33 results on '"Malinverno M."'
Search Results
2. Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial
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Lanfranconi, S., Scola, E., Bertani, G. A., Zarino, B., Pallini, Roberto, D'Alessandris, Quintino Giorgio, Mazzon, E., Marino, S., Carriero, M. R., Scelzo, E., Farago, G., Castori, M., Fusco, C., Petracca, A., D'Agruma, L., Tassi, L., D'Orio, P., Lampugnani, M. G., Nicolis, E. B., Vasami, A., Novelli, D., Torri, V., Meessen, J. M. T. A., Salman, R. A. -S., Dejana, E., Latini, R., Pignotti, Fabrizio, Sturiale, Carmelo Lucio, Albanese, Alessio, Valcamonica, G., Ronchi, D., Pogliani, S., De Grazia, U., Bossi, C., Ciurleo, R., Raggi, P., Simeone, A., Balconi, G., Foresta, A., Buratti, M. G., Carrara, M., Ojeda-Fernandez, M. L., Treglia, R., Maggioni, A. P., Beghi, E., Tettamanti, M., Regna-Gladin, C., Prelle, A., Mangiavacchi, M., Poloni, M., Lazzaroni, F., Malinverno, M., Ungaro, C., and Raucci, F.
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Male ,Hemangioma, Cavernous, Central Nervous System ,Pediatrics ,medicine.medical_treatment ,Settore MED/27 - NEUROCHIRURGIA ,Medicine (miscellaneous) ,Anxiety ,Severity of Illness Index ,law.invention ,Study Protocol ,Mice ,0302 clinical medicine ,Randomized controlled trial ,law ,Medicine ,Pharmacology (medical) ,Prospective Studies ,Depression (differential diagnoses) ,0303 health sciences ,lcsh:R5-920 ,medicine.diagnostic_test ,Depression ,Propranolol ,Treatment Outcome ,Italy ,Models, Animal ,Disease Progression ,Female ,Epileptic seizure ,Safety ,medicine.symptom ,lcsh:Medicine (General) ,Intracranial Hemorrhages ,medicine.drug ,Adult ,medicine.medical_specialty ,Adrenergic beta-Antagonists ,Radiosurgery ,03 medical and health sciences ,Magnetic resonance imaging ,Cerebral cavernous malformation ,Animals ,Humans ,Adverse effect ,030304 developmental biology ,business.industry ,Case-Control Studies ,Quality of Life ,Nervous System Diseases ,business ,030217 neurology & neurosurgery - Abstract
Background Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. Methods Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40–80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). Discussion Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. Trial registration ClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018.
- Published
- 2020
3. 5.1-O3Prevalence of cervical dysplasia among migrant women with female genital mutilation
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Azuaga, A, primary, Petignat, P, additional, Undurraga Malinverno, M, additional, and Abdulcadir, J, additional
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- 2018
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4. Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis
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Campanelli, R., Fois, G., Catarsi, P., Poletto, V., Villani, L., Erba, B. G., Maddaluno, L., Jemos, B., Salmoiraghi, S., Guglielmelli, P., Abbonante, V., Di Buduo, C. A., Balduini, A., Iurlo, A., Barosi, G., Rosti, V., Massa, M., Vannucchi, A. M., Balliu, M., Bartalucci, N., Bogani, C., Bosi, A., Calabresi, L., Corbizzi Fattori, G., Fanelli, T., Fjerza, R., Gesullo, F., Mannarelli, C., Merli, L., Pacilli, A., Pancrazzi, A., Paoli, C., Pieri, L., Rotunno, G., Sant'Antonio, E., Bonetti, E., Cazzola, M., Ambaglio, I., Bernasconi, P., Casetti, C. I., Catricala, S., Elena, C., Fugazza, E., Galli, A., Malcovati, L., Milanesi, C., Pascutto, C., Pietra, D., Ripamonti, F., Rossi, M., Rumi, E., Dejana, E., Breviario, F., Corada, M., Malinverno, M., Rambaldi, A., Chioda, G., Ferrari, M. L., Finazzi, G., Finazzi, M. C., Belotti, C., Boroni, C., Amaru, A., Golay, J., Bortoluzzi, S., Bisognin, A., Coppe, A., Saccoman, C., Manfredini, R., Artuso, L., Bernardis, I., Bianchi, E., Montanari, M., Pennucci, V., Prudente, Z., Rontauroli, S., Rossi, C., Ruberti, S., Salati, S., Tagliafico, E., Tenedini, E., and Zini, R.
- Subjects
Male ,0301 basic medicine ,Pathology ,Physiology ,Angiogenesis ,CD34 ,Gene Expression ,lcsh:Medicine ,Medicine (all) ,Biochemistry, Genetics and Molecular Biology (all) ,Agricultural and Biological Sciences (all) ,Cardiovascular Physiology ,Monocytes ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Blood and Lymphatic System Procedures ,Electron Microscopy ,lcsh:Science ,Microscopy ,Multidisciplinary ,Neovascularization, Pathologic ,Cell Differentiation ,Hematology ,Middle Aged ,Receptor, TIE-2 ,Haematopoiesis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Splenectomy ,cardiovascular system ,Female ,Cellular Types ,Receptor ,Research Article ,medicine.medical_specialty ,Aged ,Case-Control Studies ,Humans ,Primary Myelofibrosis ,Spleen ,Patients ,Immune Cells ,CD14 ,Immunology ,Surgical and Invasive Medical Procedures ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Genetics ,medicine ,Progenitor cell ,TIE-2 ,Myelofibrosis ,Neovascularization ,Pathologic ,Blood Cells ,lcsh:R ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,Hematopoiesis ,Health Care ,030104 developmental biology ,Transmission Electron Microscopy ,lcsh:Q ,Bone marrow ,Developmental Biology - Abstract
Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph-) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62-CCR2- (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ.
