88 results on '"Giovanni Marfia"'
Search Results
2. Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of Sphingolipid Rheostat
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Stefania Elena Navone, Laura Guarnaccia, Massimiliano D. Rizzaro, Laura Begani, Emanuela Barilla, Giovanni Alotta, Emanuele Garzia, Manuela Caroli, Antonella Ampollini, Aniello Violetti, Noreen Gervasi, Rolando Campanella, Laura Riboni, Marco Locatelli, and Giovanni Marfia
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glioblastoma stem cells ,luteolin ,sphingosine-1-phosphate ,ceramide ,sphingolipid rheostat ,temozolomide ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.
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- 2023
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3. Microgravity and the intervertebral disc: The impact of space conditions on the biomechanics of the spine
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Giovanni Marfia, Laura Guarnaccia, Stefania Elena Navone, Antonella Ampollini, Melissa Balsamo, Francesca Benelli, Chiara Gaudino, Emanuele Garzia, Claudia Fratocchi, Claudia Di Murro, Gianfranco Kim Ligarotti, Carmelo Campanella, Angelo Landolfi, Pietro Perelli, Marco Locatelli, and Giuseppe Ciniglio Appiani
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microgravity ,intervertebral disc ,disc degeneration ,low back pain ,space ,Physiology ,QP1-981 - Abstract
The environmental conditions to which astronauts and other military pilots are subjected represent a unique example for understanding and studying the biomechanical events that regulate the functioning of the human body. In particular, microgravity has shown a significant impact on various biological systems, such as the cardiovascular system, immune system, endocrine system, and, last but not least, musculoskeletal system. Among the potential risks of flying, low back pain (LBP) has a high incidence among astronauts and military pilots, and it is often associated with intervertebral disc degeneration events. The mechanisms of degeneration determine the loss of structural and functional integrity and are accompanied by the aberrant production of pro-inflammatory mediators that exacerbate the degenerative environment, contributing to the onset of pain. In the present work, the mechanisms of disc degeneration, the conditions of microgravity, and their association have been discussed in order to identify possible molecular mechanisms underlying disc degeneration and the related clinical manifestations in order to develop a model of prevention to maintain health and performance of air- and space-travelers. The focus on microgravity also allows the development of new proofs of concept with potential therapeutic implications.
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- 2023
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4. Hyperandrogenism and menstrual imbalance are the best predictors of metformin response in PCOS patients
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Emanuele Garzia, Valentina Galiano, Giovanni Marfia, Stefania Navone, Enzo Grossi, and Anna Maria Marconi
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PCOS ,Insulin resistance ,Hyperandrogenism ,Metformin ,Oligo-amenorrhea ,Gynecology and obstetrics ,RG1-991 ,Reproduction ,QH471-489 - Abstract
Abstract Background Moving from the correlation between insulin-resistance and PCOS, metformin has been administered in some PCOS women improving ovulatory and metabolic functions and decreasing androgen levels. Inconsistency and unpredictability of response to metformin limit its extensive use. Aim of this study was to identify reliable predictors of response to metformin therapy for weight loss and reduction in plasma androgen levels using ANNs (artificial neural networks). Methods One hundred eight consecutive women with PCOS (ESHRE/ASRM 2003 Rotterdam criteria) treated with metformin 1500 mg/day, at inclusion and every 6 months underwent to a complete clinical, endocrine/metabolic assessment and ultrasonographic evaluation. Therapy outcomes were BMI reduction (≥1 kg/m2) in overweight/obese and free-androgen-index (FAI) decrease (≥1%) in hyperandrogenemic women. Semantic connectivity maps (SCMs) were obtained through Auto-CM, a fourth generation ANN, to compare patients’ baseline clinical features to the treatment outcomes. Multivariate logistic regression analysis was used to assess the major predictor in drop-out patients and the associated risk. Results At 6 months 54 out of 103 (52,4%) obese patients showed BMI reduction and 45 out of 89 (50,6%) hyperandrogenemic women showed FAI decrease. The further response rates at 12 months were 30,6 and 47%, respectively. SCMs showed a clear polarization for both the outcomes with elevated accuracy. Treatment responsiveness resulted strictly related to oligo-amenorrhea and hyperandrogenemia at baseline. In addition, lower serum testosterone levels at baseline were found to be the major predictor of treatment discontinuation. Conclusions In women with PCOS, menstrual pattern imbalance and ovarian androgens excess are the best predictors of metformin response. They may pave the way for a rethinking of the criteria for evaluating hyperandrogenism in order to better define the large population included in the diagnosis of PCOS. Baseline plasma testosterone level can serve as a sensitive marker to predict treatment compliance.
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- 2022
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5. Incidence of intra-procedural complications according to the timing of endovascular treatment in ruptured intracranial aneurysms
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Chiara Gaudino, Stefania Elena Navone, Valerio Da Ros, Laura Guarnaccia, Giovanni Marfia, Patrizia Pantano, Simone Peschillo, Fabio Maria Triulzi, and Francesco Biraschi
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ruptured intracranial aneurysm ,endovascular treatment ,intra-procedural complications ,timing of endovascular treatment ,subarachnoid hemorrhage ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
BackgroundAlthough endovascular treatment of ruptured intracranial aneurysms is well-established, some critical issues have not yet been clarified, such as the effects of timing on safety and effectiveness of the procedure. The aim of our study was to analyze the incidence of intra-procedural complications according to the timing of treatment, as they can affect morbidity and mortality.Materials and methodsWe retrospectively analyzed all patients who underwent endovascular treatment for ruptured intracranial aneurysms at three high flow center. For all patients, imaging and clinical data, aneurysm's type, mean dimension and different treatment techniques were analyzed. Intra-procedural complications were defined as thrombus formation at the aneurysm's neck, thromboembolic events, and rupture of the aneurysm. Patients were divided into three groups according to time between subarachnoid hemorrhage and treatment (36 h delayed).ResultsThe final study population included 215 patients. In total, 84 patients (39%) underwent hyper-early, 104 (48%) early, and 27 (13%) delayed endovascular treatment. Overall, 69% of the patients were treated with simple coiling, 23% with balloon-assisted coiling, 1% with stent-assisted coiling, 3% with a flow-diverter stent, 3% with an intrasaccular flow disruptor device, and 0.5% with parent vessel occlusion. Delayed endovascular treatment was associated with an increased risk of total intra-procedural complications compared to both hyper-early (p = 0.009) and early (p = 0.004) treatments with a rate of complications of 56% (vs. 29% in hyper-early and 26% in early treated group—p = 0.011 and p = 0.008). The delayed treatment group showed a higher rate of thrombus formation and thromboembolic events. The increased risk of total intra-procedural complications in delayed treatment was confirmed, also considering only the patients treated with simple coiling and balloon-assisted coiling (p = 0.005 and p = 0.003, respectively, compared to hyper-early and early group) with a rate of complications of 62% (vs. 28% in hyper-early and 26% in early treatments—p = 0.007 and p = 0.003). Also in this subpopulation, delayed treated patients showed a higher incidence of thrombus formation and thromboembolic events.ConclusionsEndovascular treatment of ruptured intracranial aneurysms more than 36 h after SAH seems to be associated with a higher risk of intra-procedural complications, especially thrombotic and thromboembolic events.
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- 2023
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6. Overview of Curcumin and Piperine Effects on Glucose Metabolism: The Case of an Insulinoma Patient’s Loss of Consciousness
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Simona Servida, Elena Panzeri, Laura Tomaino, Giovanni Marfia, Emanuele Garzia, Giuseppe Ciniglio Appiani, Gianluca Moroncini, Vito De Gennaro Colonna, Carlo La Vecchia, and Luisella Vigna
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hypoglycemia ,insulinoma ,curcumin ,piperine ,bioavailability ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The hypoglycemic properties of curcumin supplements in therapeutic doses are well-known and may represent a useful tool for the treatment of chronic diseases such as metabolic syndrome, insulin resistance and type 2 diabetes. The poor bioavailability of curcumin can be improved with the concomitant administration of piperine, with no severe adverse effects on glycemia reported so far in the literature. In this article, we further discuss a previously reported case of a helicopter pilot, affected by grade I obesity who, under curcumin and piperine treatment, experienced a transient loss of consciousness (TLOC), during a low-altitude flight. This episode led to a diagnosis of insulinoma, previously asymptomatic. We hypothesized that the combined effects of curcumin and piperine might have caused a severe hypoglycemic episode and subsequent TLOC. Therefore, further studies should be conducted to evaluate the safety of curcumin and piperine supplementation in subjects with impaired glucose metabolism and insulin secretion.
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- 2023
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7. Safety and Effectiveness of Cell Therapy in Neurodegenerative Diseases: Take-Home Messages From a Pilot Feasibility Phase I Study of Progressive Supranuclear Palsy
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Rosaria Giordano, Margherita Canesi, Maurizio Isalberti, Giovanni Marfia, Rolando Campanella, Daniele Vincenti, Viviana Cereda, Alessandra Ranghetti, Chiara Palmisano, Ioannis Ugo Isaias, Riccardo Benti, Giorgio Marotta, Lorenza Lazzari, Tiziana Montemurro, Mariele Viganò, Silvia Budelli, Elisa Montelatici, Cristiana Lavazza, Araceli Rivera-Ordaz, and Gianni Pezzoli
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progressive supranuclear palsy (PSP) ,Parkinson’s disease ,cell therapy ,mesenchymal stromal cells (MSCs) ,posture ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.
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- 2021
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8. A Targeted Next-Generation Sequencing Panel to Genotype Gliomas
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Maria Guarnaccia, Laura Guarnaccia, Valentina La Cognata, Stefania Elena Navone, Rolando Campanella, Antonella Ampollini, Marco Locatelli, Monica Miozzo, Giovanni Marfia, and Sebastiano Cavallaro
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glioblastoma ,glioma ,targeted sequencing ,precision medicine ,genomics ,Science - Abstract
Gliomas account for the majority of primary brain tumors. Glioblastoma is the most common and malignant type. Based on their extreme molecular heterogeneity, molecular markers can be used to classify gliomas and stratify patients into diagnostic, prognostic, and therapeutic clusters. In this work, we developed and validated a targeted next-generation sequencing (NGS) approach to analyze variants or chromosomal aberrations correlated with tumorigenesis and response to treatment in gliomas. Our targeted NGS analysis covered 13 glioma-related genes (ACVR1, ATRX, BRAF, CDKN2A, EGFR, H3F3A, HIST1H3B, HIST1H3C, IDH1, IDH2, P53, PDGFRA, PTEN), a 125 bp region of the TERT promoter, and 54 single nucleotide polymorphisms (SNPs) along chromosomes 1 and 19 for reliable assessment of their copy number alterations (CNAs). Our targeted NGS approach provided a portrait of gliomas’ molecular heterogeneity with high accuracy, specificity, and sensitivity in a single workflow, enabling the detection of variants associated with unfavorable outcomes, disease progression, and drug resistance. These preliminary results support its use in routine diagnostic neuropathology.
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- 2022
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9. Decreased serum level of sphingosine‐1‐phosphate: a novel predictor of clinical severity in COVID‐19
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Giovanni Marfia, Stefania Navone, Laura Guarnaccia, Rolando Campanella, Michele Mondoni, Marco Locatelli, Alessandra Barassi, Laura Fontana, Fabrizio Palumbo, Emanuele Garzia, Giuseppe Ciniglio Appiani, Davide Chiumello, Monica Miozzo, Stefano Centanni, and Laura Riboni
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Coronavirus ,COVID‐19 ,intensive care unit ,prognostic biomarker ,sphingosine‐1‐phosphate ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract The severity of coronavirus disease 2019 (COVID‐19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine‐1‐phosphate (S1P) along with severity markers, in COVID‐19 patients. One hundred eleven COVID‐19 patients and forty‐seven healthy subjects were included. The severity of COVID‐19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil‐to‐lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C‐reactive protein (CRP), and D‐dimer. Serum S1P level was inversely associated with COVID‐19 severity, being significantly correlated with CRP, LDH, ferritin, and D‐dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient’s outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID‐19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID‐19.
