19 results on '"Biffoni, M"'
Search Results
2. [Diagnostic value of out-patient lymph node biopsy]
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Biffoni, M., Macrina, N., Amabile, M. I., Scipioni, P., Palmieri, A., Alessandro MATURO, La Gumina, G., Petulla, M., and Monti, M.
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Adult ,Aged, 80 and over ,Male ,Lymphoma ,Lymphoma, Non-Hodgkin ,Biopsy, Fine-Needle ,Middle Aged ,Prognosis ,Sensitivity and Specificity ,Predictive Value of Tests ,Ambulatory Care ,Humans ,Female ,Lymph Nodes ,Aged ,Retrospective Studies - Abstract
Authors review their outpatient lymph node biopsies in order to verify safety and diagnostic accuracy. They didn't observe any complication and in every case, the procedure provided the correct diagnosis. Lymph node biopsy is the procedure of choice to study the pharmacologic therapy non responsive lymph node pathology that is not surely defined by fine needle aspiration, as almost always in lymphomas.
- Published
- 2008
3. Human neural progenitor cells display limited cytotoxicity and increased oligodendrogenesis during inflammation [2]
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Ricci-Vitiani, L., Lombardi, D. G., Signore, M., Biffoni, M., Pallini, Roberto, Parati, E., Peschle, C., and De Maria Marchiano, Ruggero
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Inflammation ,Cultured ,Cells ,Cytotoxicity ,Stem Cells ,Animals ,Cells, Cultured ,Cytotoxicity, Immunologic ,Demyelinating Autoimmune Diseases, CNS ,Humans ,Mice ,Nerve Tissue Proteins ,Oligodendroglia ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,Cell Biology ,Demyelinating Autoimmune Diseases ,Immunologic ,Settore MED/04 - PATOLOGIA GENERALE ,CNS - Published
- 2007
4. ARS Component B: structural characterization, tissue expression and regulation of the gene and protein (SLURP-1) associated with Mal de Meleda
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Mastrangeli, R., Donini, S., Kelton, C. A., C. M., He, Bressan, A., Milazzo, F., Ciolli, V., Borrelli, F., Martelli, F., Biffoni, M., Serlupi Crescenzi, O., Serani, S., Micangeli, E., El Tayar, N., Vaccaro, Rosa, Renda, Tindaro Giuseppe, Lisciani, R., Rossi, M., and Papoian, R.
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Keratinocytes ,mal de meleda ,Mice, Inbred BALB C ,hyperkeratosis ,Molecular Structure ,Reverse Transcriptase Polymerase Chain Reaction ,slurp-1 ,Molecular Sequence Data ,ars component b ,keratinocytes ,Immunohistochemistry ,Urokinase-Type Plasminogen Activator ,Mice ,Keratoderma, Palmoplantar ,Animals ,Antigens, Ly ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Cells, Cultured - Abstract
The ARS Component B gene (EMBL ID: HSARS81S, AC: X99977) encodes a 9 kD non-glycosylated polypeptide (also known as SLURP-1, SwissProt/TrEMBL: P55000), a soluble member of the human Ly6/uPAR superfamily. ARS Component B gene mutations have been implicated in Mal de Meleda. In this study we show by immunohistochemistry that SLURP-1 (secreted Ly-6/uPAR related protein, the protein product of the ARS Component B gene) is localized to human skin, exocervix, gums, stomach and esophagus. In the epidermis, keratinocytes underlying the stratum corneum are highly positive for SLURP1 immunostaining and cultured keratinocytes secrete the expected 9 kD protein. Circulating SLURP1 is detected in human plasma and urine. In the mouse, expression is evident in skin, eye, whole lung, trachea, esophagus and stomach. Human ARS Component B mRNA expression is regulated by retinoic acid, epidermal growth factor and interferon-gamma. The tissue localization and the association with Mal de Meleda suggest that ARS Component B and its protein product SLURP1 are implicated in maintaining the physiological and structural integrity of the keratinocyte layers of the skin.
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- 2004
5. [In vitro effect of alpha-interferon and thymomodulin on natural killer activity in patients with AIDS-related complex]
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Marino PAROLI, Balsano, C., Valesini, G., Biffoni, M., Perrone, A., and Barnaba, V.
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Cytotoxicity, Immunologic ,Killer Cells, Natural ,Male ,AIDS-Related Complex ,Interferon Type I ,Humans ,Female ,In Vitro Techniques ,Thymus Extracts - Published
- 1988
6. [Indications, technics and results of lymphadenectomy in malignant tumors of the parotid and submandibular glands]
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Fp, Campana, Marchesi M, Domenico MASCAGNI, Tartaglia F, Biffoni M, and Corbellini L
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Submandibular Gland Neoplasms ,Evaluation Studies as Topic ,Lymphatic Metastasis ,Humans ,Lymph Node Excision ,Neck Dissection ,Neoplasm Recurrence, Local ,Salivary Gland Neoplasms ,Combined Modality Therapy ,Parotid Neoplasms - Published
- 1987
7. [Advantages and limits of tumescent anesthesia in outpatient surgery]
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Pasta, V., Urciuoli, P., Macrina, N., Amabile, M. I., Chiarini, S., Alessandro MATURO, Vergine, M., Santucci, E., Biffoni, M., Scipioni, P., and Monti, M.
