79 results on '"Gianluca Storci"'
Search Results
2. Replicative senescence and high glucose induce the accrual of self-derived cytosolic nucleic acids in human endothelial cells
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Deborah Ramini, Angelica Giuliani, Katarzyna Malgorzata Kwiatkowska, Michele Guescini, Gianluca Storci, Emanuela Mensà, Rina Recchioni, Luciano Xumerle, Elisa Zago, Jacopo Sabbatinelli, Spartaco Santi, Paolo Garagnani, Massimiliano Bonafè, and Fabiola Olivieri
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Recent literature shows that loss of replicative ability and acquisition of a proinflammatory secretory phenotype in senescent cells is coupled with the build-in of nucleic acids in the cytoplasm. Its implication in human age-related diseases is under scrutiny. In human endothelial cells (ECs), we assessed the accumulation of intracellular nucleic acids during in vitro replicative senescence and after exposure to high glucose concentrations, which mimic an in vivo condition of hyperglycemia. We showed that exposure to high glucose induces senescent-like features in ECs, including telomere shortening and proinflammatory cytokine release, coupled with the accrual in the cytoplasm of telomeres, double-stranded DNA and RNA (dsDNA, dsRNA), as well as RNA:DNA hybrid molecules. Senescent ECs showed an activation of the dsRNA sensors RIG-I and MDA5 and of the DNA sensor TLR9, which was not paralleled by the involvement of the canonical (cGAS) and non-canonical (IFI16) activation of the STING pathway. Under high glucose conditions, only a sustained activation of TLR9 was observed. Notably, senescent cells exhibit increased proinflammatory cytokine (IL-1β, IL-6, IL-8) production without a detectable secretion of type I interferon (IFN), a phenomenon that can be explained, at least in part, by the accumulation of methyl-adenosine containing RNAs. At variance, exposure to exogenous nucleic acids enhances both IL-6 and IFN-β1 expression in senescent cells. This study highlights the accrual of cytoplasmic nucleic acids as a marker of senescence-related endothelial dysfunction, that may play a role in dysmetabolic age-related diseases.
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- 2024
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3. Pre-transplant CD69+ extracellular vesicles are negatively correlated with active ATLG serum levels and associate with the onset of GVHD in allogeneic HSCT patients
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Gianluca Storci, Francesco Barbato, Francesca Ricci, Pier Luigi Tazzari, Serena De Matteis, Enrica Tomassini, Michele Dicataldo, Noemi Laprovitera, Mario Arpinati, Margherita Ursi, Enrico Maffini, Elena Campanini, Elisa Dan, Silvia Manfroi, Spartaco Santi, Manuela Ferracin, Massimiliano Bonafe, and Francesca Bonifazi
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anti-T lymphocyte globulin ,graft versus host disease ,extracellular vesicles ,CD69 ,CD103 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG_AUCCD45: 241.52 ± 152.16 vs. 766.63 +/- 283.52 (μg*day)/ml, p = 1.46e-5). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG_AUCCD3: 335.83 ± 208.15 vs. 903.54 ± 378.78 (μg*day)/ml, p = 1.92e-4; ATLG_AUCCD4: 317.75 ± 170.70 vs. 910.54 ± 353.35 (μg*day)/ml, p = 3.78e-5. Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e-5). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention.
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- 2023
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4. Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity
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Serena De Matteis, Michele Dicataldo, Beatrice Casadei, Gianluca Storci, Noemi Laprovitera, Mario Arpinati, Enrico Maffini, Pietro Cortelli, Maria Guarino, Francesca Vaglio, Maria Naddeo, Barbara Sinigaglia, Luca Zazzeroni, Serafina Guadagnuolo, Enrica Tomassini, Salvatore Nicola Bertuccio, Daria Messelodi, Manuela Ferracin, Massimiliano Bonafè, Pier Luigi Zinzani, and Francesca Bonifazi
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chimeric antigen receptor ,senescence ,inflammation ,neurotoxicity ,myeloid activation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundInfusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS.MethodsThis is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation.ResultsMultivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3+CD8+ lymphocytes (38.6% vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8+CD45RA+CD57+ senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14+ and CD45+ myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8+ T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients.DiscussionOur data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8+ T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history.
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- 2023
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5. The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia
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Enrico Maffini, Margherita Ursi, Francesco Barbato, Michele Dicataldo, Marcello Roberto, Elena Campanini, Elisa Dan, Francesco De Felice, Serena De Matteis, Gianluca Storci, Massimiliano Bonafè, Mario Arpinati, and Francesca Bonifazi
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allogeneic hematopoietic cell transplantation (HCT) ,acute myeloid leukemia (AML) ,disease relapse ,donor lymphocyte infusion ,hypomethylating agents relapse prevention in AML receiving allogeneic hematopoietic cell transplantation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for manipulated cellular products such as NK-DLI. The acquisition of novel biological insights into pathobiology of leukemia relapse are translating into the clinic, with novel combinations of target therapies and novel agents, helping delineate new therapeutical landscapes. Hypomethylating agents alone or in combination with novel drugs demonstrated their efficacy in pre-clinical models and controlled trials. FLT3 inhibitors represent an essential therapeutical instrument incorporated in post-transplant maintenance strategies. The Holy grail of allogeneic transplantation lies in the separation of graft-vs.-host disease from graft vs. tumor effects and after more than five decades, is still the most ambitious goal to reach and many ways to accomplish are on their way.
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- 2022
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6. Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy
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Serena De Matteis, Beatrice Casadei, Ginevra Lolli, Michele Dicataldo, Francesco Barbato, Elisa Dan, Andrea Paccagnella, Barbara Sinigaglia, Clara Bertuzzi, Annalisa Arcari, Luca Zazzeroni, Patrizia Bernuzzi, Noemi Laprovitera, Gianluca Storci, Salvatore Nicola Bertuccio, Manuela Ferracin, Massimiliano Bonafè, Pier Luigi Zinzani, and Francesca Bonifazi
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lymphoma ,senescence ,exhaustion ,chimeric antigen receptor (CAR T) ,pembrolizumab ,resistance ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundT cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells.Case presentationWe report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8+ senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8+ T cells compartment.ConclusionsPBZ is not able to reinvigorate exhausted CAR+ T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR+ T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8+ T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity.
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- 2022
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7. TP53 drives abscopal effect by secretion of senescence-associated molecular signals in non-small cell lung cancer
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Anna Tesei, Chiara Arienti, Gianluca Bossi, Spartaco Santi, Ilaria De Santis, Alessandro Bevilacqua, Michele Zanoni, Sara Pignatta, Michela Cortesi, Alice Zamagni, Gianluca Storci, Massimiliano Bonafè, Anna Sarnelli, Antonino Romeo, Carola Cavallo, Armando Bartolazzi, Stefania Rossi, Antonella Soriani, and Lidia Strigari
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Abscopal effect ,Non-small cell lung cancer ,TP53 ,Cellular senescence ,Extracellular vesicles ,DNA:RNA hybrids ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Recent developments in abscopal effect strongly support the use of radiotherapy for the treatment of metastatic disease. However, deeper understanding of the molecular mechanisms underlying the abscopal effect are required to best benefit a larger proportion of patients with metastasis. Several groups including ours, reported the involvement of wild-type (wt) p53 in radiation-induced abscopal effects, however very little is known on the role of wtp53 dependent molecular mechanisms. Methods We investigated through in vivo and in vitro approaches how wtp53 orchestrates radiation-induced abscopal effects. Wtp53 bearing (A549) and p53-null (H1299) NSCLC lines were xenotransplanted in nude mice, and cultured in 2D monolayers and 3D tumor spheroids. Extracellular vesicles (EVs) were isolated from medium cell culture by ultracentrifugation protocol followed by Nanoparticle Tracking Analysis. Gene expression was evaluated by RT-Real Time, digital qRT-PCR, and dot blot technique. Protein levels were determined by immunohistochemistry, confocal anlysis, western blot techniques, and immunoassay. Results We demonstrated that single high-dose irradiation (20 Gy) induces significant tumor growth inhibition in contralateral non-irradiated (NIR) A549 xenograft tumors but not in NIR p53-null H1299 or p53-silenced A549 (A549sh/p53) xenografts. We further demonstrates that irradiation of A549 cells in vitro induces a senescence-associated secretory phenotype (SASP) producing extracellular vesicles (EVs) expressing CD63 and carrying DNA:RNA hybrids and LINE-1 retrotransposon. IR-A549 EVs also hamper the colony-forming capability of recipient NIR A549 cells, induce senescent phenotype, nuclear expression of DNA:RNA hybrids, and M1 macrophage polarization. Conclusions In our models, we demonstrate that high radiation dose in wtp53 tumors induce the onset of SASP and secretion of CD63+ EVs loaded with DNA:RNA hybrids and LINE-1 retrotransposons that convey senescence messages out of the irradiation field triggering abscopal effect in NIR tumors.
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- 2021
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8. Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells
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Emanuela Mensà, Michele Guescini, Angelica Giuliani, Maria Giulia Bacalini, Deborah Ramini, Giacomo Corleone, Manuela Ferracin, Gianluca Fulgenzi, Laura Graciotti, Francesco Prattichizzo, Leonardo Sorci, Michela Battistelli, Vladia Monsurrò, Anna Rita Bonfigli, Maurizio Cardelli, Rina Recchioni, Fiorella Marcheselli, Silvia Latini, Serena Maggio, Mirco Fanelli, Stefano Amatori, Gianluca Storci, Antonio Ceriello, Vilberto Stocchi, Maria De Luca, Luca Magnani, Maria Rita Rippo, Antonio Domenico Procopio, Claudia Sala, Iva Budimir, Cristian Bassi, Massimo Negrini, Paolo Garagnani, Claudio Franceschi, Jacopo Sabbatinelli, Massimiliano Bonafè, and Fabiola Olivieri
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cellular senescence ,micrornas ,dnmt1 ,sirt1 ,extracellular vesicles ,Cytology ,QH573-671 - Abstract
The role of epigenetics in endothelial cell senescence is a cutting-edge topic in ageing research. However, little is known of the relative contribution to pro-senescence signal propagation provided by microRNAs shuttled by extracellular vesicles (EVs) released from senescent cells. Analysis of microRNA and DNA methylation profiles in non-senescent (control) and senescent (SEN) human umbilical vein endothelial cells (HUVECs), and microRNA profiling of their cognate small EVs (sEVs) and large EVs demonstrated that SEN cells released a significantly greater sEV number than control cells. sEVs were enriched in miR-21-5p and miR-217, which target DNMT1 and SIRT1. Treatment of control cells with SEN sEVs induced a miR-21/miR-217-related impairment of DNMT1-SIRT1 expression, the reduction of proliferation markers, the acquisition of a senescent phenotype and a partial demethylation of the locus encoding for miR-21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40–100 years showed an inverse U-shaped age-related trend for miR-21-5p, consistent with senescence-associated biomarker profiles. Our findings suggest that miR-21-5p/miR-217 carried by SEN sEVs spread pro-senescence signals, affecting DNA methylation and cell replication.