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- 2021
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10. Platelets from glioblastoma patients promote angiogenesis of tumor endothelial cells and exhibit increased VEGF content and release
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Clara Di Vito, Stefania Elena Navone, Giovanni Marfia, Loubna Abdel Hadi, Maria Elisa Mancuso, Alessandro Pecci, Francesco Maria Crisà, Valeria Berno, Paolo Rampini, Rolando Campanella, and Laura Riboni
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glioblastoma ,platelets ,tumor endothelial cells ,vegf ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Glioblastoma multiforme (GBM) is the most common and fatal intracranial cancer in humans and exhibits intense and aberrant angiogenesis that sustains its malignancy and involves several angiogenic signals. Among them, vascular endothelial growth factor (VEGF) plays a key role and is overexpressed in GBM. Different cells appear to act as triggers of the aberrant angiogenesis, and, among them, platelets act as key participants. In order to provide further insights into the platelet features and angiogenic role in GBM, this study investigated the effects of platelet releasate on GBM-derived endothelial cells (GECs) and the levels of VEGF and endostatin, as pro- and anti-angiogenic components of platelet releasate from GBM patients. We demonstrate for the first time that: 1) platelet releasate exerts powerful pro-angiogenic effect on GECs, suggesting it might exert a role in the aberrant angiogenesis of GBM; 2) ADP and thrombin stimulation leads to significantly higher level of VEGF, but not of endostatin, in the releasate of platelets from GBM patients than those from healthy subjects; and 3) the intraplatelet concentrations of VEGF were significantly elevated in GBM patients as compared to controls. Moreover, we found a direct correlation between platelet-released VEGF and overall survival in our patient cohort. Although preliminary, these findings prompt further investigations to clarify the biologic relevance of platelet VEGF in GBM and prospective studies for screening GBM patients for anti-VEGF therapy and/or to optimize this treatment.
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- 2017
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11. The Genetic Landscape of Human Glioblastoma and Matched Primary Cancer Stem Cells Reveals Intratumour Similarity and Intertumour Heterogeneity
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Chiara Pesenti, Stefania Elena Navone, Laura Guarnaccia, Andrea Terrasi, Jole Costanza, Rosamaria Silipigni, Silvana Guarneri, Nicola Fusco, Laura Fontana, Marco Locatelli, Paolo Rampini, Rolando Campanella, Silvia Tabano, Monica Miozzo, and Giovanni Marfia
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Internal medicine ,RC31-1245 - Abstract
Glioblastoma (GBM) is the most malignant human brain tumour, characterized by rapid progression, invasion, intense angiogenesis, high genomic instability, and resistance to therapies. Despite countless experimental researches for new therapeutic strategies and promising clinical trials, the prognosis remains extremely poor, with a mean survival of less than 14 months. GBM aggressive behaviour is due to a subpopulation of tumourigenic stem-like cells, GBM stem cells (GSCs), which hierarchically drive onset, proliferation, and tumour recurrence. The morbidity and mortality of this disease strongly encourage exploring genetic characteristics of GSCs. Here, using array-CGH platform, we investigated genetic and genomic aberration profiles of GBM parent tumour (n=10) and their primarily derived GSCs. Statistical analysis was performed by using R software and complex heatmap and corrplot packages. Pearson correlation and K-means algorithm were exploited to compare genetic alterations and to group similar genetic profiles in matched pairs of GBM and derived GSCs. We identified, in both GBM and matched GSCs, recurrent copy number alterations, as chromosome 7 polysomy, chromosome 10 monosomy, and chromosome 9p21deletions, which are typical features of primary GBM, essential for gliomagenesis. These observations suggest a condition of strong genomic instability both in GBM as GSCs. Our findings showed the robust similarity between GBM mass and GSCs (Pearson corr.≥0.65) but also highlighted a marked variability among different patients. Indeed, the heatmap reporting Gain/Loss State for 21022 coding/noncoding genes demonstrated high interpatient divergence. Furthermore, K-means algorithm identified an impairment of pathways related to the development and progression of cancer, such as angiogenesis, as well as pathways related to the immune system regulation, such as T cell activation. Our data confirmed the preservation of the genomic landscape from tumour tissue to GSCs, supporting the relevance of this cellular model to test in vitro new target therapies for GBM.
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- 2019
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12. Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks
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Laura Riboni, Loubna Abdel Hadi, Stefania Elena Navone, Laura Guarnaccia, Rolando Campanella, and Giovanni Marfia
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sphingosine-1-phosphate ,cancer ,tumor microenvironment ,glioblastoma ,lysophospholipids ,cancer hallmarks ,Cytology ,QH573-671 - Abstract
As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular focus on glioblastoma, representative of a highly aggressive and deleterious neoplasm in humans. First, we highlight recent advances and emerging concepts for how tumor cells and different recruited normal cells contribute to the sphingosine-1-phosphate enrichment in the cancer microenvironment. Then, we describe and discuss how sphingosine-1-phosphate signaling contributes to favor cancer hallmarks including enhancement of proliferation, stemness, invasion, death resistance, angiogenesis, immune evasion and, possibly, aberrant metabolism. We also discuss the potential of how sphingosine-1-phosphate control mechanisms are coordinated across distinct cancer microenvironments. Further progress in understanding the role of S1P signaling in cancer will depend crucially on increasing knowledge of its participation in the tumor microenvironment.
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- 2020
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13. Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology
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Rolando Campanella, Laura Guarnaccia, Chiara Cordiglieri, Elena Trombetta, Manuela Caroli, Giorgio Carrabba, Nicla La Verde, Paolo Rampini, Chiara Gaudino, Antonella Costa, Sabino Luzzi, Giovanna Mantovani, Marco Locatelli, Laura Riboni, Stefania Elena Navone, and Giovanni Marfia
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glioblastoma ,platelets ,sphingosine-1-phosphate ,angiogenesis ,Cytology ,QH573-671 - Abstract
Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network’s complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.
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- 2020
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14. Adult neural precursors isolated from post mortem brain yield mostly neurons: An erythropoietin-dependent process
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Giovanni Marfia, Laura Madaschi, Francesca Marra, Mauro Menarini, Daniele Bottai, Alessandro Formenti, Carmelo Bellardita, Anna Maria Di Giulio, Stephana Carelli, and Alfredo Gorio
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Adult neural progenitors ,Erythropoietin ,Gene regulation ,Hypoxia- inducible factor-1 (HIF-1) ,mTOR ,Neural plasticity ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
This study was aimed at the isolation of neural precursor cells (NPCs) capable of resisting to a prolonged ischemic insult as this may occur at the site of traumatic and ischemic CNS injuries. Adult mice were anesthetized and then killed by cervical dislocation. The cadavers were maintained at room temperature or at 4 °C for different time periods. Post mortem neural precursors (PM-NPCs) were isolated, grown in vitro and their differentiation capability was investigated by evaluating the expression of different neuronal markers. PM-NPCs differentiate mostly in neurons, show activation of hypoxia-inducible factor-1 and MAPK, and express both erythropoietin (EPO) and its receptor (EPO-R). The exposure of PM-NPCs to neutralizing antibodies to EPO or EPO-R dramatically reduced the extent of neuronal differentiation to about 11% of total PM-NPCs. The functionality of mTOR and MAPK is also required for the expression of the neuronal phenotype by PM-NPCs. These results suggest that PM-NPCs can be isolated from animal cadaver even several hours after death and their self-renewable capability is comparable to normal neural precursors. Differently, their ability to achieve a neural phenotype is superior to that of NPCs, and this is mediated by the activation of hypoxia-induced factor 1 and EPO signaling. PM-NPCs may represent good candidates for transplantation studies in animal models of neurodegenerative diseases.
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- 2011
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15. Exogenous Adult Postmortem Neural Precursors Attenuate Secondary Degeneration and Promote Myelin Sparing and Functional Recovery following Experimental Spinal Cord Injury
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Stephana Carelli, Toniella Giallongo, Giovanni Marfia, Davide Merli, Luisa Ottobrini, Anna Degrassi, Michele D. Basso, Anna Maria Di Giulio, and Alfredo Gorio
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Medicine - Abstract
Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named postmortem neural precursor cells (PM-NPCs), express both erythropoietin (EPO) and its receptor. Their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic SCI. Labeled PM-NPCs were administered intravenously; then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hindlimb function that was evaluated up to 90 days after lesion. This was accompanied by reduced myelin loss, counteraction of the invasion of the lesion site by the inflammatory cells, and an attenuation of secondary degeneration. PM-NPCs migrate mostly at the injury site, where they survive at a significantly higher extent than classical NSCs. These cells accumulate at the edges of the lesion, where a reach neuropile is formed by MAP2- and β-tubulin III-positive transplanted cells that are also mostly labeled by anti-ChAT antibodies.
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- 2015
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16. Uniphasic Blanching of the Fingers, Abnormal Capillaroscopy in Nonsymptomatic Digits, and Autoantibodies: Expanding Options to Increase the Level of Suspicion of Connective Tissue Diseases beyond the Classification of Raynaud’s Phenomenon
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Francesca Ingegnoli, Roberta Gualtierotti, Annalisa Orenti, Tommaso Schioppo, Giovanni Marfia, Rolando Campanella, Claudio Mastaglio, Pier Luigi Meroni, and Patrizia Boracchi
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Immunologic diseases. Allergy ,RC581-607 - Abstract
In patients with Raynaud’s phenomenon (RP), the role of medical history, capillaroscopy, and autoantibodies in order to provide an early diagnosis of connective tissue disease (CTD) were examined. 115 consecutive adults with uni-, bi-, or triphasic colour changes of the fingers were studied. RP was bilateral in 92.7% of patients. The middle finger was significantly more affected. A lack of association between fingers affected by RP and fingers with capillary abnormalities was observed OR=0.75 (0.34–1.66). RP with the cyanotic phase had a higher risk at capillaroscopy to have hemorrhages OR=4.46 (1.50–13.30) and giant capillaries OR=24.85 (1.48–417.44). The thumb and triphasic involvement have an OR of 1.477 and 1.845, respectively. RP secondary to systemic sclerosis (SSc) had greater value of VAS pain (p=0.011). The presence of anti-centromere antibodies was significantly associated with a higher risk of SSc (p
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- 2015
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17. Sphingosine Kinase 2 and Ceramide Transport as Key Targets of the Natural Flavonoid Luteolin to Induce Apoptosis in Colon Cancer Cells.
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Loubna Abdel Hadi, Clara Di Vito, Giovanni Marfia, Anita Ferraretto, Cristina Tringali, Paola Viani, and Laura Riboni
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Medicine ,Science - Abstract
The plant flavonoid luteolin exhibits different biological effects, including anticancer properties. Little is known on the molecular mechanisms underlying its actions in colorectal cancer (CRC). Here we investigated the effects of luteolin on colon cancer cells, focusing on the balance between ceramide and sphingosine-1-phosphate (S1P), two sphingoid mediators with opposite roles on cell fate. Using cultured cells, we found that physiological concentrations of luteolin induce the elevation of ceramide, followed by apoptotic death of colon cancer cells, but not of differentiated enterocytes. Pulse studies revealed that luteolin inhibits ceramide anabolism to complex sphingolipids. Further experiments led us to demonstrate that luteolin induces an alteration of the endoplasmic reticulum (ER)-Golgi flow of ceramide, pivotal to its metabolic processing to complex sphingolipids. We report that luteolin exerts its action by inhibiting both Akt activation, and sphingosine kinase (SphK) 2, with the consequent reduction of S1P, an Akt stimulator. S1P administration protected colon cancer cells from luteolin-induced apoptosis, most likely by an intracellular, receptor-independent mechanism. Overall this study reveals for the first time that the dietary flavonoid luteolin exerts toxic effects on colon cancer cells by inhibiting both S1P biosynthesis and ceramide traffic, suggesting its dietary introduction/supplementation as a potential strategy to improve existing treatments in CRC.
