Gabriele Toietta

@ifo.it

IRCCS Regina Elena National Cancer Institute



                    

https://researchid.co/gtoietta
14

Scopus Publications

827

Scholar Citations

7

Scholar h-index

11

Scholar i10-index

Scopus Publications

  • Expression pattern and prognostic significance of aldehyde dehydrogenase 2 in lung adenocarcinoma as a potential predictor of immunotherapy efficacy
    Silvia Baldari, Annalisa Antonini, Giuliana Di Rocco, and Gabriele Toietta
    Wiley
    AbstractBackgroundThe incidence of alcohol‐associated cancers is higher within Asian populations having an increased prevalence of an inactivating mutation in aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme required for the clearance of acetaldehyde, a cytotoxic metabolite of ethanol. The role of alcohol consumption in promoting lung cancer is controversial, and little attention has been paid to the association between alcohol drinking and pulmonary ALDH2 expression.MethodsWe performed a comprehensive bioinformatic analysis of multi‐omics data available in public databases to elucidate the role of ALDH2 in lung adenocarcinoma (LUAD).ResultsTranscriptional and proteomic data indicate a substantial pulmonary expression of ALDH2, which is functional for the metabolism of alcohol diffused from the bronchial circulation. ALDH2 expression is higher in healthy lung tissue than in LUAD and inhibits cell cycle, apoptosis, and epithelial–mesenchymal transition pathways. Moreover, low ALDH2 mRNA levels predict poor prognosis and low overall survival in LUAD patients. Interestingly, ALDH2 expression correlates with immune infiltration in LUAD.ConclusionsA better understanding of the role of ALDH2 in lung tumor progression and immune infiltration might support its potential use as a prognostic marker and therapeutic target for improving immunotherapeutic response.

  • Dissecting human adipose tissue heterogeneity using single-cell omics technologies
    Giuliana Di Rocco, Angelo Trivisonno, Giovanni Trivisonno, and Gabriele Toietta
    Springer Science and Business Media LLC
    AbstractSingle-cell omics technologies that profile genes (genomic and epigenomic) and determine the abundance of mRNA (transcriptomic), protein (proteomic and secretomic), lipids (lipidomic), and extracellular matrix (matrisomic) support the dissection of adipose tissue heterogeneity at unprecedented resolution in a temporally and spatially defined manner. In particular, cell omics technologies may provide innovative biomarkers for the identification of rare specific progenitor cell subpopulations, assess transcriptional and proteomic changes affecting cell proliferation and immunomodulatory potential, and accurately define the lineage hierarchy and differentiation status of progenitor cells. Unraveling adipose tissue complexity may also provide for the precise assessment of a dysfunctional state, which has been associated with cancer, as cancer-associated adipocytes play an important role in shaping the tumor microenvironment supporting tumor progression and metastasis, obesity, metabolic syndrome, and type 2 diabetes mellitus. The information collected by single-cell omics has relevant implications for regenerative medicine because adipose tissue is an accessible source of multipotent cells; alternative cell-free approaches, including the use of adipose tissue stromal cell-conditioned medium, extracellular vesicles, or decellularized extracellular matrix, are clinically valid options. Subcutaneous white adipose tissue, which is generally harvested via liposuction, is highly heterogeneous because of intrinsic biological variability and extrinsic inconsistencies in the harvesting and processing procedures. The current limited understanding of adipose tissue heterogeneity impinges on the definition of quality standards appropriate for clinical translation, which requires consistency and uniformity of the administered product. We review the methods used for dissecting adipose tissue heterogeneity and provide an overview of advances in omics technology that may contribute to the exploration of heterogeneity and dynamics of adipose tissue at the single-cell level.

  • The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer
    Maddalena Di Nardo, Simonetta Astigiano, Silvia Baldari, Maria Michela Pallotta, Giovanni Porta, Simona Pigozzi, Annalisa Antonini, Laura Emionite, Annalisa Frattini, Roberto Valli,et al.
    Springer Science and Business Media LLC
    Abstract Background SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC. Methods At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo. Results We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes. Conclusions These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC.

  • Cancer immunity and immunotherapy beyond COVID-19
    Matteo Bellone, Arianna Brevi, Vincenzo Bronte, Silvia Dusi, Pier Francesco Ferrucci, Paola Nisticò, Antonio Rosato, Vincenzo Russo, Antonio Sica, Gabriele Toietta,et al.
    Springer Science and Business Media LLC

  • Direct CD32 T-cell cytotoxicity: implications for breast cancer prognosis and treatment
    Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, Roberto Arriga, Sara Caratelli, Ken Chen, Jinzhuang Dou, Carlo Cenciarelli,et al.
    Life Science Alliance, LLC
    The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice from subcutaneous growth of MDA-MB-468 BC cells. RNAseq analysis identified a 42 gene fingerprint predicting BC cell sensitivity and favorable outcomes in advanced BC. ICAM1 was a major regulator of CD32-CR T cell–mediated cytotoxicity. CD32-CR T cells may help identify cell surface CD32 ligand(s) and novel prognostically relevant transcriptomic signatures and develop innovative BC treatments.

