+publisher:"Università degli Studi di Milano" +contributor:("LOCATI, MASSIMO")

1. T.A. Renzi. ROLE OF MICRORNA IN THE REGULATION OF TLR SIGNALING PATHWAY.

Degree: 2015, Università degli Studi di Milano

► Toll-like receptors (TLRs) play key roles in detecting pathogens and initiating inflammatory responses via the activation of specific signaling pathways. The TLRs activity must be… (more)

▼ Toll-like receptors (TLRs) play key roles in detecting pathogens and initiating inflammatory responses via the activation of specific signaling pathways. The TLRs activity must be tightly regulated to avoid excessive inflammation and consequent immunopathology, ranging from autoimmunity to cancer. MicroRNAs (miRNAs) are a new class of negative regulators involved in setting the balance of the immune response to inflammatory triggers. In this study, we identified miR-125a~99b~let-7e cluster and miR-146b as miRNAs that, after LPS engagement on human monocytes, are induced by the anti-inflammatory IL-10 and TGFβ, but are inhibited by the pro-inflammatory IFNγ. Bioinformatic analysis predicted and experimental evidence demonstrated that miR-125a-5p, let-7e-5p and miR-146b directly target the TLR pathway at multiple levels, including receptors (TLR4, CD14), signaling molecules (IRAK1, MyD88, TRAF6), and effectors (TNFα, IL-6, CCL3, CCL7, CXCL8). We showed that over-expression or inhibition of miR-125a, let-7e and miR-146b expression with lentiviral vector in human monocytes had a significant impact on the production of pro-inflammatory cytokines in response to LPS. In particular, we identified a role for miR-125a-5p and miR-146b in mediating the LPS hyporensponsiveness observed after IL-10 or TGFβ priming or during the endotoxin tolerance, the phenomenon of reduced sensitivity to subsequent challenge of LPS. The up-regulation of miR-125a-5p and miR-146b into THP-1 cells mimicked the LPS, IL-10 or TGFβ priming, whereas the inhibition of them by lentiviral vector or a pre-treatment with IFNγ reverted, partially, the tolerant phenotype. In an in vivo model of acute inflammatory response, we obtained that miR-125a-5p, miR-99b-5p and miR-146b were induced in macrophages recruited at the site of inflammation during the resolution process, and this was impaired in macrophages of IL-10 KO mice. Our studies indicated that miRNA cluster and miR-146b represent a new negative feedback mechanism of the TLR signaling pathway. Advisors/Committee Members: tutor: M. Locati, LOCATI, MASSIMO.

Subjects/Keywords: microRNA; TLR; LPS; miR-125a; miR-99; let-7e; miR-146b; IL-10; TGFβ; THP-1; IL-10 knockout; anti-inflammatory; endotoxin tolerance; Settore MED/04 - Patologia Generale; Settore BIO/11 - Biologia Molecolare

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Renzi, T. (2015). ROLE OF MICRORNA IN THE REGULATION OF TLR SIGNALING PATHWAY. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/254528

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Renzi, T.A.. “ROLE OF MICRORNA IN THE REGULATION OF TLR SIGNALING PATHWAY.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/254528.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Renzi, T.A.. “ROLE OF MICRORNA IN THE REGULATION OF TLR SIGNALING PATHWAY.” 2015. Web. 16 Jan 2021.

Vancouver:

Renzi T. ROLE OF MICRORNA IN THE REGULATION OF TLR SIGNALING PATHWAY. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/254528.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Renzi T. ROLE OF MICRORNA IN THE REGULATION OF TLR SIGNALING PATHWAY. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/254528

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

2. C.B. Chighizola. THE PATHOGENIC ROLE OF IMMUNE COMPLEXES CONTAINING SCLERODERMA-SPECIFIC AUTOANTIBODIES.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/259694

► AIM OF THE STUDY Systemic sclerosis (SSc) is a chronic autoimmune condition characterized by excessive tissue fibrosis, microvascular alterations and immune dysfunction with the production… (more)

▼ AIM OF THE STUDY Systemic sclerosis (SSc) is a chronic autoimmune condition characterized by excessive tissue fibrosis, microvascular alterations and immune dysfunction with the production of characteristic autoantibodies. These autoantibodies are highly specific for SSc diagnosis, and provide the most reliable tool to predict disease subset and the pattern of internal organ involvement. Despite such diagnostic and prognostic role, no evidence supporting the pathogenic potential of these autoantibodies has to date been raised. The working hypothesis of this study envisaged that immune complexes (ICs) containing scleroderma specific autoantibodies -rather than the mere antibody- might be able to elicit a proinflammatory and pro-fibrotic signaling cascade in target cells, thus contributing to SSc multifaceted etiopathogenesis. Since scleroderma autoantibodies bind –either directly or via bridge proteins- to nucleic acids, it was also postulated that the effects induced by SSc-ICs might be mediated by Toll-like Receptors (TLR). MATERIALS AND METHODS Fibroblasts have been isolated from skin biopsies from healthy controls and then cultured in adequate conditions. ICs have been purified from sera of scleroderma patients bearing different autoantibody specificities (antibodies against centromeric proteins [ACA], DNA topoisomerase I [ATA], RNA polymerase [ARA] and Th/To [anti-Th/To]) or of healthy controls using polyethylen glycol precipitation. Fibroblasts were transiently silenced for tlr3 using a specific small interfering RNA (siRNA); silencing was confirmed by RT-PCR and Western Blotting. Naïve and tlr3-silenced cells have been incubated with pathologic and control ICs and with TLR3 [Poly(I:C)] and TLR4 (LPS) agonists. Several parameters of cell activation have been assessed in the different experimental conditions. In particular, mRNA levels of type I interferons (IFN-α and IFN-β) and TLR (TLR3 and TLR9) have been investigated by real-Time PCR; ICAM-1 expression has been evaluated by cell-ELISA and the secretion of IL-6 and IL-8 in culture supernatants has been measured by commercial ELISA kits. Furthermore, the involvement of intracellular signaling pathways culminating with the activation of p38 MAPK and NFκB has been assessed. RESULTS Stimulation of normal skin fibroblasts with pathologic ICs induced a significant increase in the gene expression levels of both IFN-α and IFN-β; similar results have been reported in the presence of TLR agonists but not of control ICs and medium alone. In addition, ICAM-1 expression and IL-6 and IL-8 secretion were up-regulated by Poly(I:C), LPS and ICs from scleroderma patients but not healthy controls and medium alone. Further, pathologic ICs induced the activation of both p38 MAPK and NFκB. The expression levels of TLR3 and -to a greater extent- TLR9 were significantly increased in cells treated with TLR3 agonist and ICs from SSc patients but not healthy controls. The efficiency of tlr3 silencing in skin fibroblasts was confirmed at both mRNA and protein levels. tlr3… Advisors/Committee Members: tutor: P. L. Meroni, coordinatore: M. Locati, LOCATI, MASSIMO, LOCATI, MASSIMO.

Subjects/Keywords: Settore MED/16 - Reumatologia

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Chighizola, C. (2015). THE PATHOGENIC ROLE OF IMMUNE COMPLEXES CONTAINING SCLERODERMA-SPECIFIC AUTOANTIBODIES. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/259694

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Chighizola, C.B.. “THE PATHOGENIC ROLE OF IMMUNE COMPLEXES CONTAINING SCLERODERMA-SPECIFIC AUTOANTIBODIES.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/259694.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Chighizola, C.B.. “THE PATHOGENIC ROLE OF IMMUNE COMPLEXES CONTAINING SCLERODERMA-SPECIFIC AUTOANTIBODIES.” 2015. Web. 16 Jan 2021.

Vancouver:

Chighizola C. THE PATHOGENIC ROLE OF IMMUNE COMPLEXES CONTAINING SCLERODERMA-SPECIFIC AUTOANTIBODIES. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/259694.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Chighizola C. THE PATHOGENIC ROLE OF IMMUNE COMPLEXES CONTAINING SCLERODERMA-SPECIFIC AUTOANTIBODIES. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/259694

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

3. F. Tomay. REGULATION AND FUNCTION OF THE TETRASPANIN-LIKE MOLECULE MS4A4A IN ALTERNATIVELY ACTIVATED AND TUMOR-ASSOCIATED MACROPHAGES.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/248877

► Macrophages are a heterogeneous population of the innate immune system operating at the boundary between health and disease. They represent the most plastic elements of… (more)

▼ Macrophages are a heterogeneous population of the innate immune system operating at the boundary between health and disease. They represent the most plastic elements of the hematopoietic system, they are found in all tissues, and their main sake is the response to pathogens by processing and presenting the antigens to the adaptive immune mediators. Among their functions macrophages mediate generation and resolution of inflammation, tissue repair and homeostasis maintenance [1]. These cells undergo specific differentiation based on the local microenvironment [2] and the presence of cytokines [3]. In accordance with the Th1/Th2 polarization, two extreme states of macrophages polarization can be defined: the classically activated, pro-inflammatory M1 macrophage phenotype induced by IFNγ and LPS and the alternatively activated anti-inflammatory M2 macrophage phenotype [4, 5]. Among all the intermediate subpopulations of activating and suppressive macrophages [6], tumor associated macrophages (TAM) embody a peculiar M2-like subset favoring tumor progression and survival, angiogenesis and metastatization, making of these cells a negative prognostic index in many malignances. Membrane spanning 4-domains subfamily A (MS4A) is a newly described tetraspanin-like protein family, including 26 proteins in human and mice, whose members have been poorly characterized, with few exceptions [7, 8]. Most of them have been demonstrated playing a role in the immune system, either functioning as adaptor molecules for pivotal receptors (e.g. CD20/MS4A1-BCR; MS4A4B -TCR), or clustering complexes on the plasma membrane, or regulating the cell cycle. In the present study we identified and characterized a novel MS4A protein associated with alternative macrophage polarization, in two different contexts: TAMs association and fungal infections. MS4A4A is indeed a transmembrane molecule expressed by a special subset of M2 macrophages induced by glucocorticoids. The topology of the protein resembles the one of the other MS4A members, since it is re-localizes within lipid raft microdomains only upon macrophage activation and its surface expression is abolished upon cholesterol depletion. Also the murine homologue we identified as Ms4a4a shares the same features of the human one. The target has been found in human samples of Hodgkin’s lymphoma (HL) with a characteristic distribution, and its abundance varies among different types of HL. However, no or very faint staining resulted from healthy tissues, such as lymph nodes and spleen, suggesting the molecule might be implicated in both tumorgenesis and fibrosis. Evidences of MS4A4A association with TAM also derive from the murine models in vivo. Its distribution and topology makes MS4A4A an ideal target for antibody, potentially with a therapeutic significance. In the attempt of generating a human anti-human antibody directed against MS4A4A, we identified a clone able to recognize the human and cross-reacting with the murine protein, mediating cytotoxicity of the target bearing cells.… Advisors/Committee Members: tutor: M. Locati, coordinator: M. Locati, LOCATI, MASSIMO, LOCATI, MASSIMO.

Subjects/Keywords: Macrophages; Tumor Associated Macrophages (TAM); Membrane Spanning 4-domains subfamily A (MS4A); Tetraspanins; Lipid rafts; Hodgkin Lymphoma; monoclonal antibodies; Dectin1; beta-glucans; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tomay, F. (2015). REGULATION AND FUNCTION OF THE TETRASPANIN-LIKE MOLECULE MS4A4A IN ALTERNATIVELY ACTIVATED AND TUMOR-ASSOCIATED MACROPHAGES. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/248877

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tomay, F.. “REGULATION AND FUNCTION OF THE TETRASPANIN-LIKE MOLECULE MS4A4A IN ALTERNATIVELY ACTIVATED AND TUMOR-ASSOCIATED MACROPHAGES.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/248877.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tomay, F.. “REGULATION AND FUNCTION OF THE TETRASPANIN-LIKE MOLECULE MS4A4A IN ALTERNATIVELY ACTIVATED AND TUMOR-ASSOCIATED MACROPHAGES.” 2015. Web. 16 Jan 2021.