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- 2016
5. Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy
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Kuiperij, H.B., Verbeek, M.M., Borroni, B., Gardoni, F., Malinverno, M., Padovani, A., Luca, M. Di, Kuiperij, H.B., Verbeek, M.M., Borroni, B., Gardoni, F., Malinverno, M., Padovani, A., and Luca, M. Di
- Abstract
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- Published
- 2011
6. Synaptic Localization and Activity of ADAM10 Regulate Excitatory Synapses through N-Cadherin Cleavage
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Malinverno, M., primary, Carta, M., additional, Epis, R., additional, Marcello, E., additional, Verpelli, C., additional, Cattabeni, F., additional, Sala, C., additional, Mulle, C., additional, Di Luca, M., additional, and Gardoni, F., additional
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- 2010
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7. Decreased NR2B Subunit Synaptic Levels Cause Impaired Long-Term Potentiation But Not Long-Term Depression
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Gardoni, F., primary, Mauceri, D., additional, Malinverno, M., additional, Polli, F., additional, Costa, C., additional, Tozzi, A., additional, Siliquini, S., additional, Picconi, B., additional, Cattabeni, F., additional, Calabresi, P., additional, and Di Luca, M., additional
- Published
- 2009
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8. Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer's disease.
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Epis R, Marcello E, Gardoni F, Vastagh C, Malinverno M, Balducci C, Colombo A, Borroni B, Vara H, Dell'agli M, Cattabeni F, Giustetto M, Borsello T, Forloni G, Padovani A, Di Luca M, Epis, Roberta, Marcello, Elena, Gardoni, Fabrizio, and Vastagh, Csaba
- Abstract
We describe here an innovative, non-transgenic animal model of Alzheimer's disease. This model mimics early stages of sporadic disease, which represents the vast majority of cases. The model was obtained by interfering with the complex between a disintegrin and metalloproteinase domain containing protein 10 (ADAM10), the main α-secretase candidate, and its partner, synapse-associated protein 97, a protein of the postsynaptic density-membrane associated guanylate kinase family. Association of ADAM10 with synapse-associated protein 97 governs enzyme trafficking and activity at synapses. Interfering with the ADAM10/synapse-associated protein 97 complex for 2 weeks by means of a cell-permeable peptide strategy is sufficient to shift the metabolism of the amyloid precursor protein towards amyloidogenesis and allows the reproduction of initial phases of sporadic Alzheimer's disease. After 2 weeks of treatment, we detected progressive Alzheimer's disease-like neuropathology, with an increase of β-amyloid aggregate production and of tau hyperphosphorylation, and a selective alteration of N-methyl-d-aspartic acid receptor subunit composition in the postsynaptic compartment of mouse brain. Behavioural and electrophysiological deficits were also induced by peptide treatment. [ABSTRACT FROM AUTHOR]
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- 2010
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9. Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy
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Ubaldo Bonuccelli, Matteo Malinverno, Enrico Premi, Daniela Perani, Antonella Alberici, M. Di Luca, Alessandro Padovani, Barbara Borroni, Lucilla Parnetti, Fabrizio Gardoni, Paolo Calabresi, Mario Grassi, Borroni, B, Malinverno, M, Gardoni, F, Alberici, A, Parnetti, L, Premi, E, Bonuccelli, U, Grassi, M, Perani, DANIELA FELICITA L., Calabresi, P, Di Luca, M, and Padovani, A.
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Adult ,Lewy Body Disease ,Male ,Pathology ,medicine.medical_specialty ,Neurocognitive Disorders ,CSF ,tau Proteins ,Progressive supranuclear palsy ,Atrophy ,Cerebrospinal fluid ,Progressive Supranuclear Palsy ,Biomarker ,Protein Tau ,Isoforms ,Alzheimer Disease ,Predictive Value of Tests ,mental disorders ,medicine ,Humans ,Immunoprecipitation ,Corticobasal degeneration ,Aged ,Dementia with Lewy bodies ,Brain ,Reproducibility of Results ,Parkinson Disease ,Middle Aged ,medicine.disease ,eye diseases ,Case-Control Studies ,Biomarker (medicine) ,Dementia ,Female ,Supranuclear Palsy, Progressive ,Neurology (clinical) ,Alzheimer's disease ,Psychology ,Biomarkers ,Frontotemporal dementia - Abstract
Objective: In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease. Methods: A total of 166 subjects were included in the study (21 PSP, 20 corticobasal degeneration syndrome, 44 frontotemporal dementia, 29 Alzheimer disease, 10 Parkinson disease, 15 dementia with Lewy bodies, and 27 individuals without any neurodegenerative disorder). Each patient underwent a standardized clinical and neuropsychological evaluation. In CSF, a semiquantitative immunoprecipitation was developed to evaluate CSF tau 33 kDa/55 kDa ratio. MRI assessment and VBM analysis was carried out. Results: Tau form ratio was significantly reduced in patients with PSP (0.504 ± 0.284) when compared to age-matched controls (0.989 ± 0.343), and to patients with other neurodegenerative conditions (range = 0.899–1.215). The area under the curve (AUC) of the receiver operating characteristic analysis in PSP vs other subgroups ranged from 0.863 to 0.937 (PSP vs others, AUC = 0.897, p Conclusions: Truncated tau production, which selectively affects brainstem neuron susceptibility, can be considered a specific and reliable marker for PSP. Tau form ratio was the lowest in progressive supranuclear palsy with no overlap with any other neurodegenerative illness. GLOSSARY: AD = Alzheimer disease; AUC = area under the curve; BADL = Basic Activity of Daily Living; CBDS = corticobasal degeneration; CON = controls; DLB = dementia with Lewy bodies; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; FTD = frontotemporal dementia; IADL = Instrumental Activities of Daily Living; MMSE = Mini-Mental State Examination; MSA = multiple system atrophy; PD = Parkinson disease; PSP = progressive supranuclear palsy; ROC = receiver operating characteristic; UPDRS = Unified Parkinson’s Disease Rating Scale; VBM = voxel-based morphometry.
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- 2008
10. A murine model of cerebral cavernous malformations with acute hemorrhage
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Claudio Maderna, Federica Pisati, Claudio Tripodo, Elisabetta Dejana, Matteo Malinverno, Maderna C., Pisati F., Tripodo C., Dejana E., and Malinverno M.
