Myxofibrosarcoma (MFS) is a malignant soft tissue sarcoma (STS) that originates in the body’s connective tissues. It is characterized by the presence of myxoid (gel-like) and fibrous components and typically affects patients after the... more
Myxofibrosarcoma (MFS) is a malignant soft tissue sarcoma (STS) that originates in the body’s connective tissues. It is characterized by the presence of myxoid (gel-like) and fibrous components and typically affects patients after the fifth decade of life. Considering the ongoing trend of increasing lifespans across many nations, MFS is likely to become the most common musculoskeletal sarcoma in the future. Although MFS patients have a lower risk of developing distant metastases compared with other STS cases, MFS is characterized by a high frequency of local recurrence. Notably, in 40–60% of the patients where the tumor recurs, it does so multiple times. Consequently, patients may undergo multiple local surgeries, removing the risk of potential amputation. Furthermore, because the tumor relapses generally have a higher grade, they exhibit a decreased response to radio and chemotherapy and an increased tendency to form metastases. Thus, a better understanding of MFS is required, and ...
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Wound Healing, Medicine, Angiogenesis, Humans, Mutation, and 13 moreMice, Animals, Male, Skin, Reinnervation, Rats, Topical Drug Administration, Nerve Growth Factor, Experimental Diabetes Mellitus Type 1 and 2, Pain Threshold, Pharmacology and pharmaceutical sciences, Human Umbilical Vein Endothelial Cells, and Human skin
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Research Interests:
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Present therapies of malignant tumours are still based on cytotoxic drugs that damage DNA or inhibit cell division, causing death of cancerous cells and tissues. However, most chemiotherapeutic drugs are non-specific, thus their cytoxic... more
Present therapies of malignant tumours are still based on cytotoxic drugs that damage DNA or inhibit cell division, causing death of cancerous cells and tissues. However, most chemiotherapeutic drugs are non-specific, thus their cytoxic action also affects healthy cells and tissues. One of the most widely employed chemiotherapic drug, cisplatin, shows serious ototoxic effects leading to more or less profound hearing loss. To counteract these effects, several strategies have been devised, such as the administration of antioxidants and glucocorticoids. Dexamethasone, a glucocorticoid widely employed as anti-inflammatory drug, is known to exert some protective effects against cisplatin toxicity. This study was aimed to test by cytofluorimetry the time/dose effects of dexamethasone and cisplatin, administered separately and in co-treatment, in an inner ear mouse cell line (OCK3). The results showed that, in the experimental conditions tested, dexamethasone had no cytotoxic effects at any concentration, while cisplatin had time/dose dependent cytotoxicity. Concerning the co-treatment, when OCK3 cells were pre-treated with dexamethasone before cisplatin administration, a lower cell mortality was observed at 48 h incubation time and concentrations between 50 and 250 nM. Thus dexamethasone apparently exerts in vitro protective effects against cisplatin-induced ototoxicity
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Sarcomas are heterogeneous and rare malignant tumors that develop from connective tissues. Myxofibrosarcoma (MFS) and Osteosarcoma (OS) are the main representative subtypes of Soft tissues and Bone sarcomas. Conventional treatment... more
Sarcomas are heterogeneous and rare malignant tumors that develop from connective tissues. Myxofibrosarcoma (MFS) and Osteosarcoma (OS) are the main representative subtypes of Soft tissues and Bone sarcomas. Conventional treatment consists of surgical resection and neo/adjuvant chemotherapy. However, a challenging clinical feature is a high local recurrence rate, calling for the development of novel strategies to eradicate MFS and OS. Fluorescence-guided surgery (FGS), coupled with photodynamic therapy (PDT), enables to detect and eradicate malignant tissues using a light-sensitive photosensitizer (PS). These compounds could be retained by neoplastic cells to a greater extent than by healthy tissue. Thus, when photoactivated, they lead to cancer cell death, minimizing normal tissues toxicity. The project aims to provide a preclinical proof of concept of FGS and PDT for MFS and OS, allowing us to pave the way for a more effective treatment strategy. A multimodel preclinical platform ...