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Adult ,Male ,Epinephrine ,Lidocaine ,Reproducibility of Results ,Middle Aged ,Bicarbonates ,Ambulatory Surgical Procedures ,Patient Satisfaction ,Humans ,Female ,Anesthetics, Local ,Anesthesia, Local ,Retrospective Studies - Abstract
The Authors report the results of the tumescent anesthesia in 187 patients submitted to various outpatient surgical procedures comparing with those in patients submitted to local anesthesia by direct infiltration.
8. Variability of treatment modalities and intensity in patients with severe haemophilia A on prophylaxis: results from the Italian national registry
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Lorenzo G. Mantovani, Adele Giampaolo, Francesca Abbonizio, Mauro Biffoni, Angelo Claudio Molinari, Giancarlo Castaman, Paolo Cortesi, Cortesi, P, Giampaolo, A, Abbonizio, F, Molinari, A, Castaman, G, Biffoni, M, and Mantovani, L
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,Haemophilia ,Hemophilia A ,Chemoprevention ,Severity of Illness Index ,Drug Administration Schedule ,Drug Costs ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,Humans ,In patient ,Registries ,Precision Medicine ,Prophylaxi ,Child ,FVIII consumption ,Factor VIII ,business.industry ,Age Factors ,Infant, Newborn ,Infant ,Hematology ,General Medicine ,medicine.disease ,Personalized medicine ,Regimen ,Italy ,Treatment modality ,030220 oncology & carcinogenesis ,Child, Preschool ,Severe haemophilia A ,Female ,National registry ,business ,030215 immunology - Abstract
Background: A shift from a standard to a personalized prophylaxis has been increasingly adopted in patients with severe haemophilia A (SHA). This approach has raised the likelihood of a significant variability in the prophylactic approaches and the relative Factor VIII (FVIII) consumptions. The aim of our study was to assess the treatment variability of SHA patients without inhibitors and on prophylaxis regimen in Italy. Material and methods: Data reported in the National Registry of Congenital Coagulopathies (NRCC) were analysed to assess treatment distribution within SHA patients without inhibitors, focussing on FVIII consumption in 2017, associated with prophylaxis regimen. The analysis was stratified based on age groups and Italian regions to describe the variability of FVIII consumption in Italy. Results: In 2017, the Registry reported the therapeutic plans of 1068 SHA patients without inhibitors on prophylaxis. The mean (95% CI) individual consumption ranges from 123 127 IU (99 736-146 518) in the age group 0-6 years to 345 000 IU (336 000-354 000) in the age group >20 years. A significant FVIII consumption variability was identified within the adult population. Regions with less than 50 patients reported the higher variability in mean FVIII consumption per patient-year within the different age groups. Similar difference in FVIII consumption variability was reported also in the age groups comparing “low,” “middle” and “high” patient volume regions. Discussion: A reliable estimation of FVIII consumption for patients’ treatment is necessary to manage and plan the appropriate budget and keep treatment's costs affordable. However, without the implementation of a methodology aiming to assess the overall value produced by these FVIII consumptions, the scenario will keep driven by FVIII consumptions, its costs and the budget available. An effort by haemophilic community, haemophilia treatment centres and institutions is required to develop and share this cultural shift in improving haemophilia management and assessment.
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- 2021
9. Multicentre harmonisation of a six-colour flow cytometry panel for naïve/memory T cell immunomonitoring
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Chiara Agrati, Belinda Palermo, Massimo Sanchez, Floriana Iacobone, Mauro Biffoni, Rita Casetti, Giorgio Fedele, Francesca Urbani, Valentina La Sorsa, Pasqualina Leone, Cristina Capuano, Marianna Nuti, Helena Stabile, Iole Macchia, Andrea Rozo Gonzalez, Filippo Belardelli, Carla Buccione, Giovanna Schiavoni, Ilaria Grazia Zizzari, Paola Rizza, Maria Carollo, Cinzia Fionda, Matilde Sinibaldi, Irene Ruspantini, Valentina Tirelli, Concetta Quintarelli, Aurelia Rughetti, Paola Nisticò, Roberta Maggio, Angela Gismondi, Stefania Morrone, Macchia, I., La Sorsa, V., Ruspantini, I., Sanchez, M., Tirelli, V., Carollo, M., Fedele, G., Leone, P., Schiavoni, G., Buccione, C., Rizza, P., Nistico, P., Palermo, B., Morrone, S., Stabile, H., Rughetti, A., Nuti, M., Zizzari, I. G., Fionda, C., Maggio, R., Capuano, C., Quintarelli, C., Sinibaldi, M., Agrati, C., Casetti, R., Rozo Gonzalez, A., Iacobone, F., Gismondi, A., Belardelli, F., Biffoni, M., and Urbani, F.