Vancouver:

Tomay F. REGULATION AND FUNCTION OF THE TETRASPANIN-LIKE MOLECULE MS4A4A IN ALTERNATIVELY ACTIVATED AND TUMOR-ASSOCIATED MACROPHAGES. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/248877.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tomay F. REGULATION AND FUNCTION OF THE TETRASPANIN-LIKE MOLECULE MS4A4A IN ALTERNATIVELY ACTIVATED AND TUMOR-ASSOCIATED MACROPHAGES. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/248877

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

4. S. Gentile. THE PROTECTIVE ROLE OF PTX3 IN MOUSE SKIN CARCINOGENESIS.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/251045

► Abstract The implication of the innate immune system on inflammatory carcinogenesis is a central topic in tumor biology. The humoral pattern recognition molecule PTX3 plays… (more)

Subjects/Keywords: PTX3; DMBA/TPA-induced skin cancer; cancer-related inflammation; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gentile, S. (2015). THE PROTECTIVE ROLE OF PTX3 IN MOUSE SKIN CARCINOGENESIS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/251045

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Gentile, S.. “THE PROTECTIVE ROLE OF PTX3 IN MOUSE SKIN CARCINOGENESIS.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/251045.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Gentile, S.. “THE PROTECTIVE ROLE OF PTX3 IN MOUSE SKIN CARCINOGENESIS.” 2015. Web. 16 Jan 2021.

Vancouver:

Gentile S. THE PROTECTIVE ROLE OF PTX3 IN MOUSE SKIN CARCINOGENESIS. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/251045.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gentile S. THE PROTECTIVE ROLE OF PTX3 IN MOUSE SKIN CARCINOGENESIS. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/251045

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

5. N.G. Sukubo. NO CODING RNAs IN MACROPHAGE POLARIZATION: THE RELEVANCE OF THE "JUNK" RNA.

Degree: 2016, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/365870

► Abstract Form the central dogma of the biology formulated by Crick in 1958, to the detection of “junk RNA”, a new prospective has been open.… (more)

▼ Abstract Form the central dogma of the biology formulated by Crick in 1958, to the detection of “junk RNA”, a new prospective has been open. Macrophages are essential cell of the innate immunity system important in onset and resolve inflammation. Moreover they are important in the cross-talk with adaptive immunology. It is also clear that macrophages are involved in many chronic diseases such as atherosclerosis, asthma, rheumatoid arthritis. In these pathologies there is an anomalous prolongation/amplification of the macrophage challenge to lead homeostasis. In this landscape favor macrophage activation and re-programming. Mantovani and colleagues have schematically categorized macrophages in “classical” (M1) activated, triggered with microbial stimuli (e.g. LPS) alone or together with the TLR eliciting; and “alternative” (M2) cell types, activated by IL-4/IL-13. The identification of the underlying molecular mechanisms on the base of this process may suggest new approaches to interfere with chronic inflammation and other inflammatory disease, such as cancer. The aim of this presented work was to characterize the epigenetic mechanism involved in macrophage polarization. To better elucidate this purpose the thesis was divided in three macro chapter: • MicroRNA-135b: the pivot of the macrophage polarization balance; • The “junk” RNA controlled by glucocorticoids: miR-135b and its host gene BLACAT1; • MicroRNA-135b in gouty arthritis. Overall, we identified a specific miRNome in human classic and alternative polarized macrophages (69 differential expressed miRNAs among the subsets). In addition, we pointed out the impact of miR-135b a de novo expressed miRNA in M1 macrophages, and for the first time associated with macrophages in an inflammatory diseases such as gouty arthritis. Indeed we demonstrated that miR-135b locus is activated by the inflammatory stimulus, LPS, which discharge the repressor complex polycomb2. Although, we can classified miR-135 as M1-associated or induced, which damps M2 phenotype in favor of the M1 thru the targeting of important the transcription factor, c-MYC, STAT6 and KLF4, sustaining the inflammation. In addition miR-135b expression is inhibited by the anti-inflammatory cytokine IL-10, to highlight its pro-inflammatory role; the same results was assess for miR-155. We have shown in the model of gouty arthritis, miR-135b is induced during the progression of the inflammation by macrophages. However it provides a negative feedback to limit excessive macrophage response to MSU crystal, thru the targeting of the IL-1β pathway. These results confirm the relevance of miR-135b as an important hinge of macrophage polarity. At the light of these observations, the identification of the underlying process that regulates the expression of miR-135b will be essential. miR-135b is located in the intron of the lncRNA, BLACAT1. We glimpsed that the induction of miR-135b and BLACAT1 is not correlated; on the contrary BLACAT1 is induced by anti-inflammatory stimulation, influencing miR-135b. Although… Advisors/Committee Members: tutor: M. Locati : coordinator: M. Locati, LOCATI, MASSIMO, LOCATI, MASSIMO.

Subjects/Keywords: macrophages; miRNAs; miR-135b; polarization; long non-coding RNA; MSU; Polycomb 2; gouty arthritis; IL-1β pathway; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sukubo, N. (2016). NO CODING RNAs IN MACROPHAGE POLARIZATION: THE RELEVANCE OF THE "JUNK" RNA. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/365870

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Sukubo, N.G.. “NO CODING RNAs IN MACROPHAGE POLARIZATION: THE RELEVANCE OF THE "JUNK" RNA.” 2016. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/365870.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Sukubo, N.G.. “NO CODING RNAs IN MACROPHAGE POLARIZATION: THE RELEVANCE OF THE "JUNK" RNA.” 2016. Web. 16 Jan 2021.

Vancouver:

Sukubo N. NO CODING RNAs IN MACROPHAGE POLARIZATION: THE RELEVANCE OF THE "JUNK" RNA. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/365870.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Sukubo N. NO CODING RNAs IN MACROPHAGE POLARIZATION: THE RELEVANCE OF THE "JUNK" RNA. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/365870

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

6. S. GONZALVO FEO. CCRL2, A PUTATIVE CHEMOTACTIC RECEPTOR, PARTICIPATES IN THE LUNG DENDRITIC CELL TRAFFICKING.

Degree: 2010, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/150132

► CCRL2 (chemokine CC motif receptor-like 2) is an orphan heptahelic serpentine receptor that is rapidly induced in dendritic cells (DC) during maturation. CCRL2 shares the… (more)

▼ CCRL2 (chemokine CC motif receptor-like 2) is an orphan heptahelic serpentine receptor that is rapidly induced in dendritic cells (DC) during maturation. CCRL2 shares the highest homology with the inflammatory chemokine receptors CCR1 and CCR5 and the ligand, chemerin, with the chemotactic receptor ChemR23. Although both CCRL2 and ChemR23 are expressed by DC, they show an opposite regulation during DC maturation. In addition, CCRL2 is apparently unable to signal in response to chemerin and was shown to function as a presenting protein of chemerin to ChemR23-expressing cells. In order to evaluate the biological relevance of this receptor, we used CCRL2 deficient mice in an established model of allergen-induced airway inflammation in which DC are known to play a crucial role. CCRL2-/- mice were protected in a model of OVA-induced airway inflammation with reduced leukocyte recruitment in the BAL (eosinophils and mononuclear cells) and reduced production of the Th2 cytokines IL-4 and IL-5 and chemokines CCL11 and CCL17. CCRL2-/- mice showed normal recruitment of circulating DC into the lung but a defective trafficking of antigen-loaded lung DC to mediastinal lymph nodes. This defect was associated to a reduction in lymph node cellularity and reduced priming of Th2 response. Chemerin was expressed by mouse lung vascular endothelial cells and by lymphatic endothelial cells and was found to be upregulated by retinoic acid. Retinoic acid stimulated endothelial cells (EC) promoted the transmigration of DC in a ChemR23-dependent manner, suggesting a role for membrane associated chemerin. The results here reported define chemerin as a new relevant protein for DC trafficking across lymphatic and blood endothelial barriers. In addition, these results highlight a nonredundant role for CCRL2 in the migration of lung DC and in the induction of Th2-polarized airway allergic inflammation. Altogether, this study proposes the CCRL2/chemerin axis as a new potential target for therapeutic strategies aimed at controlling lung hypersensitivity. Advisors/Committee Members: Tutore: Antonio Sica, Supervisore: Massimo Locati, Coordinatore: Alberto Mantovani, LOCATI, MASSIMO, LOCATI, MASSIMO, MANTOVANI, ALBERTO.

Subjects/Keywords: CCRL2; chemerin; ChemR23; dendritic cell; asthma; airway hyperresponsiveness; endothelial cell; dendritic cell traffic; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

FEO, S. G. (2010). CCRL2, A PUTATIVE CHEMOTACTIC RECEPTOR, PARTICIPATES IN THE LUNG DENDRITIC CELL TRAFFICKING. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/150132

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

FEO, S. GONZALVO. “CCRL2, A PUTATIVE CHEMOTACTIC RECEPTOR, PARTICIPATES IN THE LUNG DENDRITIC CELL TRAFFICKING.” 2010. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/150132.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

FEO, S. GONZALVO. “CCRL2, A PUTATIVE CHEMOTACTIC RECEPTOR, PARTICIPATES IN THE LUNG DENDRITIC CELL TRAFFICKING.” 2010. Web. 16 Jan 2021.

Vancouver:

FEO SG. CCRL2, A PUTATIVE CHEMOTACTIC RECEPTOR, PARTICIPATES IN THE LUNG DENDRITIC CELL TRAFFICKING. [Internet] [Thesis]. Università degli Studi di Milano; 2010. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/150132.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

FEO SG. CCRL2, A PUTATIVE CHEMOTACTIC RECEPTOR, PARTICIPATES IN THE LUNG DENDRITIC CELL TRAFFICKING. [Thesis]. Università degli Studi di Milano; 2010. Available from: http://hdl.handle.net/2434/150132

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

7. F. Cavaciocchi. T CELL SUBTYPES IN MANAGEMENT OF OSTEOPOROSIS WITH BISPHOSPHONATES AND THE AUTOIMMUNE REACTION TO THE COLLAGEN IN RHEUMATOID ARTHRITIS.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/251417

► T lymphocytes with different T cell receptors are at the crossroad of inflammation and autoimmunity. We investigated the role of γδTCR and αβTCR T lymphocytes… (more)

▼ T lymphocytes with different T cell receptors are at the crossroad of inflammation and autoimmunity. We investigated the role of γδTCR and αβTCR T lymphocytes (γδT, αβT cells) in two model conditions represented by zoledronic acid (ZA)-induced acute phase reactions (APR) and in the immune reaction against collagen in rheumatoid arthritis (RA). First, γδTCR T lymphocytes (γδTcells) are specifically activated by ZA infusion in the treatment of osteoporosis and is frequently associated with the onset of APR, possibly via 25-OH vitamin D (25-OHvD) levels. 50% of patients reported ZA-associated APR (APR+). APR+ cases had a higher percentage of central memory Th1-like γδTcells before treatment. One week after ZA infusion, a decreased percentage of central memory Th1-like γδTcells, an increase in the percentage and activation of effector memory Th1-like γδTcells, and an increase in Th17-like γδTcells were observed in the patients with APR. Lower 25-OHvD levels were significantly associated to APR, but no correlation was found between 25-OHvD level and γδTcell percentage or subsets. Second, αβTCR T lymphocytes (αβTcells) in RA recognize the DR4/DR1-restricted epitope 261-273 of the human type II collagen, whereas B cells recognize the epitope 359-369. We investigated the role of B and T cell epitopes and their post-translational modifications on the RA adaptive immune response. PBMCs from 5 HLA-DR4+ monozygotic twins, two HLA-DR4+ and one HLA-DR3+ healthy donor and synovial fluids (SF) from an HLA-DR4+ RA patient and HLA-DR3+ patient were used and cells cultured with the native form of the collagen T epitope (261-273T), its K264 carbamylated form (homocit261-273T), the native form of the collagen B epitope (359-369B), its R360 citrullinated form (cit359-369B) or the combination of the native and modified epitopes. We may conclude that the collagen T epitope 261-273 has a role in the pathogenesis of RA, but the carbamilation of this epitope dos not seem to be influent in the T cell response. Advisors/Committee Members: tutor: C.F. Selmi, M. De Santis, coordinatore: M. Locati, LOCATI, MASSIMO, LOCATI, MASSIMO.

