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Article: EBV and the Pathogenesis of NK/T Cell Lymphoma.

Montes-Mojarro, Ivonne A / Fend, Falko / Quintanilla-Martinez, Leticia

2021 Volume 13, Issue 6

Abstract: Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an ... ...

Abstract	Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as
Language	English
Publishing date	2021-03-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13061414
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Article ; Online: Exploring the relationship between epigenetic DNA methylation and cardiac fibrosis through Raman microspectroscopy.

Becker, Lucas / Montes-Mojarro, Ivonne A / Layland, Shannon Lee / Nsair, Ali / Fend, Falko / Marzi, Julia / Schenke-Layland, Katja

American journal of physiology. Cell physiology

2023 Volume 325, Issue 1, Page(s) C332–C343

Abstract: Cardiomyopathies are associated with fibrotic remodeling of the heart, which is characterized by the excessive accumulation of collagen type I (COL I) due to chronic inflammation and suspected epigenetic influences. Despite the severity and high ... ...

Abstract	Cardiomyopathies are associated with fibrotic remodeling of the heart, which is characterized by the excessive accumulation of collagen type I (COL I) due to chronic inflammation and suspected epigenetic influences. Despite the severity and high mortality rate of cardiac fibrosis, current treatment options are often inadequate, underscoring the importance of gaining a deeper understanding of the disease's underlying molecular and cellular mechanisms. In this study, the extracellular matrix (ECM) and nuclei in fibrotic areas of different cardiomyopathies were molecularly characterized by Raman microspectroscopy and imaging and compared with the control myocardium. Patient samples were obtained from heart tissue affected by ischemia, hypertrophy, and dilated cardiomyopathy and analyzed for fibrosis through conventional histology and marker-independent Raman microspectroscopy (RMS). Prominent differences between control myocardium and cardiomyopathies were revealed by spectral deconvolution of COL I Raman spectra. Statistically significant differences were identified in the amide I region of spectral subpeak at 1,608 cm
MeSH term(s)	Humans ; DNA Methylation ; Collagen Type I/metabolism ; Cardiomyopathies/pathology ; Epigenesis, Genetic ; Fibrosis
Chemical Substances	Collagen Type I
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00209.2023
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Article ; Online: Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib.

Prokoph, Nina / Matthews, Jamie D / Trigg, Ricky M / Montes-Mojarro, Ivonne A / Burke, G A Amos / Fend, Falko / Merkel, Olaf / Kenner, Lukas / Geoerger, Birgit / Johnston, Robert / Murray, Matthew J / Riguad, Charlotte / Brugières, Laurence / Turner, Suzanne D

British journal of haematology

2023 Volume 202, Issue 5, Page(s) 985–994

Abstract: Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) ... ...

Abstract	Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.
MeSH term(s)	Child ; Humans ; Anaplastic Lymphoma Kinase ; Crizotinib/pharmacology ; Crizotinib/therapeutic use ; Carcinoma, Non-Small-Cell Lung ; Receptor Protein-Tyrosine Kinases/therapeutic use ; Lymphoma, Large-Cell, Anaplastic/drug therapy ; Lymphoma, Large-Cell, Anaplastic/pathology ; Heterografts ; Lung Neoplasms/drug therapy ; Neoplasm Recurrence, Local/drug therapy ; Organophosphorus Compounds/pharmacology ; Organophosphorus Compounds/therapeutic use ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; Crizotinib (53AH36668S) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; brigatinib (HYW8DB273J) ; Organophosphorus Compounds ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-06-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.18953
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Article ; Online: CD24: A Marker for an Extended Expansion Potential of Urothelial Cancer Cell Organoids In Vitro?

Geng, Ruizhi / Harland, Niklas / Montes-Mojarro, Ivonne A / Fend, Falko / Aicher, Wilhelm K / Stenzl, Arnulf / Amend, Bastian

International journal of molecular sciences

2022 Volume 23, Issue 10

Abstract: Background: Bladder cancer is the most cost-intensive cancer due to high recurrence rates and long follow-up times. Bladder cancer organoids were considered interesting tools for investigating better methods for the detection and treatment of this ... ...

