 336–345

    Abstract: Problem: Histologic and immunohistologic workup of tumor material from metastases of a previously unknown primary tumor is important for identifying their origin, but is often insufficient for this purpose without clinical oncologic and radiologic ... ...

    Title translation CUP syndrome-diagnostics from the perspective of pathology.
    Abstract Problem: Histologic and immunohistologic workup of tumor material from metastases of a previously unknown primary tumor is important for identifying their origin, but is often insufficient for this purpose without clinical oncologic and radiologic evaluation.
    Procedure: In the initial cancer of unknown primary (CUP) situation, histologic and immunohistochemical workup together with clinicoradiologic correlations contribute significantly to the identification of the primary tumor. There are now accepted guidelines to follow when there is an initial CUP situation. Molecular diagnostic tools can be used to investigate changes at the nucleic acid level, which can provide clues about the primary tumor, including potential targets for therapy. If, despite broad and interdisciplinary diagnostics, it is not possible to identify the primary tumor, the diagnosis is CUP syndrome. If a true CUP situation is present, it is important to assign the tumor to a tumor class or a specific therapy-sensitive subgroup as best as possible so that the best possible treatment can be given. However, for a final assignment to a primary tumor or a final classification as CUP, a comparison with medical oncological and imaging findings is indispensable.
    Conclusion: When CUP is suspected, close interdisciplinary collaboration between pathology, medical oncology, and imaging is essential to achieve a viable classification as CUP or identification of a presumptive primary tumor, in the interest of providing the most specific and effective therapy for affected individuals.
    MeSH term(s) Humans ; Neoplasms, Unknown Primary/diagnosis ; Neoplasms, Unknown Primary/pathology ; Neoplasms, Unknown Primary/therapy ; Syndrome ; Diagnostic Imaging/methods ; Biological Phenomena ; Interdisciplinary Studies
    Language German
    Publishing date 2023-04-20
    Publishing country Germany
    Document type English Abstract ; Journal Article ; Review
    ISSN 2731-7056
    ISSN (online) 2731-7056
    DOI 10.1007/s00117-023-01143-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A systematic comparison of pan-Trk immunohistochemistry assays among multiple cancer types.

    Haberecker, Martina / Töpfer, Antonia / Melega, Francesca / Moch, Holger / Pauli, Chantal

    Histopathology

    2023  Volume 82, Issue 7, Page(s) 1003–1012

    Abstract: Aims: NTRK rearranged tumours are rare but can be successfully treated using anti-TRK-targeted therapies, making NTRK testing important for treatment choices in patients with advanced cancers. Pan-Trk immunohistochemistry (IHC) has become a valuable and ...

    Abstract Aims: NTRK rearranged tumours are rare but can be successfully treated using anti-TRK-targeted therapies, making NTRK testing important for treatment choices in patients with advanced cancers. Pan-Trk immunohistochemistry (IHC) has become a valuable and affordable screening tool in many laboratories. Unfortunately, the choice of antibodies and IHC protocols to investigate biomarkers is not standardised. In this study, we compared the performance of four pan-Trk IHC methods, using three different clones, primarily in NTRK fusion-positive tumours.
    Methods and results: We studied the performance of four pan-Trk IHC methods using three different clones: EPR17341 (Abcam and Ventana), EP1058Y (Abcam) and A7H6R (Cell Signaling) in 22 molecularly confirmed NTRK rearranged tumours. Additionally, selected NTRK fusion-negative tumours were further included: NTRK mutated (n = 8) and amplified (n = 15) tumours as well as NTRK fusion-negative tumours driven by other gene fusions, such as ALK, ROS1 and BCOR (n = 20), as well as salivary gland tumours (n = 16). Inter-rater agreement of three pathologists was additionally calculated, including H-score. With clone EPR17341 (Abcam in-house and ready-to-use Ventana protocol), all molecularly confirmed NTRK1-3 rearranged tumours were positively detected by immunohistochemistry, while the other clones missed NTRK2-3 rearranged tumours. For the fusion-negative cohort we found the best performance (least false-positive cases) using the clone A7H6R (Cell Signalling).
    Conclusion: Given the therapeutic importance, testing for NTRK rearrangements in daily practice has become necessary and, despite IHC being a fast and affordable tool, using it in routine diagnostics is complicated and requires a high level of expertise.
    MeSH term(s) Humans ; Receptor, trkA/genetics ; Immunohistochemistry ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins ; Neoplasms/diagnosis ; Neoplasms/genetics ; Neoplasms/drug therapy ; Salivary Gland Neoplasms/pathology ; Biomarkers, Tumor/genetics ; Oncogene Proteins, Fusion/genetics
    Chemical Substances Receptor, trkA (EC 2.7.10.1) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins ; Biomarkers, Tumor ; Oncogene Proteins, Fusion
    Language English
    Publishing date 2023-02-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 131914-0
    ISSN 1365-2559 ; 0309-0167
    ISSN (online) 1365-2559
    ISSN 0309-0167
    DOI 10.1111/his.14884
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  3. Article: Conservative surgical treatment with fertility preservation in a young adult with

    Bühler, Marco M / Honcharova-Biletska, Hanna / Pauli, Chantal / Chronas, Dimitrios / Bolten, Kristina

    Gynecologic oncology reports

    2023  Volume 48, Page(s) 101233

    Abstract: In depth molecular studies are constantly expanding our understanding and refining the classification of gynecological neoplasms. ...