Subjects/Keywords: Osteoporosis; zoledronic acid; γδTCR T lymphocytes; rheumatoid arthritis; human collagen epitopes; citrullinations; carbamylation; Settore MED/16 - Reumatologia; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cavaciocchi, F. (2015). T CELL SUBTYPES IN MANAGEMENT OF OSTEOPOROSIS WITH BISPHOSPHONATES AND THE AUTOIMMUNE REACTION TO THE COLLAGEN IN RHEUMATOID ARTHRITIS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/251417

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Cavaciocchi, F.. “T CELL SUBTYPES IN MANAGEMENT OF OSTEOPOROSIS WITH BISPHOSPHONATES AND THE AUTOIMMUNE REACTION TO THE COLLAGEN IN RHEUMATOID ARTHRITIS.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/251417.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Cavaciocchi, F.. “T CELL SUBTYPES IN MANAGEMENT OF OSTEOPOROSIS WITH BISPHOSPHONATES AND THE AUTOIMMUNE REACTION TO THE COLLAGEN IN RHEUMATOID ARTHRITIS.” 2015. Web. 16 Jan 2021.

Vancouver:

Cavaciocchi F. T CELL SUBTYPES IN MANAGEMENT OF OSTEOPOROSIS WITH BISPHOSPHONATES AND THE AUTOIMMUNE REACTION TO THE COLLAGEN IN RHEUMATOID ARTHRITIS. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/251417.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Cavaciocchi F. T CELL SUBTYPES IN MANAGEMENT OF OSTEOPOROSIS WITH BISPHOSPHONATES AND THE AUTOIMMUNE REACTION TO THE COLLAGEN IN RHEUMATOID ARTHRITIS. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/251417

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

8. S. Muggeo. A STEP-BY-STEP PROCESS TO GENERATE FUNCTIONAL OSTEOCLASTS FROM SITE SPECIFIC GENE-CORRECTED INDUCED PLURIPOTENT STEM CELLS: AN AUTOLOGOUS CELL THERAPY APPROACH TO TREAT AUTOSOMAL RECESSIVE OSTEOPETROSIS.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/252730

► Autosomal recessive osteopetrosis (ARO) is a human severe inherited disorder leading to increased bone mass, decreased bone strength with risk of multiple fractures and progressive… (more)

▼ Autosomal recessive osteopetrosis (ARO) is a human severe inherited disorder leading to increased bone mass, decreased bone strength with risk of multiple fractures and progressive narrowing of the medullary cavity. Among the heterogeneous group of osteopetrosis, ARO shows the most severe phenotype, leading to death early in life if not treated. The most frequently mutated gene is the T-cell immune regulator 1 (TCIRG1), encoding the a3 subunit of the vacuolar-type proton transporting ATPase pump, which mediates the acidification of the bone/osteoclast interface, causing defects in the resorbing activity of osteoclasts. The spontaneous mouse model oc/oc well recapitulates the disease features. Hematopoietic stem cell (HSC) transplantation is the only treatment so far available to cure the disease, due to the hematopoietic origin of osteoclasts, however its success is limited to the restricted number of available matched donors. Thus, the transplant of autologous corrected hematopoietic cells represents a valid alternative therapeutic option. In particular, due to the limitations in performing gene targeting of primary cells, induced pluripotent stem cells (iPSc) obtained from patients could represent an unlimited source of autologous cells in which it is possible to perform target gene correction. They can be subsequently differentiated towards hematopoietic progenitors to perform an autologous transplantation. In the present thesis, I have exploited murine iPSc as a potential source of cells to be differentiated into functional osteoclasts able to resorb bone. To this end, I have pursued the following strategy: (a) generation of vector-free iPSc from wild type (wt) and oc/oc mice employing a third generation Cre-excisable lentiviral vector carrying the reprogramming genes Oct4, Sox2, Klf4; (b) correction of oc/oc iPSc replacing the entire mutated Tcirg1 gene through homologous recombination, by using a BAC engineered vector; (c) set up a protocol for the differentiation of wt, uncorrected and corrected oc/oc iPSc into the hematopoietic lineage, generating both mature cells and high proliferative potential colony-forming progenitors; (d) further differentiation of obtained myeloid precursors into osteoclasts with rescued bone resorbing activity upon gene-correction. The process is aimed at generating transplantable hematopoietic cells, including osteoclast precursors, with the final goal of transplanting them in the ARO mouse model oc/oc to revert the phenotype, thus providing a proof of principle for an autologous cell therapy approach to treat ARO. Advisors/Committee Members: tutor: A. Villa, supervisore: F. Ficara, coordinator: M. Locati, LOCATI, MASSIMO, LOCATI, MASSIMO.

Subjects/Keywords: induced pluripotent stem cells; hematopoiesis; osteopetrosis; Settore MED/03 - Genetica Medica; Settore MED/04 - Patologia Generale; Settore MED/05 - Patologia Clinica

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Muggeo, S. (2015). A STEP-BY-STEP PROCESS TO GENERATE FUNCTIONAL OSTEOCLASTS FROM SITE SPECIFIC GENE-CORRECTED INDUCED PLURIPOTENT STEM CELLS: AN AUTOLOGOUS CELL THERAPY APPROACH TO TREAT AUTOSOMAL RECESSIVE OSTEOPETROSIS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/252730

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Muggeo, S.. “A STEP-BY-STEP PROCESS TO GENERATE FUNCTIONAL OSTEOCLASTS FROM SITE SPECIFIC GENE-CORRECTED INDUCED PLURIPOTENT STEM CELLS: AN AUTOLOGOUS CELL THERAPY APPROACH TO TREAT AUTOSOMAL RECESSIVE OSTEOPETROSIS.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/252730.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Muggeo, S.. “A STEP-BY-STEP PROCESS TO GENERATE FUNCTIONAL OSTEOCLASTS FROM SITE SPECIFIC GENE-CORRECTED INDUCED PLURIPOTENT STEM CELLS: AN AUTOLOGOUS CELL THERAPY APPROACH TO TREAT AUTOSOMAL RECESSIVE OSTEOPETROSIS.” 2015. Web. 16 Jan 2021.

Vancouver:

Muggeo S. A STEP-BY-STEP PROCESS TO GENERATE FUNCTIONAL OSTEOCLASTS FROM SITE SPECIFIC GENE-CORRECTED INDUCED PLURIPOTENT STEM CELLS: AN AUTOLOGOUS CELL THERAPY APPROACH TO TREAT AUTOSOMAL RECESSIVE OSTEOPETROSIS. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/252730.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Muggeo S. A STEP-BY-STEP PROCESS TO GENERATE FUNCTIONAL OSTEOCLASTS FROM SITE SPECIFIC GENE-CORRECTED INDUCED PLURIPOTENT STEM CELLS: AN AUTOLOGOUS CELL THERAPY APPROACH TO TREAT AUTOSOMAL RECESSIVE OSTEOPETROSIS. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/252730

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

9. O. Bonavita. DOWN-REGULATION OF ATYPICAL CHEMOKINE RECEPTOR ACKR2/D6 EXPRESSION BY HEMATOPOIETIC PROGENITORS PROMOTES MYELOID CELL MOBILIZATION AND DIFFERENTIATION.

Degree: 2017, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/488818

► Chemokines and chemokine receptors are key mediators of inflammation and important regulators of leukocyte migration in homeostatic conditions as well as during infection and cancer.… (more)

▼ Chemokines and chemokine receptors are key mediators of inflammation and important regulators of leukocyte migration in homeostatic conditions as well as during infection and cancer. The atypical receptor ACKR2 is a scavenger receptor for many inflammatory CC chemokines, it is expressed either by non-hematopoietic cells or by hematopoietic cells, and it has been shown to prevent the development of exacerbated inflammatory reactions. In an effort to understand the contribution of this receptor in the regulation of myeloid cell mobilization and myeloid cell effector functions, we investigated the role of ACKR2 in a murine model of myeloid cell mobilization, and in a model of experimental metastasis. The deficiency of ACKR2 was associated with increased mobilization of monocytes and neutrophils from the bone marrow (BM) and with increased number of monocytes confined to BM sinusoids compared to Wild-type (WT) mice. BM chimera experiments showed that the increased mobilization was due to the absence of ACKR2 in the hematopoietic compartment. The analysis of hematopoietic progenitor cells (HPCs) revealed that ACKR2 is expressed by Lin−Sca-1+c-Kit+ cells (LSK) to faint thereafter in more mature myeloid progenitor cells (MPCs) in contrast with the canonical chemokine receptor CCR2. Moreover, HPCs from Ackr2-/- mice expressed higher levels of CCR1, CCR2 and CCR5, but not of CXCR4 and they had higher differentiation rate compared to ACKR2 sufficient LSK. Although neutrophils express low levels of ACKR2 compared to LSK, we found that neutrophils from Ackr2 deficient mice, as well as their HPCs, expressed higher level of CC chemokine receptors and exhibited a more activated phenotype compared to WT. Furthermore, neutrophil depletion and neutrophil adoptive transfer experiments demonstrated that only Ackr2 deficient neutrophils were sufficient to control the metastatic seeding of B16 melanoma cells into the lung. To enhance the metastatic protection observed in Ackr2-/- mice, we treated WT and Ackr2-/- tumor bearing mice with AMD3100, the competitive inhibitor of CXCR4, which is known to induce a rapid neutrophil mobilization from the BM. However, AMD3100 treatment did not further improve the metastatic protection in Ackr2-/- mice, whereas decreased the number of metastases in WT mice. Finally, by using the human promyelocytic cell line HL-60, we demonstrated that ACKR2 directly exerted a negative regulation of CC chemokine receptor expression and cell differentiation. Indeed, HL-60, when transfected with a vector overexpressing ACKR2, had decreased transcript levels of CCR2 and CD11b. These data suggest the ACKR2 is involved in the regulation of chemokine availability and leukocyte recruitment. Moreover, ACKR2 directly controls HPC differentiation, myeloid cell mobilization and their effector function through the inhibition of CC chemokine receptor expression. Advisors/Committee Members: supervisore: R. Bonecchi, tutor: M. Locati, coordinatore: M. Locati, LOCATI, MASSIMO, BONECCHI, RAFFAELLA, LOCATI, MASSIMO.

Subjects/Keywords: Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bonavita, O. (2017). DOWN-REGULATION OF ATYPICAL CHEMOKINE RECEPTOR ACKR2/D6 EXPRESSION BY HEMATOPOIETIC PROGENITORS PROMOTES MYELOID CELL MOBILIZATION AND DIFFERENTIATION. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/488818

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Bonavita, O.. “DOWN-REGULATION OF ATYPICAL CHEMOKINE RECEPTOR ACKR2/D6 EXPRESSION BY HEMATOPOIETIC PROGENITORS PROMOTES MYELOID CELL MOBILIZATION AND DIFFERENTIATION.” 2017. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/488818.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Bonavita, O.. “DOWN-REGULATION OF ATYPICAL CHEMOKINE RECEPTOR ACKR2/D6 EXPRESSION BY HEMATOPOIETIC PROGENITORS PROMOTES MYELOID CELL MOBILIZATION AND DIFFERENTIATION.” 2017. Web. 16 Jan 2021.

