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Díaz-Flores L, Gutiérrez R, González-Gómez M, García MDP, Carrasco-Juan JL, Martín-Vasallo P, Madrid JF, Díaz-Flores L. Phenomena of Intussusceptive Angiogenesis and Intussusceptive Lymphangiogenesis in Blood and Lymphatic Vessel Tumors. Biomedicines 2024; 12:258. [PMID: 38397861 PMCID: PMC10887293 DOI: 10.3390/biomedicines12020258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 02/25/2024] Open
Abstract
Intussusceptive angiogenesis (IA) and intussusceptive lymphangiogenesis (IL) play a key role in the growth and morphogenesis of vessels. However, there are very few studies in this regard in vessel tumors (VTs). Our objective is to assess the presence, characteristics, and possible mechanisms of the formation of intussusceptive structures in a broad spectrum of VTs. For this purpose, examples of benign and malignant blood and lymphatic VTs were studied via conventional procedures, semithin sections, and immunochemistry and immunofluorescence microscopy. The results demonstrated intussusceptive structures (pillars, meshes, and folds) in benign (lobular capillary hemangioma or pyogenic granuloma, intravascular papillary endothelial hyperplasia or Masson tumor, sinusoidal hemangioma, cavernous hemangioma, glomeruloid hemangioma, angiolipoma, and lymphangiomas), low-grade malignancy (retiform hemangioendothelioma and Dabska tumor), and malignant (angiosarcoma and Kaposi sarcoma) VTs. Intussusceptive structures showed an endothelial cover and a core formed of connective tissue components and presented findings suggesting an origin through vessel loops, endothelialized thrombus, interendothelial bridges, and/or splitting and fusion, and conditioned VT morphology. In conclusion, the findings support the participation of IA and IL, in association with sprouting angiogenesis, in VTs, and therefore in their growth and morphogenesis, which is of pathophysiological interest and lays the groundwork for in-depth molecular studies with therapeutic purposes.
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Affiliation(s)
- Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain (J.-L.C.-J.)
| | - Ricardo Gutiérrez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain (J.-L.C.-J.)
| | - Miriam González-Gómez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain (J.-L.C.-J.)
- Instituto de Tecnologías Biomédicas de Canarias, University of La Laguna, 38071 Tenerife, Spain
| | - Maria del Pino García
- Department of Pathology, Eurofins Megalab-Hospiten Hospitals, 38100 Tenerife, Spain;
| | - Jose-Luis Carrasco-Juan
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain (J.-L.C.-J.)
| | - Pablo Martín-Vasallo
- Department of Bioquímica, Microbiología, Biología Celular y Genética, University of La Laguna, 38206 Tenerife, Spain;
| | - Juan Francisco Madrid
- Department of Cell Biology and Histology, School of Medicine, Campus of International Excellence “Campus Mare Nostrum”, IMIB-Arrixaca, University of Murcia, 30100 Murcia, Spain;
| | - Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain (J.-L.C.-J.)
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Röss H, Aaldijk D, Vladymyrov M, Odriozola A, Djonov V. Transluminal Pillars-Their Origin and Role in the Remodelling of the Zebrafish Caudal Vein Plexus. Int J Mol Sci 2023; 24:16703. [PMID: 38069025 PMCID: PMC10706262 DOI: 10.3390/ijms242316703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 12/18/2023] Open
Abstract
Intussusceptive pillars, regarded as a hallmark of intussusceptive angiogenesis, have been described in developing vasculature of many organs and organisms. The aim of this study was to resolve the question about pillar formation and their further maturation employing zebrafish caudal vein plexus (CVP). The CVP development was monitored by in vivo confocal microscopy in high spatio-temporal resolution using the transgenic zebrafish model Fli1a:eGPF//Gata1:dsRed. We tracked back the formation of pillars (diameter ≤ 4 µm) and intercapillary meshes (diameter > 4 µm) and analysed their morphology and behaviour. Transluminal pillars in the CVP arose via a combination of sprouting, lumen expansion, and/or the creation of intraluminal folds, and those mechanisms were not associated directly with blood flow. The follow-up of pillars indicated that one-third of them disappeared between 28 and 48 h post fertilisation (hpf), and of the remaining ones, only 1/17 changed their cross-section area by >50%. The majority of the bigger meshes (39/62) increased their cross-section area by >50%. Plexus simplification and the establishment of hierarchy were dominated by the dynamics of intercapillary meshes, which formed mainly via sprouting angiogenesis. These meshes were observed to grow, reshape, and merge with each other. Our observations suggested an alternative view on intussusceptive angiogenesis in the CVP.