    Abstract In depth molecular studies are constantly expanding our understanding and refining the classification of gynecological neoplasms.
    Language English
    Publishing date 2023-06-24
    Publishing country Netherlands
    Document type Case Reports
    ZDB-ID 2818505-5
    ISSN 2352-5789
    ISSN 2352-5789
    DOI 10.1016/j.gore.2023.101233
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  4. Article ; Online: Establishment and functional testing of a novel ex vivo extraskeletal osteosarcoma cell model (USZ20-ESOS1).

    Harnisch, Kim / Steiner, Sabrina / Pliego-Mendieta, Alicia / Chen, Yanjiang / Planas-Paz, Lara / Pauli, Chantal

    Human cell

    2023  Volume 37, Issue 1, Page(s) 356–363

    Abstract: Extraskeletal osteosarcoma (ESOS) is a rare malignant mesenchymal tumor that originates in the soft tissue. ESOS accounts for less than 1% of all soft tissue sarcomas and exhibits an aggressive behavior with a high propensity for local recurrence and ... ...

    Abstract Extraskeletal osteosarcoma (ESOS) is a rare malignant mesenchymal tumor that originates in the soft tissue. ESOS accounts for less than 1% of all soft tissue sarcomas and exhibits an aggressive behavior with a high propensity for local recurrence and distant metastasis. Despite advances in treatment, the prognosis for ESOS remains poor, with a five-year survival rate of less than 50% and 27% for metastatic patients. Ex vivo models derived from patient samples are critical tools for studying rare diseases with poor prognoses, such as ESOS, and identifying potential new treatment strategies. In this work, we established a novel ESOS ex vivo sarco-sphere model from a metastatic lesion to the dermis for research and functional testing purposes. The ex vivo cell model accurately recapitulated the native tumor, as evidenced by histomorphology and molecular profiles. Through a functional screening approach, we were able to identify novel individual anti-cancer drug sensitivities for different drugs such as romidepsin, miverbresib and to multiple kinase inhibitors. Overall, our new ESOS ex vivo cell model represents a valuable tool for investigating disease mechanisms and answering basic and translational research questions.
    MeSH term(s) Humans ; Osteosarcoma/pathology ; Soft Tissue Neoplasms/pathology ; Bone Neoplasms/pathology
    Language English
    Publishing date 2023-11-11
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 1149134-6
    ISSN 1749-0774 ; 0914-7470
    ISSN (online) 1749-0774
    ISSN 0914-7470
    DOI 10.1007/s13577-023-01001-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Prediction of histology by B-mode and PD-mode ultrasound across different joint locations and diseases.

    Micheroli, Raphael / Pauli, Chantal / Bürki, Kristina / Rossbach, Philipp / Distler, Oliver / Ospelt, Caroline / Ciurea, Adrian

    RMD open

    2022  Volume 8, Issue 2

    MeSH term(s) Humans ; Joints/diagnostic imaging ; Ultrasonography
    Language English
    Publishing date 2022-07-09
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 2812592-7
    ISSN 2056-5933 ; 2056-5933
    ISSN (online) 2056-5933
    ISSN 2056-5933
    DOI 10.1136/rmdopen-2022-002439
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  6. Article ; Online: Establishment, characterization and functional testing of two novel ex vivo extraskeletal myxoid chondrosarcoma (EMC) cell models.

    Bangerter, Jana Lucia / Harnisch, Kim Jannis / Chen, Yanjiang / Hagedorn, Catherine / Planas-Paz, Lara / Pauli, Chantal

    Human cell

    2022  Volume 36, Issue 1, Page(s) 446–455

    Abstract: Extraskeletal myxoid chondrosarcoma (EMC) is a malignant mesenchymal neoplasm of uncertain differentiation as classified by the WHO Classification of Tumours 2020. Although often associated with pronlonged survival, EMC has high rates of distant ... ...