  • Strategies for Efficient Targeting of Tumor Collagen for Cancer Therapy
    Silvia Baldari, Francesca Di Modugno, Paola Nisticò, and Gabriele Toietta
    MDPI AG
    The tumor stroma, which comprises stromal cells and non-cellular elements, is a critical component of the tumor microenvironment (TME). The dynamic interactions between the tumor cells and the stroma may promote tumor progression and metastasis and dictate resistance to established cancer therapies. Therefore, novel antitumor approaches should combine anticancer and anti-stroma strategies targeting dysregulated tumor extracellular matrix (ECM). ECM remodeling is a hallmark of solid tumors, leading to extensive biochemical and biomechanical changes, affecting cell signaling and tumor tissue three-dimensional architecture. Increased deposition of fibrillar collagen is the most distinctive alteration of the tumor ECM. Consequently, several anticancer therapeutic strategies have been developed to reduce excessive tumor collagen deposition. Herein, we provide an overview of the current advances and challenges of the main approaches aiming at tumor collagen normalization, which include targeted anticancer drug delivery, promotion of degradation, modulation of structure and biosynthesis of collagen, and targeting cancer-associated fibroblasts, which are the major extracellular matrix producers.

  • Cancer bio-immunotherapy XVIII annual NIBIT-(Italian network for tumor biotherapy) meeting, October 15–16, 2020
    Matteo Bellone, Arianna Brevi, Vincenzo Bronte, Silvia Dusi, Pier Francesco Ferrucci, Paola Nisticò, Antonio Rosato, Vincenzo Russo, Antonio Sica, Gabriele Toietta,et al.
    Springer Science and Business Media LLC

  • HIPK2 Cooperates with KRAS Signaling and Associates with Colorectal Cancer Progression
    Micol Di Segni, Ilaria Virdia, Alessandra Verdina, Carla Azzurra Amoreo, Silvia Baldari, Gabriele Toietta, Maria Grazia Diodoro, Marcella Mottolese, Isabella Sperduti, Fabiola Moretti,et al.
    American Association for Cancer Research (AACR)
    Abstract Homeodomain-interacting protein kinase 2 (HIPK2) is an evolutionary conserved kinase that has gained attention as a fine tuner of multiple signaling pathways, among which those commonly altered in colorectal cancer. The aim of this study was to evaluate the relationship of HIPK2 expression with progression markers and mutational pattern and gain insights into the contribution of HIPK2 activity in colorectal cancer. We evaluated a retrospective cohort of colorectal cancer samples by IHC for HIPK2 expression and by next-generation sequencing (NGS) for the detection of mutations of cancer associated genes. We show that the percentage of HIPK2-positive cells increases with tumor progression, significantly correlates with tumor–node–metastasis (TNM) staging and associates with a worse outcome. In addition, we observed that high HIPK2 expression significantly associates with KRAS mutations but not with other cancer-related genes. Functional characterization of the link between HIPK2 and KRAS show that activation of the RAS pathway either due to KRAS mutation or via upstream receptor stimulation, increases HIPK2 expression at the protein level. Of note, HIPK2 physically participates in the active RAS complex while HIPK2 depletion impairs ERK phosphorylation and the growth of tumors derived from KRAS mutated colorectal cancer cells. Overall, this study identifies HIPK2 as a prognostic biomarker candidate in patients with colorectal cancer and underscores a previously unknown functional link between HIPK2 and the KRAS signaling pathway. Implications: Our data indicate HIPK2 as a new player in the complex picture of the KRAS signaling network, providing rationales for future clinical studies and new treatment strategies for KRAS mutated colorectal cancer.