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Multidisciplinary ,Neurology ,Neurologi ,Developmental neuroscience, Model organism, Vascular remodeling ,Settore MED/08 - Anatomia Patologica - Abstract
Cavernomas are multi-lumen and blood-filled vascular malformations which form in the brain and the spinal cord. They lead to hemorrhage, epileptic seizures, neurological deficits, and paresthesia. An effective medical treatment is still lacking, and the available murine models for cavernomas have several limitations for preclinical studies. These include disease phenotypes that differ from human diseases, such as restriction of the lesions to the cerebellum, and absence of acute hemorrhage. Additional limitations of current murine models include rapid development of lesions, which are lethal before the first month of age. Here, we have characterized a murine model that recapitulates features of the human disease: lesions develop after weaning throughout the entire CNS, including the spinal cord, and undergo acute hemorrhage. This provides a preclinical model to develop new drugs for treatment of acute hemorrhage in the brain and spinal cord, as an unmet medical emergency for patients with cavernomas.
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11. Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.
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Pham VC, Rödel CJ, Valentino M, Malinverno M, Paolini A, Münch J, Pasquier C, Onyeogaziri FC, Lazovic B, Girard R, Koskimäki J, Hußmann M, Keith B, Jachimowicz D, Kohl F, Hagelkruys A, Penninger JM, Schulte-Merker S, Awad IA, Hicks R, Magnusson PU, Faurobert E, Pagani M, and Abdelilah-Seyfried S
- Abstract
Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal a role of CBX7/Cbx7a in the activation of KLF2 target genes including TEK, ANGPT1, WNT9, and endoMT-associated genes. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM., (© 2024. The Author(s).)
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- 2024
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12. Circulating biomarkers in familial cerebral cavernous malformation.
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Lazzaroni F, Meessen JMTA, Sun Y, Lanfranconi S, Scola E, D'Alessandris QG, Tassi L, Carriero MR, Castori M, Marino S, Blanda A, Nicolis EB, Novelli D, Calabrese R, Agnelli NM, Bottazzi B, Leone R, Mazzola S, Besana S, Catozzi C, Nezi L, Lampugnani MG, Malinverno M, Grdseloff N, Rödel CJ, Rezai Jahromi B, Bolli N, Passamonti F, Magnusson PU, Abdelilah-Seyfried S, Dejana E, and Latini R
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- Animals, Humans, Male, Female, Proto-Oncogene Proteins genetics, Microtubule-Associated Proteins genetics, Zebrafish metabolism, Biomarkers, Seizures, Antigens, Neoplasm, Cell Adhesion Molecules, Hemangioma, Cavernous, Central Nervous System etiology, Hemangioma, Cavernous, Central Nervous System genetics
- Abstract
Background: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression., Methods: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches., Findings: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM., Interpretation: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease., Funding: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council., Competing Interests: Declaration of interests B.B is inventor of patents on PTX3 and obtains royalties on PTX3-related reagents. N.B. serves on Advisory Board and Speakers Bureau for Celgene and Janssen, and on Speakers Bureau for Takeda, Amgen., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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13. Correction: Inflammation and neutrophil extracellular traps in cerebral cavernous malformation.
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Yau ACY, Globisch MA, Onyeogaziri FC, Conze LL, Smith R, Jauhiainen S, Corada M, Orsenigo F, Huang H, Herre M, Olsson AK, Malinverno M, Sundell V, Rezai Jahromi B, Niemelä M, Laakso A, Garlanda C, Mantovani A, Lampugnani MG, Dejana E, and Magnusson PU
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- 2022
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14. Histological quantification of cerebral cavernous malformations in the murine brain.
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Maderna C, Dejana E, and Malinverno M
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- Animals, Brain diagnostic imaging, Histological Techniques, Mice, Hemangioma, Cavernous, Central Nervous System diagnostic imaging
- Abstract
In the study of cerebral cavernous malformations (CCMs), the quantification of lesion burden is the main parameter for evaluation of disease severity and efficacy of drugs. We describe a reliable and cost-effective protocol to evaluate the number and the size of vascular malformations in the murine brain. This approach is based on histology and confocal imaging and can be performed with standard laboratory equipment. We detail the preparation of brain sections followed by image acquisition and analysis. For complete details on the use and execution of this protocol, please refer to Maderna et al. (2022)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)
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- 2022
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15. Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells.
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Rath M, Schwefel K, Malinverno M, Skowronek D, Leopoldi A, Pilz RA, Biedenweg D, Bekeschus S, Penninger JM, Dejana E, and Felbor U
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- Apoptosis Regulatory Proteins genetics, Cell Proliferation, Coculture Techniques, Humans, Proto-Oncogene Proteins genetics, Endothelial Cells pathology, Hemangioma, Cavernous, Central Nervous System genetics, Hemangioma, Cavernous, Central Nervous System pathology
- Abstract
Cerebral cavernous malformations (CCM) are low-flow vascular lesions prone to cause severe hemorrhage-associated neurological complications. Pathogenic germline variants in CCM1, CCM2, or CCM3 can be identified in nearly 100% of CCM patients with a positive family history. In line with the concept that tumor-like mechanisms are involved in CCM formation and growth, we here demonstrate an abnormally increased proliferation rate of CCM3-deficient endothelial cells in co-culture with wild-type cells and in mosaic human iPSC-derived vascular organoids. The observation that NSC59984, an anticancer drug, blocked the abnormal proliferation of mutant endothelial cells further supports this intriguing concept. Fluorescence-activated cell sorting and RNA sequencing revealed that co-culture induces upregulation of proangiogenic chemokine genes in wild-type endothelial cells. Furthermore, genes known to be significantly downregulated in CCM3
-/- endothelial cell mono-cultures were upregulated back to normal levels in co-culture with wild-type cells. These results support the hypothesis that wild-type ECs facilitate the formation of a niche that promotes abnormal proliferation of mutant ECs. Thus, targeting the cancer-like features of CCMs is a promising new direction for drug development., (© 2022. The Author(s).)- Published
- 2022
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16. Transcriptome Analysis Reveals Altered Expression of Genes Involved in Hypoxia, Inflammation and Immune Regulation in Pdcd10 -Depleted Mouse Endothelial Cells.