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- 2015
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18. Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy.
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Marta Dossena, Gloria Bedini, Paola Rusmini, Elisa Giorgetti, Alessandra Canazza, Valentina Tosetti, Ettore Salsano, Anna Sagnelli, Caterina Mariotti, Cinzia Gellera, Stefania Elena Navone, Giovanni Marfia, Giulio Alessandri, Fabio Corsi, Eugenio Agostino Parati, Davide Pareyson, and Angelo Poletti
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Medicine ,Science - Abstract
Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.
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- 2014
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19. Erythropoietin: Recent Developments in the Treatment of Spinal Cord Injury
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Stephana Carelli, Giovanni Marfia, Anna Maria Di Giulio, Giorgio Ghilardi, and Alfredo Gorio
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Erythropoietin (EPO), originally identified for its critical function in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of cells and tissues. Here is presented the analysis of EPO effects on spinal cord injury (SCI), considering both animal experiments concerning to mechanisms of neurodegeneration in SCI and EPO as a neuroprotective agent, and some evidences coming from ongoing clinical trials. The evidences underling that EPO could be a promising therapeutic agent in a variety of neurological insults, including trauma, are mounting. In particular, it is highlighted that administration of EPO or other recently generated EPO analogues such as asialo-EPO and carbamylated-EPO demonstrate interesting preclinical and clinical characteristics, rendering the evaluation of these tissue-protective agents imperative in human clinical trials. Moreover the demonstration of rhEPO and its analogues’ broad neuroprotective effects in animal models of cord lesion and in human trial like stroke, should encourage scientists and clinicians to design clinical trials assessing the efficacy of these pharmacological compounds on SCI.
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- 2011
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20. Mesenchymal stromal cells primed with paclitaxel provide a new approach for cancer therapy.
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Augusto Pessina, Arianna Bonomi, Valentina Coccè, Gloria Invernici, Stefania Navone, Loredana Cavicchini, Francesca Sisto, Maura Ferrari, Lucia Viganò, Alberta Locatelli, Emilio Ciusani, Graziella Cappelletti, Daniele Cartelli, Caruso Arnaldo, Eugenio Parati, Giovanni Marfia, Roberto Pallini, Maria Laura Falchetti, and Giulio Alessandri
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Medicine ,Science - Abstract
BACKGROUND: Mesenchymal stromal cells may represent an ideal candidate to deliver anti-cancer drugs. In a previous study, we demonstrated that exposure of mouse bone marrow derived stromal cells to Doxorubicin led them to acquire anti-proliferative potential towards co-cultured haematopoietic stem cells (HSCs). We thus hypothesized whether freshly isolated human bone marrow Mesenchymal stem cells (hMSCs) and mature murine stromal cells (SR4987 line) primed in vitro with anti-cancer drugs and then localized near cancer cells, could inhibit proliferation. METHODS AND PRINCIPAL FINDINGS: Paclitaxel (PTX) was used to prime culture of hMSCs and SR4987. Incorporation of PTX into hMSCs was studied by using FICT-labelled-PTX and analyzed by FACS and confocal microscopy. Release of PTX in culture medium by PTX primed hMSCs (hMSCsPTX) was investigated by HPLC. Culture of Endothelial cells (ECs) and aorta ring assay were used to test the anti-angiogenic activity of hMSCsPTX and PTX primed SR4987(SR4987PTX), while anti-tumor activity was tested in vitro on the proliferation of different tumor cell lines and in vivo by co-transplanting hMSCsPTX and SR4987PTX with cancer cells in mice. Nevertheless, despite a loss of cells due to chemo-induced apoptosis, both hMSCs and SR4987 were able to rapidly incorporate PTX and could slowly release PTX in the culture medium in a time dependent manner. PTX primed cells acquired a potent anti-tumor and anti-angiogenic activity in vitro that was dose dependent, and demonstrable by using their conditioned medium or by co-culture assay. Finally, hMSCsPTX and SR4987PTX co-injected with human cancer cells (DU145 and U87MG) and mouse melanoma cells (B16) in immunodeficient and in syngenic mice significantly delayed tumor takes and reduced tumor growth. CONCLUSIONS: These data demonstrate, for the first time, that without any genetic manipulation, mesenchymal stromal cells can uptake and subsequently slowly release PTX. This may lead to potential new tools to increase efficacy of cancer therapy.
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- 2011
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21. Pitfalls of whole exome sequencing in undefined clinical conditions with a suspected genetic etiology
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Giada Moresco, Ornella Rondinone, Alessia Mauri, Jole Costanza, Carlo Santaniello, Patrizia Colapietro, Emanuele Micaglio, Giovanni Marfia, Chiara Pesenti, Federico Grilli, Berardo Rinaldi, Elisabetta Prada, Giulietta Scuvera, Roberta Villa, Maria Francesca Bedeschi, Monica Rosa Miozzo, Donatella Milani, and Laura Fontana
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Genetics ,Molecular Biology ,Biochemistry - Abstract
Whole-Exome Sequencing (WES) is a valuable tool for the molecular diagnosis of patients with a suspected genetic condition. In complex and heterogeneous diseases, the interpretation of WES variants is more challenging given the absence of diagnostic handles and other reported cases with overlapping clinical presentations.To describe candidate variants emerging from trio-WES and possibly associated with the clinical phenotype in clinically heterogeneous conditions.We performed WES in ten patients from eight families, selected because of the lack of a clear clinical diagnosis or suspicion, the presence of multiple clinical signs, and the negative results of traditional genetic tests.Although we identified ten candidate variants, reaching the diagnosis of these cases is challenging, given the complexity and the rarity of these syndromes and because affected genes are already associated with known genetic diseases only partially recapitulating patients' phenotypes. However, the identification of these variants could shed light into the definition of new genotype-phenotype correlations. Here, we describe the clinical and molecular data of these cases with the aim of favoring the match with other similar cases and, hopefully, confirm our diagnostic hypotheses.This study emphasizes the major limitations associated with WES data interpretation, but also highlights its clinical utility in unraveling novel genotype-phenotype correlations in complex and heterogeneous undefined clinical conditions with a suspected genetic etiology.
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- 2022
22. Basal serum level of Δ4-androstenedione reflects the ovaries’ ability to respond to stimulation in IVF cycles: setting up a new reliable index of both ovarian reserve and response
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Emanuele Garzia, Valentina Galiano, Laura Guarnaccia, Giovanni Marfia, Giulia Murru, Ellade Guermandi, Jennifer Riparini, Patrizia Sulpizio, and Anna Maria Marconi
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Anti-Mullerian Hormone ,Follicular Atresia ,Ovary ,Androstenedione ,Reproducibility of Results ,Obstetrics and Gynecology ,Fertilization in Vitro ,General Medicine ,Ovarian Follicle ,Ovulation Induction ,Reproductive Medicine ,Androgens ,Genetics ,Humans ,Female ,Follicle Stimulating Hormone ,Ovarian Reserve ,Gonadotropins ,Genetics (clinical) ,Developmental Biology - Abstract
Adequate androgen levels are necessary for regular follicular growth, progression beyond the pre-antral stage, and prevention of follicular atresia. The main purpose of this study was to investigate whether baseline androgen levels had a predictive value on stimulation outcomes in IVF cycles. The secondary purpose was to compare the possible predictive value of androgens with that of already known markers.The study included 91 infertile patients aged 30-45 years awaiting the first IVF cycle. All women underwent the same stimulation protocol and the same starting dose of recombinant FSH. As stimulation outcomes, the number of follicles recruited, estradiol and progesterone levels on the day of trigger, the total dose of gonadotropins administered, and the number of oocytes collected were recorded. Multiple linear regression and multivariate logistic regression were used to evaluate the significant predictive value of the variables for response to controlled ovarian stimulation (COS). By studying the reliability of different markers, an attempt was made to develop a single index with the highest predictive value.Pearson's correlation revealed a statistically significant inverse correlation between oocytes collected and age (r = - 0.333, p 0.001) and a positive correlation with AMH (anti-müllerian hormone) (r = 0.360, p 0.001), antral follicle count (AFC) (r = 0.639, p 0.001), and androstenedione (Δ4-A) (r = 0.359, p 0.001). No significant correlation was reported with FSH (r = - 0.133, p = 0.207) and total testosterone (r = 0.180, p = 0.088). In COS good responders, the G-index (= AMH ng/mL*AFC/Δ4-A ng/dL) revealed a significantly higher level (p 0.001) than AMH, AFC, and Δ4-A alone.Baseline serum Δ4-A, presumably crucial for ensuring a regular follicular growth, is a reliable marker of ovarian response to stimulation. Since the ovarian capacity to respond to gonadotropins does not depend exclusively on the presence of follicles, we suggest a new index, the G-index, able to contemplate both the ovarian reserve and the Δ4-A level.
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- 2022
23. Space flight and central nervous system: Friends or enemies? Challenges and opportunities for neuroscience and neuro‐oncology
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Giovanni Marfia, Stefania Elena Navone, Laura Guarnaccia, Rolando Campanella, Marco Locatelli, Monica Miozzo, Pietro Perelli, Giulio Della Morte, Leonardo Catamo, Pietro Tondo, Carmelo Campanella, Marco Lucertini, Giuseppe Ciniglio Appiani, Angelo Landolfi, and Emanuele Garzia
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neuroscience ,Central Nervous System ,Cellular and Molecular Neuroscience ,Settore MED/27 - Neurochirurgia ,Weightlessness ,aerospace medicine ,brain tumors ,central nervous system ,microgravity ,Astronauts ,Humans ,Space Flight - Abstract
Space environment provides many challenges to pilots, astronauts, and space scientists, which are constantly subjected to unique conditions, including microgravity, radiations, hypoxic condition, absence of the day and night cycle, etc. These stressful stimuli have the potential to affect many human physiological systems, triggering physical and biological adaptive changes to re-establish the homeostatic state. A particular concern regards the risks for the effects of spaceflight on the central nervous system (CNS), as several lines of evidence reported a great impact on neuroplasticity, cognitive functions, neurovestibular system, short-term memory, cephalic fluid shift, reduction in motor function, and psychological disturbances, especially during long-term missions. Aside these potential detrimental effects, the other side of the coin reflects the potential benefit of applicating space-related conditions on Earth-based life sciences, as cancer research. Here, we focused on examining the effect of real and simulated microgravity on CNS functions, both in humans and in cellular models, browsing the different techniques to experience or mime microgravity on-ground. Increasing evidence demonstrate that cancer cells, and brain cancer cells in particular, are negatively affected by microgravity, in terms of alteration in cell morphology, proliferation, invasion, migration, and apoptosis, representing an advancing novel side of space-based investigations. Overall, deeper understandings about the mechanisms by which space environment influences CNS and tumor biology may be promisingly translated into many clinical fields, ranging from aerospace medicine to neuroscience and oncology, representing an enormous pool of knowledge for the implementation of countermeasures and therapeutic applications.
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- 2022
24. Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma
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Laura Guarnaccia, Giovanni Marfia, Matteo Maria Masseroli, Stefania Elena Navone, Melissa Balsamo, Manuela Caroli, Silvia Valtorta, Rosa Maria Moresco, Rolando Campanella, Emanuele Garzia, Laura Riboni, Marco Locatelli, Guarnaccia, L, Marfia, G, Masseroli, M, Navone, S, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Garzia, E, Riboni, L, and Locatelli, M
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Brain tumor ,Angiogenesi ,Cancer Research ,angiogenesis ,Angiogenesis ,brain tumors ,glioblastoma ,metformin ,Oncology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Review ,RC254-282 ,oncology_oncogenics - Abstract
Simple Summary Glioblastoma is the most aggressive primary brain tumor, with the highest incidence and the worst prognosis. Life expectancy from diagnosis remains dismal, at around 15 months, despite surgical resection and treatment with radiotherapy and chemotherapy. Given the aggressiveness of the tumor and the inefficiency of the treatments adopted to date, the scientific research investigates innovative therapeutic approaches. Importantly, angiogenesis represents one of the main features of glioblastoma, becoming in the last few years a major candidate for target therapy. Metformin, a well-established therapy for type 2 diabetes, offered excellent results in preventing and fighting tumor progression, particularly against angiogenic mechanisms. Therefore, the purpose of this review is to summarize and discuss experimental evidence of metformin anti-cancer efficacy, with the aim of proposing this totally safe and tolerable drug as add-on therapy against glioblastoma. Abstract Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.