  • Reduction of cell proliferation by acute c2h6o exposure
    Silvia Baldari, Isabella Manni, Giuliana Di Rocco, Francesca Paolini, Belinda Palermo, Giulia Piaggio, and Gabriele Toietta
    MDPI AG
    Endogenous acetaldehyde production from the metabolism of ingested alcohol exposes hematopoietic progenitor cells to increased genotoxic risk. To develop possible therapeutic strategies to prevent or reverse alcohol abuse effects, it would be critical to determine the temporal progression of acute ethanol toxicity on progenitor cell numbers and proliferative status. We followed the variation of the cell proliferation rate in bone marrow and spleen in response to acute ethanol intoxication in the MITO-Luc mouse, in which NF-Y-dependent cell proliferation can be assessed in vivo by non-invasive bioluminescent imaging. One week after ethanol administration, bioluminescent signals in bone marrow and spleen decreased below the level corresponding to physiological proliferation, and they progressively resumed to pre-treatment values in approximately 4 weeks. Boosting acetaldehyde catabolism by administration of an aldehyde dehydrogenase activity activator or administration of polyphenols with antioxidant activity partially restored bone marrow cells’ physiological proliferation. These results indicate that in this mouse model, bioluminescent alteration reflects the reduction of the physiological proliferation rate of bone marrow progenitor cells due to the toxic effect of aldehydes generated by alcohol oxidation. In summary, this study presents a novel view of the impact of acute alcohol intake on bone marrow cell proliferation in vivo.

  • Successful Therapy of Esophageal Fistulas by Endoscopic Injection of Emulsified Adipose Tissue Stromal Vascular Fraction
    Dania Nachira, Angelo Trivisonno, Guido Costamagna, Gabriele Toietta, Stefano Margaritora, Valerio Pontecorvi, Giovanni Punzo, Venanzio Porziella, and Ivo Boškoski
    Elsevier BV

  • Regenerative medicine approaches for the management of respiratory tract fistulas
    Angelo Trivisonno, Dania Nachira, Ivo Boškoski, Venanzio Porziella, Giuliana Di Rocco, Silvia Baldari, and Gabriele Toietta
    Springer Science and Business Media LLC
    Abstract Respiratory tract fistulas (or fistulae) are abnormal communications between the respiratory system and the digestive tract or the adjacent organs. The origin can be congenital or, more frequently, iatrogenic and the clinical presentation is heterogeneous. Respiratory tract fistulas can lead to severely reduced health-related quality of life and short survival. Therapy mainly relies on endoscopic surgical interventions but patients often require prolonged hospitalization and may develop complications. Therefore, more conservative regenerative medicine approaches, mainly based on lipotransfer, have also been investigated. Adipose tissue can be delivered either as unprocessed tissue, or after enzymatic treatment to derive the cellular stromal vascular fraction. In the current narrative review, we provide an overview of the main tissue/cell-based clinical studies for the management of various types of respiratory tract fistulas or injuries. Clinical experience is limited, as most of the studies were performed on a small number of patients. Albeit a conclusive proof of efficacy cannot be drawn, the reviewed studies suggest that grafting of adipose tissue-derived material may represent a minimally invasive and conservative treatment option, alternative to more aggressive surgical procedures. Knowledge on safety and tolerability acquired in prior studies can lead to the design of future, larger trials that may exploit innovative procedures for tissue processing to further improve the clinical outcome.

  • A ruthenium(II)-curcumin compound modulates NRF2 expression balancing the cancer cell death/survival outcome according to p53 status
    Alessia Garufi, Silvia Baldari, Riccardo Pettinari, Maria Saveria Gilardini Montani, Valerio D’Orazi, Giuseppa Pistritto, Alessandra Crispini, Eugenia Giorno, Gabriele Toietta, Fabio Marchetti,et al.
    Springer Science and Business Media LLC
    Abstract Background Tumor progression and tumor response to anticancer therapies may be affected by activation of oncogenic pathways such as the antioxidant one induced by NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor and the pathways modified by deregulation of oncosuppressor p53. Often, oncogenic pathways may crosstalk between them increasing tumor progression and resistance to anticancer therapies. Therefore, understanding that interplay is critical to improve cancer cell response to therapies. In this study we aimed at evaluating NRF2 and p53 in several cancer cell lines carrying different endogenous p53 status, using a novel curcumin compound since curcumin has been shown to target both NRF2 and p53 and have anti-tumor activity. Methods We performed biochemical and molecular studies by using pharmacologic of genetic inhibition of NRF2 to evaluate the effect of curcumin compound in cancer cell lines of different tumor types bearing wild-type (wt) p53, mutant (mut) p53 or p53 null status. Results We found that the curcumin compound induced a certain degree of cell death in all tested cancer cell lines, independently of the p53 status. At molecular level, the curcumin compound induced NRF2 activation, mutp53 degradation and/or wtp53 activation. Pharmacologic or genetic NRF2 inhibition further increased the curcumin-induced cell death in both mutp53- and wtp53-carrying cancer cell lines while it did not increase cell death in p53 null cells, suggesting a cytoprotective role for NRF2 and a critical role for functional p53 to achieve an efficient cancer cell response to therapy. Conclusions These findings underline the prosurvival role of curcumin-induced NRF2 expression in cancer cells even when cells underwent mutp53 downregulation and/or wtp53 activation. Thus, NRF2 inhibition increased cell demise particularly in cancer cells carrying p53 either wild-type or mutant suggesting that p53 is crucial for efficient cancer cell death. These results may represent a paradigm for better understanding the cancer cell response to therapies in order to design more efficient combined anticancer therapies targeting both NRF2 and p53.