Vancouver:

Bonavita O. DOWN-REGULATION OF ATYPICAL CHEMOKINE RECEPTOR ACKR2/D6 EXPRESSION BY HEMATOPOIETIC PROGENITORS PROMOTES MYELOID CELL MOBILIZATION AND DIFFERENTIATION. [Internet] [Thesis]. Università degli Studi di Milano; 2017. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/488818.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bonavita O. DOWN-REGULATION OF ATYPICAL CHEMOKINE RECEPTOR ACKR2/D6 EXPRESSION BY HEMATOPOIETIC PROGENITORS PROMOTES MYELOID CELL MOBILIZATION AND DIFFERENTIATION. [Thesis]. Università degli Studi di Milano; 2017. Available from: http://hdl.handle.net/2434/488818

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

10. G. Marelli. ROLE OF INTESTINAL CX3CR1+ MACROPHAGES IN THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER: FOCUS ON THE RELEVANCE OF THE MICROBIOME AND HEME-OXYGENASE-1.

Degree: 2016, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/365306

► Gut represents a complex landscape in which commensal bacteria, harmless antigens and food proteins are strictly in contact with the immune system that has to… (more)

▼ Gut represents a complex landscape in which commensal bacteria, harmless antigens and food proteins are strictly in contact with the immune system that has to be able to maintain a balance between the immune response and tolerance. In this context, mononuclear phagocytes are the most abundant population and macrophages represent a key player in this process of discrimination by allowing a peaceful coexistence. If this crucial checkpoint is lost, immune system is activated and falls in a dangerous and prolonged inflammation. Recent studies have described CX3CR1+ cells as a population of resident macrophages able to sample the gut lumen and to produce the anti-inflammatory cytokine IL-10 in order to maintain homeostasis. These macrophages are characterized by the expression of the chemokine receptor CX3CR1; however, how this receptor is involved in the molecular mechanisms that regulate the inflammatory response is largely unknown. The global aim of this thesis is to define the role of mucosal CX3CR1+ macrophages during acute and chronic inflammation and in the process of intestinal carcinogenesis, and to investigate the molecular mechanisms by which these immune cells maintain gut homeostasis. We analyzed the behavior of these macrophages in mice lacking the CX3CR1 receptor (CX3CR1GFP/GFP) and in wild type heterozygous mice (CX3CR1GFP/+). Firstly, we characterized them as a macrophagic population expressing CX3CR1, F4/80, CD11b and CD64 confirming the data present in literature. As the behavior of these cells is less defined during the resolution of inflammation, we performed a model of recovery from colitis and we found that KO mice displayed higher signs of inflammation compared to WT mice, and they were not able to recover as WT mice did. From the molecular point of view, we found that the inflammatory mediators were up-regulated in KO mice as well as members of the IL-10 family cytokines. The only mediator resulting down-regulated in KO mice was heme-oxygenase-1 (hemox-1). Hemox-1 is an anti-inflammatory enzyme over-expressed during tissue injury that is able to promote bacteria clearance. This regulation of this molecule is very complex and involves also IL-10. However, despite KO mice produced more IL-10, in an attempt to switch off inflammation, they were not able to produce an adequate amount of hemox-1. We reproduced, in vitro, the model of colitis and we showed that macrophages from KO mice responded to the inflammatory stimulus (LPS) with an aberrant response, up-regulating both pro and anti-inflammatory mediators, but not hemox-1. Moreover, we observed a synergism between LPS and the chemokine Fracktalkine/CX3CL1 (FKN) in the production of hemox-1 in WT mice and also found that stimulation with FKN alone was sufficient to produce hemox-1 in WT mice, unveiling a previously unidentified role of the chemokine receptor CX3CR1 in the regulation of hemox-1. Using the AOM/DSS model of colitis-induced carcinogenesis (CAC), a study that has never been performed in these genetically modified mice, we found… Advisors/Committee Members: coordinator: M. Locati, supervisor: P. Allavena, LOCATI, MASSIMO, LOCATI, MASSIMO, Allavena, Paola.

Subjects/Keywords: Macrophages; microbiota; mucosal immunology; colorectal cancer; inflammation; colon; cx3cr1; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Marelli, G. (2016). ROLE OF INTESTINAL CX3CR1+ MACROPHAGES IN THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER: FOCUS ON THE RELEVANCE OF THE MICROBIOME AND HEME-OXYGENASE-1. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/365306

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Marelli, G.. “ROLE OF INTESTINAL CX3CR1+ MACROPHAGES IN THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER: FOCUS ON THE RELEVANCE OF THE MICROBIOME AND HEME-OXYGENASE-1.” 2016. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/365306.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Marelli, G.. “ROLE OF INTESTINAL CX3CR1+ MACROPHAGES IN THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER: FOCUS ON THE RELEVANCE OF THE MICROBIOME AND HEME-OXYGENASE-1.” 2016. Web. 16 Jan 2021.

Vancouver:

Marelli G. ROLE OF INTESTINAL CX3CR1+ MACROPHAGES IN THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER: FOCUS ON THE RELEVANCE OF THE MICROBIOME AND HEME-OXYGENASE-1. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/365306.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Marelli G. ROLE OF INTESTINAL CX3CR1+ MACROPHAGES IN THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER: FOCUS ON THE RELEVANCE OF THE MICROBIOME AND HEME-OXYGENASE-1. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/365306

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

11. A. Vacchini. ANALYSIS OF BIASED SIGNALING IN THE CHEMOKINE SYSTEM.

Degree: 2016, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/365864

► Chemokines constitute a family of almost 50 small secreted cytokines, recognized by about 20 different 7TM spanning G protein coupled receptors (GPCRs), that activating pertussis… (more)

▼ Chemokines constitute a family of almost 50 small secreted cytokines, recognized by about 20 different 7TM spanning G protein coupled receptors (GPCRs), that activating pertussis toxin sensitive G proteins induce cell migration. These receptor are abundantly expressed by leukocytes and, controlling cell migration, they dictate leukocyte positioning during homeostatic patrolling within peripheral tissues, their maintenance in bone marrow during maturation and in addition mediate their recruitment to inflamed tissues. Upon inflammation in fact a number of chemokines are produced or activated by inflammatory mediators and diffuse within the tissue, generating a chemical gradient along which leukocytes migrate to reach the center of inflammation to contain and remove the insulting factor. This system needs an extremely tight control, since its dysregulation has been demonstrated to be at the basis of different inflammatory diseases, auto-immunity and has also been linked to cancer development. In particular, in this thesis we focused our attention on two regulatory system: post-translational modifications of chemokines, mediated by enzymes specifically released upon inflammation also by immune cells, and on the activity of atypical chemokine receptors, a subfamily of chemokine receptors that despite high structural homology and similar binding properties compared to conventional chemokine receptors, are unable to drive chemotaxis but act instead as key regulators of the chemokine system activity. In detail we looked at the ability of these regulatory mechanisms to modulate chemokine signaling properties generating a biased signaling, an emerging feature of GPCR pharmacology that describes the ability of a given receptor to elicit different or even opposite functional activities depending on the ability of different agonists to stabilize different receptor’s active structural conformation, resulting in different phenotypes mediated by the same receptor. In the chemokine system biased signaling has already been described to occur on different receptors upon binding of their different ligands, therefore during our investigation on chemokine regulatory system signaling we maintained our focus on the ability of these systems to bias chemokine signaling properties in order to better understand how this regulation occurs. To this point we assessed the ability of differently post-translationally modified chemokines to elicit signaling activities on different receptors by measuring in HEK293 cells their potential in inhibiting adenylyl cyclase, a proximal downstream signal of Gα inhibitory proteins activation, and in inducing β-arrestin recruitment to the receptors in energy transfer-based assays. We also compared signaling properties of an atypical chemokine receptor to the ones elicited by a conventional receptor analyzing the phosphoproteome modifications occurring constitutively and after stimulation with the same agonist. Our results indicate that regulation of CXCL5 and CXCL8 chemokine activity by post-translational… Advisors/Committee Members: supervisor: M. Locati, E.M. Borroni, coordinator: M. Locati, LOCATI, MASSIMO, LOCATI, MASSIMO, BORRONI, ELENA MONICA.

Subjects/Keywords: Chemokine; Atypical Chemokine Receptor; Biased Signaling; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Vacchini, A. (2016). ANALYSIS OF BIASED SIGNALING IN THE CHEMOKINE SYSTEM. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/365864

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Vacchini, A.. “ANALYSIS OF BIASED SIGNALING IN THE CHEMOKINE SYSTEM.” 2016. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/365864.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vacchini, A.. “ANALYSIS OF BIASED SIGNALING IN THE CHEMOKINE SYSTEM.” 2016. Web. 16 Jan 2021.

Vancouver:

Vacchini A. ANALYSIS OF BIASED SIGNALING IN THE CHEMOKINE SYSTEM. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/365864.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Vacchini A. ANALYSIS OF BIASED SIGNALING IN THE CHEMOKINE SYSTEM. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/365864

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

12. L. Drufuca. ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION.

Degree: 2018, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/565701

► Macrophages are cells from the innate branch of immune system with central roles both under physiologic and pathologic conditions. Such complex behaviour relies on extreme… (more)

▼ Macrophages are cells from the innate branch of immune system with central roles both under physiologic and pathologic conditions. Such complex behaviour relies on extreme functional plasticity of these cells. Cellular activation and plasticity in macrophages are complex phenomena that require tight regulation. In recent years, microRNAs and lncRNAs emerged as important regulators of many cellular processes and have been proposed as key mediators of the plasticity observed in macrophages. In this study we investigate the possible roles of different microRNAs on macrophage activation and functionality, taking advantage of animal models selectively depleted of candidate miRNA in macrophages. We found that selective depletion of miR-125a in macrophages did not affect clinical outcome in different in vivo models of inflammation. Nonetheless it altered macrophage activation and functions, as evidenced by reduced secretion of TNFα after endotoxin challenges. Consistently, macrophages deficient in miR-125a displayed reduced killing of extracellular bacteria although they showed increased phagocytic rate as compared to miR-125a competent cells. With a similar approach, we confirmed that miR-9 is induced in macrophages upon inflammatory stimuli. Increased expression of miR-9 mature form in mice was sustained by the synchronous activation of transcription in both pri-miR-9.1 and pri-miR-9.3 loci, in contrast to human. Finally we identified a lncRNA interfering with the processing of a pro-inflammatory miRNA in differentially activated human macrophages, highlighting a new layer of regulation of macrophage activation. The finding of the present project give new insights into the complex mechanism regulating macrophage activation and underscores the need for future studies to thoroughly identify the molecular mechanisms and the involvement of different miRNA in macrophage activation. Moreover, such studies could set the basis for the transition from basic research to new therapeutic options enabling precise regulation of macrophages activation in different immune pathologies. Advisors/Committee Members: tutor: M. LOCATI, phd program coordinator: M. LOCATI, LOCATI, MASSIMO, LOCATI, MASSIMO.

Subjects/Keywords: Settore BIO/13 - Biologia Applicata

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Drufuca, L. (2018). ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/565701

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Drufuca, L.. “ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION.” 2018. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/565701.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Drufuca, L.. “ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION.” 2018. Web. 16 Jan 2021.