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Fusco C, Nardella G, Di Filippo L, Dejana E, Cacchiarelli D, Petracca A, Micale L, Malinverno M, and Castori M
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- Animals, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Gene Expression Profiling, Hemangioma, Cavernous, Central Nervous System, Hypoxia metabolism, Mice, Endothelial Cells metabolism, Inflammation genetics, Inflammation metabolism
- Abstract
Cerebral cavernous malformations (CCM) are capillary malformations affecting the central nervous system and commonly present with headaches, epilepsy and stroke. Treatment of CCM is symptomatic, and its prevention is limited. CCM are often sporadic but sometimes may be multifocal and/or affect multiple family members. Heterozygous pathogenic variants in PDCD10 cause the rarest and apparently most severe genetic variant of familial CCM. We carried out an RNA-Seq and a Q-PCR validation analysis in Pdcd10-silenced and wild-type mouse endothelial cells in order to better elucidate CCM molecular pathogenesis. Ninety-four differentially expressed genes presented an FDR-corrected p-value < 0.05. A functionally clustered dendrogram showed that differentially expressed genes cluster in cell proliferation, oxidative stress, vascular processes and immune response gene-ontology functions. Among differentially expressed genes, the major cluster fell in signaling related to inflammation and pathogen recognition, including HIF1α and Nos2 signaling and immune regulation. Validation analysis performed on wild-type, Pdcd10-null and Pdcd10-null reconstituted cell lines was consistent with RNA-Seq data. This work confirmed previous mouse transcriptomic data in endothelial cells, which are recognized as a critical tissue for CCM formation and expands the potential molecular signatures of PDCD10-related familial CCM to alterations in inflammation and pathogen recognition pathways.
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- 2022
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17. Inflammation and neutrophil extracellular traps in cerebral cavernous malformation.
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Yau ACY, Globisch MA, Onyeogaziri FC, Conze LL, Smith R, Jauhiainen S, Corada M, Orsenigo F, Huang H, Herre M, Olsson AK, Malinverno M, Sundell V, Rezai Jahromi B, Niemelä M, Laakso A, Garlanda C, Mantovani A, Lampugnani MG, Dejana E, and Magnusson PU
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- Animals, Apoptosis Regulatory Proteins genetics, Endothelial Cells metabolism, Humans, Inflammation pathology, Membrane Proteins metabolism, Mice, Extracellular Traps metabolism, Hemangioma, Cavernous, Central Nervous System genetics, Hemangioma, Cavernous, Central Nervous System metabolism, Hemangioma, Cavernous, Central Nervous System pathology
- Abstract
Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3
iECKO ), we show that endothelial cells from Ccm3iECKO mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3iECKO mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3iECKO mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas of patients with CCM confirms the clinical relevance of NETs in CCM., (© 2022. The Author(s).)- Published
- 2022
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18. A murine model of cerebral cavernous malformations with acute hemorrhage.
- Author
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Maderna C, Pisati F, Tripodo C, Dejana E, and Malinverno M
- Abstract
Cavernomas are multi-lumen and blood-filled vascular malformations which form in the brain and the spinal cord. They lead to hemorrhage, epileptic seizures, neurological deficits, and paresthesia. An effective medical treatment is still lacking, and the available murine models for cavernomas have several limitations for preclinical studies. These include disease phenotypes that differ from human diseases, such as restriction of the lesions to the cerebellum, and absence of acute hemorrhage. Additional limitations of current murine models include rapid development of lesions, which are lethal before the first month of age. Here, we have characterized a murine model that recapitulates features of the human disease: lesions develop after weaning throughout the entire CNS, including the spinal cord, and undergo acute hemorrhage. This provides a preclinical model to develop new drugs for treatment of acute hemorrhage in the brain and spinal cord, as an unmet medical emergency for patients with cavernomas., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)
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- 2022
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19. A dual role of YAP in driving TGFβ-mediated endothelial-to-mesenchymal transition.
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Savorani C, Malinverno M, Seccia R, Maderna C, Giannotta M, Terreran L, Mastrapasqua E, Campaner S, Dejana E, and Giampietro C
- Subjects
- Epithelial-Mesenchymal Transition, Phosphorylation, Endothelial Cells metabolism, Transforming Growth Factor beta metabolism
- Abstract
Endothelial-to-mesenchymal transition (EndMT) is the biological process through which endothelial cells transdifferentiate into mesenchymal cells. During embryo development, EndMT regulates endocardial cushion formation via TGFβ/BMP signaling. In adults, EndMT is mainly activated during pathological conditions. Hence, it is necessary to characterize molecular regulators cooperating with TGFβ signaling in driving EndMT, to identify potential novel therapeutic targets to treat these pathologies. Here, we studied YAP, a transcriptional co-regulator involved in several biological processes, including epithelial-to-mesenchymal transition (EMT). As EndMT is the endothelial-specific form of EMT, and YAP (herein referring to YAP1) and TGFβ signaling cross-talk in other contexts, we hypothesized that YAP contributes to EndMT by modulating TGFβ signaling. We demonstrate that YAP is required to trigger TGFβ-induced EndMT response, specifically contributing to SMAD3-driven EndMT early gene transcription. We provide novel evidence that YAP acts as SMAD3 transcriptional co-factor and prevents GSK3β-mediated SMAD3 phosphorylation, thus protecting SMAD3 from degradation. YAP is therefore emerging as a possible candidate target to inhibit pathological TGFβ-induced EndMT at early stages., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)
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- 2021
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20. Successful in vivo retrieval of oocytes after ovarian stimulation for fertility preservation before oophorectomy by laparotomy for a young patient with ovarian cancer: Case report and review of literature.
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Benard J, Streuli I, Biondo A, Petignat P, and Undurraga Malinverno M
- Abstract
Objective: To report a case of direct in vivo oocytes retrieval for fertility preservation before oophorectomy by open surgery in a young patient with ovarian cancer., Design: case report and literature review., Setting: University hospital., Patients: A 29-year-old nulliparous patient, recently diagnosed with low grade serous ovarian carcinoma.The patient consented to the removal of her remaining ovary but wished to preserve oocytes and declined hysterectomy. Conventional trans-vaginal US-guided oocyte retrieval was contra-indicated because of the risk of malignant cell dissemination to the abdomen and the vaginal puncture sites., Interventions: Controlled ovarian stimulation with gonadotrophins was realized. Comprehensive surgical staging was performed 35 h after ovulation triggering using rHCG. The oocytes retrieval was performed in vivo with ultrasound guidance at time of laparotomy before oophorectomy without any time of ischemia., Results: Seven mature oocytes were obtained and vitrified., Conclusions: This case highlights the feasibility of in vivo oocytes retrieval of mature oocytes during open surgery for gynecologic cancers. By avoiding transvaginal follicular retrieval, the risk of malignant cell contamination to vaginal and parametrial tissues is reduced, limiting cancer upstaging., (© 2021 The Authors. Published by Elsevier Inc.)