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Experimental models for chronic skin lesions are excision and pressure ulcer, defined as “open” and “closed” lesions, respectively, only the latter characterized by tissue hypoxia. Moreover, systemic diseases, such as diabetes mellitus,... more
Experimental models for chronic skin lesions are excision and pressure ulcer, defined as “open” and “closed” lesions, respectively, only the latter characterized by tissue hypoxia. Moreover, systemic diseases, such as diabetes mellitus, affect wound repair. Thus, models for testing new therapies should be carefully selected according to the expected targets. In this study, we present an extensive and comparative histological, immunohistochemical, and molecular characterization of these two lesions in diabetic (db/db) and non-diabetic (C57BL/6 J) mice. In db/db mice, we found significant reduction in PGP9.5-IR innervation, reduction of capillary network, and reduced expression of NGF receptors. We found an increase in VEGF receptor Kdr expression, and the PI3K-Akt signaling pathway at the core of the altered molecular network. Db/db mice with pressure ulcers showed an impairment in the molecular regulation of hypoxia-related genes (Hif1a, Flt1, and Kdr), while extracellular matrix en...
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Spinal cord injury (SCI) is an incurable condition, in which a cascade of cellular and molecular events triggered by inflammation and excitotoxicity impairs endogenous regeneration, namely remyelination and axonal outgrowth. We designed a... more
Spinal cord injury (SCI) is an incurable condition, in which a cascade of cellular and molecular events triggered by inflammation and excitotoxicity impairs endogenous regeneration, namely remyelination and axonal outgrowth. We designed a treatment solution based on an implantable biomaterial (electrospun PLLA) loaded with ibuprofen and triiodothyronine (T3) to counteract inflammation, thus improving endogenous regeneration. In vivo efficacy was tested by implanting the drug-loaded-PLLA in the rat model of T8 contusion SCI. We observed the expected recovery of locomotion beginning on day 7. In PLLA-implanted rats (i.e. controls), the recovery stabilized at 21 days post lesion (DPL), after which no further improvement was observed. On the contrary, in PLLA+Ibu+T3 rats a further recovery and a significant treatment effect were observed, also confirmed by the gait analysis on 49DPL. Glutamate release at 24 hours and 8DPL was reduced in PLLA+Ibu+T3- compared to PLLA-implanted rats, such as the estimated lesion volume at 60DPL. The myelin and 200-neurofilament-positive area-fraction was higher in PLLA+Ibu+T3 implanted rats, where the percentage of astrocytes was significantly reduced. The implant of a PLLA electrospun scaffold loaded with ibuprofen and T3 significantly improves the endogenous regeneration, leading to an improvement of the functional locomotion outcome in the SCI.
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In this chapter we illustrate protocols to investigate growth and neurotrophic factors in human and rodent (rat and mouse)-derived embryonic stem cells. The conventional two-dimensional cell monolayer system to grow embryonic stem cells... more
In this chapter we illustrate protocols to investigate growth and neurotrophic factors in human and rodent (rat and mouse)-derived embryonic stem cells. The conventional two-dimensional cell monolayer system to grow embryonic stem cells is presented, focusing on the coating strategies also using extracellular matrix components. Then, different approaches for three-dimensional stem cell culture are presented, using hydrogels and scaffolds. Quantitative polymerase chain reaction, immunocytochemistry, immunoenzymatic ELISA assay, and multiparametric assays to quantify growth and neurotrophic factor production are presented.
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Chemistry, Cell Biology, Hydrogels, Stem Cell, Medicine, and 14 moreExtracellular Matrix, Immunocytochemistry, Cell Differentiation, Humans, Mice, Animals, Embryonic Stem Cell, Embryonic Stem Cells, Rats, Cell Proliferation, Neurotrophic Factors, Biochemistry and cell biology, Tissue Scaffolds, and Cell culture techniques
Additional file 1: Figure S1. Characterization of primary cultures of rat aortic smooth muscle cells by immunofluorescent staining. Figure S2. Oil-red staining of cholesterol loaded rat aortic smooth muscle cells. Table S1. Primers used... more
Additional file 1: Figure S1. Characterization of primary cultures of rat aortic smooth muscle cells by immunofluorescent staining. Figure S2. Oil-red staining of cholesterol loaded rat aortic smooth muscle cells. Table S1. Primers used for quantitative RT-PCR. Table S2. Semiquantitative evaluation of histological characteristics and Notch receptors immunostainings. Table S3. P values associated to the results of correlations analyses among the expression levels of mRNAs and miRs analyzed. Table S4. Clinical follow up and molecular analysis.