Vancouver:

Drufuca L. ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION. [Internet] [Thesis]. Università degli Studi di Milano; 2018. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/565701.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Drufuca L. ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION. [Thesis]. Università degli Studi di Milano; 2018. Available from: http://hdl.handle.net/2434/565701

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

13. F. Roma. RUOLO DEI MICRORNA NEL DIFFERENZIAMENTO MIOGENICO NORMALE E PATOLOGICO.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/252093

► riassunto Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease, is the third most common myopathy, with an incidence of 1 in 15.000 in the… (more)

▼ riassunto Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease, is the third most common myopathy, with an incidence of 1 in 15.000 in the general population. Clinical symptoms appear during the second decade of age and are characterized by progressive muscle weakness and atrophy, initially of the facial, scapular and humeral muscles, which show marked asymmetry and later involving the abdominal muscles and the musculature of the lower limbs. This disease is generally associated with contraction of D4Z4 repeat array (1 to 10 repeats), localized on chromosome 4 (4q35 region). D4Z4 is a macrosatellite typically composed of 10 to 100 of 3.3 kb units repeated in tandem. Every unit has a complex structure, with GC-rich sequences and an open reading frame (ORF), containing two homeobox sequences. Upstream of the macrosatellite are located several genes (FRG1, FRG2, ANT1) normally not expressed, or expressed at very low levels. The whole region is indeed strongly methylated, with an overall heterochromatic state. The contraction, together or in addition to molecular mechanisms not yet totally clarified, leads to 4q35 hypomethylation, causing gene overexpression of DUX4 and another genes in cis and trans. Infact, the FSHD cells are characterized by an extensive gene expression dysregulation mainly affecting the myogenesis. In this context, miRNAs may play an important role, are powerful gene expression modulators. Moreover, there are muscle-specific microRNAs (myomiRNAs), actively regulating several myogenic factors, as MEF2, MyoD, myogenin and SRF. This thesis proposes to relate differentiation processes of both healthy and FSHD myoblasts, investigating the expression prolifes, by RNA-Seq, of miRNA . The purpose is indeed to clarify possible expression differences, the derived miRNA prolifing could represent a novel molecular signature for FSHD that includes diagnostic biomarkers and possibly therapeutic targets. MicroRNAs with a significantly different expression profile between FSHD and controls have been submitted to qRT-PCR, in order to validate the sequencing results. The subsequent investigation by bioinformatics prediction tools on the targets of these small ncRNA, allowed to define molecular pathways that could be altered in FSHD. In short, control myogenesis showed the modulation of 38 miRNAs, the majority of which (34 out 38) were up-regulated, including myomiRs (miR-1, -133a, -133b and -206). Approximately one third of the modulated miRNAs were not previously reported to be involved in muscle differentiation, and interestingly some of these ( i.e. miR-874, -1290,-95 and -146a) were previously shown to regulate cell proliferation and differentiantion. FSHD myogenesis evidenced a reduced number of modulated miRNAs than healthy muscle cells. The two processes shared nine miRNAs, including myomiRs, although with FC values lower in FSHD than in control cells. In addition, FSHD cells showed the modulation of six miRNAs ( miR-1268, -1268b, -1908, -4258, -4508 and -4516) not evidenced in… Advisors/Committee Members: tutor: E. Ginelli, coordinator: M. Locati, LOCATI, MASSIMO.

Subjects/Keywords: Settore BIO/13 - Biologia Applicata

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APA (6^th Edition):

Roma, F. (2015). RUOLO DEI MICRORNA NEL DIFFERENZIAMENTO MIOGENICO NORMALE E PATOLOGICO. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/252093

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Roma, F.. “RUOLO DEI MICRORNA NEL DIFFERENZIAMENTO MIOGENICO NORMALE E PATOLOGICO.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/252093.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Roma, F.. “RUOLO DEI MICRORNA NEL DIFFERENZIAMENTO MIOGENICO NORMALE E PATOLOGICO.” 2015. Web. 16 Jan 2021.

Vancouver:

Roma F. RUOLO DEI MICRORNA NEL DIFFERENZIAMENTO MIOGENICO NORMALE E PATOLOGICO. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/252093.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Roma F. RUOLO DEI MICRORNA NEL DIFFERENZIAMENTO MIOGENICO NORMALE E PATOLOGICO. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/252093

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

14. R. Gualtierotti. ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS.

Degree: 2016, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/366559

► Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by systemic and intrarticular inflammation. Fibroblast-like synoviocytes (FLSs) in RA have an activated phenotype with increased… (more)

Subjects/Keywords: Settore MED/04 - Patologia Generale; Settore MED/16 - Reumatologia; Settore MED/09 - Medicina Interna

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gualtierotti, R. (2016). ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/366559

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Gualtierotti, R.. “ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS.” 2016. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/366559.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Gualtierotti, R.. “ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS.” 2016. Web. 16 Jan 2021.

Vancouver:

Gualtierotti R. ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/366559.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gualtierotti R. ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/366559

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

15. E. Toffolo. POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION OF LSD1 IN MAMMALIAN BRAIN.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/286318

► Epigenetic mechanisms play important roles in brain development, orchestrating proliferation, differentiation, and morphogenesis. Lysine-Specific Demethylase 1 (LSD1 also known as KDM1A and AOF2) is a… (more)

Subjects/Keywords: EPIGENETICS; LSD1; NEURONAL MATURATION; Settore BIO/13 - Biologia Applicata

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APA (6^th Edition):

Toffolo, E. (2015). POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION OF LSD1 IN MAMMALIAN BRAIN. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/286318

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Toffolo, E.. “POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION OF LSD1 IN MAMMALIAN BRAIN.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/286318.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Toffolo, E.. “POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION OF LSD1 IN MAMMALIAN BRAIN.” 2015. Web. 16 Jan 2021.

Vancouver:

Toffolo E. POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION OF LSD1 IN MAMMALIAN BRAIN. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/286318.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Toffolo E. POST-TRANSCRIPTIONAL AND POST-TRANSLATIONAL REGULATION OF LSD1 IN MAMMALIAN BRAIN. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/286318

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

16. M. Rubino. EPIGENETIC MODIFICATIONS ABOLISH THE EXPRESSION OF THE LONG PENTRAXIN PTX3 IN HUMAN TUMORS.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/254345

► PTX3 is a fluid-phase pattern recognition receptor that participates in innate immunity and inflammation by modulating complement activation, leukocyte recruitment, extracellular matrix deposition and angiogenesis.… (more)

▼ PTX3 is a fluid-phase pattern recognition receptor that participates in innate immunity and inflammation by modulating complement activation, leukocyte recruitment, extracellular matrix deposition and angiogenesis. PTX3 is a biomarker of inflammatory conditions in different pathologies in humans, including acute myocardial infarction to autoimmune diseases, infections and cancer associated inflammation. Moreover, in vivo studies indicate that PTX3 is involved in cancer development, possibly by regulating inflammation. Several tumors lack PTX3 expression, such as human esophageal squamous cell carcinoma, where PTX3 is silenced through pro¬moter hypermethylation. Taken together, these data suggest that PTX3 is potentially involved in cancer development. The aim of this study was to identify the regulatory elements involved in the modulation of PTX3 expression and gain insight into their mechanisms of action in basal condition, inflammatory responses and cancer. Using in silico analysis of PTX3 gene we identified two putative PTX3 enhancers located 230 kbp upstream of the promoter and in the second exon of the gene, overlapping a CpG island, respectively. We performed ChIP assay for histone modifications and epigenetic complexes for the analysis of these genetic elements in human cell lines, before and after treatment with TNFα, that induces PTX3 expression. The results show that these regions are enhancers, but in basal condition are enriched with repressive markers H3K27me3 and polycomb group subunities (SUZ12 and EZH2). After TNFα treatment, the two enhancers became active gaining H3K27ac and the RNA Polymerase II and the first enhancer also acquired the binding for NF-kB. We also analysed the effect of the microRNAs, which were predicted to directly target PTX3, using bioinformatics analysis. miR-9, miR-29 family and miR-181 family were shown to directly target the PTX3 3’-UTR and to significantly reduce both PTX3 mRNA expression and protein production. Luciferase assay with PTX3 promoter and with a reporter vector for NF-kb showed that these miRNAs are also involved in signalling pathways controlling PTX3 transcription. Moreover, RNA Immuno Precipitation assay demonstrated that miR-9, miR-29 family and miR-181 family members and PTX3 mRNA were enriched in the RISC complex of macrophages after 6h of stimulation with lipopolysaccharide. Moreover, inflammatory miRNAs, such as miR-146a, miR-155 and miR-132 regulate PTX3 messenger and protein expression, as well, targeting the network upstream of PTX3 expression. This suggests that PTX3 gene is strictly regulated by several miRNAs acting at different points during inflammatory response. Bioinformatics analysis showed that PTX3 is not express in several cancer, including colorectal cancer (CRC). ELISA and gene expression analysis in CRC cells confirmed bioinformatics data and the treatment with the demethylating agent 5'aza-dC restored PTX3 expression and production. ChIP assay for histone modifications and transcription factors in CRC cells showed that PTX3… Advisors/Committee Members: relatore: M. Locati, tutore: C. Garlanda, LOCATI, MASSIMO.

Subjects/Keywords: PTX3; cancer; epigenetics modifications; enhancers; miRNAs; DNA methylation; histone modifications; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rubino, M. (2015). EPIGENETIC MODIFICATIONS ABOLISH THE EXPRESSION OF THE LONG PENTRAXIN PTX3 IN HUMAN TUMORS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/254345

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rubino, M.. “EPIGENETIC MODIFICATIONS ABOLISH THE EXPRESSION OF THE LONG PENTRAXIN PTX3 IN HUMAN TUMORS.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/254345.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rubino, M.. “EPIGENETIC MODIFICATIONS ABOLISH THE EXPRESSION OF THE LONG PENTRAXIN PTX3 IN HUMAN TUMORS.” 2015. Web. 16 Jan 2021.

Vancouver:

Rubino M. EPIGENETIC MODIFICATIONS ABOLISH THE EXPRESSION OF THE LONG PENTRAXIN PTX3 IN HUMAN TUMORS. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/254345.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rubino M. EPIGENETIC MODIFICATIONS ABOLISH THE EXPRESSION OF THE LONG PENTRAXIN PTX3 IN HUMAN TUMORS. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/254345

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

17. M.C. Filomena. THE ROLE OF THE SARCOMERIC PROTEIN MYOPALLADIN IN SKELETAL AND CARDIAC MUSCLE STRUCTURE, FUNCTION AND DISEASE.

Degree: 2016, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/365482

► Myopalladin (MYPN) is a striated muscle-specific sarcomeric protein belonging to the small palladin/myopalladin/myotilin family of actin-associated immunoglobulin-containing proteins [1]. Within the sarcomeric Z-line, MYPN binds… (more)

▼ Myopalladin (MYPN) is a striated muscle-specific sarcomeric protein belonging to the small palladin/myopalladin/myotilin family of actin-associated immunoglobulin-containing proteins [1]. Within the sarcomeric Z-line, MYPN binds to α-actinin, nebulin, and PDZ-LIM proteins [1, 2]. Furthermore, it is present in the nucleus and the I-band where it binds to the stress-inducible transcriptional cofactor CARP/Ankrd1, which, in turn, binds to the I-band region of titin, suggesting a role of MYPN in mechanosensing [1, 3]. The important role of MYPN in striated muscle is illustrated by the identification of MYPN mutations in human patients with dilated (DCM), hypertrophic (HCM), and restrictive (RCM) cardiomyopathy [4-6]. In our biochemical studies we demonstrated that MYPN, like PALLD, can bind and bundle filamentous actin (F-actin), thereby promoting actin polymerization. Moreover, we found that, similar to PALLD, MYPN interacts with MRTF-A and strongly increases MRTF-A-mediated activation of serum response factor (SRF) signaling, required for skeletal and cardiac muscle growth, maturation, and differentiation [7-11]. To determine the role of MYPN in vivo, we generated MYPN knockout (MKO) mice. MKO mice were significantly smaller compared to wildtype (WT) mice and had an about 30% reduction in skeletal muscle cross-sectional area (CSA) at all ages. Consistently, reduced differentiation rate and myotube width was observed in primary skeletal muscle cultures derived from MKO mice. Furthermore, studies of muscle performance in 2-month-old MKO mice showed reduced isometric force and power during isotonic shortening at any load as a result of the reduced cross sectional area, whereas the force developed by each myosin molecular motor was unaffected. By up- and downhill treadmill running, MKO and WT mice performed similarly. However, while the performance of WT mice was unaffected following four consecutive days of downhill running, the performance of MKO mice decreased progressively and Z-line damage was observed. Consistent with a higher susceptibility to muscle damage, progressive Z-line widening was observed in MKO skeletal muscle from about 8 months of age. RNAseq revealed downregulation of actin isoforms and other SRF-target genes in MKO muscle both at 2 and 4 weeks of age, suggesting that the smaller skeletal muscle fiber size in MKO mice is due to reduced SRF activity. Cardiac analyses of MKO mice showed no cardiac phenotype at young age but the development of progressive cardiac dilation and decreased fractional shortening. On the other hand, in response to mechanical pressure overload induced by transaortic constriction (TAC), MKO mice quickly developed cardiac dilation and reduced cardiac function accompanied by activation of the MAPK and AKT signaling pathways. Ongoing investigations are focused on studying the precise mechanism by which MYPN modulates actin dynamics through the Rho-MRTF-SRF signaling pathway as well as understanding the mechanisms leading from MYPN mutations to cardiomyopathy. Advisors/Committee Members: SUPERVISOR: M. LOCATI, TUTOR: M. L. BANG, LOCATI, MASSIMO.