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CD4-Positive T-Lymphocytes ,0301 basic medicine ,Oncology ,Receptors, CCR7 ,medicine.medical_specialty ,CD3 Complex ,Article Subject ,Operating procedures ,Immunology ,T cells ,Color ,CD8-Positive T-Lymphocytes ,flow cytometry ,harmonization ,Immunophenotyping ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,T-Lymphocyte Subsets ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Observer Variation ,medicine.diagnostic_test ,business.industry ,General Medicine ,RC581-607 ,Clinical trial ,030104 developmental biology ,Lazio region ,medicine.anatomical_structure ,Italy ,030220 oncology & carcinogenesis ,Leukocytes, Mononuclear ,Leukocyte Common Antigens ,Immunologic diseases. Allergy ,business ,Observer variation ,Immunologic Memory ,Immunologic memory ,Memory T cell ,Biomarkers ,Research Article - Abstract
Background. Personalised medicine in oncology needs standardised immunological assays. Flow cytometry (FCM) methods represent an essential tool for immunomonitoring, and their harmonisation is crucial to obtain comparable data in multicentre clinical trials. The objective of this study was to design a harmonisation workflow able to address the most effective issues contributing to intra- and interoperator variabilities in a multicentre project. Methods. The Italian National Institute of Health (Istituto Superiore di Sanità, ISS) managed a multiparametric flow cytometric panel harmonisation among thirteen operators belonging to five clinical and research centres of Lazio region (Italy). The panel was based on a backbone mixture of dried antibodies (anti-CD3, anti-CD4, anti-CD8, anti-CD45RA, and anti-CCR7) to detect naïve/memory T cells, recognised as potential prognostic/predictive immunological biomarkers in cancer immunotherapies. The coordinating centre distributed frozen peripheral blood mononuclear cells (PBMCs) and fresh whole blood (WB) samples from healthy donors, reagents, and Standard Operating Procedures (SOPs) to participants who performed experiments by their own equipment, in order to mimic a real-life scenario. Operators returned raw and locally analysed data to ISS for central analysis and statistical elaboration. Results. Harmonised and reproducible results were obtained by sharing experimental set-up and procedures along with centralising data analysis, leading to a reduction of cross-centre variability for naïve/memory subset frequencies particularly in the whole blood setting. Conclusion. Our experimental and analytical working process proved to be suitable for the harmonisation of FCM assays in a multicentre setting, where high-quality data are required to evaluate potential immunological markers, which may contribute to select better therapeutic options.
- Published
- 2020
10. Laryngeal neuroendocrine tumor with elevated serum calcitonin: a diagnostic and therapeutic challenge. Case report and review of literature
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Tiziana Feola, Giulia Puliani, Franz Sesti, Roberta Modica, Marco Biffoni, Cira Di Gioia, Raffaella Carletti, Emanuela Anastasi, Valentina Di Vito, Roberta Centello, Andrea Lenzi, Andrea M. Isidori, Antongiulio Faggiano, Elisa Giannetta, Feola, T., Puliani, G., Sesti, F., Modica, R., Biffoni, M., Di Gioia, C., Carletti, R., Anastasi, E., Di Vito, V., Centello, R., Lenzi, A., Isidori, A. M., Faggiano, A., and Giannetta, E.