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The recent increase in human lifespan, coupled with unhealthy diets and lifestyles have led to an unprecedented increase in cardiovascular diseases. Even in the presence of a wide range of therapeutic options with variable efficacy,... more
The recent increase in human lifespan, coupled with unhealthy diets and lifestyles have led to an unprecedented increase in cardiovascular diseases. Even in the presence of a wide range of therapeutic options with variable efficacy, mortality due to heart failure is still high and there is a need to identify new therapeutic targets. Genetic and in vitro studies have implicated the Notch signalling in the development and maintenance of the cardiovascular system through a direct effect on biological functions of vascular cells (endothelial and vascular smooth muscle cells) and cardiomyocytes. Notch signalling is also involved in the modulation of inflammation, which plays a major role in causing and exacerbating cardiovascular diseases. The Notch pathway could represent a new therapeutic target for the treatment of cardiovascular diseases.
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Research Interests:
Biology, Biological Chemistry, Apoptosis, Medicine, NOTCH Pathway, and 15 moreEstrogen Receptor, Biological Sciences, Humans, Estrogen, Phosphorylation, Endothelial dysfunction, Notch, CHEMICAL SCIENCES, Akt, Protease Inhibitors, Estradiol, Estrogen receptor alpha, Estrogen Receptor beta, Medical and Health Sciences, and Human Umbilical Vein Endothelial Cells
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Estrogens play a protective role in coronary artery disease. The mechanisms of action are still poorly understood, although a role for estrogens in stimulation of angiogenesis has been suggested. In several cell types, estrogens modulate... more
Estrogens play a protective role in coronary artery disease. The mechanisms of action are still poorly understood, although a role for estrogens in stimulation of angiogenesis has been suggested. In several cell types, estrogens modulate the Notch pathway, which is involved in controlling angiogenesis downstream of vascular endothelial growth factor A (VEGF-A). The goal of our study was to establish whether estrogens modulate Notch activity in endothelial cells and the possible consequences on angiogenesis. Human umbilical vein endothelial cells (HUVECs) were treated with 17b-estradiol (E2) and the effects on Notch signalling were evaluated. E2 increased Notch1 processing as indicated by i) decreased levels of Notch1 transmembrane subunit ii) increased amount of Notch1 in nuclei iii) unaffected level of mRNA. Similarly, E2 increased the levels of the active form of Notch4 without altering Notch4 mRNA. Conversely, protein and mRNA levels of Notch2 were both reduced suggesting transcr...
Targeting the Notch pathway is a new promising therapeutic approach for cancer patients. Inhibition of Notch is effective in the oncology setting because it causes a reduction of highly proliferative tumor cells and it inhibits survival... more
Targeting the Notch pathway is a new promising therapeutic approach for cancer patients. Inhibition of Notch is effective in the oncology setting because it causes a reduction of highly proliferative tumor cells and it inhibits survival of cancer stem cells, which are consid-ered responsible for tumor recurrence and metastasis. Additionally, since Delta-like ligand 4 (Dll4)-activated Notch signaling is a major modulator of angiogenesis, anti-Dll4 agents are being investigated to reduce vascularization of the tumor. Notch plays a major role in the heart during the development and, after birth, in response to cardiac damage. There-fore, agents used to inhibit Notch in the tumors (gamma secretase inhibitors and anti-Dll4 agents) could potentially affect myocardial repair. The past experience with trastuzumab and other tyrosine kinase inhibitors used for cancer therapy demonstrates that the pos-sible cardiotoxicity of agents targeting shared pathways between cancer and heart and the vas...
In this thesis I want to evaluate the Dexamethasone and Cisplatin effects in vitro (OC-k3) and in vivo (Rats Wistar) model. On more I want to get the protocol for future gene therapy, using the new non-viral transposable element Sleeping... more
In this thesis I want to evaluate the Dexamethasone and Cisplatin effects in vitro (OC-k3) and in vivo (Rats Wistar) model. On more I want to get the protocol for future gene therapy, using the new non-viral transposable element Sleeping Beauty in vitro model (Human Fetal Auditory Stem Cells (hFASC). The Cisplatin is an antineoplastic agent used to contrast different types of malignant tumors (testicolaris, ovaric, bladder, neck and head). This drug is very toxic and it generates many side effects like ototoxicity. This agent destroys the inner ear tissues, but they are not able to regenerate for this manner it is very important to study the otoprotective drugs mechanisms. There are many agents otoprotective and I want to remember the Dexamethasone. Dexamethasone is a glucocorticoid and usually it is used to contrast the inflammatory processes. The aim of this thesis is evaluating the drugs effects and protective effect of Dexamethasone against the Cisplatin toxicity. I used the cel...