Subjects/Keywords: Settore MED/11 - Malattie dell'Apparato Cardiovascolare

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Filomena, M. (2016). THE ROLE OF THE SARCOMERIC PROTEIN MYOPALLADIN IN SKELETAL AND CARDIAC MUSCLE STRUCTURE, FUNCTION AND DISEASE. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/365482

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Filomena, M.C.. “THE ROLE OF THE SARCOMERIC PROTEIN MYOPALLADIN IN SKELETAL AND CARDIAC MUSCLE STRUCTURE, FUNCTION AND DISEASE.” 2016. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/365482.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Filomena, M.C.. “THE ROLE OF THE SARCOMERIC PROTEIN MYOPALLADIN IN SKELETAL AND CARDIAC MUSCLE STRUCTURE, FUNCTION AND DISEASE.” 2016. Web. 16 Jan 2021.

Vancouver:

Filomena M. THE ROLE OF THE SARCOMERIC PROTEIN MYOPALLADIN IN SKELETAL AND CARDIAC MUSCLE STRUCTURE, FUNCTION AND DISEASE. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/365482.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Filomena M. THE ROLE OF THE SARCOMERIC PROTEIN MYOPALLADIN IN SKELETAL AND CARDIAC MUSCLE STRUCTURE, FUNCTION AND DISEASE. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/365482

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

18. G. DI CARO. ADAPTIVE AND NATIVE IMMUNE CELLS AS PROGNOSTIC AND PREDICTIVE BIOMARKERS ALONG COLORECTAL CANCER PROGRESSION.

Degree: 2013, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/218989

► Inflammation and cells of the innate immune system are known to contribute to tumour initiation and progression. Differently, the adaptive immune response controls growth and… (more)

▼ Inflammation and cells of the innate immune system are known to contribute to tumour initiation and progression. Differently, the adaptive immune response controls growth and dissemination of established tumours . The double edge role of inflammatory and adaptive components of immune system in solid tumours are well represented in CRC. The progression and survival of patients with CRC is known to be modified by the interactions generated between the tumour and the host’s response in a milieu named tumour microenvironment, composed by local immune responses. The quantification of the density and the type of immune cells in the tumour microenvironment has been a challenge since the early 60’s of the last century. However their role and clinical significance in different human cancers has not been unequivocally addressed and still there is a strong interest in determining the dynamics of immunosurveillance and immunoevasion, and the role of immune cells infiltrating CRC. Recently, experimental support was provided that cancer infiltrating immune cells might be a crucial factor in chemotherapy mediated tumour cell death. Despite effort in this field there’s still no clinical evidence in CRC regarding any effect modification by tumour infiltrating cells in enhancing the benefit of chemotherapy treatment, or whether this parameter might help to identify patients who would benefit from adjuvant therapy. In this context, tumour associated macrophages (TAM) represent the prevailing population in different cancers and are thought to enhance tumour cells proliferation and survival. Tissue macrophages are players of the innate immune response capable of phagocytosis and antigen presentation, that play a key role in directing immune responses through secretion of a plethora of factors. In CRC data regarding TAM and tumour progression are controversial. Of interest, in an experimental model of cancer TAM “re-educated” by CD40 ligand treatment, were found to be necessary to mediate antitumour activity, whereas tumour infiltrating lymphocytes (TILs) were irrelevant, supporting the hypothesis that TAM might mediate anti-tumour activity in certain conditions. The aim of this thesis was to study the prognostic significance of different populations (CD3+ and FOXP3+ TILs and CD68+ TAMs) of immune cells in the tumour microenvironment, and their interactions with demographic and clinicopathological variables in a large dataset of stage II and III CRC patients. We first found that the cellular mediators of immunosurveillance seems to change along with the lymph-nodal involvement at diagnosis. Higher densities of TILs (both CD3+ and FOXP3+ cells) were associated with better prognosis among stage II CRC patients, but not in stage III. On the other hand, higher densities of TAM were associated with better prognosis only among stage III CRC patients, but not in stage II. This data suggest that TILs mediate immunosurveillance in early stages of disease, while when the tumour has the ability to invade and spread to metastatic lymphnodes the… Advisors/Committee Members: tutor: R. Bonecchi, coordinatore: M. Locati, A. Mantovani, supervisore: L. Laghi, LOCATI, MASSIMO, LOCATI, MASSIMO, MANTOVANI, ALBERTO.

Subjects/Keywords: colorectal cancer; immune infiltration; chemotherapy; Settore MED/03 - Genetica Medica; Settore MED/04 - Patologia Generale; Settore MED/05 - Patologia Clinica

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

CARO, G. D. (2013). ADAPTIVE AND NATIVE IMMUNE CELLS AS PROGNOSTIC AND PREDICTIVE BIOMARKERS ALONG COLORECTAL CANCER PROGRESSION. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/218989

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

CARO, G. DI. “ADAPTIVE AND NATIVE IMMUNE CELLS AS PROGNOSTIC AND PREDICTIVE BIOMARKERS ALONG COLORECTAL CANCER PROGRESSION.” 2013. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/218989.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

CARO, G. DI. “ADAPTIVE AND NATIVE IMMUNE CELLS AS PROGNOSTIC AND PREDICTIVE BIOMARKERS ALONG COLORECTAL CANCER PROGRESSION.” 2013. Web. 16 Jan 2021.

Vancouver:

CARO GD. ADAPTIVE AND NATIVE IMMUNE CELLS AS PROGNOSTIC AND PREDICTIVE BIOMARKERS ALONG COLORECTAL CANCER PROGRESSION. [Internet] [Thesis]. Università degli Studi di Milano; 2013. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/218989.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

CARO GD. ADAPTIVE AND NATIVE IMMUNE CELLS AS PROGNOSTIC AND PREDICTIVE BIOMARKERS ALONG COLORECTAL CANCER PROGRESSION. [Thesis]. Università degli Studi di Milano; 2013. Available from: http://hdl.handle.net/2434/218989

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

19. C. Cancellieri. BETA-ARRESTIN DEPENDENT REGULATION OF CYTOSKELETON DYNAMICS AND SIGNALLING OF CHEMOKINE RECEPTOR ACKR2.

Degree: 2014, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/229565

► Chemokines promote leukocyte migration through the activation of dedicated G-protein coupled receptors. Beyond conventional chemokine receptors, which directly induce cell migration through heterotrimeric Gαi-mediated signalling… (more)

Subjects/Keywords: chemokine; atypical chemokine receptor; sytoskeleton; actin; microtubules; myosin; beta-arrestin; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cancellieri, C. (2014). BETA-ARRESTIN DEPENDENT REGULATION OF CYTOSKELETON DYNAMICS AND SIGNALLING OF CHEMOKINE RECEPTOR ACKR2. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/229565

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Cancellieri, C.. “BETA-ARRESTIN DEPENDENT REGULATION OF CYTOSKELETON DYNAMICS AND SIGNALLING OF CHEMOKINE RECEPTOR ACKR2.” 2014. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/229565.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Cancellieri, C.. “BETA-ARRESTIN DEPENDENT REGULATION OF CYTOSKELETON DYNAMICS AND SIGNALLING OF CHEMOKINE RECEPTOR ACKR2.” 2014. Web. 16 Jan 2021.

Vancouver:

Cancellieri C. BETA-ARRESTIN DEPENDENT REGULATION OF CYTOSKELETON DYNAMICS AND SIGNALLING OF CHEMOKINE RECEPTOR ACKR2. [Internet] [Thesis]. Università degli Studi di Milano; 2014. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/229565.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Cancellieri C. BETA-ARRESTIN DEPENDENT REGULATION OF CYTOSKELETON DYNAMICS AND SIGNALLING OF CHEMOKINE RECEPTOR ACKR2. [Thesis]. Università degli Studi di Milano; 2014. Available from: http://hdl.handle.net/2434/229565

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

20. L. Petti. ROLE OF SPHINGOSINE-1-PHOSPATE PATHWAY IN INTESTINAL EPITHELIAL CELLS AND ITS INVOLVEMENT IN INTESTINAL TUMORIGENESIS.

Degree: 2017, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/487921

► Title: Role of Sphingosine-1-phosphate pathway in intestinal epithelial cells and its involvement in intestinal tumorigenesis. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite, involved in several… (more)

▼ Title: Role of Sphingosine-1-phosphate pathway in intestinal epithelial cells and its involvement in intestinal tumorigenesis. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite, involved in several cellular processes. S1P is both an intracellular second messenger and the ligand of five EDG family G protein-coupled receptors 1-5 (S1PR1-5). S1PRs are widely expressed on many cell types of different tissues including the gut. However, so far there are no evidences about which S1P receptor is expressed on intestinal epithelial layer. Therefore, the first proposal of this project is to characterize the S1P pathway on intestinal epithelial cells and to explore the physiological functions of the S1PRs on intestinal epithelial cells. I characterized the expression of the ubiquitous expressed S1P receptors S1PR1, S1PR2 and S1PR3 on human and murine primary intestinal epithelial cells isolated from healthy controls by qRT-PCR and western blot. Interestingly, both the analyses revealed that the S1PR2 is the most abundantly expressed S1PR in the colonic epithelium, among the three S1PRs analyzed. Consequentially, I decided to focus specifically on S1PR2 for the study of the physiological functions of the S1PRs in the epithelium. Recently, in vitro studies have been highlighted the capacity of S1P to enhance epithelial barrier function suggesting this pathway as new potential target of intestinal barrier restoration (Vetrano et al., 2011; Greenspoon et al., 2011). However, so far there are no evidences of which receptor mediates this effect. Since the expression of the S1PR1 and S1PR3 transcript is very low also in the human epithelial cell line Caco-2, whereas the S1PR2 transcript is constitutively expressed, I assessed the hypothesis of the S1PR2 involvement in the S1P-mediated regulation of the epithelial barrier permeability. I evaluated the intestinal permeability in vivo in S1pr2 knock out mice (S1P2-/-) at baseline and after DSS-induced colitis by the Evans Blue method. Surprisingly, no difference in terms of intestinal permeability and susceptibility to DSS-induced colitis was found between S1P2-/- and WT mice. In line with this, the expression of tight junction (TJ) proteins at baseline in S1P2-/- mice was comparable to WT mice thus excluding direct defects of the epithelial junction proteins in absence of S1PR2. Several studies reported that the S1P signalling controls the cell growth and few papers bring to light the anti-proliferative role of the S1PR2 in vitro and in vivo in different cell lines (Ikeda et al., 2003; Goparaju et al., 2005). Therefore, it was of interest to analyse the role of S1PR2 in the proliferation of the colonic epithelial cells. I evaluated the proliferation in vitro and in vivo respectively in Caco-2 cell line under the treatment with different concentrations of S1PR2 inhibitor and in S1P2-/- mice by BrdU incorporation assay. Both analyses have showed an increase in the epithelial proliferation rate in absence of S1PR2. Since the abnormal proliferation is associated with… Advisors/Committee Members: tutor non afferenti all'Ateneo: S. Danese, S. Vetrano, tutor: M. Locati, coordinatore dottorato: M. Locati, LOCATI, MASSIMO, LOCATI, MASSIMO.