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0301 basic medicine ,Larynx ,Calcitonin ,Male ,medicine.medical_specialty ,calcium gluconate infusion test ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Case Report ,everolimus ,larynx ,medullary thyroid carcinoma ,neck ,neuroendocrine tumor ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Gastroenterology ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Humans ,Lymph node ,Laryngeal Neoplasms ,lcsh:RC648-665 ,medicine.diagnostic_test ,business.industry ,Thyroid ,everolimu ,Middle Aged ,medicine.disease ,Primary tumor ,Neuroendocrine Tumors ,030104 developmental biology ,medicine.anatomical_structure ,Fine-needle aspiration ,Differential diagnosis ,business - Abstract
Introduction: Laryngeal neuroendocrine neoplasms (NENs) are a rare group of NENs of the neck, which commonly show immunostaining for calcitonin. Laryngeal NENs with calcitonin hypersecretion and lymph node metastases represent a diagnostic and therapeutic challenge, which should be included in the differential diagnosis of medullary thyroid carcinoma (MTC). We report a complex case of laryngeal NEN with calcitonin hypersecretion and a review of the literature. Case Presentation: A 59-year-old man presented with dysphagia, dyspnea, and lateral cervical mass; he was a smoker. At first imaging, a laryngeal lesion with lateral cervical lymphadenopathies was found, and it resulted as a moderately differentiated neuroendocrine tumor (G2), Ki67 = 5%, positive for calcitonin. Increased levels of serum calcitonin (50 pg/ml) were found. The patient started somatostatin analogs for lesions positivity to somatostatin receptor-based imaging. After 5 months, the disease progressed at 18F-fluorodeoxyglucose (18F-FDG) PET-CT, and also new painful cutaneous lesions occurred. Considering high serum levels of calcitonin, differential diagnosis with MTC was required. Patient performed a thyroid color Doppler ultrasound, nodule fine needle aspiration, calcitonin dosage in fine needle washout fluid, and a calcium gluconate stimulation test. After multidisciplinary evaluation, we decided to perform a total thyroidectomy associated with lateral cervical lymphadenectomy and resection of skin metastases. No MTC was found. Two of the five resected lymph nodes, left upper parathyroid, and skin lesions were metastases of NEN G2, positive for calcitonin. After 2 months, new painful skin lesions occurred, and a target therapy with everolimus 10 mg/day was started. After 6 months of therapy, partial metabolic response with a reduction of 53.7% of radiotracer uptake at primary tumor was detected together with an improvement of patient's quality of life. Conclusions: The present case is the seventh described in the literature of laryngeal NEN associated with elevated serum calcitonin levels and the first case with parathyroid metastasis, suggesting the importance of a correct differential diagnosis between MTC and calcitonin-secreting laryngeal NEN, using an integrated approach of biochemistry and advanced imaging. This is also the first time that somatostatin analogs and then everolimus were used in this setting, resulting in clinical and partial metabolic response.
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- 2020
11. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells
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Roberto Pallini, Mauro Biffoni, Eugenio Parati, Giorgio Stassi, Ruggero De Maria, Giulio Maira, Luigi Maria Larocca, Matilde Todaro, Tonia Cenci, Lucia Ricci-Vitiani, Gloria Invernici, Ricci-Vitiani, L, Pallini, R, Biffoni, M, Todaro, M, Invernici, G, Cenci, T, Maira, G, Parati, EA, Stassi, G, Larocca, LM, and De Maria, R
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Endothelium ,Angiogenesis ,Transplantation, Heterologous ,Settore MED/27 - NEUROCHIRURGIA ,Mice, Transgenic ,Mice, SCID ,Biology ,Models, Biological ,Mice ,Vasculogenesis ,Neural Stem Cells ,Mice, Inbred NOD ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Lineage ,Vasculogenic mimicry ,glioblastoma, tumor vascularization ,In Situ Hybridization, Fluorescence ,Chromosome Aberrations ,Multidisciplinary ,Neovascularization, Pathologic ,Endothelial Cells ,Cell Differentiation ,Vascular endothelial growth factor B ,Endothelial stem cell ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Vascular endothelial growth factor C ,Tumor Markers, Biological ,Immunology ,Cancer research ,Endothelium, Vascular ,Glioblastoma ,Neoplasm Transplantation - Abstract
Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor(VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.
- Published
- 2010
12. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells
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Alfredo Pagliuca, Matilde Todaro, Marcello Maugeri-Saccà, Emanuela Pilozzi, A Di Benedetto, Marcella Mottolese, Francesca Sperati, Giulia Federici, M Patrizii, Stefano Piccolo, Chiara Moriconi, Giorgio Stassi, Rosanna Dattilo, Monica Bartucci, Marco Biffoni, R De Maria, Maria Ida Amabile, Bartucci, M, Dattilo, R, Moriconi, C, Pagliuca, A, Mottolese, M, Federici, G, Benedetto, AD, Todaro, M, Stassi, G, Sperati, F, Amabile, MI, Pilozzi, E, Patrizii, M, Biffoni, M, Maugeri-Saccà, M, Piccolo, S, and De Maria, R
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cancer stem cells ,TAZ ,Animals ,Biomarkers, Tumor ,Breast Neoplasms ,Cell Line, Tumor ,Disease-Free Survival ,Female ,Gene Expression Regulation, Neoplastic ,Humans ,Mice ,Neoplasm Metastasis ,Neoplasm Recurrence, Local ,Neoplastic Stem Cells ,Transcription Factors ,Xenograft Model Antitumor Assays ,Cancer Research ,Bioinformatics ,chemotherapy ,Metastasis ,taz ,breast cancer ,education.field_of_study ,Tumor ,Intracellular Signaling Peptides and Proteins ,Cell cycle ,Local ,metastasis ,Molecular Biology ,Genetics ,Stem cell ,Population ,Biology ,Cell Line ,breast cancer , cancer stem cells, TAZ ,Breast cancer ,Cancer stem cell ,Settore MED/04 - PATOLOGIA GENERALE ,medicine ,education ,Hippo signaling pathway ,Neoplastic ,Cancer ,medicine.disease ,Neoplasm Recurrence ,Gene Expression Regulation ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Cancer research ,Trans-Activators ,Biomarkers - Abstract
Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
- Published
- 2015
13. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer
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Matilde Todaro, Federica Francescangeli, M L De Angelis, Giovanni Sette, R De Maria, Giorgio Stassi, Tiziana Apuzzo, G Zapparelli, Paola Contavalli, Adriana Eramo, Ann Zeuner, Mauro Biffoni, Marta Baiocchi, Zeuner, A., Francescangeli, F., Contavalli, P., Zapparelli, G., Apuzzo, T., Eramo, A., Baiocchi, M., De Angelis, M., Biffoni, M., Sette, G., Todaro, M., Stassi, G., and De Maria, R.