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- 2020
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9. HPV DNA Associates With Breast Cancer Malignancy and It Is Transferred to Breast Cancer Stromal Cells by Extracellular Vesicles
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Sabrina De Carolis, Gianluca Storci, Claudio Ceccarelli, Claudia Savini, Lara Gallucci, Pasquale Sansone, Donatella Santini, Renato Seracchioli, Mario Taffurelli, Francesco Fabbri, Fabrizio Romani, Gaetano Compagnone, Cristina Giuliani, Paolo Garagnani, Massimiliano Bonafè, and Monica Cricca
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Human Papillomavirus (HPV) ,extracellular vesicles (EVs) ,triple negative BC ,stromal cells ,circulating HPV DNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
A causal link between Human Papillomavirus (HPV) and breast cancer (BC) remains controversial. In spite of this, the observation that HPV DNA is over-represented in the Triple Negative (TN) BC has been reported. Here we remark the high prevalence of HPV DNA (44.4%) in aggressive BC subtypes (TN and HER2+) in a population of 273 Italian women and we convey the presence of HPV DNA in the epithelial and stromal compartments by in situ hybridization. As previously reported, we also found that serum derived-extracellular vesicles (EVs) from BC affected patients contain HPV DNA. Interestingly, in one TNBC patient, the same HPV DNA type was detected in the serum-derived EVs, cervical and BC tissue samples. Then, we report that HPV DNA can be transferred by EVs to recipient BC stromal cells that show an activated phenotype (e.g., CD44, IL6 expression) and an enhanced capability to sustain mammospheres (MS) formation. These data suggest that HPV DNA vehiculated by EVs is a potential trigger for BC niche aggressiveness.
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- 2019
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10. Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver
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Noémie Gensous, Francesco Ravaioli, Chiara Pirazzini, Roberto Gramignoli, Ewa Ellis, Gianluca Storci, Miriam Capri, Stephen Strom, Ezio Laconi, Claudio Franceschi, Paolo Garagnani, Fabio Marongiu, and Maria Giulia Bacalini
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aging ,dna methylation ,liver ,ribosomal rna ,caloric restriction ,Nutrition. Foods and food supply ,TX341-641 - Abstract
A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.
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- 2020
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11. Short Interfering RNA Directed against the SLUG Gene Increases Cell Death Induction in Human Melanoma Cell Lines Exposed to Cisplatin and Fotemustine
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Ivan Vannini, Massimiliano Bonafe, Anna Tesei, Marco Rosetti, Francesco Fabbri, Gianluca Storci, Paola Ulivi, Giovanni Brigliadori, Dino Amadori, and Wainer Zoli
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Background: Melanoma remains largely resistant to currently available chemotherapy, and new strategies have been proposed to flank standardized therapeutic protocols in an effort to improve efficacy. Such an approach requires good knowledge of the mechanisms involved in the resistance and survival of melanoma cells. In this context, the SLUG gene has recently been characterized as a major regulator of melanocytes and melanoma cell survival. Methods: We tested the hypothesis that an oligonucleotide-based short interfering RNA (siRNA) directed against the SLUG gene increases the susceptibility of melanoma cells to drugs such as cisplatin and fotemustine, which are frequently used to treat this cancer. Results: It was found that SLUG siRNA increased cisplatin-induced cell death and rendered the drug active in vitro at half its plasmatic peak concentration. Such activity was correlated with an upregulation of the pro-apoptotic gene, PUMA. Furthermore, SLUG siRNA increased the capacity of fotemustine to elicit cell death and induced p21WAF1 upregulation, resulting in cell cycle arrest. Interestingly, this pathway did not require functional p53. Conclusion: These findings suggest that SLUG siRNA enhances the efficacy of two of the most widely used drugs to treat melanoma.
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- 2007
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12. Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation
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Francesca Bonifazi, Gianluca Storci, Giuseppe Bandini, Elena Marasco, Elisa Dan, Elena Zani, Fiorenzo Albani, Sara Bertoni, Andrea Bontadini, Sabrina De Carolis, Maria Rosaria Sapienza, Simonetta Rizzi, Maria Rosa Motta, Martina Ferioli, Paolo Garagnani, Michele Cavo, Vilma Mantovani, and Massimiliano Bonafè
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36±570.06 vs. 838.10±282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280±0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism.
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- 2014
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13. Peroxisome proliferator activated receptor-α/hypoxia inducible factor-1α interplay sustains carbonic anhydrase IX and apoliprotein E expression in breast cancer stem cells.
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Alessio Papi, Gianluca Storci, Tiziana Guarnieri, Sabrina De Carolis, Sara Bertoni, Nicola Avenia, Alessandro Sanguinetti, Angelo Sidoni, Donatella Santini, Claudio Ceccarelli, Mario Taffurelli, Marina Orlandi, and Massimiliano Bonafé
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Medicine ,Science - Abstract
AIMS: Cancer stem cell biology is tightly connected to the regulation of the pro-inflammatory cytokine network. The concept of cancer stem cells "inflammatory addiction" leads to envisage the potential role of anti-inflammatory molecules as new anti-cancer targets. Here we report on the relationship between nuclear receptors activity and the modulation of the pro-inflammatory phenotype in breast cancer stem cells. METHODS: Breast cancer stem cells were expanded as mammospheres from normal and tumor human breast tissues and from tumorigenic (MCF7) and non tumorigenic (MCF10) human breast cell lines. Mammospheres were exposed to the supernatant of breast tumor and normal mammary gland tissue fibroblasts. RESULTS: In mammospheres exposed to the breast tumor fibroblasts supernatant, autocrine tumor necrosis factor-α signalling engenders the functional interplay between peroxisome proliferator activated receptor-α and hypoxia inducible factor-1α (PPARα/HIF1α). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPARγ. Further, the PPARα/HIF1α interplay regulates the expression of the pro-inflammatory cytokine interleukin-6, the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E. CONCLUSION: Our data demonstrate the importance of exploring the role of nuclear receptors (PPARα/PPARγ) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning.
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- 2013
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14. Beta-catenin/HuR post-transcriptional machinery governs cancer stem cell features in response to hypoxia.
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Gabriele D'Uva, Sara Bertoni, Mattia Lauriola, Sabrina De Carolis, Annalisa Pacilli, Laura D'Anello, Donatella Santini, Mario Taffurelli, Claudio Ceccarelli, Yosef Yarden, Lorenzo Montanaro, Massimiliano Bonafé, and Gianluca Storci
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Medicine ,Science - Abstract
Hypoxia has been long-time acknowledged as major cancer-promoting microenvironment. In such an energy-restrictive condition, post-transcriptional mechanisms gain importance over the energy-expensive gene transcription machinery. Here we show that the onset of hypoxia-induced cancer stem cell features requires the beta-catenin-dependent post-transcriptional up-regulation of CA9 and SNAI2 gene expression. In response to hypoxia, beta-catenin moves from the plasma membrane to the cytoplasm where it binds and stabilizes SNAI2 and CA9 mRNAs, in cooperation with the mRNA stabilizing protein HuR. We also provide evidence that the post-transcriptional activity of cytoplasmic beta-catenin operates under normoxia in basal-like/triple-negative breast cancer cells, where the beta-catenin knockdown suppresses the stem cell phenotype in vitro and tumor growth in vivo. In such cells, we unravel the generalized involvement of the beta-catenin-driven machinery in the stabilization of EGF-induced mRNAs, including the cancer stem cell regulator IL6. Our study highlights the crucial role of post-transcriptional mechanisms in the maintenance/acquisition of cancer stem cell features and suggests that the hindrance of cytoplasmic beta-catenin function may represent an unprecedented strategy for targeting breast cancer stem/basal-like cells.
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- 2013
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15. Supplementary Figure 4 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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Brett M. Hall, Massimiliano Bonafé, Thomas J. Rosol, Frank C. Marini, Michael W.Y. Chan, Tim Huang, Simona Tavolari, A. Kate Sasser, Pasquale Sansone, Jillian L. Werbeck, Gianluca Storci, and Adam W. Studebaker
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Supplementary Figure 4 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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- 2023
16. Data from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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Brett M. Hall, Massimiliano Bonafé, Thomas J. Rosol, Frank C. Marini, Michael W.Y. Chan, Tim Huang, Simona Tavolari, A. Kate Sasser, Pasquale Sansone, Jillian L. Werbeck, Gianluca Storci, and Adam W. Studebaker
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Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor α (ERα)–positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ERα-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3–dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics. [Cancer Res 2008;68(21):9087–95]
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- 2023
17. Supplementary Figures 1-4, Table 1 from Novel Dyskerin-Mediated Mechanism of p53 Inactivation through Defective mRNA Translation
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Massimo Derenzini, Davide Treré, Massimiliano Bonafè, Maurizio Brigotti, Domenica Carnicelli, Mario Taffurelli, Claudio Ceccarelli, Donatella Santini, Gianluca Storci, Pasquale Sansone, Laura Rocchi, Sara Bertoni, Maria Calienni, and Lorenzo Montanaro
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Supplementary Figures 1-4, Table 1 from Novel Dyskerin-Mediated Mechanism of p53 Inactivation through Defective mRNA Translation
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- 2023
18. Data from Novel Dyskerin-Mediated Mechanism of p53 Inactivation through Defective mRNA Translation
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Massimo Derenzini, Davide Treré, Massimiliano Bonafè, Maurizio Brigotti, Domenica Carnicelli, Mario Taffurelli, Claudio Ceccarelli, Donatella Santini, Gianluca Storci, Pasquale Sansone, Laura Rocchi, Sara Bertoni, Maria Calienni, and Lorenzo Montanaro
- Abstract
In up to 60% of human cancers, p53 gene mutations are responsible for direct inactivation of the tumor suppressor function of p53. Alternative mechanisms of p53 inactivation described thus far mainly affect its posttranslational regulation. In X-linked dyskeratosis congenita, a multisystemic syndrome characterized by increased cancer susceptibility, mutations of the DKC1 gene encoding dyskerin cause a selective defect in the translation of a subgroup of internal ribosome entry site (IRES)–containing cellular mRNAs. In this study, we show that impairment of dyskerin function can cause p53 inactivation due to a defect in p53 mRNA translation. siRNA-mediated reduction of dyskerin levels caused a decrease of p53 mRNA translation, protein levels, and functional activity, both in human breast cancer cells and in primary mammary epithelial progenitor cells. These effects seemed to be independent of the known role of dyskerin in telomerase function, and they were associated with a specific impairment of translation initiation mediated by IRES elements present in p53 mRNA. In a series of human primary breast cancers retaining wild-type p53, we found that low levels of dyskerin expression were associated with reduced expression of p53-positive target genes. Our findings suggest that a dyskerin-mediated mechanism of p53 inactivation may occur in a subset of human tumors. Cancer Res; 70(11); 4767–77. ©2010 AACR.