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Affiliation(s)
- Helena Röss
- Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; (H.R.); (D.A.); (A.O.)
| | - Dea Aaldijk
- Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; (H.R.); (D.A.); (A.O.)
| | | | - Adolfo Odriozola
- Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; (H.R.); (D.A.); (A.O.)
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, 3012 Bern, Switzerland; (H.R.); (D.A.); (A.O.)
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Díaz-Flores L, Gutiérrez R, García MP, González-Gómez M, Díaz-Flores L, Gayoso S, Carrasco JL, Álvarez-Argüelles H. Ultrastructural Study of Platelet Behavior and Interrelationship in Sprouting and Intussusceptive Angiogenesis during Arterial Intimal Thickening Formation. Int J Mol Sci 2021; 22:ijms222313001. [PMID: 34884806 PMCID: PMC8657547 DOI: 10.3390/ijms222313001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/23/2021] [Accepted: 11/29/2021] [Indexed: 12/13/2022] Open
Abstract
Platelets in atherosclerosis, bypass stenosis, and restenosis have been extensively assessed. However, a sequential ultrastructural study of platelets in angiogenesis during the early phases of these lesions has received less attention. Our objective was the study of platelets in angiogenesis and vessel regression during intimal thickening (IT) formation, a precursor process of these occlusive vascular diseases. For this purpose, we used an experimental model of rat occluded arteries and procedures for ultrastructural observation. The results show (a) the absence of platelet adhesion in the de-endothelialized occluded arterial segment isolated from the circulation, (b) that intraarterial myriad platelets contributed from neovessels originated by sprouting angiogenesis from the periarterial microvasculature, (c) the association of platelets with blood components (fibrin, neutrophils, macrophages, and eosinophils) and non-polarized endothelial cells (ECs) forming aggregates (spheroids) in the arterial lumen, (d) the establishment of peg-and-socket junctions between platelets and polarized Ecs during intussusceptive angiogenesis originated from the EC aggregates, with the initial formation of IT, and (e) the aggregation of platelets in regressing neovessels (‘transitory paracrine organoid’) and IT increases. In conclusion, in sprouting and intussusceptive angiogenesis and vessel regression during IT formation, we contribute sequential ultrastructural findings on platelet behavior and relationships, which can be the basis for further studies using other procedures.
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Affiliation(s)
- Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (L.D.-F.J.); (S.G.); (J.L.C.); (H.Á.-A.)
- Correspondence: ; Tel.: +34-922-319317; Fax: +34-922-319279
| | - Ricardo Gutiérrez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (L.D.-F.J.); (S.G.); (J.L.C.); (H.Á.-A.)
| | - Maria Pino García
- Department of Pathology, Eurofins Megalab–Hospiten Hospitals, 38100 Tenerife, Spain;
| | - Miriam González-Gómez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (L.D.-F.J.); (S.G.); (J.L.C.); (H.Á.-A.)
- Instituto de Tecnologías Biomédicas de Canarias, University of La Laguna, 38071 Tenerife, Spain
| | - Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (L.D.-F.J.); (S.G.); (J.L.C.); (H.Á.-A.)
| | - Sara Gayoso
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (L.D.-F.J.); (S.G.); (J.L.C.); (H.Á.-A.)
| | - Jose Luis Carrasco
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (L.D.-F.J.); (S.G.); (J.L.C.); (H.Á.-A.)
| | - Hugo Álvarez-Argüelles
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain; (R.G.); (M.G.-G.); (L.D.-F.J.); (S.G.); (J.L.C.); (H.Á.-A.)
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Min FH, Li J, Tao BQ, Liu HM, Yang ZJ, Chang L, Li YY, Liu YK, Qin YW, Liu WW. Parotid mammary analogue secretory carcinoma: A case report and review of literature. World J Clin Cases 2021; 9:4052-4062. [PMID: 34141766 PMCID: PMC8180236 DOI: 10.12998/wjcc.v9.i16.4052] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/17/2021] [Accepted: 03/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mammary analogue secretory carcinoma (MASC) is a rare low-grade malignant salivary gland tumor. The morphological and immunohistochemical features of MASC closely resemble those of breast secretory carcinoma. The key characteristics of the lesion are a lack of pain and slow growth. There is no obvious specificity in the clinical manifestations and imaging features. The diagnosis of the disease mainly depends on the detection of the MASC-specific ETV6-NTRK3 fusion gene.
CASE SUMMARY This report describes a rare case of a 32-year-old male patient who presented with a gradually growing lesion that was initially diagnosed as breast-like secretory carcinoma of the right parotid gland. Imaging and histological investigations were used to overcome the diagnostic difficulties. The lesion was managed with right parotidectomy, facial nerve preservation, biological patch implantation to restore the resulting defect, and postoperative radiotherapy. On postoperative follow-up, the patient reported a mild facial deformity with no complications, signs of facial paralysis, or Frey’s syndrome.