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Lung Neoplasms ,Mice, SCID ,Pharmacology ,Piperazines ,Antineoplastic Agent ,Nitrophenols ,Mice ,Mice, Inbred NOD ,Carcinoma, Non-Small-Cell Lung ,Cytotoxic T cell ,Non-Small-Cell Lung ,education.field_of_study ,Sulfonamides ,Tumor ,Animals ,Antineoplastic Agents ,Biphenyl Compounds ,Cell Line, Tumor ,Cell Proliferation ,Cell Survival ,Female ,Humans ,Neoplastic Stem Cells ,Tumor Burden ,Xenograft Model Antitumor Assays ,bcl-X Protein ,Molecular Biology ,Cell Biology ,Stem cell ,Human ,medicine.drug ,Xenograft Model Antitumor Assay ,Population ,Biology ,SCID ,Sulfonamide ,Cell Line ,Cancer stem cell ,medicine ,education ,Lung cancer ,Piperazine ,Settore MED/04 - Patologia Generale ,Original Paper ,Nitrophenol ,Animal ,Cell growth ,Carcinoma ,medicine.disease ,Gemcitabine ,Lung Neoplasm ,Cell culture ,Biphenyl Compound ,Cancer research ,Inbred NOD ,Neoplastic Stem Cell - Abstract
Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.
- Published
- 2014
14. Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy
- Author
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Flora Iovino, Rosanna Dattilo, Giorgio Stassi, Monica Bartucci, Giulia Federici, Alice Turdo, Ruggero De Maria, Matilde Todaro, Marco Biffoni, Ann Zeuner, Todaro, M, Turdo, A, Bartucci, M, Iovino, F, Dattilo, R, Biffoni, M, Stassi, G, Federici, G, De Maria, R, and Zeuner, A
- Subjects
MAPK/ERK pathway ,Oncology ,Cancer Research ,medicine.medical_treatment ,Fluorescent Antibody Technique ,Apoptosis ,Mice, SCID ,Immunoenzyme Techniques ,Mice ,Cell Movement ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Cultured ,Blotting ,Anemia ,Flow Cytometry ,Tumor Cells ,TRIALS ,Disease Progression ,Neoplastic Stem Cells ,Female ,Western ,Signal Transduction ,medicine.drug ,STIMULATING AGENTS ,EXPRESSION ,medicine.medical_specialty ,Blotting, Western ,Antineoplastic Agents ,Breast Neoplasms ,SCID ,RECOMBINANT-HUMAN-ERYTHROPOIETIN, STIMULATING AGENTS, EXPRESSION, MORTALITY, TRIALS, ANEMIA, ALPHA, ALDH1 ,Breast cancer ,In vivo ,Internal medicine ,medicine ,Animals ,Humans ,Breast cancer, Cancer stem cells ,ALDH1 ,Erythropoietin ,Protein kinase B ,Cell Proliferation ,Settore MED/04 - Patologia Generale ,Chemotherapy ,business.industry ,MORTALITY ,Cancer ,RECOMBINANT-HUMAN-ERYTHROPOIETIN ,medicine.disease ,ALPHA ,Tumor progression ,Inbred NOD ,business - Abstract
Recombinant erythropoietin (EPO) analogs [erythropoiesis-stimulating agents (ESA)] are clinically used to treat anemia in patients with cancer receiving chemotherapy. After clinical trials reporting increased adverse events and/or reduced survival in ESA-treated patients, concerns have been raised about the potential role of ESAs in promoting tumor progression, possibly through tumor cell stimulation. However, evidence is lacking on the ability of EPO to directly affect cancer stem–like cells, which are thought to be responsible for tumor progression and relapse. We found that breast cancer stem–like cells (BCSC) isolated from patient tumors express the EPO receptor and respond to EPO treatment with increased proliferation and self-renewal. Importantly, EPO stimulation increased BCSC resistance to chemotherapeutic agents and activated cellular pathways responsible for survival and drug resistance. Specifically, the Akt and ERK pathways were activated in BCSC at early time points following EPO treatment, whereas Bcl-xL levels increased at later times. In vivo, EPO administration counteracted the effects of chemotherapeutic agents on BCSC-derived orthotopic tumor xenografts and promoted metastatic progression both in the presence and in the absence of chemotherapy treatment. Altogether, these results indicate that EPO acts directly on BCSC by activating specific survival pathways, resulting in BCSC protection from chemotherapy and enhanced tumor progression. Cancer Res; 73(21); 6393–400. ©2013 AACR.