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- 2021
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21. Propranolol Reduces the Development of Lesions and Rescues Barrier Function in Cerebral Cavernous Malformations: A Preclinical Study.
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Oldenburg J, Malinverno M, Globisch MA, Maderna C, Corada M, Orsenigo F, Conze LL, Rorsman C, Sundell V, Arce M, Smith RO, Yau ACY, Billström GH, Mägi CÖ, Beznoussenko GV, Mironov AA, Fernando D, Daniel G, Olivari D, Fumagalli F, Lampugnani MG, Dejana E, and Magnusson PU
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- Animals, Disease Models, Animal, Female, Male, Mice, Mice, Knockout, Central Nervous System Neoplasms pathology, Hemangioma, Cavernous, Central Nervous System pathology, Propranolol pharmacology
- Abstract
[Figure: see text].
- Published
- 2021
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22. Gestational trophoblastic disease in Switzerland: retrospective study of the impact of a regional reference centre.
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Fehlmann A, Benkortbi K, Rosseel G, Meyer-Hamme U, Tille JC, Sloan-Bena F, Paoloni-Giacobino A, Rougemont AL, Bodmer A, Botsikas D, Mathevet P, Petignat P, and Undurraga Malinverno M
- Subjects
- Chorionic Gonadotropin, Female, Humans, Pregnancy, Retrospective Studies, Switzerland epidemiology, Gestational Trophoblastic Disease diagnosis, Gestational Trophoblastic Disease drug therapy, Gestational Trophoblastic Disease epidemiology, Hydatidiform Mole
- Abstract
Aims of the Study: The European Society of Medical Oncology (ESMO) recommends that countries should have reference centres to provide adequate diagnosis and treatment of gestational trophoblastic disease. A trophoblastic disease centre in the French-speaking part of Switzerland was inaugurated in 2009. The objectives of this study were to report the activity of the centre during the last 10 years and analyse gestational trophoblastic disease outcomes., Methods: This was a retrospective study with data collected from all cases of gestational trophoblastic disease referred to the centre from 2009 to 2018. All histological specimens as well as data for treatment and follow-up of gestational trophoblastic disease and neoplasia were reviewed. Clinical features, including age, prognostic score and International Federation of Gynecology and Obstetrics (FIGO) stages (in the case of gestational trophoblastic neoplasia), human chorionic gonadotropin (hCG) follow-up, treatment and outcome were reported., Results: The centre registered 354 patients, and these patients presented 156 cases of partial hydatidiform moles, 163 cases of complete hydatidiform moles and 14 cases of gestational trophoblastic neoplasia. During follow-up, 35 gestational trophoblastic neoplasms were diagnosed after hCG persistence. After pathology review, the overall agreement rates between our centre and a participating provider hospital was 82%. Methotrexate was the first line of single-agent chemotherapy for most patients, with resistance rates of 23%. Multi-agent chemotherapy was used as first-line treatment for five patients. None of the patients followed up by the centre died from gestational trophoblastic disease., Conclusions: This study reflects the activity of the Swiss trophoblastic disease centre from the French-speaking part of Switzerland created in 2009, and its role as local and national reference centre, in terms of global health, for women with gestational trophoblastic disease.
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- 2021
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23. The multifaceted PDCD10/CCM3 gene.
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Valentino M, Dejana E, and Malinverno M
- Abstract
The programmed cell death 10 ( PDCD10 ) gene was originally identified as an apoptosis-related gene, although it is now usually known as CCM3 , as the third causative gene of cerebral cavernous malformation (CCM). CCM is a neurovascular disease that is characterized by vascular malformations and is associated with headaches, seizures, focal neurological deficits, and cerebral hemorrhage. The PDCD10/CCM3 protein has multiple subcellular localizations and interacts with several multi-protein complexes and signaling pathways. Thus PDCD10/CCM3 governs many cellular functions, which include cell-to-cell junctions and cytoskeleton organization, cell proliferation and apoptosis, and exocytosis and angiogenesis. Given its central role in the maintenance of homeostasis of the cell, dysregulation of PDCD10/CCM3 can result in a wide range of altered cell functions. This can lead to severe diseases, including CCM, cognitive disability, and several types of cancers. Here, we review the multifaceted roles of PDCD10/CCM3 in physiology and pathology, with a focus on its functions beyond CCM., (© 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.)
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- 2020
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24. Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution.
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Orsenigo F, Conze LL, Jauhiainen S, Corada M, Lazzaroni F, Malinverno M, Sundell V, Cunha SI, Brännström J, Globisch MA, Maderna C, Lampugnani MG, Magnusson PU, and Dejana E
- Subjects
- Animals, Apoptosis Regulatory Proteins metabolism, Arteries pathology, Brain blood supply, Brain pathology, Cell Differentiation, Disease Models, Animal, Gene Deletion, Immunohistochemistry, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Mitosis, Neovascularization, Pathologic, Phenotype, RNA-Seq, Sequence Analysis, RNA, Signal Transduction genetics, Single-Cell Analysis, Tamoxifen pharmacology, Transcriptome, Endothelial Cells cytology, Hemangioma, Cavernous, Central Nervous System physiopathology
- Abstract
Cerebral cavernous malformation (CCM) is a rare neurovascular disease that is characterized by enlarged and irregular blood vessels that often lead to cerebral hemorrhage. Loss-of-function mutations to any of three genes results in CCM lesion formation; namely, KRIT1 , CCM2 , and PDCD10 (CCM3) . Here, we report for the first time in-depth single-cell RNA sequencing, combined with spatial transcriptomics and immunohistochemistry, to comprehensively characterize subclasses of brain endothelial cells (ECs) under both normal conditions and after deletion of Pdcd10 ( Ccm3) in a mouse model of CCM. Integrated single-cell analysis identifies arterial ECs as refractory to CCM transformation. Conversely, a subset of angiogenic venous capillary ECs and respective resident endothelial progenitors appear to be at the origin of CCM lesions. These data are relevant for the understanding of the plasticity of the brain vascular system and provide novel insights into the molecular basis of CCM disease at the single cell level., Competing Interests: FO, LC, SJ, MC, FL, MM, VS, SC, JB, MG, CM, ML, PM No competing interests declared, ED Reviewing editor, eLife, (© 2020, Orsenigo et al.)