CONCLUSION The imaging and histological diagnostic challenges for MASC are discussed.
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Affiliation(s)
- Feng-He Min
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
| | - Jia Li
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
| | - Bo-Qiang Tao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
| | - Hui-Min Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
| | - Zhi-Jing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
| | - Yu-Yang Li
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
- Department of Oral Implant, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
| | - Ying-Kun Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
| | - Yi-Wen Qin
- Department of Stomatology, Chongqing Medical University, Chongqing 400016, China
| | - Wei-Wei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Changchun 130021, Jilin Province, China
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Intussusceptive Angiogenesis and Peg-Socket Junctions between Endothelial Cells and Smooth Muscle Cells in Early Arterial Intimal Thickening. Int J Mol Sci 2020; 21:ijms21218049. [PMID: 33126763 PMCID: PMC7663623 DOI: 10.3390/ijms21218049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/19/2020] [Accepted: 10/26/2020] [Indexed: 12/23/2022] Open
Abstract
Angiogenesis in arterial intimal thickening (AIT) has been considered mainly in late AIT stages and only refers to sprouting angiogenesis. We assess angiogenesis during early AIT development and the occurrence of the intussusceptive type. For this purpose, we studied AIT development in (a) human arteries with vasculitis in gallbladders with acute cholecystitis and urgent (n = 25) or delayed (n = 20) cholecystectomy, using immunohistochemical techniques and (b) experimentally occluded arterial segments (n = 56), using semithin and ultrathin sections and electron microscopy. The results showed transitory angiogenic phenomena, with formation of an important microvasculature, followed by vessel regression. In addition to the sequential description of angiogenic and regressive findings, we mainly contribute (a) formation of intravascular pillars (hallmarks of intussusception) during angiogenesis and vessel regression and (b) morphological interrelation between endothelial cells (ECs) in the arterial wall and vascular smooth muscle cells (VSMCs), which adopt a pericytic arrangement and establish peg-and-socket junctions with ECs. In conclusion, angiogenesis and vessel regression play an important role in AIT development in the conditions studied, with participation of intussusceptive angiogenesis during the formation and regression of a provisional microvasculature and with morphologic interrelation between ECs and VSMCs.
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Díaz-Flores L, Gutiérrez R, Gayoso S, García MP, González-Gómez M, Díaz-Flores L, Sánchez R, Carrasco JL, Madrid JF. Intussusceptive angiogenesis and its counterpart intussusceptive lymphangiogenesis. Histol Histopathol 2020; 35:1083-1103. [PMID: 32329808 DOI: 10.14670/hh-18-222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Intussusceptive angiogenesis (IA) is currently considered an important alternative and complementary form of sprouting angiogenesis (SA). Conversely, intussusceptive lymphangiogenesis (IL) is in an initial phase of study. We compare their morphofunctional characteristics, since many can be shared by both processes. To that end, the following aspects are considered: A) The concept of IA and IL as the mechanism by which blood and lymphatic vessels split, expand and remodel through transluminal pillar formations (hallmarks of intussusception). B) Terminology and historical background, with particular reference to the group of Burri, including Djonov and Patan, who initiated and developed the vessel intussusceptive concept in blood vessels. C) Incidence in normal (e.g. in the sinuses of developing lymph nodes) and pathologic conditions, above all in vessel diseases, such as dilated veins in hemorrhoidal disease, intravascular papillary endothelial hyperplasia (IPEH), sinusoidal hemangioma, lobular capillary hemangioma, lymphangiomas/lymphatic malformations and vascular transformation of lymph nodes. D) Differences and complementarity between vessel sprouting and intussusception. E) Characteristics of the cover (endothelial cells) and core (connective tissue components) of pillars and requirements for pillar identification. F) Structures involved in pillar formation, including endothelial contacts of opposite vessel walls, interendothelial bridges, merged adjacent capillaries, vessel loops and spilt pillars. G) Structures resulting from pillars with intussusceptive microvascular growth, arborization, remodeling and segmentation (compartmentalization). H) Influence of intussusception in the morphogenesis of vessel tumors/ pseudotumors; and I) Hemodynamic and molecular control of vessel intussusception, including VEGF, PDGF BB, Hypoxia, Notch, Endoglobin and Nitric oxide.