Subjects/Keywords: Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Petti, L. (2017). ROLE OF SPHINGOSINE-1-PHOSPATE PATHWAY IN INTESTINAL EPITHELIAL CELLS AND ITS INVOLVEMENT IN INTESTINAL TUMORIGENESIS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/487921

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Petti, L.. “ROLE OF SPHINGOSINE-1-PHOSPATE PATHWAY IN INTESTINAL EPITHELIAL CELLS AND ITS INVOLVEMENT IN INTESTINAL TUMORIGENESIS.” 2017. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/487921.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Petti, L.. “ROLE OF SPHINGOSINE-1-PHOSPATE PATHWAY IN INTESTINAL EPITHELIAL CELLS AND ITS INVOLVEMENT IN INTESTINAL TUMORIGENESIS.” 2017. Web. 16 Jan 2021.

Vancouver:

Petti L. ROLE OF SPHINGOSINE-1-PHOSPATE PATHWAY IN INTESTINAL EPITHELIAL CELLS AND ITS INVOLVEMENT IN INTESTINAL TUMORIGENESIS. [Internet] [Thesis]. Università degli Studi di Milano; 2017. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/487921.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Petti L. ROLE OF SPHINGOSINE-1-PHOSPATE PATHWAY IN INTESTINAL EPITHELIAL CELLS AND ITS INVOLVEMENT IN INTESTINAL TUMORIGENESIS. [Thesis]. Università degli Studi di Milano; 2017. Available from: http://hdl.handle.net/2434/487921

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

21. L. Mori. REGULATORY ROLE OF MICRORNAS ON INFLAMMATORY SIGNALING PATHWAYS.

Degree: 2012, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/168371

► Innate immunity is the primary defense mechanism that recognizes and respond to invading infectious microbes or their components, known as pathogen-associated molecular patterns (PAMPs), or… (more)

▼ Innate immunity is the primary defense mechanism that recognizes and respond to invading infectious microbes or their components, known as pathogen-associated molecular patterns (PAMPs), or to danger signals that comes from self components, known as danger-associated molecular patterns (DAMPs). These molecules are recognized in our body by the so called pattern recognition receptors (PRRs), whose activation quickly gives rise to an important cascade of events known as acute inflammatory response. Within few hours, pro-inflammatory cytokines, such as TNFα, IL-1β and IL6, and chemokine, such as CCL2, CCL3 or CXCL8, are released in the blood stream, and innate immune cellular components are induced to combat the pathogens to the site of injury. Circulating neutrophils and monocytes are implicated as essential players in defense against a range of microbial pathogens. The acute inflammation process is a double-edge sword. Normally, it terminated once triggering insult is eliminated, the infection is cleared and damage tissue is repaired. Misregulation of one or more step from initiation to resolution can significantly contribute to the pathogenesis of autoimmune, chronic inflammatory or infectious diseases. For this reason, the inflammatory response itself and its termination phase are active and highly regulated processes involving several key regulatory mechanisms. MicroRNAs (miRNAs) are small noncoding RNAs recently emerged as powerful posttranscriptional regulators in various biological processes. A growing number of evidence suggests that the development and function of cells in the immune system is also subject to regulation by miRNAs, and in 2006 the first evidence on their potential involvement in inflammation control was provided by Taganov and colleagues, who reported a unique set of microRNAs (miR-146a, miR-155 and miR-132) overexpressed in the THP-1 monocytic cell line after TLR4 agonist engagement, and postulated that miR-146a may operate a negative feedback loop acting on TRAF6 and IRAK1, two keys adaptors in TLR4 signaling pathway. Moving from these information, this thesis project has characterized the complete microRNA expression profile induced by TLR4 activation in freshly purified human blood monocytes and neutrophils. Beyond the aforementioned miR-155, miR-146a and miR-132, a new set of molecules were first described as LPS-responsive miRNAs in monocytes, including mi-9, miR-187, and the miR-99b~7e~125a miR cluster. This study also identified miR-9 as the only microRNA also up-regulated in neutrophils in a MyD88- and NF-κB-dependent manner and highlighted a new feedback regulatory loop acting at the NF-kB level, as miR-9 was demonstrated to directly target NFKB1 mRNA and post-transcriptionally modulating its expression. Inflammatory response triggers an important number of events that bring not only to propagation (producing pro-inflammatory mediators such as TNFα or IL-1β) but also to resolution. Two fundamental anti-inflammatory mediators whose release is induced by inflammation itself are IL-10… Advisors/Committee Members: tutor: M. Locati, coordinatore: A. Mantovani, LOCATI, MASSIMO, MANTOVANI, ALBERTO.

Subjects/Keywords: microRNA; post-transcriptional regulation; inflammation; monocyte; neutrophil; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Mori, L. (2012). REGULATORY ROLE OF MICRORNAS ON INFLAMMATORY SIGNALING PATHWAYS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/168371

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Mori, L.. “REGULATORY ROLE OF MICRORNAS ON INFLAMMATORY SIGNALING PATHWAYS.” 2012. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/168371.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Mori, L.. “REGULATORY ROLE OF MICRORNAS ON INFLAMMATORY SIGNALING PATHWAYS.” 2012. Web. 16 Jan 2021.

Vancouver:

Mori L. REGULATORY ROLE OF MICRORNAS ON INFLAMMATORY SIGNALING PATHWAYS. [Internet] [Thesis]. Università degli Studi di Milano; 2012. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/168371.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Mori L. REGULATORY ROLE OF MICRORNAS ON INFLAMMATORY SIGNALING PATHWAYS. [Thesis]. Università degli Studi di Milano; 2012. Available from: http://hdl.handle.net/2434/168371

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

22. I. Mattiola. CROSS-TALK BETWEEN HUMAN NK CELLS AND MACROPHAGES: INFLUENCE OF THE TUMOR MICRO-ENVIRONMENT.

Degree: 2014, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/229562

► Natural killer (NK) cells are important effectors of innate immune responses providing cellular immunity against tumor-transformed and virally-infected cells. The existence of cross-talks between NK… (more)

▼ Natural killer (NK) cells are important effectors of innate immune responses providing cellular immunity against tumor-transformed and virally-infected cells. The existence of cross-talks between NK cells and myeloid cells, in particular dendritic cells, is well established, but information on the cross-talk between NK cells and macrophages is scanty. These interactions have been analyzed using an in vitro reconstituted tumoral micro-environment, as a simplified model to define soluble factors involved and/or cell contact dependency. Autologous human NK cells and monocyte-derived macrophages were obtained from buffy coats of healthy donors after magnetic beads cell purification. Macrophages were polarized into M0, M1 and M2, using well described stimuli. First, the influence of human polarized macrophages on NK cell anti-tumoral activities was studied. The co-cultures between NK cells and macrophages were performed in direct contact or by treating NK cells with macrophage-conditioned media. Activating receptors expression and degranulation ability (CD107a assay) of NK cells were evaluated by flow cytometry. IFN-γ production by NK cells was quantified by RT-PCR and ELISA. Then, the effect of NK cell-derived IFN-γ on macrophage polarization was assessed. Gene expression of markers, cytokines and chemokines well described to characterized M1 or M2 polarization were evaluated by RT-PCR. In parallel, cytokine and chemokine secretion were detected by ELISA. M1 polarization was required to enhance IFN-γ production and degranulation by resting NK cells. M1 ability to activate NK cells was further confirmed by the upregulation of CD69 activation marker. Importantly, either soluble mediators and direct contact interactions were involved in this process. However, the level of expression of NKp44 and NKG2D resulted increased only when NK cells were treated with M1-conditioned medium (M1-primed NK cells). Higher NKp44 and NKG2D expression correlated with enhanced NK cell degranulation towards altered cells. Although both NK cell subsets upregulated both receptors, M1-secreted IL-1β was responsible for NKp44 induction on CD56dim population, whereas IFN-β released by M1 favored increased expression of NKG2D by the CD56bright counterpart. Importantly, M1 secretion of IFN-β triggered NK cell expression of IL-15 and IL-15Rα, inducing a mechanism of IL-15 cis-presentation. IL-15 cis-presentation strongly enhanced IFN-γ secretion, that was further sustained by 2B4-CD48 interactions during direct co-cultures. On the contrary, NKG2D upregulation was responsible for increased degranulation by M1-primed NK cells. In parallel, IL-15 trans-presentation mediated by M1, together with NKG2D and NKp30 engagement, were needed to trigger NK cell degranulation during direct contact interactions. On the other hand, IFN-γ secreted by M1-primed NK cells was sufficient not only to downmodulate CD206 and ALOX15 expression by alternatively-activated macrophages, but also to induce pro-inflammatory cytokine (IL-1β and IL-15) and chemokine (CCL-5, CXCL-9… Advisors/Committee Members: Tutor: M. Locati, Supervisore: D. Mavilio, LOCATI, MASSIMO, MAVILIO, DOMENICO.

Subjects/Keywords: NK cells; Macrophages; Cross-talk; Cancer; Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Mattiola, I. (2014). CROSS-TALK BETWEEN HUMAN NK CELLS AND MACROPHAGES: INFLUENCE OF THE TUMOR MICRO-ENVIRONMENT. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/229562

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Mattiola, I.. “CROSS-TALK BETWEEN HUMAN NK CELLS AND MACROPHAGES: INFLUENCE OF THE TUMOR MICRO-ENVIRONMENT.” 2014. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/229562.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Mattiola, I.. “CROSS-TALK BETWEEN HUMAN NK CELLS AND MACROPHAGES: INFLUENCE OF THE TUMOR MICRO-ENVIRONMENT.” 2014. Web. 16 Jan 2021.