  • DHA Affects Microtubule Dynamics Through Reduction of Phospho-TCTP Levels and Enhances the Antiproliferative Effect of T-DM1 in Trastuzumab-Resistant HER2-Positive Breast Cancer Cell Lines
    Silvia D’Amico, Ewa Krasnowska, Isabella Manni, Gabriele Toietta, Silvia Baldari, Giulia Piaggio, Marco Ranalli, Alessandra Gambacurta, Claudio Vernieri, Flavio Di Giacinto,et al.
    MDPI AG
    Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugated to the microtubule-targeting agent emtansine (DM1). T-DM1 is an effective agent in the treatment of patients with HER2-positive breast cancer whose disease has progressed on the first-line trastuzumab containing chemotherapy. However, both primary and acquired tumour resistance limit its efficacy. Increased levels of the phosphorylated form of Translationally Controlled Tumour Protein (phospho-TCTP) have been shown to be associated with a poor clinical response to trastuzumab therapy in HER2-positive breast cancer. Here we show that phospho-TCTP is essential for correct mitosis in human mammary epithelial cells. Reduction of phospho-TCTP levels by dihydroartemisinin (DHA) causes mitotic aberration and increases microtubule density in the trastuzumab-resistant breast cancer cells HCC1954 and HCC1569. Combinatorial studies show that T-DM1 when combined with DHA is more effective in killing breast cells compared to the effect induced by any single agent. In an orthotopic breast cancer xenograft model (HCC1954), the growth of the tumour cells resumes after having achieved a complete response to T-DM1 treatment. Conversely, DHA and T-DM1 treatment induces a severe and irreversible cytotoxic effect, even after treatment interruption, thus, improving the long-term efficacy of T-DM1. These results suggest that DHA increases the effect of T-DM1 as poison for microtubules and supports the clinical development of the combination of DHA and T-DM1 for the treatment of aggressive HER2-overexpressing breast cancer.

  • Current biomedical use of copper chelation therapy
    Silvia Baldari, Giuliana Di Rocco, and Gabriele Toietta
    MDPI AG
    Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.

  • Extracellular vesicles-encapsulated MicroRNA-125b produced in genetically modified mesenchymal Stromal cells inhibits hepatocellular carcinoma cell proliferation
    Silvia Baldari, Giuliana Di Rocco, Alessandra Magenta, Mario Picozza, and Gabriele Toietta
    MDPI AG
    Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and one of the prominent causes of cancer mortality, leading to approximately 780,000 deaths per year worldwide. Down-regulation of microRNA-125b (miR-125b) is a prognostic indicator in HCC patients. Conversely, over-expression of miR-125b in HCC cells induces cell cycle arrest, inhibits proliferation, migration and invasion. Extracellular vesicles (EVs) function as intercellular messengers transferring proteins, RNAs, DNAs, carbohydrates, and lipids. Since EVs protect their cargo from degradation, delivery of therapeutic bioactive molecules, in particular miRNAs, through EVs represents an innovative avenue for cancer therapy. In this study, we evaluated a replacement strategy for the treatment of HCC via delivery of EVs secreted from human adipose tissue-derived mesenchymal stromal/medicinal signaling cells (ASCs) genetically modified with a lentiviral vector expressing miR-125b with a specific ExoMotif sequence tag to enhance the loading into extracellular vesicles. In particular, we determined that the delivery of miR-125b-loaded EVs produced in engineered ASCs specifically reduces HCC cell proliferation in vitro modulating a series of miR-125b targets, which belong to the p53 signaling pathway. This proof-of-concept study supports the development of innovative therapeutic strategies for HCC via EV-mediated miRNA delivery.