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Affiliation(s)
- L Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain.
| | - R Gutiérrez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - S Gayoso
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - M P García
- Department of Pathology, Eurofins® Megalab-Hospiten Hospitals, Tenerife, Spain
| | - M González-Gómez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - L Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - R Sánchez
- Department of Internal Medicine, Dermatology and Psychiatry, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - J L Carrasco
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - J F Madrid
- Department of Cell Biology and Histology, School of Medicine, Campus of International Excellence "Campus Mare Nostrum", IMIB-Arrixaca, University of Murcia, Murcia, Spain
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Participation of Intussusceptive Angiogenesis in the Morphogenesis of Lobular Capillary Hemangioma. Sci Rep 2020; 10:4987. [PMID: 32193418 PMCID: PMC7081232 DOI: 10.1038/s41598-020-61921-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/02/2020] [Indexed: 11/08/2022] Open
Abstract
In lobular capillary hemangioma (LCH), misnamed pyogenic granuloma, only sprouting angiogenesis (SA) has been considered. We assess the occurrence of intussusceptive angiogenesis (IA) in LCH and whether IA determines the specific and other focal patterns in the lesion. For this purpose, we study specimens of 120 cases of LCH, using semithin sections (in 10), immunohistochemistry, and confocal microscopy (in 20). In addition to SA, the results in LCH showed (1) intussusceptive phenomena, including pillars/folds and associated vessel loops, which encircled interstitial tissue structures (ITSs). (2) Two types of evolved loops depending on interendothelial contacts from opposite walls: (a) numerous interendothelial contacts, alternating with capillary-sized lumens (main capillary pattern of the lesion) and (b) few interendothelial contacts, wide open lumens, and intravascular transport of pillars/folds, which were arranged linearly, forming septa (focal sinusoidal-like pattern) or were irregularly grouped (focal intravascular papillary endothelial hyperplasia, IPEH-like pattern). In conclusion, we demonstrate that IA participates in synergistic interaction with SA in LCH development and that the prevalence of specific intussusceptive phenomena determines the predominant capillary pattern and associated sinusoidal hemangioma-like and IPEH-like patterns in the lesion, which suggest a role of IA as conditioner of vessel tumour/pseudo-tumour morphology.
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Rajabi M, Adeyeye M, Mousa SA. Peptide-Conjugated Nanoparticles as Targeted Anti-angiogenesis Therapeutic and Diagnostic in Cancer. Curr Med Chem 2019; 26:5664-5683. [DOI: 10.2174/0929867326666190620100800] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 03/11/2019] [Accepted: 03/21/2019] [Indexed: 12/25/2022]
Abstract
:Targeting angiogenesis in the microenvironment of a tumor can enable suppression of tumor angiogenesis and delivery of anticancer drugs into the tumor. Anti-angiogenesis targeted delivery systems utilizing passive targeting such as Enhanced Permeability and Retention (EPR) and specific receptor-mediated targeting (active targeting) should result in tumor-specific targeting. One targeted anti-angiogenesis approach uses peptides conjugated to nanoparticles, which can be loaded with anticancer agents. Anti-angiogenesis agents can suppress tumor angiogenesis and thereby affect tumor growth progression (tumor growth arrest), which may be further reduced with the targetdelivered anticancer agent. This review provides an update of tumor vascular targeting for therapeutic and diagnostic applications, with conventional or long-circulating nanoparticles decorated with peptides that target neovascularization (anti-angiogenesis) in the tumor microenvironment.
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Affiliation(s)
- Mehdi Rajabi
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, United States
| | - Mary Adeyeye
- Department of Chemistry, University of Albany, State University of New York, Albany, NY 12222, United States
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, United States
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Díaz-Flores L, Gutiérrez R, García MDP, Carrasco JL, Sáez FJ, Díaz-Flores L, González-Gómez M, Madrid JF. Intussusceptive Lymphangiogenesis in Lymphatic Malformations/Lymphangiomas. Anat Rec (Hoboken) 2019; 302:2003-2013. [PMID: 31228317 DOI: 10.1002/ar.24204] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 01/10/2019] [Accepted: 03/09/2019] [Indexed: 12/20/2022]
Abstract
Intussusception in lymphatic vessels has received less attention than in blood vessels. In tumors and pseudotumors of blood vessels with intravascular papillary structures, including sinusoidal hemangioma and intravascular papillary endothelial hyperplasia, we observed exuberant intussusceptive angiogenesis, as well as the similarity between papillae (term used by pathologists) and pillars/folds (hallmarks of intussusceptive angiogenesis). A similar response could be expected in lymphangiomas (lymphatic malformations and reactive processes rather than tumors) with papillae. The aim of this work is to assess whether papillae/pillars/folds and associated structures (vessel loops and septa) are present in lymphangiomas, and to establish the characteristics and formation of these structures. For this purpose, we selected lymphangiomas with intraluminal papillae (n = 18), including cystic, cavernous, circumscriptum, and progressive types, of which two cases of each type with a greater number of papillae were used for serial histologic sections and immunohistochemistry. The studies showed a) dilated lymphatic spaces giving rise to lymphatic-lymphatic vascular loops, which dissected and encircled perilymphatic structures (interstitial tissue structures/ITSs and pillars/posts), b) ITSs and pillars, surrounded by anti-podoplanin-positive endothelial cells, protruding into the lymphatic spaces (papillary aspect), and c) splitting, remodeling, linear arrangement, and fusion of papillae/pillars/folds, forming papillary networks and septa. In conclusion, as occurs in blood vessel diseases, the development of lymphatic vessel loops, papillae/pillars/folds, and septa (segmentation) supports intussusceptive lymphangiogenesis and suggests a piecemeal form of intussusception. This intussusceptive lymphangiogenesis in lymphatic diseases can provide a basis for further studies of lymphatic intussusception in other conditions, with clinical and therapeutic implications. Anat Rec, 302:2003-2013, 2019. © 2019 American Association for Anatomy.