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The self-repair ability of tissues and organs in case of injury and disease is a fundamental biological mechanism and an important therapeutic target. The tissue plasticity and the presence of adult stem cell niches open a new path in the... more
The self-repair ability of tissues and organs in case of injury and disease is a fundamental biological mechanism and an important therapeutic target. The tissue plasticity and the presence of adult stem cell niches open a new path in the development of pharmacological and non-pharmacological treatments finalized to improve the intrinsic regeneration.In this context, nerve growth factor (NGF) is widely studied for its capability of driving endogenous regeneration of ectoderm-derived tissues, directly acting on the cell targets and through the regulation of the stem cell niches. In fact, this growth factor is very promising for its key role in the development and multiplicity of the cellular targets.In this chapter, we have traveled across the recent history of NGF pleiotropic role in ectodermal tissue generation and repair, from embryonic development to skin wound healing, axonal regrowth, and remyelination.The better understanding of both the biological mechanisms underlying regeneration and the physiological role of NGF in development and injury response will open new therapeutic strategies, driven by the potential applications of this growth factor as an agent for improving endogenous regeneration processes.
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Nerve growth factor (NGF) is recognized as a pleiotropic molecule, exerting a variety of biological effects on different cell types and pathophysiological conditions, and its role in tissue wound healing has been recently highlighted.... more
Nerve growth factor (NGF) is recognized as a pleiotropic molecule, exerting a variety of biological effects on different cell types and pathophysiological conditions, and its role in tissue wound healing has been recently highlighted. However, the preferential cellular target of NGF is still elusive in the complex cellular and molecular cross talk that accompanies wound healing. Thus, to explore possible NGF cellular targets in skin wound healing, we investigated the in vitro NGF responsiveness of keratinocytes (cell line HEKa), fibroblasts (cell line BJ), and endothelial cells (cell line HUVEC), also in the presence of adverse microenvironmental conditions, e.g., hyperglycemia. The main results are summarized as follows: 1) NGF stimulates keratinocyte proliferation and HUVEC proliferation and angiogenesis in a dose-dependent manner although it has no effect on fibroblast proliferation; 2) NGF stimulates keratinocyte but not fibroblast migration in the wound healing assay; and 3) NG...
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Research Interests:
Perfluoro–alkyl substances (PFAS) are chemical pollutants with prevalent stability and environmental persistence. Exposure to PFAS, particularly perfluoro-octanoic acid (PFOA), has been associated with increased diabetes-related... more
Perfluoro–alkyl substances (PFAS) are chemical pollutants with prevalent stability and environmental persistence. Exposure to PFAS, particularly perfluoro-octanoic acid (PFOA), has been associated with increased diabetes-related cardiovascular mortality in subjects residing areas of high environmental contamination, however the exact pathogenic mechanism remains elusive. Here we used HepG2 cells, an in vitro model of human hepatocyte, to investigate the possible role of PFOA exposure in the alteration of hepatic glucose metabolism. HepG2 cells were exposed for 24 hours to PFOA at increasing concentration from 0 to 1000 ng/mL and then stimulated with 100 nm Insulin (Ins). The consequent effect on glycogen synthesis, glucose uptake and Glut-4 glucose transporter translocation was then evaluated by, respectively, Periodic Acid Schiff (PAS) staining, 2-deoxyglucose (2-DG) uptake assay and immunofluorescence. Exposure to PFOA was associated with reduced glycogen synthesis and glucose upt...
While the role of thyroid hormones (THs) during fetal and postnatal life is well-established, their role at preimplantation and during blastocyst development remains unclear. In this study, we used an embryonic stem cell line isolated... more
While the role of thyroid hormones (THs) during fetal and postnatal life is well-established, their role at preimplantation and during blastocyst development remains unclear. In this study, we used an embryonic stem cell line isolated from rat (RESC) to study the effects of THs and retinoic acid (RA) on early embryonic development during the pre-implantation stage. The results showed that THs play an important role in the differentiation/maturation processes of cells obtained from embryoid bodies (EB), with thyroid hormone nuclear receptors (TR) (TRα and TRβ), metabolic enzymes (deiodinases 1, 2, 3) and membrane transporters (Monocarboxylate transporters -MCT- 8 and 10) being expressed throughout in vitro differentiation until the Embryoid body (EB) stage. Moreover, thyroid hormone receptor antagonist TR (1-850) impaired RA-induced neuroectodermal lineage specification. This effect was significantly higher when cells were treated with retinoic acid (RA) to induce neuroectodermal lin...