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- 2022
25. The 'Parachute' Technique for the Endoscopic Repair of High-Flow Anterior Skull-Base CSF Leaks
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Giulio Bertani, Claudio Guastella, Giulia Letizia Gribaudi, Andrea Di Cristofori, Giorgio Fiore, Giovanni Marfia, Leonardo Tariciotti, Giovanna Mantovani, Giorgio Carrabba, and Marco Locatelli
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medicine.medical_specialty ,Leak ,rhinorrhea ,Sphenoidal sinus ,business.industry ,Fistula ,Cribriform plate ,medicine.disease ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Etiology ,Cribriform ,Medicine ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Objective This study aims to assess the feasibility and reliability of our endoscopic trans-nasal technique for the repair of cribriform and sellar high-flow cerebrospinal fluid (CSF) leaks. Methods A comparison between patients suffering from high-flow rhinorrhea and treated through a free grafting endoscopic technique or the “parachute” technique, our nasal packing proposal, was performed. Results Thirty-three patients were included. The mean age was 52 years (range: 36–68 years). The etiology of the CSF leaks was iatrogenic in 16 cases (48.5%), traumatic in 5 cases (15.2%), spontaneous in 11 cases (33.3%), and related to anterior skull base tumors in 1 case (3%). The bone defect affected the sphenoidal sinus in 20 cases (60.6%), the cribriform plate of the ethmoid in 10 cases (30.3%), and both the sphenoid and ethmoid in 3 cases (9.1%). The mean size of bone defects was 8.5 ± 3.9 mm. The median follow-up was 28 (64) months. A CSF leak recurrence occurred in no cases treated with the parachute technique and in 3 cases that underwent conventional endoscopic treatments. The CSF leak recurrences were associated with 2 iatrogenic and 1 post-traumatic fistula. All the CSF leak recurrences underwent the parachute technique, not showing second recurrences. Conclusions Our results suggest that the parachute technique is simple, safe, and effective. We recommend it as an alternative treatment to vascular flaps for the treatment of high-flow and recurrent fistulas.
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- 2021
26. Anterolateral Approach for Retrostyloid Superior Parapharyngeal Space Schwannomas Involving the Jugular Foramen Area: A 20-Year Experience
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Mattia Del Maestro, Alvaro Campero, Matias Baldoncini, Maximiliano Nuñez, Sabino Luzzi, Giovanni Marfia, Stefania Elena Navone, Alice Giotta Lucifero, Samer K. Elbabaa, and Renato Galzio
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Adult ,Male ,Accessory nerve ,Schwannoma ,Neurosurgical Procedures ,Young Adult ,03 medical and health sciences ,Parapharyngeal Space ,0302 clinical medicine ,Jugular Foramina ,Supine Position ,Parapharyngeal space ,Humans ,Medicine ,Cranial Nerve Neoplasms ,Aged ,Neurilemoma ,business.industry ,Incidence ,Anatomy ,Middle Aged ,medicine.disease ,Neurovascular bundle ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Glossopharyngeal Nerve Diseases ,Pharyngeal Muscles ,cardiovascular system ,Pharynx ,Female ,Surgery ,Neurology (clinical) ,Tomography, X-Ray Computed ,business ,Sternocleidomastoid muscle ,Neurilemmoma ,030217 neurology & neurosurgery ,Jugular foramen - Abstract
Background Schwannomas encompassing the superior parapharyngeal space are challenging lesions because of the anatomical complexity of this region and the frequent involvement of the neurovascular structures of the jugular foramen. The purpose of this study is to report the technical aspects and the advantages of the anterolateral approach, here proposed for schwannomas of this complex area. Methods The main steps of the anterolateral approach are described in detail, along with the results of a consecutive series of 38 patients with a retrostyloid superior parapharyngeal schwannoma involving the jugular foramen operated on by means of this route between 1999 and 2019. Results The supine position is generally preferred. The medial border of the sternocleidomastoid muscle, mastoid tip, and superior nuchal line are the landmarks for the hockey-stick skin incision. The accessory nerve is retrieved and mobilized cranially. Detachment of the sternocleidomastoid, digastric, and nuchal muscles allows for a 180° exposure of the extracranial side of the jugular foramen. Three working corridors, namely the pre-carotid, pre-jugular, and retro-jugular, allow access to the deeper part of the jugular foramen area and the superior parapharyngeal space. In the present series, a gross total resection was achieved in 89.4% of the patients. Three recurrences occurred after an average follow-up of 80.5 ± 51 months. Conclusions The anterolateral approach is highly effective in the treatment of retrostyloid superior parapharyngeal space schwannomas involving the jugular foramen. Its simplicity of execution, versatility, and very low morbidity are among its main strengths.
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- 2019
27. Determinants of outcome of transsphenoidal surgery for Cushing disease in a single-centre series
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Marco Locatelli, Giulio Bertani, Elisa Sala, Andreea Liliana Serban, Giulia Rodari, Rita Indirli, Maura Arosio, Claudia Giavoli, Giorgio Carrabba, Emanuele Ferrante, G. Del Sindaco, Giulia Carosi, Giovanna Mantovani, and Giovanni Marfia
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Adenoma ,Adult ,Male ,medicine.medical_specialty ,genetic structures ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Disease ,Neurosurgical Procedures ,Young Adult ,03 medical and health sciences ,remission ,0302 clinical medicine ,Endocrinology ,Pituitary adenoma ,medicine ,Humans ,Pituitary Neoplasms ,Pituitary ACTH Hypersecretion ,Retrospective Studies ,Transsphenoidal surgery ,Surgical team ,hypercortisolism ,business.industry ,Cushing disease ,transsphenoidal surgery ,Middle Aged ,bacterial infections and mycoses ,medicine.disease ,Cushing Disease ,Surgery ,Single centre ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Neurosurgery ,business - Abstract
First-line therapy of Cushing disease (CD) is transsphenoidal surgery (TSS) aimed to obtain a complete removal of the pituitary adenoma and remission of disease. To analyse the surgical outcome of patients with CD who underwent TSS in our Centre. Retrospective analysis on patients with CD who underwent TSS between 1990 and 2016. We analysed 102 TSS that included: 84 first TSS and 18 second and third TSS. The overall remission rate after surgery was 76.5%, with a significant higher percentage of remitted patients after the first TSS compared to the subsequent TSS (82% vs 50%, p = 0.014). The remission after the first TSS was significantly higher when performed by a dedicated surgical team (DST) (89.8% vs 71% p = 0.04) and when the immunohistochemical examination confirmed the adrenocorticotropic adenoma (87% vs 55%, p = 0.04). Neuroradiological findings influenced the surgical outcome in a non-significant manner. Post-TSS complications were reported in 32 patients, with no significant variation when TSS was performed by DST. In case of reintervention, remission of disease was obtained in 72.7% of microadenoma, while no remitted patients were observed in case of macroadenomas. The DST did not significantly improve the outcome. Cushing disease is characterized by a broad spectrum of neuroradiological presentation. Despite the availability of a DST make the TSS a safe and effective first-line treatment among all these patients, a precise pre-treatment evaluation is needed in order to define the aim of neurosurgery and to schedule the management of recurrent disease.
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- 2019
28. Loss of consciousness in a helicopter pilot as plausible first sign of insulinoma: a case report
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Simone, Pratò, Vittoria, Didonna, Francesca, Garletti, Giovanni, Marfia, Adriano, Barbaresi, Fabrizio, Palumbo, Emanuele, Garzia, Giuseppe, Ciniglio Appiani, Luciano, Riboldi, and Luisella, Vigna
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Male ,Pancreatic Neoplasms ,Pilots ,Aircraft ,Consciousness ,Humans ,Insulinoma ,Unconsciousness ,Middle Aged - Abstract
A 50-year-old man who worked as a helicopter rescue pilot transiently lost consciousness while piloting a helicopter rescue. In the diagnostic process, all tests for the main possible differential diagnoses of loss of consciousness (cardiological and neurological) were performed and yielded normal results. Blood chemistry tests revealed recurrent fasting hypoglycemia and Chromogranin A was at the upper limit of normal. Fine needle aspiration guided by endoscopic ultrasonography was used to diagnose insulinoma-type neuroendocrine tumor of the pancreas. According to the Italian policies, the occupational physician aims to maintain professional skills without neglecting flight safety. A careful analysis of the relationship between the characteristics of the state of health of the aviator and his specific work needs was carried out, and he was given the opportunity to continue working as a rescue pilot thanks to medical therapies associated with organizational interventions in the workplace.
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- 2021
29. The Genetic Landscape of Human Glioblastoma and Matched Primary Cancer Stem Cells Reveals Intratumour Similarity and Intertumour Heterogeneity
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Paolo Rampini, Giovanni Marfia, Rolando Campanella, Laura Guarnaccia, Jole Costanza, Nicola Fusco, Marco Locatelli, Chiara Pesenti, Andrea Terrasi, Laura Fontana, Monica Miozzo, Silvia Tabano, Stefania Elena Navone, Silvana Guarneri, and Rosamaria Silipigni
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Genome instability ,lcsh:Internal medicine ,Monosomy ,Article Subject ,Angiogenesis ,T cell ,Chromosome ,Cancer ,Cell Biology ,Disease ,Biology ,medicine.disease ,medicine.anatomical_structure ,medicine ,Cancer research ,Stem cell ,lcsh:RC31-1245 ,Molecular Biology ,Research Article - Abstract
Glioblastoma (GBM) is the most malignant human brain tumour, characterized by rapid progression, invasion, intense angiogenesis, high genomic instability, and resistance to therapies. Despite countless experimental researches for new therapeutic strategies and promising clinical trials, the prognosis remains extremely poor, with a mean survival of less than 14 months. GBM aggressive behaviour is due to a subpopulation of tumourigenic stem-like cells, GBM stem cells (GSCs), which hierarchically drive onset, proliferation, and tumour recurrence. The morbidity and mortality of this disease strongly encourage exploring genetic characteristics of GSCs. Here, using array-CGH platform, we investigated genetic and genomic aberration profiles of GBM parent tumour (n=10) and their primarily derived GSCs. Statistical analysis was performed by using R software and complex heatmap and corrplot packages. Pearson correlation and K-means algorithm were exploited to compare genetic alterations and to group similar genetic profiles in matched pairs of GBM and derived GSCs. We identified, in both GBM and matched GSCs, recurrent copy number alterations, as chromosome 7 polysomy, chromosome 10 monosomy, and chromosome 9p21deletions, which are typical features of primary GBM, essential for gliomagenesis. These observations suggest a condition of strong genomic instability both in GBM as GSCs. Our findings showed the robust similarity between GBM mass and GSCs (Pearson corr.≥0.65) but also highlighted a marked variability among different patients. Indeed, the heatmap reporting Gain/Loss State for 21022 coding/noncoding genes demonstrated high interpatient divergence. Furthermore, K-means algorithm identified an impairment of pathways related to the development and progression of cancer, such as angiogenesis, as well as pathways related to the immune system regulation, such as T cell activation. Our data confirmed the preservation of the genomic landscape from tumour tissue to GSCs, supporting the relevance of this cellular model to test in vitro new target therapies for GBM.