Abstract	Background: Bladder cancer is the most cost-intensive cancer due to high recurrence rates and long follow-up times. Bladder cancer organoids were considered interesting tools for investigating better methods for the detection and treatment of this cancer. Methods: Organoids were generated from urothelial carcinoma tissue samples, then expanded and characterized; the expression of immune modulatory antigens and tumor stem cells markers CD24 and CD44 was explored in early (P ≤ 3) and later (P ≥ 5) passages (P) by immunofluorescence and by quantitative PCR of cDNA. The expression of these factors was investigated in the corresponding cancer tissue samples by immunohistochemistry. Results: The expression of the PD-L1 was detected on some but not all organoids. CD276 and CD47 were observed on organoids in all passages investigated. Organoids growing beyond passage 8 expressed both CD24 and CD44 at elevated levels in early and late cultures. Organoids proliferating to the eighth passage initially expressed both CD24 and CD44, but lost CD24 expression over time, while CD44 remained. Organoids growing only up to the 6th passage failed to express CD24 but expressed CD44. Conclusions: The data indicate that the expression of CD24 in urothelial cancer cell organoids may serve as an indicator for the prolonged proliferation potential of the cells.
MeSH term(s)	B7 Antigens/metabolism ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; CD24 Antigen/metabolism ; Carcinoma, Transitional Cell/metabolism ; Humans ; Neoplastic Stem Cells/metabolism ; Organoids/metabolism ; Urinary Bladder Neoplasms/metabolism
Chemical Substances	B7 Antigens ; Biomarkers, Tumor ; CD24 Antigen ; CD24 protein, human ; CD276 protein, human
Language	English
Publishing date	2022-05-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23105453
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Article ; Online: Raman microspectroscopy identifies fibrotic tissues in collagen-related disorders via deconvoluted collagen type I spectra.

Becker, Lucas / Lu, Chuan-En / Montes-Mojarro, Ivonne A / Layland, Shannon L / Khalil, Suzan / Nsair, Ali / Duffy, Garry P / Fend, Falko / Marzi, Julia / Schenke-Layland, Katja

Acta biomaterialia

2023 Volume 162, Page(s) 278–291

Abstract: Fibrosis is a consequence of the pathological remodeling of extracellular matrix (ECM) structures in the connective tissue of an organ. It is often caused by chronic inflammation, which over time, progressively leads to an excess deposition of collagen ... ...

Abstract	Fibrosis is a consequence of the pathological remodeling of extracellular matrix (ECM) structures in the connective tissue of an organ. It is often caused by chronic inflammation, which over time, progressively leads to an excess deposition of collagen type I (COL I) that replaces healthy tissue structures, in many cases leaving a stiff scar. Increasing fibrosis can lead to organ failure and death; therefore, developing methods that potentially allow real-time monitoring of early onset or progression of fibrosis are highly valuable. In this study, the ECM structures of diseased and healthy human tissue from multiple organs were investigated for the presence of fibrosis using routine histology and marker-independent Raman microspectroscopy and Raman imaging. Spectral deconvolution of COL I Raman spectra allowed the discrimination of fibrotic and non-fibrotic COL I fibers. Statistically significant differences were identified in the amide I region of the spectral subpeak at 1608 cm
MeSH term(s)	Humans ; Collagen Type I ; Extracellular Matrix ; Spectrum Analysis, Raman/methods ; Cicatrix ; Biomarkers
Chemical Substances	Collagen Type I ; Biomarkers
Language	English
Publishing date	2023-03-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2023.03.016
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Article: Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases.

Kim, Wook Youn / Montes-Mojarro, Ivonne A / Fend, Falko / Quintanilla-Martinez, Leticia

Frontiers in pediatrics

2019 Volume 7, Page(s) 71

Abstract: EBV-associated T and NK-cell lymphoproliferative diseases (EBV-T/NK LPDs) are characterized by the transformation and proliferation of EBV-infected T or NK cells. The 2016 revised World Health Organization classification recognizes the following EBV- ... ...