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- 2023
19. Supplementary Figure 1 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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Brett M. Hall, Massimiliano Bonafé, Thomas J. Rosol, Frank C. Marini, Michael W.Y. Chan, Tim Huang, Simona Tavolari, A. Kate Sasser, Pasquale Sansone, Jillian L. Werbeck, Gianluca Storci, and Adam W. Studebaker
- Abstract
Supplementary Figure 1 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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- 2023
20. Supplementary Figure 2 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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Brett M. Hall, Massimiliano Bonafé, Thomas J. Rosol, Frank C. Marini, Michael W.Y. Chan, Tim Huang, Simona Tavolari, A. Kate Sasser, Pasquale Sansone, Jillian L. Werbeck, Gianluca Storci, and Adam W. Studebaker
- Abstract
Supplementary Figure 2 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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- 2023
21. Supplementary Figure 3 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
- Author
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Brett M. Hall, Massimiliano Bonafé, Thomas J. Rosol, Frank C. Marini, Michael W.Y. Chan, Tim Huang, Simona Tavolari, A. Kate Sasser, Pasquale Sansone, Jillian L. Werbeck, Gianluca Storci, and Adam W. Studebaker
- Abstract
Supplementary Figure 3 from Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
- Published
- 2023
22. Old age: the crown of life, our play's last act. Question and answers on older patients undergoing allogeneic hematopoietic cell transplantation
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Enrico Maffini, Moreno Festuccia, Margherita Ursi, Francesco Barbato, Michele Dicataldo, Marcello Roberto, Elena Campanini, Elisa Dan, Francesco De Felice, Serena De Matteis, Gianluca Storci, Massimiliano Bonafè, Mario Arpinati, and Francesca Bonifazi
- Subjects
Hematology - Abstract
Several studies showed that age alone should not be used as an arbitrary parameter to exclude patients from allogeneic hematopoietic cell transplantation (HCT). The accessibility to allogeneic HCT programs for older patients with hematological diseases is growing up constantly. The Center for International Blood and Marrow Transplant Research has recently shown that over 30% of allogeneic HCT recipients are at least 60 years old and that nearly 4% are aged 70 or more. Historically, the use of allogeneic HCT among elderly patients has been limited by age restrictions, reflecting physicians' concerns regarding prohibitive transplant-related mortality and HCT-associated morbidity.The introduction of reduced intensity/toxicity conditioning regimens has allowed transplant Centers to carry out allogeneic HCT on patients previously considered not ideal candidates. The integration of specific risk scores could lead to better capture mental and physical frailties of older patients. Older adults less frequently have available medically fit siblings, able to donate, so, unrelated donors, familial haploidentical donors or umbilical cord blood grafts could potentially abrogate such a difficulty, allowing the curative potential of allogeneic HCT.The appropriate assessing of allogeneic HCT feasibility for elderly patients should be the resonate application of different clinical and biological principles.
- Published
- 2022
23. Allogeneic stem cell transplantation is capable of healing a case of bone marrow aplasia following CAR-T cell therapy in a lymphoma patient
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Ginevra Lolli, Margherita Ursi, Michele Dicataldo, Beatrice Casadei, Gianluca Storci, Lisa Argnani, Francesca Bonifazi, and Pier Luigi Zinzani
- Subjects
Cancer Research ,Receptors, Chimeric Antigen ,Lymphoma ,Oncology ,Bone Marrow ,Hematopoietic Stem Cell Transplantation ,Humans ,Anemia, Aplastic ,Hematology ,Bone Marrow Transplantation - Published
- 2022
24. A Multiparameter Prognostic Risk Score of Chronic Graft-versus-Host Disease Based on CXCL10 and Plasmacytoid Dendritic Cell Levels in the Peripheral Blood at 3 Months after Allogeneic Hematopoietic Stem Cell Transplantation
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Gabriella Chirumbolo, Michele Dicataldo, Martina Barone, Gianluca Storci, Serena De Matteis, Noemi Laprovitera, Barbara Sinigaglia, Francesco Barbato, Enrico Maffini, Michele Cavo, Francesca Bonifazi, and Mario Arpinati
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
25. Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes
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Angelica Giuliani, Jacopo Sabbatinelli, Francesco Prattichizzo, Fabiola Olivieri, Gianluca Storci, Massimiliano Bonafè, Bonafe' M., Prattichizzo F., Giuliani A., Storci G., Sabbatinelli J., and Olivieri F.
- Subjects
Male ,0301 basic medicine ,Aging ,Endocrinology, Diabetes and Metabolism ,pathology_pathobiology ,Comorbidity ,Disease ,Severe Acute Respiratory Syndrome ,Systemic inflammation ,0302 clinical medicine ,Interferon ,Immunopathology ,Immunology and Allergy ,Medicine ,Subclinical infection ,Aged, 80 and over ,biology ,Mortality rate ,Immunosenescence ,Cardiovascular disease ,Acquired immune system ,Cardiovascular diseases ,030220 oncology & carcinogenesis ,Interferon Type I ,Female ,Angiotensin-Converting Enzyme 2 ,medicine.symptom ,Coronavirus Infections ,medicine.drug ,Human ,Pneumonia, Viral ,Immunology ,Inflammation ,Peptidyl-Dipeptidase A ,Antibodies, Monoclonal, Humanized ,Article ,General Biochemistry, Genetics and Molecular Biology ,Host-directed therapies ,Betacoronavirus ,03 medical and health sciences ,Immune system ,Humans ,Interleukin 6 ,Pandemics ,Aged ,Betacoronaviru ,Pandemic ,SARS-CoV-2 ,Coronavirus Infection ,Interleukin-6 ,business.industry ,fungi ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,Inflamm-aging ,030104 developmental biology ,biology.protein ,business ,Host-directed therapie - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and iv. accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state. Though typical of the aged, especially of elderly men, it is conceivable that these features are also shared by some subsets of the younger population. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.
- Published
- 2020
26. Leukocyte-mimicking nanovesicles for effective doxorubicin delivery to treat breast cancer and melanoma
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Claudia Corbo, Assaf Zinger, Gianluca Storci, Nupur Basu, Roberto Molinaro, Enrica De Rosa, Alessandro De Vita, Ennio Tasciotti, Jonathan O. Martinez, Noemi Arrighetti, Nima Taghipour, Kelly A. Hartman, Molinaro, R, Martinez, J, Zinger, A, De Vita, A, Storci, G, Arrighetti, N, De Rosa, E, Hartman, K, Basu, N, Taghipour, N, Corbo, C, and Tasciotti, E
- Subjects
Cell Survival ,Biomedical Engineering ,Breast Neoplasms ,Kaplan-Meier Estimate ,biomimetic nanoparticles, breast cancer, melanoma ,Mice ,Immune system ,Breast cancer ,Stroma ,Biomimetic Materials ,Cell Line, Tumor ,Leukocytes ,medicine ,Animals ,Transplantation, Homologous ,General Materials Science ,Doxorubicin ,Melanoma ,business.industry ,Cancer ,Mononuclear phagocyte system ,medicine.disease ,Liposomes ,Drug delivery ,Cancer research ,Nanoparticles ,Female ,business ,medicine.drug - Abstract
In the last decades, several approaches were developed to design drug delivery systems to address the multiple biological barriers encountered after administration while safely delivering a payload. In this scenario, bio-inspired and bio-mimetic approaches have emerged as promising solutions to evade the mononuclear phagocytic system while simultaneously negotiating the sequential transport across the various biological barriers. Leukocytes freely circulate in the bloodstream and selectively target the inflamed vasculature in response to injury, infection, and cancer. Recently we have shown the use of biomimetic nanovesicles, called leukosomes, which combine both the physical and biological properties of liposomes and leukocytes, respectively, to selectively deliver drugs to the inflamed vasculature. Here we report the use of leukosomes to target and deliver doxorubicin, a model chemotherapeutic, to tumors in syngeneic murine models of breast cancer and melanoma. Exploiting the inflammatory pathway responsible for recruiting immune cells to the site of injury, leukosomes exhibited increased targeting of cancer vasculature and stroma. Furthermore, delivery of doxorubicin with leukosomes enabled significant tumor growth inhibition compared with free doxorubicin in both breast and melanoma tumors. This study demonstrates the promise of using biomimetic nanovesicles for effective cancer management in solid tumors.
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- 2020
27. TP53 drives abscopal effect by secretion of senescence-associated molecular signals in non small cell lung cancer
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Carola Cavallo, Gianluca Storci, Massimiliano Bonafè, Sara Pignatta, Alessandro Bevilacqua, Lidia Strigari, Armando Bartolazzi, Chiara Arienti, Antonella Soriani, Anna Sarnelli, Anna Tesei, Stefania Rossi, Antonino Romeo, Alice Zamagni, Michele Zanoni, Ilaria De Santis, Spartaco Santi, Gianluca Bossi, Michela Cortesi, Anna Tesei, Chiara Arienti, Gianluca Bossi, Spartaco Santi, Ilaria De Santi, Alessandro Bevilacqua, Michele Zanoni, Sara Pignatta, Michela Cortesi, Alice Zamagni, Gianluca Storci, Massimiliano Bonafè, Anna Sarnelli, Antonino Romeo, Carola Cavallo, Armando Bartolazzi, Stefania Rossi, Antonella Soriani, and Lidia Strigari
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Macrophage polarization ,Mice, Nude ,Abscopal effect ,Cellular senescence ,lcsh:RC254-282 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Western blot ,Non-small cell lung cancer ,In vivo ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,DNA:RNA hybrid ,Gene expression ,medicine ,Animals ,Humans ,Retrotransposon ,TP53 ,Cell Proliferation ,A549 cell ,medicine.diagnostic_test ,Chemistry ,DNA:RNA hybrids ,Research ,Extracellular vesicles ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,In vitro ,030104 developmental biology ,RAW 264.7 Cells ,Oncology ,Cell culture ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer research ,Heterografts ,Female ,Tumor Suppressor Protein p53 ,Extracellular vesicle - Abstract
Background Recent developments in abscopal effect strongly support the use of radiotherapy for the treatment of metastatic disease. However, deeper understanding of the molecular mechanisms underlying the abscopal effect are required to best benefit a larger proportion of patients with metastasis. Several groups including ours, reported the involvement of wild-type (wt) p53 in radiation-induced abscopal effects, however very little is known on the role of wtp53 dependent molecular mechanisms. Methods We investigated through in vivo and in vitro approaches how wtp53 orchestrates radiation-induced abscopal effects. Wtp53 bearing (A549) and p53-null (H1299) NSCLC lines were xenotransplanted in nude mice, and cultured in 2D monolayers and 3D tumor spheroids. Extracellular vesicles (EVs) were isolated from medium cell culture by ultracentrifugation protocol followed by Nanoparticle Tracking Analysis. Gene expression was evaluated by RT-Real Time, digital qRT-PCR, and dot blot technique. Protein levels were determined by immunohistochemistry, confocal anlysis, western blot techniques, and immunoassay. Results We demonstrated that single high-dose irradiation (20 Gy) induces significant tumor growth inhibition in contralateral non-irradiated (NIR) A549 xenograft tumors but not in NIR p53-null H1299 or p53-silenced A549 (A549sh/p53) xenografts. We further demonstrates that irradiation of A549 cells in vitro induces a senescence-associated secretory phenotype (SASP) producing extracellular vesicles (EVs) expressing CD63 and carrying DNA:RNA hybrids and LINE-1 retrotransposon. IR-A549 EVs also hamper the colony-forming capability of recipient NIR A549 cells, induce senescent phenotype, nuclear expression of DNA:RNA hybrids, and M1 macrophage polarization. Conclusions In our models, we demonstrate that high radiation dose in wtp53 tumors induce the onset of SASP and secretion of CD63+ EVs loaded with DNA:RNA hybrids and LINE-1 retrotransposons that convey senescence messages out of the irradiation field triggering abscopal effect in NIR tumors.