  • Intraoperative Strategies for Minimal Manipulation of Autologous Adipose Tissue for Cell- and Tissue-Based Therapies: Concise Review
    Angelo Trivisonno, Robert W. Alexander, Silvia Baldari, Steven R. Cohen, Giuliana Di Rocco, Pietro Gentile, Guy Magalon, Jérémy Magalon, Randy B. Miller, Hayley Womack,et al.
    Oxford University Press (OUP)
    Abstract The stromal vascular fraction (SVF) is a heterogeneous population of stem/stromal cells isolated from perivascular and extracellular matrix (ECM) of adipose tissue complex (ATC). Administration of SVF holds a strong therapeutic potential for regenerative and wound healing medicine applications aimed at functional restoration of tissues damaged by injuries or chronic diseases. SVF is commonly divided into cellular stromal vascular fraction (cSVF) and tissue stromal vascular fraction (tSVF). Cellular SVF is obtained from ATC by collagenase digestion, incubation/isolation, and pelletized by centrifugation. Enzymatic disaggregation may alter the relevant biological characteristics of adipose tissue, while providing release of complex, multiattachment of cell-to-cell and cell-to-matrix, effectively eliminating the bioactive ECM and periadventitial attachments. In many countries, the isolation of cellular elements is considered as a “more than minimal” manipulation, and is most often limited to controlled clinical trials and subject to regulatory review. Several alternative, nonenzymatic methods of adipose tissue processing have been developed to obtain via minimal mechanical manipulation an autologous tSVF product intended for delivery, reducing the procedure duration, lowering production costs, decreasing regulatory burden, and shortening the translation into the clinical setting. Ideally, these procedures might allow for the integration of harvesting and processing of adipose tissue for ease of injection, in a single procedure utilizing a nonexpanded cellular product at the point of care, while permitting intraoperative autologous cellular and tissue-based therapies. Here, we review and discuss the options, advantages, and limitations of the major strategies alternative to enzymatic processing currently developed for minimal manipulation of adipose tissue. Stem Cells Translational Medicine  2019;8:1265&1271

  • In vivo bioluminescence-based monitoring of liver metastases from colorectal cancer: An experimental model
    Giuseppe Nigri, Paolo Magistri, Cecilia Battistelli, Gabriele Toietta, Raffaele Strippoli, Andrea Sagnotta, Antonello Forgione, Fabrizio Di Benedetto, Stefania Uccini, Paola Vittorioso,et al.
    Medknow
    Background: In this study we aimed to develop a new in vivo bioluminescence-based tool to monitor and to quantify colon cancer (CC) liver metastasis development. Methods: HCT 116 cells were transducted with pLenti6/V5-DEST-fLuc for constitutive expression of firefly luciferase. Infection was monitored analyzing endogenous bioluminescence using the IVIS Lumina II In vivo Imaging System and a positive clone constitutively expressing luciferase (HCT 116-fLuc) was isolated. HCT 116-fLuc cells were left untreated or treated with 1 μM GDC-0449, a Hedgehog pharmacological inhibitor. Moreover, 1 x 106 HCT 116-fLuc cells were implanted via intra-splenic injection in nude mice. Bioluminescence was analyzed in these mice every 7 days for 5 weeks. After that, mice were sacrificed and bioluminescence was analyzed on explanted livers. Results: We found that in vitro bioluminescence signal was significantly reduced when HCT 116-fLuc cells were treated with GDC-0449. Regarding in vivo data, bioluminescence sources consistent with hepatic anatomical localization were detected after 21 days from HCT 116-fLuc intrasplenic injection and progressively increased until the sacrifice. The presence of liver metastasis was further confirmed by ex-vivo bioluminescence analysis of explanted livers. Conclusions: Our in vitro results suggest that inhibition of Hedgehog pathway may hamper CC cell proliferation and impel for further studies. Regarding in vivo data, we set-up a strategy for liver metastasis visualization, that may allow follow-up and quantification of the entire metastatic process. This cost-effective technique would reduce experimental variability, as well as the number of sacrificed animals.

  • Effects of copper chelation on BRAF<sup>v600e</sup> positive colon carcinoma cells
    Silvia Baldari, Giuliana Di Rocco, Marie C. Heffern, Timothy A. Su, Christopher J. Chang, and Gabriele Toietta
    MDPI AG
    High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAFV600E). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson’s disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAFV600E mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAFV600E mutation compared to BRAFwt acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAFV600E cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAFV600E mutation.

  • Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development
    Patrizia Sarogni, Orazio Palumbo, Adele Servadio, Simonetta Astigiano, Barbara D’Alessio, Veronica Gatti, Dubravka Cukrov, Silvia Baldari, Maria Michela Pallotta, Paolo Aretini,et al.
    Springer Science and Business Media LLC

  • Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells
    Giuliana Di Rocco, Silvia Baldari, Giovambattista Pani, and Gabriele Toietta
    Springer Science and Business Media LLC