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Affiliation(s)
- Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - Ricardo Gutiérrez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | | | - José L Carrasco
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - Francisco J Sáez
- Department of Cell Biology and Histology UFI11/44, School of Medicine and Dentistry, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - Miriam González-Gómez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - Juan F Madrid
- Department of Cell Biology and Histology, School of Medicine, Regional Campus of International Excellence. "Campus Mare Nostrum", University of Murcia, Espinardo, Spain
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Díaz-Flores L, Gutiérrez R, Pino García M, González-Gómez M, Díaz-Flores L, Carrasco JL. Intussusceptive lymphangiogenesis in the sinuses of developing human foetal lymph nodes. Ann Anat 2019; 226:73-83. [PMID: 31279869 DOI: 10.1016/j.aanat.2019.06.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 03/28/2019] [Accepted: 06/17/2019] [Indexed: 02/07/2023]
Abstract
A meshwork of intraluminal processes in lymph node (LN) sinuses originates during LN development. Lymph flows through the meshwork, which has an important role in immunology and pathology. However, the formation mechanism of intraluminal processes has not been sufficiently studied. Our objective is to assess whether this mechanism is by intussusception, as occurs in transcapillary pillar formation in blood vessel intussusceptive angiogenesis. For this purpose, LNs with developing intrasinusal processes were used (human foetuses, 13-18GW) for serial histologic sections and immunohistochemical procedures. The studies showed (a) sinuses originating from lymphatic sacs around expanded LN anlagen, (b) intra-sinus structures (lined by anti-podoplanin+, VEGFR3+, Prox-1+, CD31+ lymphatic endothelial cells) with characteristics (in serial sections and 3D images) similar to those considered the hallmarks of intussusceptive angiogenesis, including pillars (≤2.5μm, with a collagen core), interstitial tissue structures (ITSs) or larger pillars (>2.5μm, with a more cellular core) and folds (that form pillars when spanning), and (c) remodelled and fused pillars, ITSs and folds, which formed meshworks, compartmentalizing the sinuses into small intercommunicating spaces (segmentation). In conclusion, intussusception participates in the formation of the meshwork of processes in LN sinuses during LN development. This mechanism is also of interest because it contributes to the general knowledge of intussusceptive lymphangiogenesis (which has received less attention than intussusception in blood vessels), provides a basis for further studies and supports a new role for vessel intussusception (formation of an intraluminal meshwork with known action in fluid filtering, cell interactions and immunology).
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Affiliation(s)
- Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain.
| | - Ricardo Gutiérrez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | | | - Miriam González-Gómez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
| | - José Luis Carrasco
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, Tenerife, Spain
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Intussusceptive lymphangiogenesis in vascular transformation of lymph node sinuses. Acta Histochem 2019; 121:392-399. [PMID: 30850131 DOI: 10.1016/j.acthis.2019.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 02/08/2019] [Accepted: 03/01/2019] [Indexed: 02/07/2023]
Abstract
Numerous lymphatic anastomosing channels in the lymph nodes are the most demonstrative finding of the rare lesion termed "vascular transformation of lymph node sinuses" (VTS). The mechanism of lymphatic vessel formation in VTS has not been studied. Vessel intussusception contributes to vascular expansion, and intraluminal pillars/posts, interstitial tissue structures or larger pillars (ITSs) and folds are the hallmarks of this process in blood vessels. The aim of this work is to assess whether these hallmarks of intussusception occur in VTS lymphatic vessels, indicating intussusceptive lymphangiogenesis. For this purpose, specimens of five cases of VTS were used for serial histological sections, immunohistochemistry and immunofluorescence in confocal microscopy, which enabled us to demonstrate the 3D image that defines the pillars. The studies showed a) meshworks of lymphatic vessels, which form complex loops, resembling sinuses of lymph nodes, b) presence of intralymphatic pillars, ITSs and folds, with a cover of lymphatic endothelial cells expressing podoplanin and a varying-sized connective core (e.g. collagen), and c) increase of vessel meshwork and linear arrangement, splitting and fusion of ITSs, pillars and folds, with remodelling and segmentation. In conclusion, the development of lymphatic vessel loops, ITSs, pillars and folds with segmentation in VTS supports intussusceptive lymphangiogenesis. This mechanism of intussusception is of interest because it participates in VTS histogenesis, contributes to general knowledge of intussusceptive lymphangiogenesis, which has received less attention than intussusception in blood vessels, and provides a basis for further studies in other lymphatic conditions.