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- 2021
28. Senescent macrophages in the human adipose tissue as a source of inflammaging
- Author
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Giulia Matacchione, Jessica Perugini, Eleonora Di Mercurio, Jacopo Sabbatinelli, Francesco Prattichizzo, Martina Senzacqua, Gianluca Storci, Christian Dani, Giovanni Lezoche, Mario Guerrieri, Antonio Giordano, Massimiliano Bonafè, and Fabiola Olivieri
- Subjects
Inflammation ,Aging ,Glucose ,Diabetes Mellitus, Type 2 ,Adipose Tissue ,Macrophages ,Animals ,Humans ,Insulin ,Obesity ,Geriatrics and Gerontology ,Insulin Resistance ,Biomarkers - Abstract
Obesity is a major risk factor for type 2 diabetes and a trigger of chronic and systemic inflammation. Recent evidence suggests that an increased burden of senescent cells (SCs) in the adipose tissue of obese/diabetic animal models might underlie such pro-inflammatory phenotype. However, the role of macrophages as candidate SCs, their phenotype, the distribution of SCs among fat depots, and clinical relevance are debated. The senescence marker β-galactosidase and the macrophage marker CD68 were scored in visceral (vWAT) and subcutaneous (scWAT) adipose tissue from obese patients (n=17) undergoing bariatric surgery and control patients (n=4) subjected to cholecystectomy. A correlation was made between the number of SCs and BMI, serum insulin, and the insulin resistance (IR) index HOMA. The monocyte cell line (THP-1) was cultured in vitro in high glucose milieu (60 mM D-glucose) and subsequently co-cultured with human adipocytes (hMADS) to investigate the reciprocal inflammatory activation. In obese patients, a significantly higher number of SCs was observed in vWAT compared to scWAT; about 70% of these cells expressed the macrophage marker CD68; and the number of SCs in vWAT, but not in scWAT, positively correlated with BMI, HOMA-IR, and insulin. THP-1 cultured in vitro in high glucose milieu acquired a senescent-like phenotype (HgSMs), characterized by a polarization toward a mixed M1/M2-like secretory phenotype. Co-culturing HgSMs with hMADS elicited pro-inflammatory cytokine expression in both cell types, and defective insulin signaling in hMADS. In morbid obesity, expansion of visceral adipose depots involves an increased burden of macrophages with senescent-like phenotype that may promote a pro-inflammatory profile and impair insulin signaling in adipocytes, supporting a framework where senescent macrophages fuel obesity-induced systemic inflammation and possibly contribute to the development of IR.
- Published
- 2021
29. Stem Cells
- Author
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Gian Paolo Bagnara, Laura Bonsi, Francesco Alviano, Angeletti Andrea, Vito Antonio Baldassarro, Nicola Baldini, Barbar Lilianne, Francesca Bianchi, Massimiliano Bonafè, Elena Bondioli, Daria Bortolotti, Suzanne Burstein, Laura Calzà, Diana Campioni, Anna Cargnoni, Claudia Cavallini, Gabriella Ciapetti, Giorgia Comai, Roberta Costa, Gemma Di Pompo, Valentina Fossati, Luciana Giardino, Brunella Grigolo, Alberto Grossi, Gaetano La Manna, Francesco Lanza, Giacomo Lanzoni, Marta Magatti, Fabio Marongiu, Davide Melandri, Paola Minghetti, Thimios Mitsiadis, Madhura Nijsure, Elena Olivi, Catuscia Orlandi, Giovanna Orsini, Ornella Parolini, Gianandrea Pasquinelli, Enrico Pozzo, Valeria Purpura, Mattia Quattrocelli, Roberta Rizzo, Damiano Rondelli, Livia Roseti, Martina Rossi, Maurilio Sampaolesi, Antonietta Rosa Silini, Gianluca Storci, Riccardo Tassinari, Sabrina Valente, Silvia Velasco, Carlo Ventura, and Gian Paolo Bagnara, Laura Bonsi, Francesco Alviano, Angeletti Andrea, Vito Antonio Baldassarro, Nicola Baldini, Barbar Lilianne, Francesca Bianchi, Massimiliano Bonafè, Elena Bondioli, Daria Bortolotti, Suzanne Burstein, Laura Calzà, Diana Campioni, Anna Cargnoni, Claudia Cavallini, Gabriella Ciapetti, Giorgia Comai, Roberta Costa, Gemma Di Pompo, Valentina Fossati, Luciana Giardino, Brunella Grigolo, Alberto Grossi, Gaetano La Manna, Francesco Lanza, Giacomo Lanzoni, Marta Magatti, Fabio Marongiu, Davide Melandri, Paola Minghetti, Thimios Mitsiadis, Madhura Nijsure, Elena Olivi, Catuscia Orlandi, Giovanna Orsini, Ornella Parolini, Gianandrea Pasquinelli, Enrico Pozzo, Valeria Purpura, Mattia Quattrocelli, Roberta Rizzo, Damiano Rondelli, Livia Roseti, Martina Rossi, Maurilio Sampaolesi, Antonietta Rosa Silini, Gianluca Storci, Riccardo Tassinari, Sabrina Valente, Silvia Velasco, Carlo Ventura
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Cell therapy, Stem cells, Perinatal cells, Mesenchymal cells, Stem cell niche, Pluripotent stem cells, Adult stem cells ,humanities - Abstract
The main objective of this book is to present a thorough update on stem cell research and the potential therapeutic applications of stem cells. The text is structured following a path that starts from the molecular basics and the biological properties of pluripotent, embryonic or reprogrammed stem cells, and it compares the different degrees of stemness, while describing the adult stem populations residing in the various tissues and organs of the human body. Starting from basic research, the book discusses examples of regenerative medicine that translate the experimental findings into clinical applications of cell therapy. Finally, the book reviews how stem cells represent a model to understand not only the physiological mechanisms that control their fate, but also the pathological mechanisms involved in the aberrant biology of cancer stem cells. Each chapter has been conceived by distinguished researchers in the field who provide detailed and updated contributions that distill knowledge in a very readable text. Laura Bonsi is Associate Professor of Histology at the Department of Experimental, Diagnostic and Specialty Medicine of the University of Bologna. Francesco Alviano is Assistant Professor of Histology at the Department of Experimental, Diagnostic and Specialty Medicine of the University of Bologna. Prof. Bonsi and Dr. Alviano are authors of numerous scientific papers published in international journals. They coordinate the Biotechnology Laboratory of Human Stem Cells at the University of Bologna, that is focused on the study of stem cells isolated from different sources, above all from extraembryonic tissues such as the placenta, the umbilical cord, and the fetal membranes. They are longterm members of the International Placenta Stem Cell Society (IPLASS).
- Published
- 2020
30. Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians
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Silvia Latini, Francesco Fabbri, Manuela Ferracin, Anna Tesei, Sabrina De Carolis, Stefano Salvioli, Elena Marasco, Noémie Gensous, Fabiola Olivieri, Maria Giulia Bacalini, Chiara Arienti, Massimiliano Bonafè, Michele Zanoni, Gianluca Storci, Emanuela Mensà, Anna Sarnelli, Alessio Papi, Spartaco Santi, Claudio Franceschi, Paolo Garagnani, Storci G., De Carolis S., Papi A., Bacalini M.G., Gensous N., Marasco E., Tesei A., Fabbri F., Arienti C., Zanoni M., Sarnelli A., Santi S., Olivieri F., Mensa E., Latini S., Ferracin M., Salvioli S., Garagnani P., Franceschi C., and Bonafe M.
- Subjects
Adult ,Male ,0301 basic medicine ,DNA repair ,DNA damage ,Longevity ,Ribonuclease H ,Breast Neoplasms ,Inflammation ,Biology ,Methylation ,Article ,Extracellular Vesicles ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,medicine ,Humans ,Molecular Biology ,Cellular Senescence ,Aged ,Aged, 80 and over ,Interleukin-6 ,Telomere Homeostasis ,Interferon-beta ,Cell Biology ,Fibroblasts ,Middle Aged ,Phenotype ,Plaque, Atherosclerotic ,DNA damage response, centenarians, RNA:DNA hybrids, inflammation ,3. Good health ,Telomere ,Cell biology ,Comet assay ,MicroRNAs ,030104 developmental biology ,Genetic Loci ,030220 oncology & carcinogenesis ,Cancer cell ,Female ,medicine.symptom ,DNA Damage ,medicine.drug - Abstract
Current literature agrees on the notion that efficient DNA repair favors longevity across evolution. The DNA damage response machinery activates inflammation and type I interferon signaling. Both pathways play an acknowledged role in the pathogenesis of a variety of age-related diseases and are expected to be detrimental for human longevity. Here, we report on the anti-inflammatory molecular make-up of centenarian’s fibroblasts (low levels of IL-6, type 1 interferon beta, and pro-inflammatory microRNAs), which is coupled with low level of DNA damage (measured by comet assay and histone-2AX activation) and preserved telomere length. In the same cells, high levels of the RNAseH2C enzyme subunit and low amounts of RNAseH2 substrates, i.e. cytoplasmic RNA:DNA hybrids are present. Moreover, RNAseH2C locus is hypo-methylated and RNAseH2C knock-down up-regulates IL-6 and type 1 interferon beta in centenarian’s fibroblasts. Interestingly, RNAseH2C locus is hyper-methylated in vitro senescent cells and in tissues from atherosclerotic plaques and breast tumors. Finally, extracellular vesicles from centenarian’s cells up-regulate RNAseH2C expression and dampen the pro-inflammatory phenotype of fibroblasts, myeloid, and cancer cells. These data suggest that centenarians are endowed with restrained DNA damage-induced inflammatory response, that may facilitate their escape from the deleterious effects of age-related chronic inflammation.
- Published
- 2019
31. Changes in the biochemical taste of cytoplasmic and cell-free DNA are major fuels for inflamm-aging
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Gianluca Storci, Sabrina De Carolis, Fabiola Olivieri, Massimiliano Bonafè, Storci, Gianluca, De Carolis, Sabrina, Olivieri, Fabiola, and Bonafè, Massimiliano
- Subjects
0301 basic medicine ,Senescence ,Aging ,Immunology ,Cell ,Inflammation ,Biology ,Cell-free DNA ,03 medical and health sciences ,chemistry.chemical_compound ,DNA:RNA hybrid ,medicine ,Extracellular ,Animals ,Humans ,Immunology and Allergy ,Cellular Senescence ,Telomere Shortening ,Innate immune system ,RNA ,Telomere ,Inflamm-aging ,Immunity, Innate ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Extracellular vesicle ,medicine.symptom ,Cell-Free Nucleic Acids ,DNA - Abstract
Inflamm-aging depicts the progressive activation of the innate immune system that accompanies human aging. Its role as a disease-predisposing condition has been proposed, but its molecular basis is still poorly understood. A wealth of literature conveys that, particularly upon stress, nuclear and mitochondrial genomes are released into the cytoplasmic and extracellular compartments. Cytoplasmic (cy) and cell-free (cf) DNA pools trigger inflammation and innate immunity at local and systemic level. In particular, cyDNA plays a crucial role in the phenomenon of cell senescence and in the cognate pro-inflammatory secretome. Here we propose that changes in a variety of biochemical characteristics “tastes” of cy- and cf-DNA (e.g. the amount of 8-oxo-deoxy-guanosine and 5-methyl-deoxy-cytosine, the proportion of DNA hybridized with RNA) potentially affect the capability of these DNA pools to ignite the innate immune system. We also underpin that telomeric sequences are major components of the cy/cfDNA payload. Telomere shortening, a hallmark of aging, causes the depletion of telomeric sequences in cy/cfDNA pool, thus unleashing their potential to exert an age-related activation of the innate immune system. Finally, we posit that various sources of DNA (extracellular vesicles, the commensal metagenome and food) contribute to the cy/cfDNA payloads. We speculate that changes in the biochemical “taste” of cy/cfDNA are major modifiers of inflamm-aging.