- Published
- 2020
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25. JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function.
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Kakogiannos N, Ferrari L, Giampietro C, Scalise AA, Maderna C, Ravà M, Taddei A, Lampugnani MG, Pisati F, Malinverno M, Martini E, Costa I, Lupia M, Cavallaro U, Beznoussenko GV, Mironov AA, Fernandes B, Rudini N, Dejana E, and Giannotta M
- Subjects
- Adult, Aged, Animals, Brain Neoplasms metabolism, Brain Neoplasms pathology, CCAAT-Enhancer-Binding Proteins genetics, Cell Adhesion Molecules genetics, Cell Line, Claudin-5 genetics, Female, Glioblastoma metabolism, Glioblastoma pathology, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Neovascularization, Pathologic, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Receptors, Cell Surface genetics, Signal Transduction, Tight Junctions genetics, Up-Regulation, CCAAT-Enhancer-Binding Proteins metabolism, Capillary Permeability, Cell Adhesion Molecules metabolism, Claudin-5 metabolism, Endothelial Cells metabolism, Receptors, Cell Surface metabolism, Tight Junctions metabolism
- Abstract
Rationale: Intercellular tight junctions are crucial for correct regulation of the endothelial barrier. Their composition and integrity are affected in pathological contexts, such as inflammation and tumor growth. JAM-A (junctional adhesion molecule A) is a transmembrane component of tight junctions with a role in maintenance of endothelial barrier function, although how this is accomplished remains elusive., Objective: We aimed to understand the molecular mechanisms through which JAM-A expression regulates tight junction organization to control endothelial permeability, with potential implications under pathological conditions., Methods and Results: Genetic deletion of JAM-A in mice significantly increased vascular permeability. This was associated with significantly decreased expression of claudin-5 in the vasculature of various tissues, including brain and lung. We observed that C/EBP-α (CCAAT/enhancer-binding protein-α) can act as a transcription factor to trigger the expression of claudin-5 downstream of JAM-A, to thus enhance vascular barrier function. Accordingly, gain-of-function for C/EBP-α increased claudin-5 expression and decreased endothelial permeability, as measured by the passage of fluorescein isothiocyanate (FITC)-dextran through endothelial monolayers. Conversely, C/EBP-α loss-of-function showed the opposite effects of decreased claudin-5 levels and increased endothelial permeability. Mechanistically, JAM-A promoted C/EBP-α expression through suppression of β-catenin transcriptional activity, and also through activation of EPAC (exchange protein directly activated by cAMP). C/EBP-α then directly binds the promoter of claudin-5 to thereby promote its transcription. Finally, JAM-A-C/EBP-α-mediated regulation of claudin-5 was lost in blood vessels from tissue biopsies from patients with glioblastoma and ovarian cancer., Conclusions: We describe here a novel role for the transcription factor C/EBP-α that is positively modulated by JAM-A, a component of tight junctions that acts through EPAC to up-regulate the expression of claudin-5, to thus decrease endothelial permeability. Overall, these data unravel a regulatory molecular pathway through which tight junctions limit vascular permeability. This will help in the identification of further therapeutic targets for diseases associated with endothelial barrier dysfunction. Graphic Abstract: An graphic abstract is available for this article.
- Published
- 2020
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26. Endothelial cell clonal expansion in the development of cerebral cavernous malformations.
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Malinverno M, Maderna C, Abu Taha A, Corada M, Orsenigo F, Valentino M, Pisati F, Fusco C, Graziano P, Giannotta M, Yu QC, Zeng YA, Lampugnani MG, Magnusson PU, and Dejana E
- Subjects
- Animals, Apoptosis Regulatory Proteins metabolism, Biomarkers metabolism, Brain blood supply, Brain cytology, Brain pathology, Cell Differentiation genetics, Cell Line, Central Nervous System Neoplasms genetics, Disease Models, Animal, Endothelial Cells metabolism, Endothelium, Vascular cytology, Endothelium, Vascular pathology, Female, Gene Knockout Techniques, Hemangioma, Cavernous, Central Nervous System genetics, Humans, Intracellular Signaling Peptides and Proteins metabolism, Loss of Function Mutation, Membrane Proteins metabolism, Mesenchymal Stem Cells metabolism, Mice, Mice, Knockout, Proto-Oncogene Proteins metabolism, Apoptosis Regulatory Proteins genetics, Central Nervous System Neoplasms pathology, Endothelial Cells pathology, Hemangioma, Cavernous, Central Nervous System pathology, Intracellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.
- Published
- 2019
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27. A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing.
- Author
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Angiolini F, Belloni E, Giordano M, Campioni M, Forneris F, Paronetto MP, Lupia M, Brandas C, Pradella D, Di Matteo A, Giampietro C, Jodice G, Luise C, Bertalot G, Freddi S, Malinverno M, Irimia M, Moulton JD, Summerton J, Chiapparino A, Ghilardi C, Giavazzi R, Nyqvist D, Gabellini D, Dejana E, Cavallaro U, and Ghigna C
- Subjects
- Cells, Cultured, Humans, Neuro-Oncological Ventral Antigen, Alternative Splicing, Angiogenic Proteins metabolism, Endothelial Cells metabolism, Nerve Tissue Proteins metabolism, Neural Cell Adhesion Molecule L1 metabolism, Protein Isoforms metabolism, RNA-Binding Proteins metabolism
- Abstract
The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies., Competing Interests: EB, MG, MC, FF, PP, ML, CB, DP, AD, CG, GJ, CL, GB, SF, MM, MI, CG, RG, DN, DG No competing interests declared, JM, JS Affiliated with Gene Tools, LLC. Funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. ED Reviewing editor, eLife, CG Consultant for Gene-Tools, LLC. Funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript., (© 2019, Angiolini et al.)