- Published
- 2013
15. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis
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Francesco Dieli, Veronica Catalano, Gianfranco Cocorullo, Ruggero De Maria, Silvia Volpe, Giorgio Stassi, Flora Iovino, Mauro Biffoni, Gaspare Gulotta, Matilde Todaro, Tiziana Apuzzo, Miriam Gaggianesi, Antonina Benfante, Isabella Sperduti, Todaro, M, Gaggianesi, M, Catalano, V, Benfante, A, Iovino, F, Biffoni, M, Apuzzo, T, Sperduti, I, Volpe, S, Cocorullo, G, Gulotta, G, Dieli, F, De Maria, R, and Stassi, G
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CA15-3 ,Animals ,Biomarkers, Tumor ,Bone Morphogenetic Proteins ,Carcinogenesis ,Colonic Neoplasms ,Fibroblasts ,Humans ,Hyaluronan Receptors ,Mice, SCID ,Neoplasm Metastasis ,Neoplasm Proteins ,Neoplastic Stem Cells ,Phosphatidylinositol 3-Kinases ,Prognosis ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-met ,Signal Transduction ,Treatment Outcome ,Wnt Proteins ,Cellular Reprogramming ,Molecular Medicine ,Genetics ,Cell Biology ,Wnt Protein ,medicine.disease_cause ,Antigens, CD44 ,Metastasis ,Mice ,CD44 ,Carcinogenesi ,Phosphoinositide-3 Kinase Inhibitors ,Colonic Neoplasm ,Tumor ,biology ,Neoplasm Metastasi ,Fibroblast ,Hepatocyte growth factor ,Stem cell ,Human ,medicine.drug ,Prognosi ,Protein Kinase Inhibitor ,SCID ,Neoplasm Protein ,Cancer stem cell ,Settore MED/04 - PATOLOGIA GENERALE ,medicine ,Antigens ,Progenitor cell ,Settore MED/04 - Patologia Generale ,Animal ,Bone Morphogenetic Protein ,cancer, metastasis ,medicine.disease ,Settore MED/18 - Chirurgia Generale ,Immunology ,Cancer research ,biology.protein ,Neoplastic Stem Cell ,Phosphatidylinositol 3-Kinase ,Biomarkers - Abstract
SummaryCancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6− progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target.
- Published
- 2012
16. Proliferation state and polo-like kinase1 dependence of tumorigenic colon cancer cells
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Mauro Biffoni, Lucia Ricci Vitiani, Ruggero De Maria, Federica Francescangeli, Matilde Todaro, Ann Zeuner, M Patrizii, Alfredo Pagliuca, Simone Di Franco, Marta Baiocchi, Michele Signore, Giulia Federici, Francescangeli, F, Patrizii, M, Signore, M, Federici, G, Di Franco, S, Pagliuca, A, Baiocchi, M, Biffoni, M, Ricci Vitiani, L, Todaro, M, De Maria, R, and Zeuner, A.
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Colorectal cancer ,Cancer stem cells,colorectal cancer,cell proliferation,cell cycle ,Cell Cycle Proteins ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,AC133 Antigen ,RNA, Small Interfering ,0303 health sciences ,education.field_of_study ,Pteridines ,Cell Cycle ,Cell cycle ,Immunohistochemistry ,3. Good health ,Mitochondria ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Molecular Medicine ,Female ,Stem cell ,Population ,Transplantation, Heterologous ,Cell Growth Processes ,Biology ,Protein Serine-Threonine Kinases ,PLK1 ,03 medical and health sciences ,Cancer stem cell ,Antigens, CD ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,education ,Protein Kinase Inhibitors ,030304 developmental biology ,Glycoproteins ,Settore MED/04 - Patologia Generale ,Cell growth ,Cell Biology ,medicine.disease ,Tumor progression ,Immunology ,Cancer research ,Peptides ,Developmental Biology - Abstract
Tumor-initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibitors killed CD133+ colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133+ cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor-initiating cells. Quiescent CD133+ cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor-initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer.