    Abstract Extraskeletal myxoid chondrosarcoma (EMC) is a malignant mesenchymal neoplasm of uncertain differentiation as classified by the WHO Classification of Tumours 2020. Although often associated with pronlonged survival, EMC has high rates of distant recurrences and disease-associated death. EMCs are translocation sarcomas and harbor in > 90% of the cases an NR4A3 rearrangement. The molecular consequences of the NR4A3 gene fusions are not yet fully elucidated as well-characterized ex vivo cell models for EMC are lacking. Patient-derived ex vivo models are important and essential tools for investigating disease mechanisms associated with diseases that are rare, that exhibit poor prognosis and for the identification of potential novel treatment options. We established two novel EMC ex vivo models (USZ20-EMC1 and USZ22-EMC2) for functional testing and research purposes. USZ20-EMC1 and USZ22-EMC2 were established and maintained as sarco-sphere cell models for several months in culture. The cells were molecularly characterized using DNA sequencing and methylation profiling. Both cell models represent their native tumor tissue as confirmed by histomorphology and their molecular profiles, suggesting that native tumor cell function can be recapitulated in the ex vivo models. Using a functional screening approach, novel anti-cancer drug sensitivities including potential synergistic combinations were identified. In conclusion, two novel EMC ex vivo cell models (USZ20-EMC1 and USZ22-EMC2) were successfully established and characterized from native tumor tissues. Both cell models will be useful tools for further investigating disease mechanisms and for answering basic and translational research questions.
    MeSH term(s) Humans ; Chondrosarcoma/genetics ; Chondrosarcoma/metabolism ; Chondrosarcoma/pathology ; Neoplasms, Connective and Soft Tissue/genetics ; Soft Tissue Neoplasms/genetics ; Sarcoma
    Language English
    Publishing date 2022-11-01
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 1149134-6
    ISSN 1749-0774 ; 0914-7470
    ISSN (online) 1749-0774
    ISSN 0914-7470
    DOI 10.1007/s13577-022-00818-x
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  7. Article: Cross-species evaluation of fibroblast activation protein alpha as potential imaging target for soft tissue sarcoma: a comparative immunohistochemical study in humans, dogs, and cats.

    Beer, Patricia / Pauli, Chantal / Haberecker, Martina / Grest, Paula / Beebe, Erin / Fuchs, Daniel / Markkanen, Enni / Krudewig, Christiane / Nolff, Mirja Christine

    Frontiers in oncology

    2023  Volume 13, Page(s) 1210004

    Abstract: Introduction: Complete surgical tumor resection is paramount in the management of soft tissue sarcoma (STS) in humans, dogs, and cats alike. Near-infrared targeted tracers for fluorescence-guided surgery (FGS) could facilitate intraoperative ... ...

    Abstract Introduction: Complete surgical tumor resection is paramount in the management of soft tissue sarcoma (STS) in humans, dogs, and cats alike. Near-infrared targeted tracers for fluorescence-guided surgery (FGS) could facilitate intraoperative visualization of the tumor and improve resection accuracy. Target identification is complicated in STS due to the rarity and heterogeneity of the disease. This study aims to validate the expression of fibroblast activation protein alpha (FAP) in selected human, canine, and feline STS subtypes to assess the value of FAP as a target for FGS and to validate companion animals as a translational model.
    Methods: Formalin-fixed and paraffin-embedded tissue samples from 53 canine STSs (perivascular wall tumor (PWT), canine fibrosarcoma (cFS), and STS not further specified (NOS)), 24 feline fibrosarcomas, and 39 human STSs (myxofibrosarcoma, undifferentiated pleomorphic sarcoma, dermatofibrosarcoma protuberans, and malignant peripheral nerve sheath tumor) as well as six canine and seven feline healthy controls and 10 inflamed tissue samples were immunohistochemically stained for their FAP expression. FAP labeling in tumor, peritumoral, healthy skin, and inflamed tissue samples was quantified using a visually assessed semiquantitative expression score and digital image analysis. Target selection criteria (TASC) scoring was subsequently performed as previously described.
    Results: Eighty-five percent (85%) of human (33/39), 76% of canine (40/53), and 92% of feline (22/24) STSs showed FAP positivity in over 10% of the tumor cells. A high expression was determined in 53% canine (28/53), 67% feline (16/24), and 44% human STSs (17/39). The average FAP-labeled area of canine, feline, and human STSs was 31%, 33%, and 42%, respectively (
    Conclusion: This study represents the first cross-species target evaluation of FAP for STS. Our results demonstrate that FAP expression is increased in various STS subtypes compared to non-cancerous tissues across species, thereby validating dogs and cats as suitable animal models. Based on a TASC score, FAP could be considered a target for FGS.
    Language English
    Publishing date 2023-09-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1210004
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  8. Article ; Online: NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

    Glauser, Salomé / Ameline, Baptiste / Andrei, Vanghelita / Harder, Dorothee / Pauli, Chantal / Trautmann, Marcel / Hartmann, Wolfgang / Baumhoer, Daniel

    Pathology

    2023  Volume 55, Issue 5, Page(s) 621–628

    Abstract: Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance ... ...