Abstract	EBV-associated T and NK-cell lymphoproliferative diseases (EBV-T/NK LPDs) are characterized by the transformation and proliferation of EBV-infected T or NK cells. The 2016 revised World Health Organization classification recognizes the following EBV-positive lymphoproliferative disorders (LPD): chronic active EBV infection (CAEBV) of T- and NK-cell type (cutaneous and systemic forms), systemic EBV-positive T-cell lymphoma of childhood, aggressive NK-cell leukemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity primary EBV-positive nodal T/NK-cell lymphoma. EBV-associated hemophagocytic lymphohistiocytosis (HLH), although not included in the WHO classification because it is a reactive, inflammatory disease, is included in this review because it can be life-threatening and may have overlapping features with other EBV+ T/NK LPDs. EBV+ T/NK LPDs are rare diseases difficult to diagnose and manage properly, because some LPDs have unusual presentations, and discrepancies between clinical and histological findings might be encountered. Furthermore, EBV+ T/NK disorders share some clinico-pathological features, and may evolve into other categories during the clinical course, including malignant transformation of CAEBV. Here, we review the EBV+ T/NK LPDs in terms of their definitions, clinical features, histology, immunophenotype, molecular findings, and pathogenesis. This review aims to increase our understanding and awareness of the differential diagnosis among the different EBV+ T/NK LPDs. New insights into the genetic characteristics of these disorders will also be discussed.
Language	English
Publishing date	2019-03-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2711999-3
ISSN	2296-2360
ISSN	2296-2360
DOI	10.3389/fped.2019.00071
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Article: Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis.

Montes-Mojarro, Ivonne A / Kim, Wook Youn / Fend, Falko / Quintanilla-Martinez, Leticia

Seminars in diagnostic pathology

2019 Volume 37, Issue 1, Page(s) 32–46

Abstract: The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, ...

Abstract	The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) "primary EBV-positive nodal T or NK cell lymphoma". Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms - which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.
MeSH term(s)	Epstein-Barr Virus Infections/complications ; Humans ; Killer Cells, Natural/pathology ; Killer Cells, Natural/virology ; Lymphoproliferative Disorders/pathology ; Lymphoproliferative Disorders/virology ; T-Lymphocytes/pathology ; T-Lymphocytes/virology
Language	English
Publishing date	2019-12-17
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	605834-6
ISSN	1930-1111 ; 0740-2570
ISSN (online)	1930-1111
ISSN	0740-2570
DOI	10.1053/j.semdp.2019.12.004
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Article ; Online: CD24

Ruizhi Geng / Niklas Harland / Ivonne A. Montes-Mojarro / Falko Fend / Wilhelm K. Aicher / Arnulf Stenzl / Bastian Amend

International Journal of Molecular Sciences, Vol 23, Iss 5453, p

A Marker for an Extended Expansion Potential of Urothelial Cancer Cell Organoids In Vitro?

2022 Volume 5453

Abstract	Background: Bladder cancer is the most cost-intensive cancer due to high recurrence rates and long follow-up times. Bladder cancer organoids were considered interesting tools for investigating better methods for the detection and treatment of this cancer. Methods: Organoids were generated from urothelial carcinoma tissue samples, then expanded and characterized; the expression of immune modulatory antigens and tumor stem cells markers CD24 and CD44 was explored in early (P ≤ 3) and later (P ≥ 5) passages (P) by immunofluorescence and by quantitative PCR of cDNA. The expression of these factors was investigated in the corresponding cancer tissue samples by immunohistochemistry. Results: The expression of the PD-L1 was detected on some but not all organoids. CD276 and CD47 were observed on organoids in all passages investigated. Organoids growing beyond passage 8 expressed both CD24 and CD44 at elevated levels in early and late cultures. Organoids proliferating to the eighth passage initially expressed both CD24 and CD44, but lost CD24 expression over time, while CD44 remained. Organoids growing only up to the 6th passage failed to express CD24 but expressed CD44. Conclusions: The data indicate that the expression of CD24 in urothelial cancer cell organoids may serve as an indicator for the prolonged proliferation potential of the cells.
Keywords	bladder cancer organoids ; immune checkpoint antigens ; CD24 ; CD44 ; bladder cancer stem-cell marker ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Elevated Expression of the Immune Checkpoint Ligand CD276 (B7-H3) in Urothelial Carcinoma Cell Lines Correlates Negatively with the Cell Proliferation.