- Published
- 2019
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28. Endothelial trans-differentiation in glioblastoma recurring after radiotherapy.
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De Pascalis I, Morgante L, Pacioni S, D'Alessandris QG, Giannetti S, Martini M, Ricci-Vitiani L, Malinverno M, Dejana E, Larocca LM, and Pallini R
- Subjects
- Animals, Brain Neoplasms genetics, Brain Neoplasms radiotherapy, Endothelial Cells metabolism, Endothelial Cells radiation effects, ErbB Receptors genetics, ErbB Receptors metabolism, Glioblastoma genetics, Glioblastoma radiotherapy, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells pathology, Human Umbilical Vein Endothelial Cells radiation effects, Humans, In Situ Hybridization, Fluorescence, Mice, Neoplasm Recurrence, Local genetics, Brain Neoplasms pathology, Cell Transdifferentiation physiology, Endothelial Cells pathology, Glioblastoma pathology, Neoplasm Recurrence, Local pathology
- Abstract
We hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7 chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (α Smooth Muscle Actin). Five EGFRvIII-expressing paired primary/recurrent glioblastoma samples, in which the tumor cells showed EGFR/CEP7 amplification, were then assessed by CD31 and α Smooth Muscle Actin immunofluorescence. In glomeruloid bodies, the ratio between CD31+ cells with amplified EGFR/CEP7 signal and the total CD31+ cells was 0.23 ± 0.09 (mean ± sem) and 0.63 ± 0.07 in primary tumors and in recurrent ones, respectively (p < 0.002, Student-t test). In capillaries, the ratio of CD31+ cells with amplified EGFR/CEP7 over the total CD31+ cells lining the capillary lumen was 0.21 ± 0.06 (mean ± sem) and 0.42 ± 0.07 at primary surgery and at recurrence, respectively (p < 0.005, Student-t test). Expression of α Smooth Muscle Actin by cells with EGFR/CEP7 amplification was not observed. Then, in glioblastoma recurring after radiotherapy, where the brain endothelium suffers from radiation-induced cell senescence, tumor-derived endothelium plays a role in neo-vascularization.
- Published
- 2018
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29. Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling.
- Author
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Krispin S, Stratman AN, Melick CH, Stan RV, Malinverno M, Gleklen J, Castranova D, Dejana E, and Weinstein BM
- Subjects
- Animals, Animals, Genetically Modified, Antigens, CD genetics, Antigens, CD metabolism, Cadherins genetics, Cadherins metabolism, Cells, Cultured, Gene Expression Regulation, Developmental, Growth Differentiation Factor 6 genetics, Human Umbilical Vein Endothelial Cells metabolism, Humans, Mitogen-Activated Protein Kinase 3 metabolism, Neovascularization, Physiologic, Phosphorylation, Signal Transduction, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Zebrafish embryology, Zebrafish genetics, Zebrafish Proteins genetics, Capillary Permeability, Embryo, Nonmammalian blood supply, Endothelial Cells metabolism, Growth Differentiation Factor 6 metabolism, Vascular Endothelial Growth Factor A metabolism, Zebrafish metabolism, Zebrafish Proteins metabolism
- Abstract
Objective: The assembly of a functional vascular system requires a coordinated and dynamic transition from activation to maturation. High vascular endothelial growth factor activity promotes activation, including junction destabilization and cell motility. Maturation involves junctional stabilization and formation of a functional endothelial barrier. The identity and mechanism of action of prostabilization signals are still mostly unknown. Bone morphogenetic protein receptors and their ligands have important functions during embryonic vessel assembly and maturation. Previous work has suggested a role for growth differentiation factor 6 (GDF6; bone morphogenetic protein 13) in vascular integrity although GDF6's mechanism of action was not clear. Therefore, we sought to further explore the requirement for GDF6 in vascular stabilization., Approach and Results: We investigated the role of GDF6 in promoting endothelial vascular integrity in vivo in zebrafish and in cultured human umbilical vein endothelial cells in vitro. We report that GDF6 promotes vascular integrity by counteracting vascular endothelial growth factor activity. GDF6-deficient endothelium has increased vascular endothelial growth factor signaling, increased vascular endothelial-cadherin Y658 phosphorylation, vascular endothelial-cadherin delocalization from cell-cell interfaces, and weakened endothelial cell adherence junctions that become prone to vascular leak., Conclusions: Our results suggest that GDF6 promotes vascular stabilization by restraining vascular endothelial growth factor signaling. Understanding how GDF6 affects vascular integrity may help to provide insights into hemorrhage and associated vascular pathologies in humans., (© 2017 American Heart Association, Inc.)
- Published
- 2018
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30. Peg3/PW1 Is a Marker of a Subset of Vessel Associated Endothelial Progenitors.
- Author
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Malinverno M, Corada M, Ferrarini L, Formicola L, Marazzi G, Sassoon D, and Dejana E
- Subjects
- Animals, Biomarkers metabolism, Blood Vessels embryology, Blood Vessels metabolism, Cell Proliferation drug effects, Cell Separation, Embryonic Development drug effects, Endothelial Progenitor Cells drug effects, Gene Expression Profiling, Intercellular Signaling Peptides and Proteins pharmacology, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Mice, Inbred C57BL, Neovascularization, Physiologic drug effects, Phenotype, Blood Vessels cytology, Endothelial Progenitor Cells cytology, Endothelial Progenitor Cells metabolism, Kruppel-Like Transcription Factors metabolism
- Abstract
Vascular associated endothelial cell (ECs) progenitors are still poorly studied and their role in the newly forming vasculature at embryonic or postnatal stage remains elusive. In the present work, we first defined a set of genes highly expressed during embryo development and strongly downregulated in the adult mouse. In this group, we then concentrated on the progenitor cell marker Peg3/PW1. By in vivo staining of the vasculature we found that only a subset of cells coexpressed endothelial markers and PW1. These cells were quite abundant in the embryo vasculature but declined in number at postnatal and adult stages. Using a reporter mouse for PW1 expression, we have been able to isolate PW1-positive (PW1posECs) and negative endothelial cells (PW1negECs). PW1-positive cells were highly proliferative in comparison to PW1negECs and were able to form colonies when seeded at clonal dilution. Furthermore, by RNAseq analysis, PW1posECs expressed endothelial cell markers together with mesenchymal and stem cell markers. When challenged by endothelial growth factors in vitro, PW1posECs were able to proliferate more than PW1negECs and to efficiently form new vessels in vivo. Taken together these data identify a subset of vessel associated endothelial cells with characteristics of progenitor cells. Considering their high proliferative potential these cells may be of particular importance to design therapies to improve the perfusion of ischemic tissues or to promote vascular repair. Stem Cells 2017;35:1328-1340., (© 2017 AlphaMed Press.)