- Published
- 2018
32. The role of extracellular DNA in COVID-19: Clues from inflamm-aging
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Paolo Garagnani, Francesca Bonifazi, Gianluca Storci, Fabiola Olivieri, Massimiliano Bonafè, Storci G., Bonifazi F., Garagnani P., Olivieri F., and Bonafe' M.
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0301 basic medicine ,Male ,Mitochondrial DNA ,DNA sensing receptors ,Aging ,Inflamm aging ,Coronavirus disease 2019 (COVID-19) ,Inflammation ,Review ,Systemic inflammation ,DNA, Mitochondrial ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Extracellular ,Medicine ,Humans ,Molecular Biology ,Aged ,business.industry ,Misplaced DNA ,SARS-CoV-2 ,COVID-19 ,Telomere ,Extracellular dna ,Inflamm-aging ,Ageing ,030104 developmental biology ,Neurology ,Immunology ,DNA sensing receptor ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Human ,Biotechnology - Abstract
Epidemiological data convey severe prognosis and high mortality rate for COVID-19 in elderly men affected by age-related diseases. These subjects develop local and systemic hyper-inflammation, which are associated with thrombotic complications and multi-organ failure. Therefore, understanding SARS-CoV-2 induced hyper-inflammation in elderly men is a pressing need. Here we focus on the role of extracellular DNA, mainly mitochondrial DNA (mtDNA) and telomeric DNA (telDNA) in the modulation of systemic inflammation in these subjects. In particular, extracellular mtDNA is regarded as a powerful trigger of the inflammatory response. On the contrary, extracellular telDNA pool is estimated to be capable of inhibiting a variety of inflammatory pathways. In turn, we underpin that telDNA reservoir is progressively depleted during aging, and that it is scarcer in men than in women. We propose that an increase in extracellular mtDNA, concomitant with the reduction of the anti-inflammatory telDNA reservoir may explain hyper-inflammation in elderly male affected by COVID-19. This scenario is reminiscent of inflamm-aging, the portmanteau word that depicts how aging and aging related diseases are intimately linked to inflammation.
- Published
- 2021
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33. Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice
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Giovanna Lattanzi, Elisa Schena, Giuseppe Sarli, Gianluca Storci, Elisabetta Mattioli, Davide Andrenacci, Anna Zaghini, Massimiliano Bonafè, Patrizia Sabatelli, Catia Barboni, Valeria Pellegrino, Vittoria Cenni, Cristina Capanni, Maria Rosaria D'Apice, Stefano Squarzoni, Mara Sanapo, Fabio Baruffaldi, Anna Festa, Squarzoni S., Schena E., Sabatelli P., Mattioli E., Capanni C., Cenni V., D'Apice M.R., Andrenacci D., Sarli G., Pellegrino V., Festa A., Baruffaldi F., Storci G., Bonafe M., Barboni C., Sanapo M., Zaghini A., and Lattanzi G.
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0301 basic medicine ,Premature aging ,anti‐aging ,Aging ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Adipose tissue ,Inflammation ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Progeria ,0302 clinical medicine ,Tocilizumab ,Internal medicine ,medicine ,cytokine ,Animals ,Humans ,accelerated aging ,cellular senescence ,Interleukin 6 ,laminopathie ,biology ,integumentary system ,Interleukin-6 ,laminopathies ,anti-aging ,nutritional and metabolic diseases ,Original Articles ,Cell Biology ,medicine.disease ,Progerin ,cytokines ,3. Good health ,030104 developmental biology ,Endocrinology ,chemistry ,ageing ,inflammation ,biology.protein ,Original Article ,medicine.symptom ,Lipodystrophy ,030217 neurology & neurosurgery ,nuclear lamina - Abstract
Hutchinson–Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin‐6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin‐6 activity by tocilizumab, a neutralizing antibody raised against interleukin‐6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G / G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging‐related disorders., Signs of premature ageing are improved by tocilizumab treatment. A study in a murine model of Hutchinson‐Gilford Progeria shows that neutralization of interleukin 6 preserves motor activity and slows‐down tissue deterioration.
- Published
- 2021
34. Response to: Letter to the Editor on 'Bonafè M, Prattichizzo F, Giuliani A, Storci G, Sabbatinelli J, Olivieri F. Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev' by Eugenia Quiros-Roldan, Giorgio Biasiotto and Isabella Zanella
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Gianluca Storci, Angelica Giuliani, Francesco Prattichizzo, Massimiliano Bonafè, Fabiola Olivieri, Andrea Costantini, and Jacopo Sabbatinelli
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2019-20 coronavirus outbreak ,Inflamm aging ,Letter to the editor ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,medicine.medical_treatment ,Endocrinology, Diabetes and Metabolism ,Immunology ,Virology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cytokine ,Medicine ,Immunology and Allergy ,business - Published
- 2020
35. How studies on inflamm-aging may help to understand and combat COVID-19 pandemic
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Fabiola Olivieri, Gianluca Storci, Massimiliano Bonafè, Francesca Bonifazi, and Paolo Garagnani
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Inflamm aging ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,Pandemic ,Medicine ,business - Abstract
More than 1,000,000 confirmed cases of COVID-19 have been registered worldwide since the beginning of the pandemic in Wuhan on December 2019. The high mortality rate of COVID-19 is associated with age, gender and the presence of comorbidities. Biochemical data have shown that COVID-19 patients develop a local and systemic hyper-inflammatory response associated with poor outcome. Therefore, the understanding of the biological mechanisms underlying SARS-CoV-2-induced inflammation is a compelling need. Following this reasoning, here we will focus on the importance of the progressive age-related development of a pro-inflammatory state (aka inflamm-aging) in the understanding of the unbalanced inflammatory response against SARS-CoV-2 in aged people. In particular, we underpin the role of mitochondrial DNA and genomic DNA telomeric sequences in local and systemic mechanisms of inflammation. Indeed, the leakage of mtDNA out of its natural compartment (i.e. the mitochondrion), into the cytoplasm and in the extracellular environment is a powerful trigger of innate immunity and inflammation, as part of an evolutionary-conserved signaling mechanism of cellular damage (e.g. viral infection). High levels of circulating mtDNA are increased in aged people and set up as inflammatory markers of poor prognosis in intensive care unit patients. In turn, telomeric DNA, which can be released into the cytoplasm and in the extracellular environment upon cell damage, has been proven to exert potent anti-inflammatory activity. Since that aged people (particularly those affected by co-morbidity) are equipped with shortened telomeres, we posit that, in aged people affected by COVID-19 the release of mtDNA, coupled with insufficient telomeric DNA favors the onset of a detrimental inflammatory response. In this regard, we highlight that the mechanism of action of some currently used drugs, as well as potential new ones may be better understood under the light of the above-depicted theoretical framework thus explaining how studies on inflamm-aging may help to understand and combat COVID-19 pandemic.
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- 2020
36. Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver
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Francesco Ravaioli, Paolo Garagnani, Fabio Marongiu, Miriam Capri, Roberto Gramignoli, Chiara Pirazzini, Noémie Gensous, Ewa Ellis, Claudio Franceschi, Maria Giulia Bacalini, Gianluca Storci, Stephen C. Strom, Ezio Laconi, Gensous N., Ravaioli F., Pirazzini C., Gramignoli R., Ellis E., Storci G., Capri M., Strom S., Laconi E., Franceschi C., Garagnani P., Marongiu F., and Bacalini M.G.
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0301 basic medicine ,Male ,Longevity ,lcsh:TX341-641 ,Locus (genetics) ,Biology ,liver ,DNA, Ribosomal ,Article ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Protein biosynthesis ,Animals ,Humans ,Epigenetics ,Promoter Regions, Genetic ,Ribosomal DNA ,Nutrition and Dietetics ,DNA methylation ,aging ,Methylation ,Ribosomal RNA ,Molecular biology ,3. Good health ,Rats ,030104 developmental biology ,Genetic Loci ,RNA, Ribosomal ,caloric restriction ,ribosomal RNA ,lcsh:Nutrition. Foods and food supply ,030217 neurology & neurosurgery ,Food Science - Abstract
A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5&prime, of the 18S and the 5&prime, of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.
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- 2020
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37. Ribosomal DNA instability: An evolutionary conserved fuel for inflammaging
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Fabiola Olivieri, Stefano Salvioli, Paolo Garagnani, Massimiliano Bonafè, Francesca Bonifazi, Gianluca Storci, Sabrina De Carolis, Maria Giulia Bacalini, Storci G., Bacalini M.G., Bonifazi F., Garagnani P., De Carolis S., Salvioli S., Olivieri F., and Bonafe' M.
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0301 basic medicine ,Genome instability ,DNA Replication ,Aging ,Saccharomyces cerevisiae ,Biochemistry ,DNA, Ribosomal ,Genomic Instability ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,DNA hybrid ,Extrachromosomal DNA ,Humans ,Molecular Biology ,Ribosomal DNA ,Aged ,Genetics ,Innate immune system ,biology ,Ribosomal DNA (rDNA) ,RNA ,Helicase ,Phenotype ,Inflammaging ,Biological Evolution ,030104 developmental biology ,Neurology ,chemistry ,biology.protein ,Extrachromosomal rDNA circle (ERC) ,030217 neurology & neurosurgery ,DNA ,Biotechnology ,Human - Abstract
Across eukaryotes, ribosomal DNA (rDNA) loci are characterized by intrinsic genomic instability due to their repetitive nature and their base composition that facilitate DNA double strand breaks and RNA:DNA hybrids formation. In the yeast, ribosomal DNA instability affects lifespan via the formation of extrachromosomal rDNA circles (ERC) that accrue into aged cells. In humans, rDNA instability has long been reported in a variety of progeric syndromes caused by the dysfunction of DNA helicases, but its role in physiological aging and longevity still needs to be clarified. Here we propose that rDNA instability leads to the activation of innate immunity and inflammation via the interaction with the cytoplasmic DNA sensing machinery. Owing to the recent clarified role of cytoplasmic DNA in the pro-inflammatory phenotype of senescent cells, we hypothesize that the accrual of rDNA derived molecules (i.e. ERC and RNA:DNA hybrids) may have a role in aging by contributing to inflammaging i.e. the systemic pro-inflammatory drift that associates with the onset of geriatric syndromes and age related dysfunctions in humans.