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- 2012
17. EGFR inhibition abrogates Leiomyosarcoma cell chemoresistance through inactivation of survival pathways and impairment of CSC potential
- Author
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Cristina Colarossi, Lorenzo Memeo, Adriana Eramo, Valentina Salvati, Giovanni Sette, Enrico De Antoni, Paola Di Matteo, Katia Fecchi, Mauro Biffoni, Ruggero De Maria, Vincenzo Canzonieri, Vito D'Andrea, Michele Signore, Sette, G, Salvati, V, Memeo, L, Fecchi, K, Colarossi, C, Di Matteo, P, Signore, M, Biffoni, M, D'Andrea, V, De Antoni, E, Canzonieri, V, De Maria, R, and Eramo, A.
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Leiomyosarcoma ,Pathology ,Cellular differentiation ,Cancer Treatment ,lcsh:Medicine ,Tumor initiation ,Metastasis ,Mice ,Molecular Cell Biology ,Basic Cancer Research ,lcsh:Science ,Extracellular Signal-Regulated MAP Kinases ,Animals ,Cell Differentiation ,Cell Proliferation ,Cell Survival ,Drug Resistance, Neoplasm ,Female ,Humans ,Neoplasm Grading ,Neoplastic Stem Cells ,Phenotype ,Phosphoproteins ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-akt ,Quinazolines ,Receptor, Epidermal Growth Factor ,Signal Transduction ,Vincristine ,Xenograft Model Antitumor Assays ,Biochemistry, Genetics and Molecular Biology (all) ,Agricultural and Biological Sciences (all) ,Multidisciplinary ,Cell Death ,Gefitinib ,ErbB Receptors ,Oncology ,Medicine ,Oncology Agents ,Sarcoma ,Research Article ,medicine.medical_specialty ,EGFR ,Biology ,Cell Growth ,Side population ,Settore MED/04 - PATOLOGIA GENERALE ,Cancer stem cell ,medicine ,lcsh:R ,Mesenchymal stem cell ,Chemotherapy and Drug Treatment ,medicine.disease ,Embryonic stem cell ,Cancer research ,lcsh:Q - Abstract
BACKGROUND: Tumor cells with stem-like phenotype and properties, known as cancer stem cells (CSC), have been identified in most solid tumors and are presumed to be responsible for driving tumor initiation, chemoresistance, relapse, or metastasis. A subpopulation of cells with increased stem-like potential has also been identified within sarcomas. These cells are endowed with increased tumorigenic potential, chemoresistance, expression of embryonic markers, and side population(SP) phenotype. Leiomyosarcomas (LMS) are soft tissue sarcomas presumably arising from undifferentiated cells of mesenchymal origin, the Mesenchymal Stem Cells (MSC). Frequent recurrence of LMS and chemoresistance of relapsed patients may likely result from the failure to target CSC. Therefore, therapeutic cues coming from the cancer stem cell (CSC) field may drastically improve patient outcome. METHODOLOGY/PRINCIPAL FINDINGS: We expanded LMS stem-like cells from patient samples in vitro and examined the possibility to counteract LMS malignancy through a stem-like cell effective approach. LMS stem-like cells were in vitro expanded both as "tumor spheres" and as "monolayers" in Mesenchymal Stem Cell (MSC) conditions. LMS stem-like cells displayed MSC phenotype, higher SP fraction, and increased drug-extrusion, extended proliferation potential, self-renewal, and multiple differentiation ability. They were chemoresistant, highly tumorigenic, and faithfully reproduced the patient tumor in mice. Such cells displayed activation of EGFR/AKT/MAPK pathways, suggesting a possibility in overcoming their chemoresistance through EGFR blockade. IRESSA plus Vincristine treatment determined pathway inactivation, impairment of SP phenotype, high cytotoxicity in vitro and strong antitumor activity in stem-like cell-generated patient-like xenografts, targeting both stem-like and differentiated cells. CONCLUSIONS/SIGNIFICANCE: EGFR blockade combined with vincristine determines stem-like cell effective antitumor activity in vitro and in vivo against LMS, thus providing a potential therapy for LMS patients.
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- 2012
18. Isolation and characterization of CD146+ multipotent mesenchymal stromal cells
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Marta Baiocchi, Mauro Valtieri, Giada Tomaselli, Cesare Peschle, Massimo Negrini, Alessandro Fatica, Germana Castelli, Mauro Biffoni, Antonio Sorrentino, Manuela Ferracin, Sorrentino A., Ferracin M., Castelli G., Biffoni M., Tomaselli G., Baiocchi M., Fatica A., Negrini M., Peschle C., and Valtieri M.