  • Fluid cartilage as new autologous biomaterial in the treatment of minor nose defects: Clinical and microscopic difference amongst diced, crushed, and fluid cartilage
    Angelo Trivisonno, Steven R. Cohen, Guy Magalon, Jèrèmy Magalon, Aris Sterodimas, Michele Pascali, Valerio Cervelli, Gabriele Toietta, Alfredo Colaprietra, Filippo Calcagni,et al.
    MDPI AG
    Developing cartilage constructs with injectability, appropriate matrix composition, and persistent cartilaginous phenotype remains an enduring challenge in cartilage repair. Fourteen patients with minor contour deformity were treated with fluid cartilage filler gently injected as autologous fluid graft in deep planes of defect of the nose that were close to the bone or the cartilage. A computerized tomographic scan control was performed after 12 months. Pearson’s Chi-square test was used to investigate differences in cartilage density between native and newly formed cartilages. The endpoints were the possibility of using fluid cartilage as filler with aesthetic and functional improvement and versatility. Patients were followed up for two years. The constructs of fluid cartilage graft that were injected in the deep plane resulted in a persistent cartilage tissue with appropriate morphology, adequate central nutritional perfusion without central necrosis or ossification, and further augmented nasal dorsum without obvious contraction and deformation. This report demonstrated that fluid cartilage grafts are useful for cartilage regeneration in patients with outcomes of rhinoplasty, internal nasal valve collapse, and minor congenital nose aesthetics deformity.

  • Protein disulfide isomerase as a prosurvival factor in cell therapy for muscular and vascular diseases
    Giuliana Di Rocco, Silvia Baldari, Antonietta Gentile, Maurizio Capogrossi, and Gabriele Toietta
    Springer Science and Business Media LLC

  • Exosomes and other extracellular vesicles-mediated microRNA delivery for cancer therapy
    Giuliana Di Rocco, Silvia Baldari, and Gabriele Toietta
    AME Publishing Company

  • Challenges and strategies for improving the regenerative effects of mesenchymal stromal cell-based therapies
    Silvia Baldari, Giuliana Di Rocco, Martina Piccoli, Michela Pozzobon, Maurizio Muraca, and Gabriele Toietta
    MDPI AG
    Cell-based therapies have the potential to revolutionize current treatments for diseases with high prevalence and related economic and social burden. Unfortunately, clinical trials have made only modest improvements in restoring normal function to degenerating tissues. This limitation is due, at least in part, to the death of transplanted cells within a few hours after transplant due to a combination of mechanical, cellular, and host factors. In particular, mechanical stress during implantation, extracellular matrix loss upon delivery, nutrient and oxygen deprivation at the recipient site, and host inflammatory response are detrimental factors limiting long-term transplanted cell survival. The beneficial effect of cell therapy for regenerative medicine ultimately depends on the number of administered cells reaching the target tissue, their viability, and their promotion of tissue regeneration. Therefore, strategies aiming at improving viable cell engraftment are crucial for regenerative medicine. Here we review the major factors that hamper successful cell engraftment and the strategies that have been studied to enhance the beneficial effects of cell therapy. Moreover, we provide a perspective on whether mesenchymal stromal cell-derived extracellular vesicle delivery, as a cell-free regenerative approach, may circumvent current cell therapy limitations.

  • P53-Dependent PUMA to DRAM antagonistic interplay as a key molecular switch in cell-fate decision in normal/high glucose conditions
    Alessia Garufi, Giuseppa Pistritto, Silvia Baldari, Gabriele Toietta, Mara Cirone, and Gabriella D’Orazi
    Springer Science and Business Media LLC

RECENT SCHOLAR PUBLICATIONS

  • The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody
    S Caratelli, F De Paolis, DA Silvestris, S Baldari, I Salvatori, A Tullo, ...
    Experimental Hematology & Oncology 14 (1), 1-21 2025

  • Expression pattern and prognostic significance of aldehyde dehydrogenase 2 in lung adenocarcinoma as a potential predictor of immunotherapy efficacy
    S Baldari, A Antonini, G Di Rocco, G Toietta
    Cancer Innovation 4 (1), e149 2025

  • Dissecting human adipose tissue heterogeneity using single‐cell omics technologies
    G Di Rocco, A Trivisonno, G Trivisonno, G Toietta
    Stem Cell Research & Therapy 15, 322 2024

  • The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer
    M Di Nardo, S Astigiano, S Baldari, MM Pallotta, G Porta, S Pigozzi, ...
    Journal of Experimental & Clinical Cancer Research 43, 49 2024

  • Cancer immunity and immunotherapy beyond COVID-19
    M Bellone, A Brevi, V Bronte, S Dusi, PF Ferrucci, P Nistic, A Rosato, ...
    Cancer Immunology, Immunotherapy 72 (7), 2541-2548 2023

  • Direct CD32 T-cell cytotoxicity: implications for breast cancer prognosis and treatment
    G Sconocchia, V Lanzilli, G: Cesarini, DA Silvestris, K Rezvani, R Arriga, ...
    Life Science Alliance 5 (12), e202201590 2022