    Abstract Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.
    MeSH term(s) Humans ; Chondrosarcoma, Mesenchymal/diagnosis ; Chondrosarcoma, Mesenchymal/genetics ; Chondrosarcoma, Mesenchymal/pathology ; Immunohistochemistry ; Epigenome ; Bone and Bones/pathology ; Cell Differentiation ; Bone Neoplasms/diagnosis ; Bone Neoplasms/genetics ; Bone Neoplasms/pathology
    Language English
    Publishing date 2023-05-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 7085-3
    ISSN 1465-3931 ; 0031-3025
    ISSN (online) 1465-3931
    ISSN 0031-3025
    DOI 10.1016/j.pathol.2023.03.003
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  9. Article ; Online: Acquired NF2 mutation confers resistance to TRK inhibition in an ex vivo LMNA::NTRK1-rearranged soft-tissue sarcoma cell model.

    Chen, Yanjiang / Steiner, Sabrina / Hagedorn, Catherine / Kollar, Sarah / Pliego-Mendieta, Alicia / Haberecker, Martina / Plock, Jan / Britschgi, Christian / Planas-Paz, Lara / Pauli, Chantal

    The Journal of pathology

    2024  Volume 263, Issue 2, Page(s) 257–269

    Abstract: Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted ... ...

    Abstract Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK-targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium-throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1-rearranged soft-tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    MeSH term(s) Humans ; Lamin Type A/genetics ; Lamin Type A/metabolism ; Drug Resistance, Neoplasm/genetics ; Receptor, trkA/genetics ; Receptor, trkA/antagonists & inhibitors ; Receptor, trkA/metabolism ; Sarcoma/genetics ; Sarcoma/drug therapy ; Sarcoma/pathology ; Sarcoma/metabolism ; Protein Kinase Inhibitors/pharmacology ; Mutation ; Neurofibromin 2/genetics ; Neurofibromin 2/metabolism ; Gene Rearrangement ; Pyridones/pharmacology ; Benzamides/pharmacology ; Pyrimidinones/pharmacology ; Sirolimus/pharmacology ; Soft Tissue Neoplasms/genetics ; Soft Tissue Neoplasms/drug therapy ; Soft Tissue Neoplasms/pathology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Signal Transduction/drug effects ; Drug Synergism ; Indazoles
    Chemical Substances Lamin Type A ; Receptor, trkA (EC 2.7.10.1) ; LMNA protein, human ; Protein Kinase Inhibitors ; NF2 protein, human ; trametinib (33E86K87QN) ; NTRK1 protein, human ; Neurofibromin 2 ; entrectinib (L5ORF0AN1I) ; Pyridones ; Benzamides ; Pyrimidinones ; Sirolimus (W36ZG6FT64) ; Indazoles
    Language English
    Publishing date 2024-04-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3119-7
    ISSN 1096-9896 ; 0022-3417
    ISSN (online) 1096-9896
    ISSN 0022-3417
    DOI 10.1002/path.6282
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  10. Article ; Online: Ex vivo modeling of acquired drug resistance in BRAF - mutated pancreatic cancer organoids uncovers individual therapeutic vulnerabilities.

    Steiner, Sabrina / Pliego-Mendieta, Alicia / Haberecker, Martina / Hussung, Saskia / Kollár, Anna / Fritsch, Ralph / Arnold, Fabian / Lenggenhager, Daniela / Planas-Paz, Lara / Pauli, Chantal

    Cancer letters

    2024  Volume 584, Page(s) 216650

    Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to late detection and limited treatment options. Some PDAC patients harbor alterations that qualify for targeted treatment strategies but develop acquired resistance, leading to treatment ... ...

    Abstract Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to late detection and limited treatment options. Some PDAC patients harbor alterations that qualify for targeted treatment strategies but develop acquired resistance, leading to treatment failure. We here report the ex vivo modeling of acquired drug resistance by creating a PDAC patient-derived tumor organoid (PDTO) model harboring a rare BRAF R506_K507ins VLR mutation resulting in a resistance to trametinib, a MEK inhibitor. Genomic and transcriptomic analyses revealed upregulated WNT signaling in resistant PDTO clones compared to treatment-naïve parental control cells. By combining genomic and transcriptomic analysis with a functional drug testing approach, we uncovered a de novo upregulation and circumventive reliance on WNT signaling in resistant PDTO clones. Ex vivo models such as PDTOs represent valuable tools for resistance modelling and offer the discovery of novel therapeutic approaches for patients in need where clinical diagnostic tools are currently at the limit.
    MeSH term(s) Humans ; Proto-Oncogene Proteins B-raf/genetics ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Mutation ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Drug Resistance, Neoplasm/genetics ; Organoids/pathology
    Chemical Substances Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; BRAF protein, human (EC 2.7.11.1)
    Language English
    Publishing date 2024-01-20
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2024.216650
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