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- 2020
38. Age-related M1/M2 phenotype changes in circulating monocytes from healthy/unhealthy individuals
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Fabiola Olivieri, Nadia Viola, Daniele Caraceni, Roberto Antonicelli, Luca Butini, Andrea Costantini, Antonio Domenico Procopio, Roberta Galeazzi, Jacopo Sabbatinelli, Maria Rita Rippo, Massimiliano Bonafè, Antonella Berretta, Giulia Matacchione, Serena De Matteis, Gianluca Storci, Costantini, Andrea, Viola, Nadia, Berretta, Antonella, Galeazzi, Roberta, Matacchione, Giulia, Sabbatinelli, Jacopo, Storci, Gianluca, De Matteis, Serena, Butini, Luca, Rippo, Maria Rita, Procopio, Antonio Domenico, Caraceni, Daniele, Antonicelli, Roberto, Olivieri, Fabiola, and Bonafè, Massimiliano
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Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,T-Lymphocytes ,CD14 ,Myocardial Infarction ,Macrophage polarization ,acute myocardial infarction ,chemical and pharmacologic phenomena ,CD16 ,Monocytes ,M1/M2 monocytes ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Internal medicine ,medicine ,Humans ,Myocardial infarction ,Age-related changes of M1/M2 circulating monocyte ,Aged ,Inflammation ,NK/NK-T cells ,business.industry ,Macrophages ,hemic and immune systems ,Cell Biology ,Middle Aged ,Flow Cytometry ,medicine.disease ,Phenotype ,Killer Cells, Natural ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Biomarker (medicine) ,Female ,business ,CD163 ,Biomarkers ,CD80 ,Research Paper ,030215 immunology - Abstract
Macrophage polarization is a candidate biomarker of disease-related inflammatory status, but its modulation during aging has not been investigated. To do this, the M1/M2 profile was assessed by CD80/CD163 gating in classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14lowCD16+) monocytes from 31 healthy subjects (CTRs) of different ages. Cytofluorimetric analysis showed a significantly different CD80/CD163 distribution in the three subsets, as more than 80% of classical and intermediate monocytes were CD80+CD163+, whereas most non-classical monocytes were CD80-CD163- and CD163+. Non-classical CD163+ monocytes were significantly higher whereas classical CD163+ and CD80-CD163- monocytes significantly lower in older than younger CTRs (cut-off, 65 years), suggesting different age-related trends for M2 subsets. To establish whether an M1/M2 imbalance could be associated with disease, 21 patients with acute myocardial infarction (AMI) were compared with older CTRs. The AMI patients showed a significantly decreased proportion of CD163+CD80+ and an increased proportion of CD163+ and CD163-CD80- cells among classical monocytes, opposite trends to those observed in healthy aging. Moreover, a significantly greater proportion of intermediate and non-classical CD80+ monocytes suggested a shift to a pro-inflammatory phenotype. Overall, CD163/CD80 cytofluorimetric characterization of circulating monocytes provides additional information about their polarization and could be an innovative tool to monitor aging.
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- 2018
39. Convergent adaptation of cellular machineries in the evolution of large body masses and long life spans
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Gianluca Storci, Silvia Marchionni, Claudio Franceschi, Eleonora Croco, Thomas D. Stamato, Massimiliano Bonafè, Antonello Lorenzini, Christian Sell, Croco, E, Marchionni, S, Storci, G, Bonafè, M, Franceschi, C, Stamato, Td, Sell, C, and Lorenzini, A.
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Genomic stability ,0301 basic medicine ,Genome instability ,Aging ,DNA damage ,Cellular differentiation ,media_common.quotation_subject ,Longevity ,Review Article ,Biology ,Models, Biological ,Genomic Instability ,03 medical and health sciences ,Convergent evolution ,Animals ,Humans ,Cellular Senescence ,media_common ,Genetics ,Natural selection ,Age Factors ,Telomere Homeostasis ,Body size ,Biological Evolution ,030104 developmental biology ,Evolutionary biology ,Replicative senescence ,Geriatrics and Gerontology ,Adaptation ,Energy Metabolism ,Gerontology ,Developmental biology - Abstract
In evolutionary terms, life on the planet has taken the form of independently living cells for the majority of time. In comparison, the mammalian radiation is a relatively recent event. The common mammalian ancestor was probably small and short-lived. The "recent" acquisition of an extended longevity and large body mass of some species of mammals present on the earth today suggests the possibility that similar cellular mechanisms have been influenced by the forces of natural selection to create a convergent evolution of longevity. Many cellular mechanisms are potentially relevant for extending longevity; in this assay, we review the literature focusing primarily on two cellular features: (1) the capacity for extensive cellular proliferation of differentiated cells, while maintaining genome stability; and (2) the capacity to detect DNA damage. We have observed that longevity and body mass are both positively linked to these cellular mechanisms and then used statistical tools to evaluate their relative importance. Our analysis suggest that the capacity for extensive cellular proliferation while maintaining sufficient genome stability, correlates to species body mass while the capacity to correctly identify the presence of DNA damage seems more an attribute of long-lived species. Finally, our data are in support of the idea that a slower development, allowing for better DNA damage detection and handling, should associate with longer life span.
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- 2017
40. NMR-Based Metabolomic Approach Tracks Potential Serum Biomarkers of Disease Progression in Patients with Type 2 Diabetes Mellitus
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Francesco Prattichizzo, Gianluca Storci, Francesco Paolo Fanizzi, Emanuela Mensà, Sara Bravaccini, Anna Rita Bonfigli, Andrea Ragusa, Massimiliano Bonafè, Andrea Casadei-Gardini, Daniele Vergara, Jacopo Sabbatinelli, Francesca Pirini, Serena De Matteis, Anna Maria Giudetti, Michele Maffia, Laura Del Coco, Fabiola Olivieri, Del Coco, Laura, Vergara, Daniele, De Matteis, Serena, Mensà, Emanuela, Sabbatinelli, Jacopo, Prattichizzo, Francesco, Bonfigli, Anna Rita, Storci, Gianluca, Bravaccini, Sara, Pirini, Francesca, Ragusa, Andrea, Casadei-Gardini, Andrea, Bonafè, Massimiliano, Maffia, Michele, Fanizzi, Francesco Paolo, Olivieri, Fabiola, Giudetti, Anna Maria, Del Coco, L, Vergara, D, De Matteis, S, Mensà, E, Sabbatinelli, J, Prattichizzo, F, Bonfigli, Ar, Storci, G, Bravaccini, S, Pirini, F, Ragusa, A, Casadei-Gardini, A, Bonafè, M, Maffia, M, Fanizzi, Fp, Olivieri, F, and Giudetti, Am
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medicine.medical_specialty ,branched-chain amino acid ,endocrine system diseases ,type 2 diabetes mellitus ,medicine.medical_treatment ,Protein metabolism ,lcsh:Medicine ,Gastroenterology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,NMR spectroscopy ,Valine ,Internal medicine ,medicine ,Metabolome ,branched-chain amino acids ,030304 developmental biology ,0303 health sciences ,Methionine ,business.industry ,Insulin ,Metabolic disorder ,lcsh:R ,Type 2 Diabetes Mellitus ,nutritional and metabolic diseases ,General Medicine ,medicine.disease ,metabolomics ,Glutamine ,chemistry ,030220 oncology & carcinogenesis ,business ,metabolomic - Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia associated with alterations in carbohydrate, lipid, and protein metabolism. The prognosis of T2DM patients is highly dependent on the development of complications, and therefore the identification of biomarkers of T2DM progression, with minimally invasive techniques, is a huge need. In the present study, we applied a 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomic approach coupled with multivariate data analysis to identify serum metabolite profiles associated with T2DM development and progression. To perform this, we compared the serum metabolome of non-diabetic subjects, treatment-naï, ve non-complicated T2DM patients, and T2DM patients with complications in insulin monotherapy. Our analysis revealed a significant reduction of alanine, glutamine, glutamate, leucine, lysine, methionine, tyrosine, and phenylalanine in T2DM patients with respect to non-diabetic subjects. Moreover, isoleucine, leucine, lysine, tyrosine, and valine levels distinguished complicated patients from patients without complications. Overall, the metabolic pathway analysis suggested that branched-chain amino acid (BCAA) metabolism is significantly compromised in T2DM patients with complications, while perturbation in the metabolism of gluconeogenic amino acids other than BCAAs characterizes both early and advanced T2DM stages. In conclusion, we identified a metabolic serum signature associated with T2DM stages. These data could be integrated with clinical characteristics to build a composite T2DM/complications risk score to be validated in a prospective cohort.
- Published
- 2019
41. Electrospun Patch Functionalized with Nanoparticles Allows for Spatiotemporal Release of VEGF and PDGF-BB Promoting In Vivo Neovascularization
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Aaron Shi, Laura Pandolfi, Silvia Minardi, Ennio Tasciotti, Francesca Taraballi, Xin Wang, Gianluca Storci, Troy Hendrickson, Cristina Lupo, Christopher Tsao, Michael Evangelopoulos, Tsao, Christopher J., Pandolfi, Laura, Wang, Xin, Minardi, Silvia, Lupo, Cristina, Evangelopoulos, Michael, Hendrickson, Troy, Shi, Aaron, Storci, Gianluca, Taraballi, Francesca, and Tasciotti, Ennio
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0301 basic medicine ,Vascular Endothelial Growth Factor A ,Materials science ,Becaplermin ,Nanoparticle ,Neovascularization, Physiologic ,cardiomyocyte ,02 engineering and technology ,Nanomaterials ,Neovascularization ,03 medical and health sciences ,Tissue engineering ,Polylactic Acid-Polyglycolic Acid Copolymer ,In vivo ,medicine ,Animals ,General Materials Science ,Myocytes, Cardiac ,electrospinning ,Cell Proliferation ,Drug Implants ,biology ,Tissue Engineering ,growth factor ,021001 nanoscience & nanotechnology ,Silicon Dioxide ,Electrospinning ,Rats ,030104 developmental biology ,Toxicity ,biology.protein ,Biophysics ,Nanoparticles ,porous silica ,Materials Science (all) ,neovascularization ,medicine.symptom ,0210 nano-technology ,Porosity ,Platelet-derived growth factor receptor - Abstract
The use of nanomaterials as carriers for the delivery of growth factors has been applied to a multitude of applications in tissue engineering. However, issues of toxicity, stability, and systemic effects of these platforms have yet to be fully understood, especially for cardiovascular applications. Here, we proposed a delivery system composed of poly(dl-lactide- co-glycolide) acid (PLGA) and porous silica nanoparticles (pSi) to deliver vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The tight spatiotemporal release of these two proteins has been proven to promote neovascularization. In order to minimize tissue toxicity, localize the release, and maintain a stable platform, we conjugated two formulations of PLGA-pSi to electrospun (ES) gelatin to create a combined ES patch releasing both PDGF and VEGF. When compared to freely dispersed particles, the ES patch cultured in vitro with neonatal cardiac cells had significantly less particle internalization (2.0 ± 1.3%) compared to free PLGA-pSi (21.5 ± 6.1) or pSi (28.7 ± 2.5) groups. Internalization was positively correlated to late-stage apoptosis with PLGA-pSi and pSi groups having increased apoptosis compared to the untreated group. When implanted subcutaneously, the ES patch was shown to have greater neovascularization than controls evidenced by increased expression of α-SMA and CD31 after 21 days. Quantitative reverse transcription-polymerase chain reaction results support increased angiogenesis by the upregulation of VEGFA, VEGFR2, vWF, and COL3A1, exhibiting a synergistic effect with the release of VEGF-A164 and PDGF-BB after 21 days in vivo. The results of this study proved that the ES patch reduced cellular toxicity and may be tailored to have a dual release of growth factors promoting localized neovascularization.