  • Strategies for efficient targeting of tumor collagen for cancer therapy
    S Baldari, F Di Modugno, P Nistic, G Toietta
    Cancers 14 (19), 4706 2022

  • HIPK2 cooperates with KRAS signaling and associates with colorectal cancer progression
    M Di Segni, I Virdia, A Verdina, CA Amoreo, S Baldari, G Toietta, ...
    Molecular Cancer Research 20 (5), 686–698 2022

  • Cancer bio-immunotherapy XVIII annual NIBIT-(Italian network for tumor biotherapy) meeting, October 15-16, 2020
    M Bellone, A Brevi, V Bronte, S Dusi, PF Ferrucci, P Nistic, A Rosato, ...
    Cancer Immunology, Immunotherapy 71 (7), 1787-1794 2022

  • Antibody-Independent Antitumor Effects of Cd32A-Chimeric Receptor T Cells: Implications for Breast Cancer Prognosis and Treatment
    G Sconocchia, G Lanzilli, V Cesarini, DA Silvestris, R Arriga, K Rezvani, ...
    bioRxiv, 2021.12. 22.473841 2021

  • Reduction of cell proliferation by acute C2H6O exposure
    S Baldari, I Manni, G Di Rocco, F Paolini, B Palermo, G Piaggio, G Toietta
    Cancers 13 (19), 4999 2021

  • Successful therapy of esophageal fistulas by endoscopic injection of emulsified adipose tissue stromal vascular fraction
    D Nachira, A Trivisonno, G Costamagna, G Toietta, S Margaritora, ...
    Gastroenterology 160 (4), 1026-1028 2021

  • A ruthenium (II)-curcumin compound modulates NRF2 expression balancing the cancer cell death/survival outcome according to p53 status
    A Garufi, S Baldari, R Pettinari, MS Gilardini Montani, V D’Orazi, G Pistritto, ...
    Journal of Experimental & Clinical Cancer Research 39, 1-15 2020

  • DHA affects microtubule dynamics through reduction of phospho-TCTP levels and enhances the antiproliferative effect of T-DM1 in trastuzumab-resistant HER2-positive breast
    S D’Amico, EK Krasnowska, I Manni, G Toietta, S Baldari, G Piaggio, ...
    Cells 9 (5), 1260 2020

  • Regenerative medicine approaches for the management of respiratory tract fistulas
    A Trivisonno, D Nachira, I Boškoski, V Porziella, G Di Rocco, S Baldari, ...
    Stem Cell Research & Therapy 11 (1), 451 2020

  • Current biomedical use of copper chelation therapy
    S Baldari, G Di Rocco, G Toietta
    International Journal of Molecular Sciences 21 (3), 1069 2020

  • Extracellular vesicles–encapsulated microRNA-125b produced in genetically modified mesenchymal stromal cells inhibits hepatocellular carcinoma cell proliferation
    S Baldari, G Di Rocco, A Magenta, M Picozza, G Toietta
    Cells 8 (12), 1560 2019

  • Intraoperative strategies for minimal manipulation of autologous adipose tissue for cell- and tissue-based therapies: Concise Review
    A Trivisonno, RW Alexander, S Baldari, SR Cohen, G Di Rocco, P Gentile, ...
    Stem Cells Translational Medicine 8, 1265-1271 2019

  • Effects of copper chelation on BRAFV600E positive colon carcinoma cells
    S Baldari, G Di Rocco, MC Heffern, TA Su, CJ Chang, G Toietta
    Cancers 11 (5), 659 2019

  • Fluid cartilage as new autologous biomaterial in the treatment of minor nose defects: Clinical and microscopic difference amongst diced, crushed, and fluid cartilage
    A Trivisonno, SR Cohen, G Magalon, J Magalon, A Sterodimas, M Pascali, ...
    Materials 12 (7), 1062 2019

MOST CITED SCHOLAR PUBLICATIONS

  • Effects of the olive-derived polyphenol oleuropein on human health
    B Barbaro, G Toietta, R Maggio, M Arciello, M Tarocchi, A Galli, C Balsano
    International Journal of Molecular Sciences 15 (10), 18508-18524 2014
    Citations: 391

  • Diabetes impairs adipose tissue–derived stem cell function and efficiency in promoting wound healing
    F Cianfarani, G Toietta, G Di Rocco, E Cesareo, G Zambruno, T Odorisio
    Wound Repair and Regeneration 21 (4), 545-553 2013
    Citations: 255