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- 2019
30. Correlation of Preoperative Von Willebrand Factor with Magnetic Resonance Imaging Perfusion and Permeability Parameters as Predictors of Prognosis in Glioblastoma
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Stefania Elena Navone, Rolando Campanella, Paolo Rampini, Laura Guarnaccia, Antonella Costa, Paul Summers, Giovanni Marfia, Marco Locatelli, and Fabio Martino Doniselli
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Male ,medicine.medical_specialty ,Angiogenesis ,Urology ,Malignancy ,03 medical and health sciences ,0302 clinical medicine ,Von Willebrand factor ,von Willebrand Factor ,Blood plasma ,medicine ,Humans ,Aged ,Retrospective Studies ,Blood Volume ,medicine.diagnostic_test ,biology ,Brain Neoplasms ,business.industry ,Reflux ,Brain ,Magnetic resonance imaging ,Middle Aged ,Prognosis ,medicine.disease ,Cerebral blood flow ,Cerebrovascular Circulation ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Surgery ,Neurology (clinical) ,Glioblastoma ,business ,Perfusion ,Biomarkers ,Magnetic Resonance Angiography ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Background Angiogenesis has been shown to be strictly related to tumor malignancy. Glioblastoma (GBM) is highly vascularized and von Willebrand Factor (VWF) plays a potent proangiogenic role. Dynamic contrast-enhanced and dynamic susceptibility contrast magnetic resonance imaging (MRI) represent a widely accepted method to assess GBM microvasculature. Our aim was to investigate the correlation between plasma VWF:Ag, permeability, and perfusion MRI parameters and examine their potential in predicting GBM patient prognosis. Methods We retrospectively analyzed preoperative dynamic contrast-enhanced, dynamic susceptibility contrast MRI, and VWF:Ag level of 26 patients with GBM. We assessed the maximum values of relative cerebral blood flow and volume, volume transfer constant Ktrans, plasma volume (Vp) and reflux rate constant between fractional volume of the extravascular space and blood plasma (Kep). Nonparametric Mann-Whitney test and Kaplan-Meier survival analyses were conducted and a P value Results The median VWF:Ag value was 248 IU/dL and the median follow-up duration was about 13 months. We divided patients according to low-VWF:Ag and high-VWF:Ag and we found significant differences in the median follow-up duration (19 months vs. 10 months; P = 0.04) and in Ktrans (0.31/minute vs. 0.53/minute; P = 0.02), and Kep (1.79/minute vs. 3.89/minute; P = 0.005) values. The cumulative 1-year survival was significantly shorter in patients with high-VWF:Ag and high-Kep compared with patients with low-VWF:Ag and low-Kep (37.5% vs. 68%; P = 0.05). Conclusions These findings, in a small group of patients, suggest a role for VWF:Ag, similar to Ktrans, and Kep as a prognostic indicator of postoperative survival of patients with GBM.
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- 2019
31. Significance and Prognostic Value of The Coagulation Profile in Patients with Glioblastoma: Implications for Personalized Therapy
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Giovanni Marfia, Chiara Gaudino, Laura Riboni, R. Campanella, Nicla La Verde, Nora Bettinardi, Marco Locatelli, Paolo Rampini, Stefania Elena Navone, Manuela Caroli, and Laura Guarnaccia
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Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Brain tumor ,Kaplan-Meier Estimate ,Fibrinogen ,Fibrin Fibrinogen Degradation Products ,Hemoglobins ,Leukocyte Count ,03 medical and health sciences ,0302 clinical medicine ,Von Willebrand factor ,Internal medicine ,von Willebrand Factor ,Fibrinolysis ,D-dimer ,Meningeal Neoplasms ,medicine ,Humans ,Aged ,Prothrombin time ,medicine.diagnostic_test ,biology ,Brain Neoplasms ,business.industry ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Partial Thromboplastin Time ,Surgery ,Neurology (clinical) ,Glioblastoma ,Meningioma ,business ,030217 neurology & neurosurgery ,Partial thromboplastin time ,medicine.drug - Abstract
Coagulation is an important aspect of the vascular microenvironment in which brain tumors evolve. Patients with tumor often show aberrant coagulation and fibrinolysis activation. In particular, glioblastoma (GBM), the most aggressive primary brain tumor, is associated with a state of hypercoagulability, and venous thromboembolism is a common complication of this cancer and its treatment. Our study aims to investigate the clinical and prognostic significance of routine laboratory tests to assess the coagulative state of patients with brain tumors, to identify potential new prognostic factors and targets for personalized therapy.Blood samples were collected from patients with GBM (n = 58) and patients with meningioma (MNG, n = 22), before any treatment. The parameters analyzed were prothrombin time (PT), activated partial thromboplastin time (aPTT), D dimer (DD), fibrinogen, von Willebrand factor (VWF), leukocyte count, and hemoglobin levels.Plasma levels of PT and aPTT were significantly reduced in GBMs compared with MNGs (P0.05), whereas DD, VWF:Ag levels, and leukocyte count were significantly higher in GBMs than in MNGs (P0.01). Furthermore, we observed that patients with GBM with reduced PT and aPTT and high levels of DD and VWF, defined as hypercoagulable patients, showed reduced overall survival (P0.05) compared with nonhypercoagulable patients.Our data support the assumption that patients with GBM show a plasma hypercoagulable profile and that coagulation profile is related to adverse outcome in patients with GBM. If confirmed, hypercoagulability could play an important role as a prognostic factor of the disease and in the decision of an antithrombotic prophylaxis.
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- 2019
32. A Frailty-Adjusted Stratification Score to Predict Surgical Risk, Post-Operative, Long-Term Functional Outcome, and Quality of Life after Surgery in Intracranial Meningiomas
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Leonardo Tariciotti, Giorgio Fiore, Sara Carapella, Luigi Gianmaria Remore, Luigi Schisano, Stefano Borsa, Mauro Pluderi, Marco Canevelli, Giovanni Marfia, Manuela Caroli, Marco Locatelli, and Giulio Bertani
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Cancer Research ,Oncology ,meningioma ,prognostic score ,skull base surgery ,frailty index ,quality of life ,functional assessment - Abstract
Object: To investigate those parameters affecting early and follow-up functional outcomes in patients undergoing resection of meningiomas and to design a dedicated predictive score, the Milan Bio(metric)-Surgical Score (MBSS) is hereby presented. Methods: Patients undergoing transcranial surgery for intracranial meningiomas were included. The most significant parameters in the regression analyses were implemented in a patient stratification score and were validated by testing its classification consistency with a clinical–radiological grading scale (CRGS), Milan complexity scale (MCS), and Charlson Comorbidity Index (CCI) scores. Results: The ASA score, Frailty index, skull base and posterior cranial fossa locations, a diameter of >25 mm, and the absence of a brain–tumour interface were predictive of early post-operative deterioration and were collected in MBSS Part A (AUC: 0.965; 95%C.I. 0.890–1.022), while the frailty index, posterior cranial fossa location, a diameter of >25 mm, a edema/tumour volume index of >2, dural sinus invasion, DWI hyperintensity, and the absence of a brain–tumour interface were predictive of a long-term unfavourable outcome and were collected in MBSS Part B (AUC: 0.877; 95%C.I. 0.811–0.942). The score was consistent with CRGS, MCS, and CCI. Conclusion: Patients’ multi-domain evaluation and the implementation of frailty indexes might help predict the perioperative complexity of cases; the functional, clinical, and neurological early outcomes; survival; and overall QoL after surgery.
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- 2022
33. Decreased serum level of sphingosine‐1‐phosphate: a novel predictor of clinical severity in COVID‐19
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Fabrizio Palumbo, Alessandra Barassi, Rolando Campanella, Davide Chiumello, Michele Mondoni, Giuseppe Ciniglio Appiani, Stefania Elena Navone, Stefano Centanni, Laura Guarnaccia, Monica Miozzo, Emanuele Garzia, Laura Riboni, Laura Fontana, Marco Locatelli, and Giovanni Marfia
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Medicine (General) ,Apolipoprotein B ,Anemia ,QH426-470 ,Fibrinogen ,Gastroenterology ,intensive care unit ,sphingosine‐1‐phosphate ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,R5-920 ,COVID‐19 ,Internal medicine ,Lactate dehydrogenase ,medicine ,Genetics ,prognostic biomarker ,biology ,business.industry ,Albumin ,medicine.disease ,Ferritin ,Coronavirus ,030104 developmental biology ,chemistry ,biology.protein ,Molecular Medicine ,Biomarker (medicine) ,lipids (amino acids, peptides, and proteins) ,Lymphocytopenia ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The severity of coronavirus disease 2019 (COVID‐19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine‐1‐phosphate (S1P) along with severity markers, in COVID‐19 patients. One hundred eleven COVID‐19 patients and forty‐seven healthy subjects were included. The severity of COVID‐19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil‐to‐lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C‐reactive protein (CRP), and D‐dimer. Serum S1P level was inversely associated with COVID‐19 severity, being significantly correlated with CRP, LDH, ferritin, and D‐dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient’s outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID‐19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID‐19.
- Published
- 2021
34. Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics
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Laura Guarnaccia, Stefania E. Navone, Matteo M. Masseroli, Melissa Balsamo, Manuela Caroli, Silvia Valtorta, Rosa M. Moresco, Rolando Campanella, Luigi Schisano, Giorgio Fiore, Valentina Galiano, Emanuele Garzia, Giuseppe C. Appiani, Marco Locatelli, Laura Riboni, Giovanni Marfia, Guarnaccia, L, Navone, S, Masseroli, M, Balsamo, M, Caroli, M, Valtorta, S, Moresco, R, Campanella, R, Schisano, L, Fiore, G, Galiano, V, Garzia, E, Appiani, G, Locatelli, M, Riboni, L, and Marfia, G
- Subjects
Cancer Research ,glioblastoma ,metformin ,brain tumors ,angiogenesis ,Oncology ,angiogenesi ,brain tumor - Abstract
Simple Summary Glioblastoma is the most common and malignant primary brain tumor, with a median survival of around 14 months. The aggressiveness of glioblastoma is due to intense cell proliferation, angiogenesis, invasiveness, genetic instability, resistance to therapies and high frequency of relapses. These features render glioblastoma almost incurable, considered an extreme therapeutic challenge. In the last few decades, it has been observed a reduced cancer incidence in diabetic patients treated with metformin, an oral hypoglycemic drug. The reported ability of metformin to arrest cancer cell growth in in vitro and in vivo experimental tumor models, have suggested the possibility to reconsider metformin as an anti-cancer add-on therapy, but further investigations about molecular mechanisms and optimal therapeutic regimens are needed. Here, we tested the efficacy of metformin against primary glioblastoma endothelial cells, responsible for tumor angiogenesis, invasiveness and resistance to therapy, reporting promising results and advancing a novel target of metformin, the "sphingolipid rheostat". Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. Methods: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. Results: Data resulting revealed a time- and mu-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. Conclusions: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.