- Published
- 2017
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31. Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition.
- Author
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Bravi L, Malinverno M, Pisati F, Rudini N, Cuttano R, Pallini R, Martini M, Larocca LM, Locatelli M, Levi V, Bertani GA, Dejana E, and Lampugnani MG
- Subjects
- Adolescent, Adult, Aged, Central Nervous System Neoplasms surgery, Child, Female, Hemangioma, Cavernous, Central Nervous System surgery, Humans, Male, Middle Aged, Young Adult, Central Nervous System Neoplasms pathology, Endothelium, Vascular pathology, Epithelial-Mesenchymal Transition physiology, Hemangioma, Cavernous, Central Nervous System pathology
- Abstract
Background and Purpose: Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy., Methods: We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control., Results: We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad- and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones., Conclusions: Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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32. Smartphone Use for Cervical Cancer Screening in Low-Resource Countries: A Pilot Study Conducted in Madagascar.
- Author
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Catarino R, Vassilakos P, Scaringella S, Undurraga-Malinverno M, Meyer-Hamme U, Ricard-Gauthier D, Matute JC, and Petignat P
- Subjects
- Acetic Acid administration & dosage, Adult, Biopsy methods, Cervix Uteri pathology, Cervix Uteri virology, Colposcopy methods, Early Detection of Cancer methods, Female, Humans, Madagascar, Mass Screening instrumentation, Mass Screening methods, Middle Aged, Papillomaviridae pathogenicity, Papillomavirus Infections diagnosis, Papillomavirus Infections pathology, Pilot Projects, Sensitivity and Specificity, Smartphone, Uterine Cervical Neoplasms virology, Vaginal Smears methods, Uterine Cervical Dysplasia diagnosis, Uterine Cervical Dysplasia pathology, Uterine Cervical Dysplasia virology, Early Detection of Cancer instrumentation, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms pathology
- Abstract
Background: Visual inspection of the cervix after application of 5% acetic acid (VIA) is a screening technique for cervical cancer used widely in low and middle-income countries (LMIC). To improve VIA screening performance, digital images after acid acetic application (D-VIA) are taken. The aim of this study was to evaluate the use of a smartphone for on- and off-site D-VIA diagnosis., Materials and Methods: Women aged 30-65 years, living in the city of Ambanja, Madagascar, were recruited through a cervical cancer screening campaign. Each performed a human papillomavirus (HPV) self-sample as a primary screen. Women testing positive for HPV were referred for VIA followed by D-VIA, cervical biopsy and endocervical curettage according to routine protocol. In addition, the same day, the D-VIA was emailed to a tertiary care center for immediate assessment. Results were scored as either D-VIA normal or D-VIA abnormal, requiring immediate therapy or referral to a tertiary center. Each of the three off-site physicians were blinded to the result reported by the one on-site physician and each gave their individual assessment followed by a consensus diagnosis. Statistical analyses were conducted using STATA software., Results: Of the 332 women recruited, 137 (41.2%) were HPV-positive and recalled for VIA triage; compliance with this invitation was 69.3% (n = 95). Cervical intraepithelial neoplasia was detected in 17.7% and 21.7% of digital images by on-site and off-site physicians, respectively. The on-site physician had a sensitivity of 66.7% (95%CI: 30.0-90.3) and a specificity of 85.7% (95%CI: 76.7-91.6); the off-site physician consensus sensitivity was 66.7% (95%CI: 30.0-90.3) with a specificity of 82.3% (95%CI: 72.4-89.1)., Conclusion: This pilot study supports the use of telemedicine for off-site diagnosis of cervical intraepithelial neoplasia, with diagnostic performance similar to those achieved on-site. Further studies need to determine if smartphones can improve cervical cancer screening efficiency in LMIC.
- Published
- 2015
- Full Text
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33. The neuropeptide PACAP38 induces dendritic spine remodeling through ADAM10-N-cadherin signaling pathway.
- Author
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Gardoni F, Saraceno C, Malinverno M, Marcello E, Verpelli C, Sala C, and Di Luca M
- Subjects
- ADAM Proteins antagonists & inhibitors, ADAM10 Protein, Animals, Cadherins chemistry, Cadherins genetics, Glutamic Acid physiology, Hippocampus cytology, Nerve Tissue Proteins chemistry, Nerve Tissue Proteins genetics, Primary Cell Culture, Rats, ADAM Proteins physiology, Cadherins physiology, Dendritic Spines metabolism, Hippocampus metabolism, Nerve Tissue Proteins physiology, Neuronal Plasticity physiology, Pituitary Adenylate Cyclase-Activating Polypeptide physiology, Signal Transduction physiology
- Abstract
The neuropeptide pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been implicated in the induction of synaptic plasticity at the excitatory glutamatergic synapse. In particular, recent studies have shown that it is involved in the regulation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Here we demonstrate the effect of PACAP38 on the modulation of dendritic spine morphology through a disintegrin and metalloproteinase 10 (ADAM10)-N-cadherin-AMPA receptor signaling pathway. Treatment of primary hippocampal neurons with PACAP38 induced an accumulation of ADAM10 at the postsynaptic membrane. This event led to a significant decrease of dendritic spine head width and to a concomitant reduction of GluR1 colocalization with postsynaptic markers. The PACAP38-induced effect on dendritic spine head width was prevented by either treatment with the ADAM10-specific inhibitor or transfection of a cleavage-defective N-cadherin construct mutated in the ADAM10 cleavage site. Overall, our findings reveal that PACAP38 is involved in the modulation of dendritic spine morphology in hippocampal neurons, and assign to the ADAM10-N-cadherin signaling pathway a crucial role in this modification of the excitatory glutamatergic synapse.
- Published
- 2012
- Full Text
- View/download PDF
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