  • Challenges and strategies for improving the regenerative effects of mesenchymal stromal cell-based therapies
    S Baldari, G Di Rocco, M Piccoli, M Pozzobon, M Muraca, G Toietta
    International Journal of Molecular Sciences 18 (10), 2087 2017
    Citations: 249

  • A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction
    S Fusco, C Ripoli, MV Podda, SC Ranieri, L Leone, G Toietta, ...
    Proceedings of the National Academy of Sciences 109 (2), 621-626 2012
    Citations: 178

  • Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector
    G Toietta, VP Mane, WS Norona, MJ Finegold, P Ng, AF McDonagh, ...
    Proceedings of the National Academy of Sciences 102 (11), 3930-3935 2005
    Citations: 169

  • PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile
    MA Croyle, HT Le, KD Linse, V Cerullo, G Toietta, A Beaudet, L Pastore
    Gene Therapy 12 (7), 579-587 2005
    Citations: 169

  • Current biomedical use of copper chelation therapy
    S Baldari, G Di Rocco, G Toietta
    International Journal of Molecular Sciences 21 (3), 1069 2020
    Citations: 166

  • Towards therapeutic delivery of extracellular vesicles: strategies for in vivo tracking and biodistribution analysis
    G Di Rocco, S Baldari, G Toietta
    Stem Cells International 2016 (Article ID 5029619) 2016
    Citations: 143

  • Identification of protein disulfide isomerase as a cardiomyocyte survival factor in ischemic cardiomyopathy
    A Severino, M Campioni, S Straino, FN Salloum, N Schmidt, U Herbrand, ...
    Journal of the American College of Cardiology 50 (11), 1029-1037 2007
    Citations: 131

  • Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter
    G Toietta, DR Koehler, MJ Finegold, B Lee, J Hu, AL Beaudet
    Molecular Therapy 7 (5), 649-658 2003
    Citations: 113

  • Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes
    K Sukegawa, H Nakamura, Z Kato, S Tomatsu, AM Montao, T Fukao, ...
    Human Molecular Genetics 9 (9), 1283-1290 2000
    Citations: 106

  • Enhanced healing of diabetic wounds by topical administration of adipose tissue-derived stromal cells overexpressing Stromal-Derived Factor-1: biodistribution and engraftment
    G Di Rocco, A Gentile, A Antonini, F Ceradini, JC Wu, MC Capogrossi, ...
    Stem Cells International 2011 (Article ID 304562) 2010
    Citations: 88

  • Intraoperative strategies for minimal manipulation of autologous adipose tissue for cell- and tissue-based therapies: Concise Review
    A Trivisonno, RW Alexander, S Baldari, SR Cohen, G Di Rocco, P Gentile, ...
    Stem Cells Translational Medicine 8, 1265-1271 2019
    Citations: 86

  • A CREB-Sirt1-Hes1 circuitry mediates neural stem cell response to glucose availability
    S Fusco, L Leone, SA Barbati, D Samengo, R Piacentini, G Maulucci, ...
    CELL REPORTS 14 (5), 1195-1205 2016
    Citations: 78

  • Harvest of superficial layers of fat with a microcannula and isolation of adipose tissue–derived stromal and vascular cells
    A Trivisonno, G Di Rocco, C Cannistra, V Finocchi, ST Farr, M Monti, ...
    AESTHETIC SURGERY JOURNAL 34 (4), 601-613 2014
    Citations: 75

  • Extracellular vesicles–encapsulated microRNA-125b produced in genetically modified mesenchymal stromal cells inhibits hepatocellular carcinoma cell proliferation
    S Baldari, G Di Rocco, A Magenta, M Picozza, G Toietta
    Cells 8 (12), 1560 2019
    Citations: 62

  • Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells
    G Di Rocco, S Baldari, G Pani, G Toietta
    Cellular and Molecular Life Sciences 76 (2), 231-244 2019
    Citations: 62

  • Effects of copper chelation on BRAFV600E positive colon carcinoma cells
    S Baldari, G Di Rocco, MC Heffern, TA Su, CJ Chang, G Toietta
    Cancers 11 (5), 659 2019
    Citations: 59

  • Various cells retrovirally transduced with N-acetylgalactosoamine-6-sulfate sulfatase correct Morquio skin fibroblasts in vitro
    G Toietta, GM Severini, C Traversari, S Tomatsu, K Sukegawa, S Fukuda, ...
    Human Gene Therapy 12 (16), 2007-2016 2001
    Citations: 49

  • Platelet-derived growth factor-receptor α strongly inhibits melanoma growth< i> in vitro</i> and< i> in vivo</i>
    D Faraone, MS Aguzzi, G Toietta, AM Facchiano, F Facchiano, A Magenta, ...
    Neoplasia 11 (8), 732-742 2009
    Citations: 48