- Published
- 2022
35. Inflammatory interactions between degenerated intervertebral discs and microglia: Implication of sphingosine-1-phosphate signaling
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Mauro Pluderi, Jean Ouellet, Laura Riboni, Stefano Borsa, Laura Guarnaccia, Mauro Alini, Marco Locatelli, Lisbet Haglund, Chiara Gaudino, Chiara Cordiglieri, Paolo Rampini, Roberta Gualtierotti, Rolando Campanella, Giovanni Marfia, Sabino Luzzi, Giuseppe Ciniglio Appiani, and Stefania Elena Navone
- Subjects
Male ,Intervertebral Disc Degeneration ,Nitric Oxide ,Cell Line ,chemistry.chemical_compound ,Mice ,Sphingosine ,medicine ,Conditioned medium ,Animals ,Humans ,Orthopedics and Sports Medicine ,Sphingosine-1-phosphate ,Neuroinflammation ,Microglia ,Chemistry ,Chemotaxis ,Intervertebral disc ,Receptor Cross-Talk ,Middle Aged ,Sphingolipid ,Cell biology ,Crosstalk (biology) ,medicine.anatomical_structure ,Cellular Microenvironment ,Female ,Lysophospholipids - Abstract
The etiology of intervertebral disc degeneration is largely unknown, but local neuroinflammation may exert a crucial role through activation of cells as microglia and pro-inflammatory cytokines production. We aimed to compare the effect of degenerated and normal intervertebral disc microenvironment on microglial cells and the potential role of sphingosine-1-phosphate, a pro-inflammatory sphingolipid, in their crosstalk. Human degenerated intervertebral discs (Pfirrmann grade IV) were obtained at surgery for spondylolisthesis. Normal intervertebral discs were collected from cadaveric normal lumbar spines. Normal and degenerated-intervertebral discs were kept in culture to obtain media conditioning. Then, microglial cells were cocultured with conditioned media and viability, proliferation, migration, chemotaxis, and inflammatory gene expression were evaluated. The results demonstrate that conditioned media from degenerated intervertebral discs activate microglial cells, increasing chemotaxis, migration, and pro-inflammatory mediators release to a great extent than normal discs. In addition, we show that the administration of sphingosine-1-phosphate to normal intervertebral disc/microglia coculture mimicked degenerative effects. Interestingly, sphingosine-1-phosphate content in conditioned media from degenerated discs was significantly higher than that from normal ones. In addition, FTY720, a functional antagonist of sphingosine-1-phosphate, potently inhibited the effect of degenerated intervertebral discs on microglial inflammatory factor transcription and migration. Our data report, for the first time, that sphingosine-1-phosphate is involved as signal in the microenvironment of human degenerated intervertebral discs. Sphingosine-1-phosphate signaling modulation by FTY720 may induce beneficial effects in counteracting microglial activation during intervertebral disc degeneration.
- Published
- 2020
36. Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks
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Rolando Campanella, Laura Riboni, Giovanni Marfia, Loubna Abdel Hadi, Stefania Elena Navone, and Laura Guarnaccia
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Angiogenesis ,Cancer Microenvironment ,Review ,Biology ,chemistry.chemical_compound ,Immune system ,Sphingosine ,Neoplasms ,medicine ,Tumor Microenvironment ,Neoplasm ,cancer ,Animals ,Humans ,Sphingosine-1-phosphate ,lcsh:QH301-705.5 ,Tumor microenvironment ,glioblastoma ,Cancer ,Biological Transport ,General Medicine ,medicine.disease ,chemistry ,lcsh:Biology (General) ,Cancer research ,sphingosine-1-phosphate ,Neoplastic Stem Cells ,cancer hallmarks ,Lysophospholipids ,Glioblastoma ,Signal Transduction - Abstract
As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular focus on glioblastoma, representative of a highly aggressive and deleterious neoplasm in humans. First, we highlight recent advances and emerging concepts for how tumor cells and different recruited normal cells contribute to the sphingosine-1-phosphate enrichment in the cancer microenvironment. Then, we describe and discuss how sphingosine-1-phosphate signaling contributes to favor cancer hallmarks including enhancement of proliferation, stemness, invasion, death resistance, angiogenesis, immune evasion and, possibly, aberrant metabolism. We also discuss the potential of how sphingosine-1-phosphate control mechanisms are coordinated across distinct cancer microenvironments. Further progress in understanding the role of S1P signaling in cancer will depend crucially on increasing knowledge of its participation in the tumor microenvironment.
- Published
- 2020
37. Serum Sphingosine-1-Phosphate as Novel Prognostic and Predictive Biomarker for COVID-19 Severity and Morbidity and Its Implications in Clinical Management
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Laura Riboni, Laura Fontana, Stefania Elena Navone, Davide Chiumello, Emanuele Garzia, Alessandra Barassi, Rolando Campanella, Michele Mondoni, Laura Guarnaccia, Fabrizio Palumbo, Giovanni Marfia, Giuseppe Ciniglio Appiani, Stefano Centanni, Marco Locatelli, and Monica Miozzo
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medicine.medical_specialty ,Apolipoprotein B ,biology ,business.industry ,Proportional hazards model ,Lymphocyte ,Albumin ,Fibrinogen ,Intensive care unit ,law.invention ,Ferritin ,medicine.anatomical_structure ,APOM ,law ,Internal medicine ,medicine ,biology.protein ,business ,medicine.drug - Abstract
Background: Since December 2019, COVID-19 has widely spread throughout the world, causing thousands of deaths. Clinical characteristics of COVID-19 patients have been widely reported, but significative disease-associated biomarkers are needed. We aimed to evaluate the prognostic power of circulating sphingosine-1-phosphate (S1P) in COVID-19, to propose S1P as a novel prognostic and predictive biomarker. Methods: Clinical and blood parameters were investigated in 111 COVID-19 patients (COV) and 47 healthy subject (HLT), with a particular focus on patients who required intensive care unit (ICU) admission. We measured serum levels of S1P and its main transporter apolipoprotein M (apoM) by ELISA assay. Correlation with clinical and blood parameters were performed by Pearson correlations. Univariable and multivariable regression analysis were performed to assess the interaction between clinically significant factors and ICU admission. Further, Cox regression was used to evaluate the prognostic power of S1P for ICU admission and mortality. Findings: We reported statistically significant alterations of several blood parameters in COV, as an increase of white blood cells, neutrophil-to-lymphocyte ratio, ferritin, D-dimer and fibrinogen, and a decrease in hemoglobin, lymphocyte count and total proteins. Our major finding is the drop of serum S1P level in COV, strongly associated with the decrease of red blood cells, the major source of plasmatic S1P, and both apoM and albumin, the most important transporters of circulating S1P. The multivariable regression analysis revealed that S1P is the most important predictor for ICU admission (OR:39·45, [95%CI:1·51-1031·60]; p=0·027), and Cox proportional-hazards model demonstrated a high power of S1P in predicting patient’s outcome. Interpretation: COVID-19 patients showed a drastic decrease of serum S1P, suggesting that circulating S1P levels may be clinically used as negative biomarkers to predict severity/mortality of COVID-19. Taken together, our results suggest that restoring S1P at physiological level may represent a novel therapeutic strategy. Funding: Italian Ministry of Health. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement:This prospective, case-control study was approved by the Ethic Committee of Ospedale San Paolo in Milan, Lombardy, Italy (COST Action n.2020/ST/057).
- Published
- 2020
38. Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology
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Nicla La Verde, Giorgio Carrabba, Laura Riboni, Rolando Campanella, Laura Guarnaccia, Elena Trombetta, Antonella Costa, Marco Locatelli, Paolo Rampini, Stefania Elena Navone, Giovanna Mantovani, Giovanni Marfia, Chiara Gaudino, Chiara Cordiglieri, Sabino Luzzi, Manuela Caroli, Campanella, R, Guarnaccia, L, Cordiglieri, C, Trombetta, E, Caroli, M, Carrabba, G, La Verde, N, Rampini, P, Gaudino, C, Costa, A, Luzzi, S, Mantovani, G, Locatelli, M, Riboni, L, Navone, S, and Marfia, G
- Subjects
Adult ,Blood Platelets ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Platelet Membrane Glycoproteins ,Immunofluorescence ,Flow cytometry ,03 medical and health sciences ,angiogenesis ,0302 clinical medicine ,Biomarkers, Tumor ,medicine ,Humans ,Platelet ,Receptor ,Sphingosine-1-Phosphate Receptors ,lcsh:QH301-705.5 ,Cells, Cultured ,S1PR1 ,Aged ,platelet ,Vascular Endothelial Growth Factor Receptor-1 ,Neovascularization, Pathologic ,medicine.diagnostic_test ,Brain Neoplasms ,Cell growth ,business.industry ,Communication ,glioblastoma ,Endothelial Cells ,angiogenesi ,General Medicine ,Middle Aged ,Prognosis ,Vascular Endothelial Growth Factor Receptor-2 ,Peptide Fragments ,Adenosine Diphosphate ,Blot ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,lcsh:Biology (General) ,platelets ,sphingosine-1-phosphate ,Female ,business ,030217 neurology & neurosurgery - Abstract
Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network’s complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.
- Published
- 2020
39. A bidirectional crosstalk between glioblastoma and brain endothelial cells potentiates the angiogenic and proliferative signaling of sphingosine-1-phosphate in the glioblastoma microenvironment
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Laura Guarnaccia, Rolando Campanella, Giovanni Marfia, Loubna Abdel Hadi, Stefania Elena Navone, V. Anelli, Cristina Tringali, Laura Riboni, Vasile Urechie, Francesco Moccia, and Matteo Beretta
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0301 basic medicine ,Angiogenesis ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Movement ,Sphingosine ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Humans ,Sphingosine-1-phosphate ,Protein Kinase Inhibitors ,neoplasms ,Molecular Biology ,Cell Proliferation ,Tumor microenvironment ,Neovascularization, Pathologic ,Cell growth ,Cell Membrane ,Brain ,Endothelial Cells ,Cell Biology ,Coculture Techniques ,Rats ,nervous system diseases ,Endothelial stem cell ,Phosphotransferases (Alcohol Group Acceptor) ,Receptors, Lysosphingolipid ,Crosstalk (biology) ,030104 developmental biology ,chemistry ,Cancer research ,Lysophospholipids ,Signal transduction ,Glioblastoma ,Signal Transduction - Abstract
Glioblastoma is one of the most malignant, angiogenic, and incurable tumors in humans. The aberrant communication between glioblastoma cells and tumor microenvironment represents one of the major factors regulating glioblastoma malignancy and angiogenic properties. Emerging evidence implicates sphingosine-1-phosphate signaling in the pathobiology of glioblastoma and angiogenesis, but its role in glioblastoma-endothelial crosstalk remains largely unknown. In this study, we sought to determine whether the crosstalk between glioblastoma cells and brain endothelial cells regulates sphingosine-1-phosphate signaling in the tumor microenvironment. Using human glioblastoma and brain endothelial cell lines, as well as primary brain endothelial cells derived from human glioblastoma, we report that glioblastoma-co-culture promotes the expression, activity, and plasma membrane enrichment of sphingosine kinase 2 in brain endothelial cells, leading to increased cellular level of sphingosine-1-phosphate, and significant potentiation of its secretion. In turn, extracellular sphingosine-1-phosphate stimulates glioblastoma cell proliferation, and brain endothelial cells migration and angiogenesis. We also show that, after co-culture, glioblastoma cells exhibit enhanced expression of S1P1 and S1P3, the sphingosine-1-phosphate receptors that are of paramount importance for cell growth and invasivity. Collectively, our results envision glioblastoma-endothelial crosstalk as a multi-compartmental strategy to enforce pro-tumoral sphingosine-1-phosphate signaling in the glioblastoma microenvironment.