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Díaz-Flores L, Gutiérrez R, Alvarez-Argüelles H, Díaz-Flores L, González R, Martín-Vasallo P, Carrasco JL. Extracellular multivesicular bodies in tissues affected by inflammation/repair and tumors. Ultrastruct Pathol 2018; 42:448-457. [PMID: 30383502 DOI: 10.1080/01913123.2018.1534915] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Extracellular vesicles (EVs) are a heterogeneous population involved in intercellular communication. Little attention has been paid to a peculiar EV type with the appearance of a multivesicular body: extracellular multivesicular body (EMVB), also termed matrix vesicle cluster/multivesicular cargo. The aim of this work is to assess the ultrastructural characteristics, participation, and tissue location of EMVBs in inflammation/repair and tumors (with physiopathological processes involving intense intercellular communication), for which representative specimens were used. The results showed several forms of EMVBs: a) mature EMVBs, made up of clusters of vesicles surrounded by a plasma membrane, b) pre-EMVBs, with protruding grouped vesicles under the cell membrane, and c) post-EMVBs, releasing their vesicles. In tissues with inflammation/repair, EMVBs were observed in vessel lumens, interstitial spaces of vessel walls (between endothelial cells, pericytes, and smooth muscle cells) and between inflammatory and stromal cells. In tumors, such as basal cell carcinoma, craniopharyngioma, syringocystoadenoma, fibrous histiocytoma, alveolar rhabdomyosarcoma, lymphomas, neuroblastoma, astrocytomas, meningiomas, and hydatiform mole, EMVBs were present in tumor gland lumens and between tumor cells. In conclusion, in numerous physiopathological processes, we contribute EMVB ultrastructural characteristics (including different forms of mature, pre- and post-EMVBs, suggesting a more efficient EV transport), location and relationship with different types of cells. Further studies are required to assess the role of EMVBs in these physiopathological conditions.
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Affiliation(s)
- Lucio Díaz-Flores
- a Department of Basic Medical Sciences (Anatomy, Pathology and Histology) , University of La Laguna , Tenerife , Spain
| | - Ricardo Gutiérrez
- a Department of Basic Medical Sciences (Anatomy, Pathology and Histology) , University of La Laguna , Tenerife , Spain
| | - Hugo Alvarez-Argüelles
- a Department of Basic Medical Sciences (Anatomy, Pathology and Histology) , University of La Laguna , Tenerife , Spain
| | - Lucio Díaz-Flores
- a Department of Basic Medical Sciences (Anatomy, Pathology and Histology) , University of La Laguna , Tenerife , Spain
| | - Rebeca González
- b Department of Bioquímica, Microbiología, Biología Celular y Genética , University of La Laguna , Tenerife , Spain
| | - Pablo Martín-Vasallo
- b Department of Bioquímica, Microbiología, Biología Celular y Genética , University of La Laguna , Tenerife , Spain
| | - José Luis Carrasco
- a Department of Basic Medical Sciences (Anatomy, Pathology and Histology) , University of La Laguna , Tenerife , Spain
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Vimalraj S, Pichu S, Pankajam T, Dharanibalan K, Djonov V, Chatterjee S. Nitric oxide regulates intussusceptive-like angiogenesis in wound repair in chicken embryo and transgenic zebrafish models. Nitric Oxide 2018; 82:48-58. [PMID: 30439561 DOI: 10.1016/j.niox.2018.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 09/19/2018] [Accepted: 11/07/2018] [Indexed: 02/07/2023]
Abstract
Angiogenesis is the formation of new blood vessels that occurs by two distinct processes following sprouting angiogenesis (SA) and intussusceptive angiogenesis (IA). Nitric oxide (NO) is known for its pro-angiogenic functions. However, no clear mechanisms are delineated on its role in promoting angiogenesis in reparative wound healing. We propose that NO regulates SA to IA transition and vice versa in wound milieu. We have used three models which include a new chick embryo extra-vasculature (CEV) burn wound model, adult Tie2-GFP transgenic Zebrafish caudal fin regeneration model and Zebrafish skin wound model to study the mechanisms underlying behind the role of NO in wound healing. Wounds created in CEV were treated with NO donor (Spermine NONOate (SPNO)), NOS inhibitor (L-nitro-l-arginine-methyl ester (l-NAME)), NaNO2, NaNO3, and beetroot juice, a nitrite-rich juice respectively and the pattern of wound healing was assessed. Morphological and histological techniques tracked the wound healing at the cellular level, and the molecular changes were investigated by using real-time RT-PCR gene expression analysis. The result concludes that NO donor promotes wound healing by activating SA at an early phase of healing while NOS inhibitor induces wound healing via IA. At the later phase of wound healing NO donor followed IA while NOS inhibitor failed to promote wound repair. The current work underpinned a differential regulation of NO on angiogenesis in wound milieu and this study would provide new insights in designing therapeutics for promoting wound repair.