- Published
- 2018
42. Small extracellular vesicles deliver miR‐21 and miR‐217 as pro‐senescence effectors to endothelial cells
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Rina Recchioni, Massimo Negrini, Vladia Monsurrò, Gianluca Fulgenzi, Claudia Sala, Maria Giulia Bacalini, Silvia Latini, Paolo Garagnani, Stefano Amatori, Massimiliano Bonafè, Angelica Giuliani, Fiorella Marcheselli, Anna Rita Bonfigli, Deborah Ramini, Maurizio Cardelli, Mirco Fanelli, Giacomo Corleone, Jacopo Sabbatinelli, Cristian Bassi, Michela Battistelli, Francesco Prattichizzo, Gianluca Storci, Emanuela Mensà, Vilberto Stocchi, Antonio Domenico Procopio, Fabiola Olivieri, Manuela Ferracin, Serena Maggio, Michele Guescini, Leonardo Sorci, Antonio Ceriello, Laura Graciotti, Maria Rita Rippo, Luca Magnani, Claudio Franceschi, Maria De Luca, Iva Budimir, Mensa E., Guescini M., Giuliani A., Bacalini M.G., Ramini D., Corleone G., Ferracin M., Fulgenzi G., Graciotti L., Prattichizzo F., Sorci L., Battistelli M., Monsurro V., Bonfigli A.R., Cardelli M., Recchioni R., Marcheselli F., Latini S., Maggio S., Fanelli M., Amatori S., Storci G., Ceriello A., Stocchi V., De Luca M., Magnani L., Rippo M.R., Procopio A.D., Sala C., Budimir I., Bassi C., Negrini M., Garagnani P., Franceschi C., Sabbatinelli J., Bonafe M., and Olivieri F.
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0301 basic medicine ,Histology ,sirt1 ,Biology ,Cellular senescence ,Exosome ,03 medical and health sciences ,SIRT1 ,0302 clinical medicine ,Gene interaction ,dnmt1 ,microRNA ,cellular senescence ,Epigenetics ,lcsh:QH573-671 ,micrornas ,lcsh:Cytology ,DNMT1 ,Cell Biology ,Cell cycle ,microRNAs ,Cell biology ,Endothelial stem cell ,030104 developmental biology ,030220 oncology & carcinogenesis ,DNA methylation ,extracellular vesicles ,extracellular vesicle ,Cell aging ,Research Article - Abstract
The role of epigenetics in endothelial cell senescence is a cutting-edge topic in ageing research. However, little is known of the relative contribution to pro-senescence signal propagation provided by microRNAs shuttled by extracellular vesicles (EVs) released from senescent cells. Analysis of microRNA and DNA methylation profiles in non-senescent (control) and senescent (SEN) human umbilical vein endothelial cells (HUVECs), and microRNA profiling of their cognate small EVs (sEVs) and large EVs demonstrated that SEN cells released a significantly greater sEV number than control cells. sEVs were enriched in miR-21-5p and miR-217, which target DNMT1 and SIRT1. Treatment of control cells with SEN sEVs induced a miR-21/miR-217-related impairment of DNMT1-SIRT1 expression, the reduction of proliferation markers, the acquisition of a senescent phenotype and a partial demethylation of the locus encoding for miR-21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40–100 years showed an inverse U-shaped age-related trend for miR-21-5p, consistent with senescence-associated biomarker profiles. Our findings suggest that miR-21-5p/miR-217 carried by SEN sEVs spread pro-senescence signals, affecting DNA methylation and cell replication.
- Published
- 2020
43. Intrabone transplant provides full stemness of cord blood stem cells with fast hematopoietic recovery and low GVHD rate: results from a prospective study
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Francesca Bonifazi, Valeria Giudice, Maria Rosa Motta, Gianluca Storci, Mariarosaria Sessa, Viviana Guadagnuolo, Martina Ferioli, Simonetta Rizzi, Elisa Dan, Michele Cavo, Barbara Sinigaglia, Massimiliano Bonafè, Sabrina De Carolis, Giovanni Martinelli, Andrea Bontadini, Myriam Labopin, Mario Arpinati, Alma Mater Studiorum Universita' di Bologna, DIPARTIMENTO DI MEDICINA SPECIALISTICA, DIAGNOSTICA E SPERIMENTALE, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, Facolta' di MEDICINA e CHIRURGIA, Bonifazi, Francesca, Dan, Elisa, Labopin, Myriam, Sessa, Mariarosaria, Guadagnuolo, Viviana, Ferioli, Martina, Rizzi, Simonetta, De Carolis, Sabrina, Sinigaglia, Barbara, Motta, Maria Rosa, Bontadini, Andrea, Giudice, Valeria, Martinelli, Giovanni, Arpinati, Mario, Cavo, Michele, Bonafé, Massimiliano, and Storci, Gianluca
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Graft vs Host Disease ,Cell Count ,Diseases ,Cord Blood Stem Cell Transplantation ,Human leukocyte antigen ,Umbilical cord ,CXCR4 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Medical research ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,hematopoietic malignancies ,Prospective Studies ,Transplantation ,Umbilical Cord Blood ,business.industry ,Stem Cells ,Hematology ,Recovery of Function ,Middle Aged ,Hematopoiesis ,Haematopoiesis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cord blood ,Hematologic Neoplasms ,Umbilical Cord Blood, hematopoietic malignancies ,Female ,Stem cell ,business ,030215 immunology - Abstract
open 17 no We thank Rita Bertoni and Antonella Orlando for the technical assistance. This work has been supported by Bologna AIL (Italian Association against Leukemia, Lymphoma and Myeloma), Roberto and Cornelia Pallotti Legacy for Cancer Research (University of Bologna) to M.B., and REUSE with Love ONLUS, Bologna, Italy. Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 ± 9% (ANC > 0.5 × 109/L) and 70 ± 10% (platelet > 50 × 109/L) and correlated with CD34 + cells in the graft. NRM was 20 ± 9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO2), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche. none none Bonifazi, Francesca; Dan, Elisa; Labopin, Myriam; Sessa, Mariarosaria; Guadagnuolo, Viviana; Ferioli, Martina; Rizzi, Simonetta; De Carolis, Sabrina; Sinigaglia, Barbara; Motta, Maria Rosa; Bontadini, Andrea; Giudice, Valeria; Martinelli, Giovanni; Arpinati, Mario; Cavo, Michele; Bonafé, Massimiliano; Storci, Gianluca Bonifazi, Francesca; Dan, Elisa; Labopin, Myriam; Sessa, Mariarosaria; Guadagnuolo, Viviana; Ferioli, Martina; Rizzi, Simonetta; De Carolis, Sabrina; Sinigaglia, Barbara; Motta, Maria Rosa; Bontadini, Andrea; Giudice, Valeria; Martinelli, Giovanni; Arpinati, Mario; Cavo, Michele; Bonafé, Massimiliano; Storci, Gianluca
- Published
- 2018
44. Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells
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Gianluca Storci, Alberto Papi, Nicola Avenia, Massimiliano Bonafè, Angelo Sidoni, Marina Orlandi, Alessandro Sanguinetti, Donatella Santini, S De Carolis, Mario Taffurelli, Claudio Ceccarelli, Tiziana Guarnieri, Alessio Papi, Tiziana Guarnieri, Gianluca Storci, Donatella Santini, Claudio Ceccarelli, Mario Taffurelli, Sabrina De Caroli, Nicola Avenia, Alessandro Sanguinetti, Angelo Sidoni, Marina Orlandi, and Massimiliano Bonafé
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medicine.medical_specialty ,Cell Survival ,Receptors, Retinoic Acid ,Retinoic acid ,Receptors, Cytoplasmic and Nuclear ,Breast Neoplasms ,Tretinoin ,Biology ,Retinoid X receptor ,Nuclear receptors ,inflammation ,breast cancer ,stem cells ,PPAR ,NUCLEAR RECEPTOR ,chemistry.chemical_compound ,RETINOID ,CANCER STEM CELLS ,Downregulation and upregulation ,Cancer stem cell ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,skin and connective tissue diseases ,Molecular Biology ,Original Paper ,Pioglitazone ,Interleukin-6 ,NF-kappa B ,Cancer ,Cell Biology ,Phenanthrenes ,medicine.disease ,PPAR gamma ,Retinoic acid receptor ,Pyrimidines ,Retinoid X Receptors ,Endocrinology ,chemistry ,Nuclear receptor ,Neoplastic Stem Cells ,Female ,Thiazolidinediones ,Stem cell - Abstract
Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells, unravelling differences with respect to their normal counterparts. Expansion of mammospheres is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded mammospheres from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-hydroxidrofenantrene), retinoic acid receptor (all-trans retinoic acid) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone), reduce the survival of mammospheres generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-κB/Interleukin-6 axis that is hyperactive in breast cancer-derived mammospheres. The hindrance of such pathway associates with the down-regulation of mammospheres regulatory genes (SLUG, Notch3, Jagged1) and with the up-regulation of the differentiation markers estrogen receptor-α and keratin18. At variance, the PPARα agonist Wy14643 promotes mammospheres formation, up-regulating Nuclear Factor-κB/Interleukin-6 axis and mammosphere regulatory genes. These data reveal that nuclear receptors agonists (6-OH-hydroxidrofenantrene, all-trans retinoic acid, pioglitazone) reduce the inflammation dependent survival of breast cancer stem cells and that PPARα agonist Wy14643 exerts opposite effects on this phenotype.
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- 2012
45. PPARγ and RXR Ligands Disrupt the Inflammatory Cross-talk in the Hypoxic Breast Cancer Stem Cells Niche
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Mario Taffurelli, Sabrina De Carolis, Massimiliano Bonafè, Alessio Papi, Gianluca Storci, Marina Orlandi, Sara Bertoni, Donatella Santini, Virginia Sceberras, and Claudio Ceccarelli
- Subjects
chemistry.chemical_classification ,medicine.medical_specialty ,Cellular pathology ,Physiology ,Clinical Biochemistry ,Peroxisome proliferator-activated receptor ,Cell Biology ,Biology ,Retinoid X receptor ,Endocrinology ,Nuclear receptor ,chemistry ,Cancer stem cell ,Internal medicine ,Cancer cell ,medicine ,Cancer research ,Stem cell ,Receptor - Abstract
Cancer stem cells (CSCs) are affected by the local micro-environment, the niche, in which inflammatory stimuli and hypoxia act as steering factors. Here, two nuclear receptors (NRs) agonists, i.e. pioglitazone (PGZ), a ligand of peroxisome proliferator activated receptor-γ, and 6-OH-11-O-hydroxyphenanthrene (IIF), a ligand of retinoid X receptors, were investigated for their capability to interference with the cross-talk between breast CSCs and the niche compartment. We found that IIF potentiates the ability of PGZ to hamper the mammospheres-forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, Interleukin-6, Apolipoprotein E, Hypoxia inducible factor-1α and Carbonic anhydrase IX). Notably, these effects are not observed in normal-MS obtained from human breast tissue. Importantly, NRs agonists abolish the capability of hypoxic MCF7 derived exosomes to induce a pro-inflammatory phenotype in mammary glands fibroblasts. Moreover, NRs agonist also directly acts on breast tumour associated fibroblasts to downregulate nuclear factor-κB pathway and metalloproteinases (MMP2 and MMP9) expression and activity. In conclusion, NRs agonists disrupt the inflammatory cross-talk of the hypoxic breast CSCs niche.
- Published
- 2014
46. The decrease of cell membrane fluidity by the non-steroidal anti-inflammatory drug Licofelone inhibits epidermal growth factor receptor signalling and triggers apoptosis in HCA-7 colon cancer cells
- Author
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Gianluca Storci, Simona Tavolari, Tiziana Guarnieri, Stefan Laufer, Pasquale Chieco, Alessandra Munarini, Tavolari S, Munarini A, Storci G, Laufer S, Chieco P, and Guarnieri T.