- Published
- 2018
40. Mechanical loading of intervertebral disc modulates microglia proliferation, activation, and chemotaxis
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Giovanni Marfia, Moira Paroni, Matteo Beretta, Sibylle Grad, Mauro Alini, Laura Guarnaccia, Stefania Elena Navone, Chiara Cordiglieri, Mauro Pluderi, Marco Locatelli, Marianna Peroglio, Rolando Campanella, and Paolo Rampini
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Interleukin-1beta ,Biomedical Engineering ,Intervertebral Disc Degeneration ,Nitric Oxide ,Sensitivity and Specificity ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Downregulation and upregulation ,Nerve Growth Factor ,medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,Intervertebral Disc ,Cells, Cultured ,Cell Proliferation ,Inflammation ,Microglia ,biology ,Tumor Necrosis Factor-alpha ,Chemistry ,Chemotaxis ,Interleukin ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Nerve growth factor ,Cellular Microenvironment ,Culture Media, Conditioned ,biology.protein ,Cattle ,Tumor necrosis factor alpha ,Stress, Mechanical ,030217 neurology & neurosurgery ,Neurotrophin - Abstract
Summary Objective The aim of the study is to assess the effects of the neuroinflammatory microenvironment of a mechanically-induced degenerating intervertebral disc (IVD) on neuroinflammatory like cells such as microglia, in order to comprehend the role of microglial cells in degenerative disc disease. Methods Bovine caudal IVDs were kept in culture in an ex vivo bioreactor under high frequency loading and limited nutrition or in free swelling conditions as control samples. Conditioned media (CM) were collected, analysed for cytokine and neurotrophin content and applied to microglial cells for neuroinflammatory activation assessment. Results Degenerative conditioned medium (D-CM) induced a higher production of interleukin (IL)-8, nerve growth factor (NGF), interferon (IFN)-γ, IL-17 from IVD cells than unloaded control conditioned medium (U-CM). Upon 48 h of co-incubation with microglia, D-CM stimulated microglia proliferation, activation, with increased expression of ionized calcium binding adaptor molecule 1 (IBA1) and CD68, and chemotaxis. Moreover, an increment of nitrite production was observed. Interestingly, D-CM caused an upregulation of IL-1β, IL-6, tumour necrosis factor α (TNFα), inducible NO synthase (iNOS), IBA1, and vascular endothelial growth factor (VEGF) genes in microglia. Similar results were obtained when microglia were treated with the combination of the measured cytokines. Conclusions Our findings show that in IVD degenerative microenvironment, IL-8, NGF, IFN-γ, IL-17 drive activation of microglia in the spinal cord and increase upregulation of neuroinflammatory markers. This, in turn, enhances the inflammatory milieu within IVD tissues and in the peridiscal space, aggravating the cascade of degenerative events. This study provides evidence for an important role of microglia in maintaining IVD neuroinflammatory microenvironment and probably inducing low back pain.
- Published
- 2018
41. Angiogenesis in human brain tumors: screening of drug response through a patient-specific cell platform for personalized therapy
- Author
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Alessandro Cherubini, Francesco Maria Crisà, Elena Trombetta, Laura Guarnaccia, Laura Riboni, Laura Fontana, Monica Miozzo, Rolando Campanella, Marco Locatelli, Chiara Cordiglieri, Paolo Rampini, Manuela Caroli, Stefania Elena Navone, and Giovanni Marfia
- Subjects
0301 basic medicine ,Bevacizumab ,Angiogenesis ,Cell ,lcsh:Medicine ,Angiogenesis Inhibitors ,Vascular permeability ,Article ,Flow cytometry ,Neovascularization ,03 medical and health sciences ,Tumor Cells, Cultured ,medicine ,Humans ,Precision Medicine ,lcsh:Science ,Aged ,Aged, 80 and over ,Multidisciplinary ,Temozolomide ,Neovascularization, Pathologic ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,Sunitinib ,lcsh:R ,Endothelial Cells ,Middle Aged ,nervous system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,lcsh:Q ,Drug Screening Assays, Antitumor ,medicine.symptom ,Glioblastoma ,business ,medicine.drug - Abstract
Gliomas are the most common brain tumors, with diverse biological behaviour. Glioblastoma (GBM), the most aggressive and with the worst prognosis, is characterized by an intense and aberrant angiogenesis, which distinguishes it from low-grade gliomas (LGGs) and benign expansive lesions, as meningiomas (MNGs). With increasing evidence for the importance of vascularization in tumor biology, we focused on the isolation and characterization of endothelial cells (ECs) from primary GBMs, LGGs and MNGs. Gene expression analysis by Real-Time PCR, immunofluorescence and flow cytometry analysis, tube-like structures formation and vascular permeability assays were performed. Our results showed a higher efficiency of ECs to form a complex vascular architecture, as well as a greater impairment of a brain blood barrier model, and an overexpression of pro-angiogenic mediators in GBM than in LGG and MNG. Furthermore, administration of temozolomide, bevacizumab, and sunitinib triggered a different proliferative, apoptotic and angiogenic response, in a dose and time-dependent manner. An increased resistance to temozolomide was observed in T98G cells co-cultured in GBM-EC conditioned media. Therefore, we developed a novel platform to reproduce tumor vascularization as “disease in a dish”, which allows us to perform screening of sensitivity/resistance to drugs, in order to optimize targeted approaches to GBM therapy.
- Published
- 2018
42. Enhanced phosphorylation of sphingosine and ceramide sustains the exuberant proliferation of endothelial progenitors in Kaposi sarcoma
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Claudia Carenza, Lucia Brambilla, Silvia Della Bella, F. Calcaterra, Loubna Abdel Hadi, Giovanni Marfia, and Laura Riboni
- Subjects
0301 basic medicine ,Ceramide ,Immunology ,Nerve Tissue Proteins ,Biology ,Ceramides ,03 medical and health sciences ,Paracrine signalling ,chemistry.chemical_compound ,Sphingosine ,Ceramide kinase ,Humans ,Immunology and Allergy ,Sphingosine-1-phosphate ,Phosphorylation ,Progenitor cell ,Autocrine signalling ,Sarcoma, Kaposi ,Cells, Cultured ,Cell Proliferation ,RNA-Binding Proteins ,Cell Differentiation ,Cell Biology ,Cell biology ,Endothelial stem cell ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,chemistry ,Endothelium, Vascular ,Lysophospholipids ,Signal Transduction - Abstract
Endothelial colony-forming cells (ECFCs), a unique endothelial stem cell population, are highly increased in the blood of Kaposi sarcoma (KS) patients. KS-derived ECFCs (KS-ECFCs) are also endowed with increased proliferative and vasculogenic potential, thus suggesting that they may be precursors of KS spindle cells. However, the mechanisms underlying the increased proliferative activity of KS-ECFCs remain poorly understood. Sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) are metabolically interconnected sphingoid mediators crucial to cell proliferation. Here, we investigated the metabolism, release, and proliferative effects of S1P and C1P in KS-ECFCs compared with control ECFCs (Ct-ECFCs). Metabolic studies by cell labeling, chromatographic analyses, and digital autoradiography revealed that S1P and C1P biosynthesis and S1P secretion are all efficient processes in KS-ECFCs, more efficient in KS-ECFCs than Ct-ECFCs. Quantitative PCR analyses demonstrated a significantly higher ceramide kinase and sphingosine kinase-2 expression in KS-ECFCs. Notably, also the expression of S1P1 and S1P3 receptors was augmented in KS-ECFCs. Accordingly, treatment with exogenous C1P or S1P induced a significant, concentration-dependent stimulation of KS-ECFC proliferation, but was almost completely ineffective in Ct-ECFCs. Hence, we identified C1P and S1P as autocrine/paracrine proliferative signals in KS-ECFCs. A better understanding of the mechanisms that enhance S1P/C1P formation in KS-ECFCs may yield effective therapeutic modalities.
- Published
- 2017
43. Practical Management of Cardiovascular Comorbidities in Rheumatoid Arthritis
- Author
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Giovanni Marfia, Francesca Ingegnoli, Roberta Gualtierotti, and Nicola Ughi
- Subjects
030203 arthritis & rheumatology ,medicine.medical_specialty ,Accelerated atherosclerosis ,business.industry ,Psychological intervention ,Disease ,030204 cardiovascular system & hematology ,medicine.disease ,Rheumatology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Rheumatoid arthritis ,Internal medicine ,Physical therapy ,Immunology and Allergy ,Medicine ,Practical approach/CME article ,business ,Intensive care medicine ,Risk assessment ,Subclinical infection - Abstract
Cardiovascular (CV) comorbidities are a frequent extra-articular manifestation of rheumatoid arthritis (RA). Cardiovascular disease (CVD) with accelerated atherosclerosis is a major cause of morbidity and mortality in patients with RA. Subclinical CVD may be present since the early phase of RA. Not only traditional but also non-traditional CV risk factors are involved in the pathogenesis of RA-related CVD. Due to the lack of specifically designed randomized clinical trials, it is still unclear which tools to use to perform CV risk assessment, how to interpret the results and which interventions are appropriate in RA patients both to prevent and to manage CVD. Based on the available evidence, we propose a practical approach.
- Published
- 2017
44. Mass spectrometry-based assay for the molecular diagnosis of glioma: concomitant detection of chromosome 1p/19q codeletion, and IDH1, IDH2, and TERT mutation status
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Laura Fontana, Giovanni Marfia, Chiara Pesenti, Letterio Runza, Stefano Ferrero, Monica Miozzo, Silvia Tabano, Emanuela Veniani, Leda Paganini, Rosamaria Silipigni, Silvana Guerneri, Silvano Bosari, Maura Menghi, and Manuela Caroli
- Subjects
0301 basic medicine ,Sanger sequencing ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,1p/19q Codeletion ,medicine.disease ,SNP genotyping ,Transplantation ,03 medical and health sciences ,symbols.namesake ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Glioma ,medicine ,symbols ,business ,Genotyping ,Fluorescence in situ hybridization ,Comparative genomic hybridization - Abstract
// Chiara Pesenti 1, 2 , Leda Paganini 1, 2 , Laura Fontana 1 , Emanuela Veniani 2 , Letterio Runza 2 , Stefano Ferrero 2, 3 , Silvano Bosari 1, 2 , Maura Menghi 4 , Giovanni Marfia 5, 6 , Manuela Caroli 6 , Rosamaria Silipigni 7 , Silvana Guerneri 7 , Silvia Tabano 1 and Monica Miozzo 1, 2 1 Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy 2 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 3 Department of Biomedical, Surgical and Dental Sciences, Universita degli Studi di Milano, Milan, Italy 4 Diatech Pharmacogenetics, Jesi, Italy 5 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy 6 Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy 7 Laboratory of Medical Genetics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy Correspondence to: Silvia Tabano, email: silvia.tabano@unimi.it Keywords: glioma, 1p/19q LOH, massARRAY, IDH, TERT Received: March 13, 2017 Accepted: June 19, 2017 Published: July 08, 2017 ABSTRACT The World Health Organization recently revised the diagnosis of glioma, to integrate molecular parameters, including IDH mutations and codeletion (loss of heterozygosity; LOH) of chromosome arms 1p/19q, into the definitions of adult glioma histological subtypes. Mutations in the TERT promoter may also be useful for glioma diagnosis and prognosis. The integration of molecular markers into routine diagnosis requires their rapid and reliable assessment. We propose a MassARRAY (MS)-based test that can identify 1p/19q codeletion using quantitative SNP genotyping and, simultaneously, characterize hotspot mutations in the IDH1 , IDH2 , and TERT genes in tumor DNA. We determined the reliability of the MS approach testing 50 gliomas and comparing the MS results with those obtained by standard methods, such as short tandem repeat genotyping, array comparative genomic hybridization (array-CGH) and Fluorescence In Situ Hybridization (FISH) for 1p/19q codeletion and Sanger sequencing for hotspots mutations. The results indicate that MS is suitable for the accurate, rapid, and cost-effective evaluation of chromosome deletions combined with hotspot mutation detection. This MS approach could be similarly exploited in evaluation of LOH in other situations of clinical and/or research importance.