Harland, Niklas / Maurer, Florian B / Abruzzese, Tanja / Bock, Cornelia / Montes-Mojarro, Ivonne A / Fend, Falko / Aicher, Wilhelm K / Stenzl, Arnulf / Amend, Bastian

International journal of molecular sciences

2022 Volume 23, Issue 9

Abstract: The cell surface molecule CD276 (B7-H3) is an immune checkpoint antigen. The elevated expression of CD276 on tumors contributes to the suppression of anti-tumor T-cell responses and correlates with poor prognosis.: Methods: The expression of CD276 was ...

Abstract	The cell surface molecule CD276 (B7-H3) is an immune checkpoint antigen. The elevated expression of CD276 on tumors contributes to the suppression of anti-tumor T-cell responses and correlates with poor prognosis. Methods: The expression of CD276 was explored in vitro on eight urothelial carcinoma cell lines (UM-UC) in comparison to eight normal urothelial cells (NUCs) by RT-qPCR, Western blotting, and flow cytometry. Cell proliferation was enumerated over consecutive passages. The expression of cancer stem cell markers CD24 and CD44, cytokeratins, and vimentin was investigated by immunofluorescence. The expression of CD276 in bladder tumor samples and metastases was explored by immunohistochemistry. Results: Expression of CD276 on cell surfaces was elevated on UM-UCs when compared to NUCs. In UM-UCs, CD276 transcripts correlated moderately positive with CD276 protein expression (ρ = 0.660) and strongly positive with CD276 surface-expression (ρ = 0.810). CD276 mRNA expression (ρ = -0.475) and CD276 protein expression (ρ = -0.417) had a significant negative correlation with proliferation, while a significant correlation between proliferation and cell surface expression was not observed in UM-UCs. Conclusion: The expression of CD276 on UM-UC bladder tumor cell surfaces is elevated. Slow proliferating UM-UC cells express more CD276 mRNA and protein than fast proliferating cells. In patients, slow proliferating CD276
MeSH term(s)	B7 Antigens/genetics ; B7 Antigens/metabolism ; Carcinoma, Transitional Cell/genetics ; Carcinoma, Transitional Cell/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Female ; Humans ; Ligands ; Male ; RNA, Messenger ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/metabolism
Chemical Substances	B7 Antigens ; CD276 protein, human ; Ligands ; RNA, Messenger
Language	English
Publishing date	2022-04-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23094969
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Article ; Online: Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification.

Montes-Mojarro, Ivonne A / Hassas, Saki / Staehle, Sina / Sander, Philip / Harland, Niklas / Serna-Higuita, Lina Maria / Bonzheim, Irina / Bösmüller, Hans / Stenzl, Arnulf / Fend, Falko

International journal of molecular sciences

2022 Volume 23, Issue 15

Abstract: Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts ... ...

Abstract	Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in
MeSH term(s)	Carcinoma, Papillary/metabolism ; Carcinoma, Transitional Cell/pathology ; Humans ; Reproducibility of Results ; Risk Assessment ; Urinary Bladder Neoplasms/metabolism ; Urologic Neoplasms/diagnosis ; Urologic Neoplasms/genetics ; Xeroderma Pigmentosum Group D Protein
Chemical Substances	Xeroderma Pigmentosum Group D Protein (EC 3.6.4.12) ; ERCC2 protein, human (EC 5.99.-)
Language	English
Publishing date	2022-07-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23158133
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