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Cancer Research ,Time Factors ,Cellular differentiation ,Cell Culture Techniques ,Cell Separation ,Regenerative medicine ,education.field_of_study ,UMBILICAL-CORD ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Differentiation ,Hematology ,COLONY-STIMULATING FACTOR ,Cell biology ,RECEPTORS ,Phenotype ,medicine.anatomical_structure ,Intercellular Signaling Peptides and Proteins ,Stem cell ,GROWTH-FACTOR ,Stromal cell ,Blotting, Western ,Molecular Sequence Data ,Population ,CD146 Antigen ,Biology ,Cell Line ,Immunophenotyping ,Chondrocytes ,Genetics ,medicine ,Humans ,HEMATOPOIETIC STEM-CELLS ,HUMAN PERIPHERAL-BLOOD ,education ,Molecular Biology ,Cell Proliferation ,Gene Expression Profiling ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,IN-VITRO ,Microarray Analysis ,Chondrogenesis ,ENDOTHELIAL-CELLS ,MicroRNAs ,PROGENITOR CELLS ,Immunology ,Bone marrow ,Stromal Cells ,HUMAN BONE-MARROW - Abstract
Mesenchymal stromal cells (MSCs) represent a bone marrow (BM) population, classically defined by five functional properties: extensive proliferation, ability to differentiate into osteoblasts, chondrocytes, adipocytes, and stromal cells-supporting hematopoiesis. However, research progress in this area has been hampered by lack of suitable markers and standardized procedures for MSC isolation. We have isolated a CD146(+) multipotent MSC population from 20 human BM donors displaying the phenotype of self-renewing osteoprogenitors; an extensive 12-week proliferation; and the ability to differentiate in osteoblasts, chondrocytes, adipocytes, and stromal cells supporting hematopoiesis. Furthermore, the CD146(+) MSCs secrete a complex combination of growth factors (GFs) controlling hematopoietic stem cells (HSCs) function, while providing a >2-log increase in the long-term culture (LTC) colony output in 8-week LTC over conventional assays. The hematopoietic stromal function exhibited by the MSCs was further characterized by manipulating LTCs with the chemical inhibitors Imatinib or SU-5416, targeting two GF receptors (GFRs), KIT or VEGFR2/1, respectively. Both treatments similarly impaired LTC colony output, indicating key roles for these two GF/GFR interactions to support LTC-initiating cell activity. CD146(+) MSCs may thus represent a tool to explore the MSC-HSC cross-talk in an in vitro surrogate model for HSC "niches," and for regenerative therapy studies. In addition, the MSC microRNA (miRNA) expression profile was analyzed by microarrays in both basic conditions and chondrogenic differentiation. Our analysis revealed that several miRNAs are modulated during chondrogenesis, and many of their putative targets are genes involved in chondrogenic differentiation.
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- 2008
19. Identification and expansion of human colon-cancer-initiating cells
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Lucia Ricci-Vitiani, Dario Giuseppe Lombardi, Cesare Peschle, Emanuela Pilozzi, Mauro Biffoni, Matilde Todaro, Ruggero De Maria, RICCI-VITIANI L, LOMBARDI DG, PILOZZI E, BIFFONI M, TODARO M, PESCHLE C, and DE MARIA R
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AC133 Antigen ,Animals ,Antigens, CD ,Cell Differentiation ,Cell Line, Tumor ,Cell Proliferation ,Colonic Neoplasms ,Glycoproteins ,Humans ,Mice ,Mice, SCID ,Neoplasm Transplantation ,Neoplastic Stem Cells ,Peptides ,Phenotype ,Transplantation, Heterologous ,Multidisciplinary ,Colorectal cancer ,Cellular differentiation ,Population ,Tumor initiation ,Biology ,Colon carcinomas ,medicine.disease_cause ,SCID ,Cell Line ,Side population ,Cancer stem cell ,Settore MED/04 - PATOLOGIA GENERALE ,medicine ,Antigens ,education ,education.field_of_study ,Transplantation ,Heterologous ,Tumor ,Cancer ,medicine.disease ,CD ,Immunology ,Cancer research ,Carcinogenesis - Abstract
Colon carcinoma is the second most common cause of death from cancer. The isolation and characterization of tumorigenic colon cancer cells may help to devise novel diagnostic and therapeutic procedures. Although there is increasing evidence that a rare population of undifferentiated cells is responsible for tumour formation and maintenance, this has not been explored for colorectal cancer. Here, we show that tumorigenic cells in colon cancer are included in the high-density CD133+ population, which accounts for about 2.5% of the tumour cells. Subcutaneous injection of colon cancer CD133+ cells readily reproduced the original tumour in immunodeficient mice, whereas CD133- cells did not form tumours. Such tumours were serially transplanted for several generations, in each of which we observed progressively faster tumour growth without significant phenotypic alterations. Unlike CD133- cells, CD133+ colon cancer cells grew exponentially for more than one year in vitro as undifferentiated tumour spheres in serum-free medium, maintaining the ability to engraft and reproduce the same morphological and antigenic pattern of the original tumour. We conclude that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.
- Published
- 2007
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