- Published
- 2017
45. The Adipose Mesenchymal Stem Cell Secretome Inhibits Inflammatory Responses of Microglia: Evidence for an Involvement of Sphingosine-1-Phosphate Signalling
- Author
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Laura Riboni, Monica Miozzo, Vincenzo Levi, Roberta Gualtierotti, Paolo Rampini, Rolando Campanella, Loubna Abdel Hadi, Valeria Berno, Giovanni Marfia, Moira Paroni, Francesca Ingegnoli, Jens Geginat, Lorenzo Fassina, Carlo Tremolada, Matteo Beretta, and Stefania Elena Navone
- Subjects
Adult ,Lipopolysaccharides ,Male ,0301 basic medicine ,Proteome ,Sphingosine kinase ,Down-Regulation ,Adipose tissue ,Inflammation ,Cell Separation ,Biology ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,Sphingosine ,medicine ,Humans ,Sphingosine-1-phosphate ,Cell Proliferation ,Microglia ,Fingolimod Hydrochloride ,Chemotaxis ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,Middle Aged ,Cell biology ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Adipose Tissue ,chemistry ,Culture Media, Conditioned ,Immunology ,Cytokines ,Female ,Cytokine secretion ,Lysophospholipids ,medicine.symptom ,Signal Transduction ,Developmental Biology - Abstract
Central nervous system (CNS) inflammation is primarily driven by microglial cells which secrete proinflammatory cytokines and undergo proliferation upon activation, as it occurs in neurodegenerative diseases. Uncontrolled or prolonged CNS inflammation is potentially harmful and can result in cellular damage. Recently, many studies have focused on human adipose tissue as an attractive source of cytokines with immunosuppressive properties that potentially modulate inflammation. Our study aimed to evaluate if different methods of human tissue collection could affect adipose mesenchymal stem cell (ADSC)-derived cytokine secretion and investigate the effects of ADSC secretome in modulating microglia activation and the possible implication of sphingosine-1-phosphate (S1P) in these effects. Our results demonstrate that the conditioned medium (CM) of ADSCs isolated by two different processing methods (lipoaspirate and Lipogems) significantly inhibited the lipopolysaccharide (LPS)-induced effects on microglia activation, including microglial expression of CD68, cytokine secretion, proliferation, and migration. Pulse studies with radiolabeled sphingosine demonstrated that LPS treatment of resting microglia induced a significant increase of both cellular and extracellular S1P. Moreover, and of relevance, FTY720, a functional antagonist of S1P receptor, inhibited the multiple LPS-induced proinflammatory effects on microglia, and S1P suppressed the anti-inflammatory effect of ADSC-CM. This suggests that LPS-mediated microglial activation is countered by ADSC-CM through the modulation of sphingosine kinase/S1P signalling.
- Published
- 2016
46. Platelet-derived sphingosine-1-phosphate and inflammation: from basic mechanisms to clinical implications
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Rolando Campanella, Stefania Elena Navone, Loubna Abdel Hadi, Clara Di Vito, Giovanni Marfia, Maria Elisa Mancuso, and Laura Riboni
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Blood Platelets ,0301 basic medicine ,Anti-Inflammatory Agents ,Inflammation ,Biology ,03 medical and health sciences ,Paracrine signalling ,chemistry.chemical_compound ,Mediator ,Sphingosine ,Leukocytes ,medicine ,Humans ,Platelet ,Molecular Targeted Therapy ,Sphingosine-1-phosphate ,Platelet activation ,Autocrine signalling ,Biological Transport ,Thrombosis ,Hematology ,General Medicine ,Platelet Activation ,Cell biology ,Autocrine Communication ,030104 developmental biology ,chemistry ,Immunology ,Endothelium, Vascular ,Lysophospholipids ,medicine.symptom ,Signal Transduction - Abstract
Beyond key functions in hemostasis and thrombosis, platelets are recognized as key players of inflammation, an underlying feature of a variety of diseases. In this regard, platelets act as a circulating source of several pro- and anti-inflammatory molecules, which are secreted from their intracellular stores upon activation. Among them, mounting evidence highlights a crucial role of sphingosine-1-phosphate (S1P), a multifunctional sphingoid mediator. S1P-induced pleiotropic effects include those crucial in inflammatory processes, such as the maintenance of the endothelial barrier integrity, and leukocyte activation and recruitment at the injured site. This review outlines the peculiar features and molecular mechanisms that allow platelets for acting as a unique factory that produces and stores S1P in large quantities. A particular emphasis is placed on the autocrine and paracrine roles of S1P derived from the "inflamed" platelets, highlighting the role of its cross-talk with endothelial and blood cells involved in inflammation, and the mechanisms of its contribution to the development and progression of inflammatory diseases. Finally, potential clinical implications of platelet-derived S1P as diagnostic tool of inflammatory severity, and as therapeutic target in inflammation are discussed.
- Published
- 2016
47. Waldenstrom macroglobulinemia presenting as a bilateral subdural chronic hematoma
- Author
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Giulia Letizia Gribaudi, Elena Pirola, Andrea Franzini, Mauro Pluderi, Maria Goldaniga, Giovanni Marfia, and Paolo Rampini
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medicine.medical_specialty ,business.industry ,Waldenstrom macroglobulinemia ,General Medicine ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Hematoma ,Neurology ,Physiology (medical) ,Medicine ,Surgery ,Neurology (clinical) ,Radiology ,business ,030217 neurology & neurosurgery ,030215 immunology ,Bing–Neel syndrome - Published
- 2017
48. Personalized and translational approach for malignant brain tumors in the era of precision medicine: the strategic contribution of an experienced neurosurgery laboratory in a modern neurosurgery and neuro-oncology department
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Giovanni Marfia, Nicla La Verde, Barbara Zarino, Marco Locatelli, Chiara Gaudino, Stefania Elena Navone, Rolando Campanella, Angela Dele Rampini, Sabino Luzzi, Laura Riboni, Giorgio Carrabba, Manuela Caroli, and Laura Guarnaccia
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Proteomics ,medicine.medical_specialty ,Brain Neoplasms ,business.industry ,Neuro oncology ,Neurosurgery ,Translational research ,Precision medicine ,Patient care ,Patient management ,03 medical and health sciences ,0302 clinical medicine ,Neurology ,Health care ,medicine ,Humans ,Medical physics ,030212 general & internal medicine ,Neurology (clinical) ,Personalized medicine ,Precision Medicine ,Laboratories ,business ,030217 neurology & neurosurgery - Abstract
Personalized medicine (PM) aims to optimize patient management, taking into account the individual traits of each patient. The main purpose of PM is to obtain the best response, improving health care and lowering costs. Extending traditional approaches, PM introduces novel patient-specific paradigms from diagnosis to treatment, with greater precision. In neuro-oncology, the concept of PM is well established. Indeed, every neurosurgical intervention for brain tumors has always been highly personalized. In recent years, PM has been introduced in neuro-oncology also to design and prescribe specific therapies for the patient and the patient's tumor. The huge advances in basic and translational research in the fields of genetics, molecular and cellular biology, transcriptomics, proteomics, and metabolomics have led to the introduction of PM into clinical practice. The identification of a patient's individual variation map may allow to design selected therapeutic protocols that ensure successful outcomes and minimize harmful side effects. Thus, clinicians can switch from the "one-size-fits-all" approach to PM, ensuring better patient care and high safety margin. Here, we review emerging trends and the current literature about the development of PM in neuro-oncology, considering the positive impact of innovative advanced researches conducted by a neurosurgical laboratory.
- Published
- 2020
49. Aspirin Affects Tumor Angiogenesis and Sensitizes Human Glioblastoma Endothelial Cells to Temozolomide, Bevacizumab, and Sunitinib, Impairing Vascular Endothelial Growth Factor-Related Signaling
- Author
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Francesco Maria Crisà, Rolando Campanella, Laura Riboni, Stefania Elena Navone, Marco Locatelli, Giovanni Marfia, Luigi Schisano, Nicla La Verde, Manuela Caroli, Monica Miozzo, Paolo Rampini, Chiara Cordiglieri, and Laura Guarnaccia
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0301 basic medicine ,Vascular Endothelial Growth Factor A ,Angiogenesis ,Angiogenesis Inhibitors ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Sunitinib ,bcl-2-Associated X Protein ,Kinase ,Brain Neoplasms ,Anti-Inflammatory Agents, Non-Steroidal ,Drug Synergism ,Vascular endothelial growth factor ,Bevacizumab ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,medicine.drug ,Signal Transduction ,Cell Survival ,Blotting, Western ,Antineoplastic Agents ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,medicine ,Temozolomide ,Humans ,RNA, Messenger ,Protein kinase A ,Protein kinase B ,Antineoplastic Agents, Alkylating ,Mitogen-Activated Protein Kinase Kinases ,Vascular Endothelial Growth Factor Receptor-1 ,Aspirin ,business.industry ,Endothelial Cells ,Hypoxia-Inducible Factor 1, alpha Subunit ,Vascular Endothelial Growth Factor Receptor-2 ,030104 developmental biology ,chemistry ,Cancer research ,ras Proteins ,Surgery ,Neurology (clinical) ,business ,Glioblastoma ,Proto-Oncogene Proteins c-akt - Abstract
Background Glioblastoma (GBM) is the most common and fatal human brain tumor, with the worst prognosis. The aberrant microenvironment, enhanced by the activation of proangiogenic mediators such as hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and their downstream effectors, sustain GBM malignancy. Proangiogenic signaling represents an attractive chemotherapeutic target. Recent evidence suggests a therapeutic benefit from aspirin (acetylsalicylic acid, or ASA) intake in reducing risk and cancer progression. Methods In the present study, human primary GBM–endothelial cells (ECs) were used to ascertain whether ASA could inhibit angiogenesis and improve cell sensitivity to drugs. The impact of ASA was observed by measuring cell viability, tube-like structure formation, migration, VEGF production, and proliferative, proangiogenic, and apoptotic modulators expression, such as HIF-1α/VEGF/vascular endothelial growth factor receptor/(VEGFR)-1/VEGFR-2, Ras/mitogen-activated protein kinase kinase/extracellular signal–regulated kinase, phosphoinositide 3-kinase/AKT signaling axis, and Bcl-2-associated X protein/B-cell lymphoma 2 (BCL-2) ratio. Furthermore, we evaluated the effect of ASA alone or in combination with temozolomide (TMZ), bevacizumab (BEV), and sunitinib (SUN). Results Our data reported that ASA affected GBM-EC viability, tube-like structure formation, cell migration, and VEGF releasing in a dose-dependent manner and that combined treatments with TMZ, BEV, and SUN synergized to counteract proangiogenic cell ability. mRNA expression analysis displayed a marked effect of ASA in reducing VEGF, VEGFR-1, HIF-1α, RAS, mitogen-activated protein kinase kinase, AKT, and BCL-2, as well a combined anticancer effect of ASA together with TMZ, BEV, and SUN. Levels of HIF-1α, VEGFR-2, Bcl-2-associated X protein, and BCL-2 protein expression confirmed a positive trend. Conclusions ASA and antiangiogenic therapies showed synergetic anticancer efficacy in human primary GBM-ECs. Thus, the combination of conventional chemotherapy with ASA may offer a new strategy to counteract tumor malignancy.
- Published
- 2018
50. Spontaneous intracerebral hemorrhage as presentation of atypical central neurocytoma: the role of angiogenesis through the characterization of tumor endothelial cells
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Giovanni, Marfia, Elena, Pirola, Stefania Elena, Navone, Matteo, Beretta, Laura, Guarnaccia, Elena, Trombetta, Andrea, Franzini, Paolo, Rampini, and Rolando, Campanella
- Subjects
Adult ,Male ,Neovascularization, Pathologic ,Brain Neoplasms ,Endothelial Cells ,Humans ,Neurocytoma ,Cerebral Hemorrhage - Abstract
A 36-year-old white man presented with sudden-onset headache and rapid deterioration of consciousness. Computer tomography revealed a right capsular intra-parenchimal hemorrhage with an intraventricular component; therefore, emergency surgery was performed. Once the hematoma was evacuated, the cause of the hemorrhage was identified as a tumor mass and it was resected. Histopathological and immunohistochemical examinations of the surgical specimen disclosed a diagnosis of atypical central neurocytoma. By using a protocol recently set up in our laboratory, we succeeded in isolating and propagating, for the first time, human endothelial cells from central neurocytoma (CN-ECs). Different analyses revealed that isolated CN-ECs consist of a pure endothelial cell population, with the expression of endothelial markers (CD31, CD309/VEGFR2, CD105, eNOS) and with angiogenic properties, such as the uptake of LDL. Moreover, CN-ECs spontaneously organize in a vascular-like structure. The goal of this case report is to stress the need for further studies focused on understanding the causes of the onset of an intra-parenchimal hemorrhage in the presence of an atypical central neurocytoma in order to tailor treatments to each single patient and achieve the best clinical outcome.
- Published
- 2017
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