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Affiliation(s)
- Selvaraj Vimalraj
- Centre for Biotechnology, Anna University, Chennai-600025, India; Vascular Biology Lab, AU-KBC Research Centre and Department of Biotechnology, MIT Campus, Anna University, Chennai, India.
| | - Sivakamasundari Pichu
- Vascular Biology Lab, AU-KBC Research Centre and Department of Biotechnology, MIT Campus, Anna University, Chennai, India
| | - Thyagarajan Pankajam
- Vascular Biology Lab, AU-KBC Research Centre and Department of Biotechnology, MIT Campus, Anna University, Chennai, India
| | - Kasiviswanathan Dharanibalan
- Vascular Biology Lab, AU-KBC Research Centre and Department of Biotechnology, MIT Campus, Anna University, Chennai, India
| | - Valentin Djonov
- Institute of Anatomy, University of Berne, Buehlstrasse 26, CH-3012 Berne, Switzerland
| | - Suvro Chatterjee
- Vascular Biology Lab, AU-KBC Research Centre and Department of Biotechnology, MIT Campus, Anna University, Chennai, India.
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Kuwabara H, Yamamoto K, Terada T, Kawata R, Nagao T, Hirose Y. Hemorrhage of MRI and Immunohistochemical Panels Distinguish Secretory Carcinoma From Acinic Cell Carcinoma. Laryngoscope Investig Otolaryngol 2018; 3:268-274. [PMID: 30186957 PMCID: PMC6119803 DOI: 10.1002/lio2.169] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/08/2018] [Accepted: 04/26/2018] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Secretory carcinoma (SC, mammary analogue secretory carcinoma) is a salivary gland tumor with ETV6-NTRK3 gene fusion, and its differential diagnosis includes acinic cell carcinoma (ACC). As hemorrhage is often seen in SC, we hypothesized that magnetic resonance imaging (MRI) and immunohistochemical analyses could distinguish SC from ACC. STUDY DESIGN Retrospective study. METHODS We used ETV6-NTRK3 gene fusion analyses to reclassify 19 parotid gland tumors that had previously been diagnosed as SC or ACC, and then investigated hemorrhage in both hematoxylin-eosin (H&E)-stained sections and MRIs, and immunohistochemical expression of S-100, mammaglobin, DOG1, and α-amylase. RESULTS The 19 tumors were genetically reclassified into 11 (58%) SC and 8 (42%) ACC. Combined S-100 and mammaglobin were specific for SC; whereas DOG1 was specific for ACC, and α-amylase was expressed only in 4 ACC cases (50%). H&E staining showed hemorrhage with hemosiderin deposition in all SC cases, and T2-weighted MRI showed hypointense areas in all investigated SC cases, but not in ACC. CONCLUSION Hemorrhage with hemosiderin deposition is frequently present in SC, and hemorrhage findings in MRI and an immunohistochemical panels for S-100, mammaglobin and DOG1 can distinguish SC from ACC. LEVEL OF EVIDENCE 3b.