- Subjects
LICOFELONE ,MAPK/ERK pathway ,Cancer Research ,Cell Survival ,Membrane Fluidity ,Blotting, Western ,Fluorescent Antibody Technique ,Apoptosis ,COLON CANCER ,Cell membrane ,chemistry.chemical_compound ,Cell Line, Tumor ,Membrane fluidity ,medicine ,Humans ,Pyrroles ,Epidermal growth factor receptor ,Kinase activity ,Protein kinase B ,EPIDERMAL GROWTH FACTOR RECEPTOR ,biology ,Anti-Inflammatory Agents, Non-Steroidal ,Cell Membrane ,Cell biology ,ErbB Receptors ,medicine.anatomical_structure ,Oncology ,chemistry ,Colonic Neoplasms ,Cancer research ,biology.protein ,Mitogen-Activated Protein Kinases ,Signal transduction ,Licofelone ,Signal Transduction - Abstract
The ability to induce changes in cell membrane properties is nowadays considered an additional mechanism to explain the pharmacological effects of non-steroidal anti-inflammatory drugs (NSAIDs). We previously demonstrated that the NSAID Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, triggers apoptosis in HCA-7 colon cancer cells independently from the inhibition of these enzymes. Here, we provide evidence that, in HCA-7 cells, the pro-apoptotic effect of this drug relies, at least in part, on its ability to inhibit epidermal growth factor receptor (EGFR) signalling by a decrease of cell membrane fluidity. Indeed, Licofelone induced a relevant change in the relative proportions of some saturated, monounsaturated and polyunsaturated fatty acids constituting HCA-7 phospholipid fraction, and significantly increased the levels of cholesterol in HCA-7 cell membrane. All of these changes resulted in a remarkable decrease of membrane fluidity. Such phenomenon was associated with the block of EGFR kinase activity and of its downstream targets, the p44-42 mitogen-activated protein kinase (MAPK) and AKT cascades, whose inhibitions were found to induce apoptosis in HCA-7 cells. Overall, these findings provide a new additional mechanism by which NSAIDs are effective toward colon cancer cells.
- Published
- 2012
47. Novel Dyskerin-Mediated Mechanism of p53 Inactivation through Defective mRNA Translation
- Author
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Pasquale Sansone, Lorenzo Montanaro, Domenica Carnicelli, Laura Rocchi, Claudio Ceccarelli, Gianluca Storci, Davide Treré, Massimo Derenzini, Maurizio Brigotti, Sara Bertoni, Donatella Santini, Maria Calienni, Mario Taffurelli, Massimiliano Bonafè, Montanaro L, Calienni M, Bertoni S, Rocchi L, Sansone P, Storci G, Santini D, Ceccarelli C, Taffurelli M, Carnicelli D, Brigotti M, Bonafé M, Treré D, and Derenzini M
- Subjects
Cancer Research ,Telomerase ,Breast Neoplasms ,Cell Cycle Proteins ,Gene mutation ,Biology ,Dyskerin ,Cell Line, Tumor ,Protein biosynthesis ,Humans ,Gene silencing ,Gene Silencing ,RNA, Messenger ,Regulation of gene expression ,Nuclear Proteins ,Translation (biology) ,Genes, p53 ,Molecular biology ,Cell biology ,Gene Expression Regulation, Neoplastic ,Internal ribosome entry site ,Oncology ,Protein Biosynthesis ,Female ,Tumor Suppressor Protein p53 - Abstract
In up to 60% of human cancers, p53 gene mutations are responsible for direct inactivation of the tumor suppressor function of p53. Alternative mechanisms of p53 inactivation described thus far mainly affect its posttranslational regulation. In X-linked dyskeratosis congenita, a multisystemic syndrome characterized by increased cancer susceptibility, mutations of the DKC1 gene encoding dyskerin cause a selective defect in the translation of a subgroup of internal ribosome entry site (IRES)–containing cellular mRNAs. In this study, we show that impairment of dyskerin function can cause p53 inactivation due to a defect in p53 mRNA translation. siRNA-mediated reduction of dyskerin levels caused a decrease of p53 mRNA translation, protein levels, and functional activity, both in human breast cancer cells and in primary mammary epithelial progenitor cells. These effects seemed to be independent of the known role of dyskerin in telomerase function, and they were associated with a specific impairment of translation initiation mediated by IRES elements present in p53 mRNA. In a series of human primary breast cancers retaining wild-type p53, we found that low levels of dyskerin expression were associated with reduced expression of p53-positive target genes. Our findings suggest that a dyskerin-mediated mechanism of p53 inactivation may occur in a subset of human tumors. Cancer Res; 70(11); 4767–77. ©2010 AACR.
- Published
- 2010
48. Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
- Author
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Gianluca Storci, Pasquale Sansone, Thomas J. Rosol, Tim H M Huang, Michael W.Y. Chan, Simona Tavolari, A. Kate Sasser, Massimiliano Bonafè, Jillian L. Werbeck, Frank C. Marini, Adam W. Studebaker, Brett Hall, Studebaker AW., Storci G., Werbeck JL., Sansone P., Sasser AK., Tavolari S., Huang T., Chan MW., Marini FC., Rosol TJ., Bonafé M., and Hall BM.
- Subjects
STAT3 Transcription Factor ,CA15-3 ,Cancer Research ,Pathology ,medicine.medical_specialty ,CA 15-3 ,Estrogen receptor ,Breast Neoplasms ,Biology ,Breast cancer ,Cell Line, Tumor ,medicine ,Humans ,Immunoprecipitation ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Phosphorylation ,Fibroblast ,Interleukin 6 ,INTERLEUCHINA 6 ,Interleukin-6 ,Cancer ,Fibroblasts ,medicine.disease ,medicine.anatomical_structure ,CANCRO MAMMARIO ,Oncology ,INFIAMMAZIONE ,Culture Media, Conditioned ,Cancer cell ,biology.protein ,Cancer research ,RNA Interference ,Cell Division - Abstract
Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor α (ERα)–positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ERα-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3–dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics. [Cancer Res 2008;68(21):9087–95]
- Published
- 2008
49. The basal-like breast carcinoma phenotype is regulated bySLUGgene expression
- Author
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Tiziana Guarnieri, Simona Tavolari, Davide Treré, M. Pariali, Lorenzo Montanaro, Massimiliano Bonafè, Pasquale Chieco, Paola Paterini, Pasquale Sansone, Mario Taffurelli, Claudio Ceccarelli, Gianluca Storci, Donatella Santini, G. Storci, P. Sansone, D. Trere, S. Tavolari, M. Taffurelli, C. Ceccarelli, T. Guarnieri, P. Paterini, M. Pariali, L. Montanaro, D. Santini, P. Chieco, and M. Bonafè.
- Subjects
Pathology ,HYPOXIA ,SLUG ,Mice ,RNA, Neoplasm ,skin and connective tissue diseases ,Carbonic Anhydrases ,Aged, 80 and over ,Carcinoma, Ductal, Breast ,Middle Aged ,CANCER ,Cell Hypoxia ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Ductal Breast Carcinoma ,Phenotype ,embryonic structures ,BASAL-LIKE BREAST CARCINOMA ,Neoplastic Stem Cells ,Female ,Stem cell ,Breast carcinoma ,Adult ,medicine.medical_specialty ,Slug ,Mice, Nude ,Breast Neoplasms ,Biology ,Pathology and Forensic Medicine ,Breast cancer ,Antigens, Neoplasm ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,Progenitor cell ,Carbonic Anhydrase IX ,Aged ,fungi ,Estrogen Receptor alpha ,Cancer ,medicine.disease ,biology.organism_classification ,Basal-Like Breast Carcinoma ,Cancer research ,Snail Family Transcription Factors ,Neoplasm Transplantation ,STEM CELLS ,Transcription Factors - Abstract
Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence of oestrogen receptor and HER2 expression, the presence of cytokeratin 5 and epidermal growth factor receptor expression, and by the up-regulation of stem cell regulatory genes. We show here that tumour tissues expressing high levels of SLUG mRNA show a basal-like breast carcinoma phenotype and that such tumours also express high levels of stem cell-regulatory genes, ie CD133, Bmi1. Further, we show that stem/progenitor cells, isolated from ductal breast carcinoma and from normal mammary gland as mammospheres, express SLUG, CD133, and Bmi1 mRNA and show a phenotype similar to that of basal-like breast carcinoma. We also report that SLUG expression in tumour tissues correlates with that of the hypoxia survival gene carbonic anhydrase IX. In this regard, we report that the exposure of SLUG-negative/luminal-like MCF-7 cells to a hypoxic environment promotes the onset of the basal-like breast carcinoma phenotype, together with up-regulation of the SLUG gene, which in turn blunts oestrogen receptor-α and boosts carbonic anhydrase IX gene expression. Finally, we show that SLUG expression promotes the invasiveness of MCF-7 cells exposed to hypoxia and sustains the in vivo aggressiveness of hypoxia-selected, MCF-7-derived cells in xenografts. These data indicate that SLUG gene expression is part of a hypoxia-induced genetic programme which sets up a basal/stem cell-like, aggressive phenotype in breast cancer cells. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2008
50. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland
- Author
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Gianluca Storci, Mario Taffurelli, Pasquale Chieco, Simona Tavolari, Massimiliano Bonafè, Paola Paterini, Tiziana Guarnieri, Catia Giovannini, Kenneth B. Marcu, Claudio Ceccarelli, Pasquale Sansone, Donatella Santini, P. Sansone, G. Storci, S. Tavolari, T. Guarnieri, C. Giovannini, M. Taffurelli, C. Ceccarelli, D. Santini, P. Paterini, K. B. Marcu, P. Chieco, and M. Bonafè.
- Subjects
Basal-like carcinoma ,Pathology ,medicine.medical_specialty ,Mammary gland ,Cancer ,General Medicine ,Biology ,medicine.disease ,CANCER ,INTERLEUKIN 6 ,Ductal Breast Carcinoma ,medicine.anatomical_structure ,Breast cancer ,CARBONIC ANHYDRASE ,BASAL LIKE CARCINOMA ,medicine ,Stem cell ,Progenitor cell ,skin and connective tissue diseases ,Breast carcinoma ,STEM CELLS - Abstract
High serum levels of the pro-inflammatory cytokine Interleukin-6 (IL-6) correlate with poor outcome in breast cancer patients. No data are available on the relationship between IL-6 gene regulation and those cells which are currently considered at the origin of breast cancer, i.e. cancer stem cells. We here report that stem/progenitor cells of the mammary gland, isolated from node invasive breast carcinoma tissues and expanded in vitro as multicellular spheroids (mammospheres, MS), express higher IL-6 mRNA levels in respect to MS isolated from the same patient normal mammary gland. Moreover, IL-6 mRNA is detectable only in basal-like breast carcinoma tumor tissues, a type of aggressive cancer endowed with stem cell features. We then show that the stem cells regulatory gene Notch-3 is a crucial mediator of IL-6 activity. Indeed, IL-6 triggers a Notch-3 dependent up-regulation of the Notch ligand Jagged-1, whose interaction with Notch-3 promotes the growth of spheroids and MS. Moreover, IL-6 induces a Notch-3 dependent up-regulation of the hypoxia survival gene carbonic anhydrase IX, which is responsible for a hypoxia-resistant/invasive phenotype in breast cancer cells and MS. Finally, we convey that the autocrine IL-6 loop in breast cancer cells requires the presence of Notch-3 gene up-regulation. In conclusion, our data support the hypothesis that IL-6 triggers malignant features in Notch-3 expressing cells, such as putative stem cells of normal and tumor mammary gland.
- Published
- 2007
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