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Affiliation(s)
| | | | - Tetsuya Terada
- Department of and OtorhinolaryngologyOsaka Medical CollegeOsakaJapan
| | - Ryo Kawata
- Department of and OtorhinolaryngologyOsaka Medical CollegeOsakaJapan
| | - Toshitaka Nagao
- Department of Anatomic PathologyTokyo Medical UniversityTokyoJapan
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Díaz-Flores L, Gutiérrez R, González-Gómez M, García P, Sáez FJ, Díaz-Flores L, Carrasco JL, Madrid JF. Segmentation of Dilated Hemorrhoidal Veins in Hemorrhoidal Disease. Cells Tissues Organs 2018; 205:120-128. [PMID: 29913446 DOI: 10.1159/000489250] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 04/08/2018] [Indexed: 12/21/2022] Open
Abstract
Vein segmentation is a vascular remodeling process mainly studied in experimental conditions and linked to hemodynamic factors, with clinical implications. The aim of this work is to assess the morphologic characteristics, associated findings, and mechanisms that participate in vein segmentation in humans. To this end, we examined 156 surgically obtained cases of hemorrhoidal disease. Segmentation occurred in 65 and was most prominent in 15, which were selected for serial sections, immunohistochemistry, and immunofluorescence procedures. The dilated veins showed differently sized spaces, separated by thin septa. Findings associated with vein segmentation were: (a) vascular channels formed from the vein intima endothelial cells (ECs) and located in the vein wall and/or intraluminal fibrin, (b) vascular loops formed by interconnected vascular channels (venous-venous connections), which encircled vein wall components or fibrin and formed folds/pillars/papillae (FPPs; the encircling ECs formed the FPP cover and the encircled components formed the core), and (c) FPP splitting, remodeling, alignment, and fusion, originating septa. Thrombosis was observed in some nonsegmented veins, while the segmented veins only occasionally contained thrombi. Dense microvasculature was also present in the interstitium and around veins. In conclusion, the findings suggest that hemorrhoidal vein segmentation is an adaptive process in which a piecemeal angiogenic mechanism participates, predominantly by intussusception, giving rise to intravascular FPPs, followed by linear rearrangement, remodeling and fusion of FPPs, and septa formation. Identification of other markers, as well as the molecular bases, hemodynamic relevance, and possible therapeutic implications of vein segmentation in dilated hemorrhoidal veins require further studies.
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Affiliation(s)
- Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, La Laguna, Spain
| | - Ricardo Gutiérrez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, La Laguna, Spain
| | - Miriam González-Gómez
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, La Laguna, Spain
| | - Pino García
- Department of Pathology, Hospiten, Santa Cruz, Spain
| | - Francisco J Sáez
- Department of Cell Biology and Histology UFI11/44, School of Medicine and Dentistry, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Lucio Díaz-Flores
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, La Laguna, Spain
| | - José Luis Carrasco
- Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, La Laguna, Spain
| | - Juan F Madrid
- Department of Cell Biology and Histology, School of Medicine, University of Murcia, Murcia, Spain
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Díaz-Flores L, Gutiérrez R, García MP, González-Gómez M, Sáez FJ, Díaz-Flores L, Carrasco JL, Madrid JF. Sinusoidal hemangioma and intravascular papillary endothelial hyperplasia: Interrelated processes that share a histogenetic piecemeal angiogenic mechanism. Acta Histochem 2018; 120:255-262. [PMID: 29486986 DOI: 10.1016/j.acthis.2018.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 02/06/2018] [Accepted: 02/14/2018] [Indexed: 12/12/2022]
Abstract
Sinusoidal hemangioma, characterized by interconnecting thin-walled vascular spaces, may present papillae/pseudo-papillae and zones that resemble intravascular papillary endothelial hyperplasia (IPEH). Our objectives are to explore the existence of zones in IPEH with sinusoidal hemangioma characteristics, the mechanism of papillary and septa formation in sinusoidal hemangioma and the comparison of this mechanism with that in IPEH. For these purposes, specimens of 4 cases of each entity were selected and studied by serial histologic sections and by immunochemistry and immunofluorescence procedures. The results showed a) zones with characteristics of sinusoidal hemangioma in IPEH cases, b) presence in both entities of papillae with a cover formed by a monolayer of CD34+ and CD31+ endothelial cells (ECs) and a core formed by either type I collagen and αSMA+ cells (presenting a pericyte/smooth muscle cell aspect) or thrombotic components, and c) a similar piecemeal angiogenic mechanism in papillary formation, including sprouting of intimal ECs toward the vessel wall itself or intravascular thrombi, formation of vascular loops that encircle and separate vessel wall or thrombus components, and parietal or thrombotic papillae development. The major differences between both entities were the number, arrangement and substrate of papillae: myriad, densely grouped, parietal and thrombotic papillae in IPEH, and a linear arrangement of predominant parietal papillae in sinusoidal hemangioma, originating septa (segmentation). In conclusion, sinusoidal hemangioma and IPEH are interrelated processes, which share morphologic findings and a piecemeal angiogenic mechanism, combining sprouting and intussusceptive angiogenesis, and leading to papillary formation and vessel segmentation.
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