Vancouver:

Mattiola I. CROSS-TALK BETWEEN HUMAN NK CELLS AND MACROPHAGES: INFLUENCE OF THE TUMOR MICRO-ENVIRONMENT. [Internet] [Thesis]. Università degli Studi di Milano; 2014. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/229562.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Mattiola I. CROSS-TALK BETWEEN HUMAN NK CELLS AND MACROPHAGES: INFLUENCE OF THE TUMOR MICRO-ENVIRONMENT. [Thesis]. Università degli Studi di Milano; 2014. Available from: http://hdl.handle.net/2434/229562

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

23. I. Ferrari. THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS.

Degree: 2015, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/250654

► The insulin receptor substrate protein of 53 kDa is a critical factor in determining neuronal polarisation, as it initiates membrane protrusions to form filopodia and… (more)

▼ The insulin receptor substrate protein of 53 kDa is a critical factor in determining neuronal polarisation, as it initiates membrane protrusions to form filopodia and neurites by coupling membrane deformation with F-actin polymerization. With its C-terminal tail, IRSp53 can bind to PDZ domain containing proteins including LIN7, a small scaffold protein possessing a single L27 domain, necessary for membrane recruitment. Here, we investigated the role of the IRSp53-LIN7 complex in cellular mechanisms that heavily rely on membrane deformation, such as the formation of filopodia and neurites or mitochondrial fission. Concerning the role of the IRSp53:LIN7 complex in filopodia and neurite induction, our findings indicate that the formation of actin-filled filopodia and neurites depends on motifs mediating IRSp53-LIN7 association and filopodia tip localisation. We further showed that co-expression of LIN7 with IRSp53 enhanced the formation of filopodia protrusions in neuronal NSC34 cells, while also preventing the appearance of actin-deficient protrusions induced by the overexpression of IRSp53 alone. The positive regulatory role of LIN7 in IRSp53-mediated extension of filopodia was further demonstrated by live-cell imaging experiments in neuronal N2A cells. Moreover, LIN7 silencing in N2A cells prevented the extension of filopodia and neurites, induced by either the ectopic expression of IRSp53 or serum starvation. Defective neuritogenesis could be rescued by the expression of RNAi-resistant full length LIN7 or chimeric L27-IRSp53, whereas the expression of full length IRSp53 or the LIN7ΔPDZ mutant lacking the domain for association with IRSp53 was unable to restore neuritogenesis in LIN7 silenced cells. Finally, LIN7 silencing prevented the recruitment of IRSp53 in Triton X-100 insoluble complexes, otherwise occurring in differentiated cells. Collectively, this first set of data identify in LIN7 a novel regulator of the filopodia- and neurites-promoting activity of IRSp53, whose role is to spatially restrict its activity to the plasma membrane for filopodia and neurite initiation, and to further promote the stabilisation of these actin–rich structures. More recently, we tested the hypothesis of a role for the IRSp53-LIN7 complex in the modification of intracellular membranes. To this regard, we found that endogenous LIN7 and IRSp53 localized in punctuate structures along mitochondria, a fact that prompted us to further investigate the possible effects of modifications in the expression levels of IRSp53/LIN7 on mitochondrial morphology. Eukaryotic cells, in fact, strictly regulate the overall morphology of their mitochondrial network thanks to the existence of protein complexes able to control fission and fusion events. We found that, upon overexpression of LIN7 and/or IRSp53, mitochondria morphology was altered, with a significant increase in the percentage of cells showing a less interconnected mitochondrial network compared to GFP-transfected control cells, a phenotype that was blocked by co-expression of the K38A… Advisors/Committee Members: coordinatore: M. Locati, tutor: G. Pietrini, PIETRINI, GRAZIA, LOCATI, MASSIMO.

Subjects/Keywords: IRSp53; LIN7; IRSp53-LIN7 complex; N2A cells; NSC34 cells; filopodia; neurites; tip complex; mitochondrial morphology; mitochondrial fission; mitochondria pre-constriction sites; Settore BIO/13 - Biologia Applicata

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ferrari, I. (2015). THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/250654

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ferrari, I.. “THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS.” 2015. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/250654.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ferrari, I.. “THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS.” 2015. Web. 16 Jan 2021.

Vancouver:

Ferrari I. THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS. [Internet] [Thesis]. Università degli Studi di Milano; 2015. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/250654.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ferrari I. THE ROLE OF THE IRSP53-LIN7 COMPLEX IN CELL MEMBRANE DYNAMICS. [Thesis]. Università degli Studi di Milano; 2015. Available from: http://hdl.handle.net/2434/250654

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

24. C.L. Politano. TRANSCRIPTOME ANALYSIS OF TUMOR INFILTRATING T REGULATORY CELLS UNVEILS SPECIFIC CODING AND NON CODING GENE SIGNATURE.

Degree: 2019, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/613244

► CD4+ Regulatory T cells (Treg cells) are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. These… (more)

▼ CD4+ Regulatory T cells (Treg cells) are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. These cells play a critical role in preventing autoimmunity infections, and cancer. Treg cells can infiltrate tumor tissues where they suppress anti-tumor immune responses, contributing to the development of an immunosuppressive tumor microenvironment thus promoting immune evasion and cancer progression. Tumor infiltrating Treg cells can display function heterogeneity, depending on both the tumor type and the inflammatory milieu, therefore molecular characterization of Treg cells is crucial to understand how these cells can be modulated in the tumor to unleash effective anti-tumor T cell responses. To this aim, we investigated the transcriptional blueprints of Treg cells both in tumors and in the peripheral blood of healthy donors to define both coding and non-coding transcripts that best define the identity of these cells and might therefore represent novel prognostic markers or therapeutic targets. We performed a transcriptome analysis of both CD4+ Treg cells and effector cells (Th1 and Th17) infiltrating two of the most frequent types of human cancer defining the molecular signatures of tumor-infiltrating Treg cells in these two cancer types. We found tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine enriched in tumor infiltrating Treg cells compared to both the peripheral blood of patients and healthy donors. Given the high specificity of long non-coding RNA compared to coding sequences, we also performed bioinformatic analysis to assess the expression of known and novel non-coding transcripts. With this analysis we identified specific Treg cell non-coding transcript in proximity of CTLA4 locus. Since lncRNAs are by now considered as key regulatory elements in immune cell differentiation and maintenance of their identity, we characterized the identified lncRNAs in Treg cells in healthy donors, defining their epigenetic organization, expression level, localization and whether they contributed to the established Treg cell suppressive activity. All these findings unveiled another layer of the complexity of Treg cells biology and warrants for more detailed functional studies that can fully explain the pathways and the cellular networks that are affected by the identified coding and non-coding transcripts. Advisors/Committee Members: tutor: M. Pagani, coordinatore: M. Locati, PAGANI, MASSIMILIANO, LOCATI, MASSIMO.

Subjects/Keywords: Settore BIO/11 - Biologia Molecolare

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Politano, C. (2019). TRANSCRIPTOME ANALYSIS OF TUMOR INFILTRATING T REGULATORY CELLS UNVEILS SPECIFIC CODING AND NON CODING GENE SIGNATURE. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/613244

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Politano, C.L.. “TRANSCRIPTOME ANALYSIS OF TUMOR INFILTRATING T REGULATORY CELLS UNVEILS SPECIFIC CODING AND NON CODING GENE SIGNATURE.” 2019. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/613244.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Politano, C.L.. “TRANSCRIPTOME ANALYSIS OF TUMOR INFILTRATING T REGULATORY CELLS UNVEILS SPECIFIC CODING AND NON CODING GENE SIGNATURE.” 2019. Web. 16 Jan 2021.

Vancouver:

Politano C. TRANSCRIPTOME ANALYSIS OF TUMOR INFILTRATING T REGULATORY CELLS UNVEILS SPECIFIC CODING AND NON CODING GENE SIGNATURE. [Internet] [Thesis]. Università degli Studi di Milano; 2019. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/613244.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Politano C. TRANSCRIPTOME ANALYSIS OF TUMOR INFILTRATING T REGULATORY CELLS UNVEILS SPECIFIC CODING AND NON CODING GENE SIGNATURE. [Thesis]. Università degli Studi di Milano; 2019. Available from: http://hdl.handle.net/2434/613244

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

25. M. Fazzari. NOVEL APPROACHES OF ¿PERSONALISED MEDICINE¿ AS PROOF-OF-PRINCIPLE FOR CDKL5-RELATED PATHOLOGIES.

Degree: 2018, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/548108

► Alterations of CDKL5 give rise to several forms of neurological disorders generally characterised by epileptic encephalopathy, severe developmental delay, hypotonia and RTT-like features. To date… (more)

▼ Alterations of CDKL5 give rise to several forms of neurological disorders generally characterised by epileptic encephalopathy, severe developmental delay, hypotonia and RTT-like features. To date no cure exists and only secondary symptoms can be treated. About 15% of CDKL5 patients carry a nonsense mutation and might benefit of a readthrough strategy as “personalised” medicine approach. The read-through process occurs when a near-cognate aminoacyl-tRNA binds a premature stop codon (PTC), allowing its suppression and the subsequent protein elongation. This mispairing event can rarely occur, but can be facilitated using a wide range of drugs. In order to test PTC suppression, we have chosen some human pathogenic CDKL5 nonsense mutations located in the two main domains of the protein: the catalytic N-terminus (R59X, R134X) or the C-terminal tail (Q347X, E364X, R550X, S855X). We then evaluated the read-through process using aminoglycoside and non-aminoglycoside drugs in cells transfected with the mutagenized constructs. In this study, we have demonstrated that tested CDKL5 PTCs can be suppressed by gentamicin and geneticin (G418) in a dose-dependent manner and that PTC position can be critical for read-through. In particular, G418 was found to be more effective than gentamicin. Considering the known aminoglycosides toxicity, we evaluated the activity of PTC124 and GJ072 but no PTC suppression was detectable in our experimental conditions. Finally, in order to understand whether the full-length derivatives may maintain the proper function of WT CDKL5, we analysed some features of read-through products compared to the WT protein. In particular, while premature truncated proteins showed an altered subcellular localisation, read-through products demonstrated a nucleo-cytoplasmic distribution more similar to the WT one. Moreover, by evaluating the auto-phosphorylation of the TEY motif, the read-through derivatives demonstrated to recover some catalytic activity, although remaining highly hypomorphic. Nevertheless, preliminary studies on Cdkl5-null neurons transfected with R134X construct suggested that G418 treatment can ameliorate impaired neuronal morphology. Collectively, our results indicate that: (i) aminoglycosides are able to induce read-through of different CDKL5 PTCs; (ii) the read-through derivatives recover some features characterizing the WT protein; (iii) PTC position can be crucial for read-though and for rescue of a proper function and (iv) neuronal morphological defects might be rescued by small amount of a possible hypomorphic CDKL5, therefore supporting the potential validity of a read-through therapy. Advisors/Committee Members: supervisore: N. Landsberger, coordinatore: M. Locati, LANDSBERGER, NICOLETTA, LOCATI, MASSIMO.

Subjects/Keywords: Settore BIO/11 - Biologia Molecolare

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fazzari, M. (2018). NOVEL APPROACHES OF ¿PERSONALISED MEDICINE¿ AS PROOF-OF-PRINCIPLE FOR CDKL5-RELATED PATHOLOGIES. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/548108

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Fazzari, M.. “NOVEL APPROACHES OF ¿PERSONALISED MEDICINE¿ AS PROOF-OF-PRINCIPLE FOR CDKL5-RELATED PATHOLOGIES.” 2018. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/548108.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Fazzari, M.. “NOVEL APPROACHES OF ¿PERSONALISED MEDICINE¿ AS PROOF-OF-PRINCIPLE FOR CDKL5-RELATED PATHOLOGIES.” 2018. Web. 16 Jan 2021.

Vancouver:

Fazzari M. NOVEL APPROACHES OF ¿PERSONALISED MEDICINE¿ AS PROOF-OF-PRINCIPLE FOR CDKL5-RELATED PATHOLOGIES. [Internet] [Thesis]. Università degli Studi di Milano; 2018. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/548108.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fazzari M. NOVEL APPROACHES OF ¿PERSONALISED MEDICINE¿ AS PROOF-OF-PRINCIPLE FOR CDKL5-RELATED PATHOLOGIES. [Thesis]. Università degli Studi di Milano; 2018. Available from: http://hdl.handle.net/2434/548108

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

26. L. Brioschi. SPHINGOLIPID SIGNALING AND DISEASE: THE KEY ROLE OF CERAMIDE TRAFFIC IN CELL FATE REGULATION.

Degree: 2016, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/362927

► Cancer and diabetes are among the most common diseases in western societies. Sphingolipids, a class of lipids ubiquitously present in eukaryotic membranes, play a key… (more)

▼ Cancer and diabetes are among the most common diseases in western societies. Sphingolipids, a class of lipids ubiquitously present in eukaryotic membranes, play a key role in the regulation of different signal transduction pathways involved in the modulation of many cellular functions [1, 2]. The past two decades have seen increased interest in the bioactive sphingolipids ceramide (Cer) and sphingosine-1 phosphate (S1P). Cer, a central molecule of sphingolipid metabolism, is involved in the control of many cell-stress responses, including growth arrest, senescence and cell death [3]. On the other hand, several studies have proposed a crucial role of S1P in cell growth and survival, cell migration, angiogenesis, and inflamma¬tion [3]. Thus, Cer and S1P can differentially regulate cell death and survival by controlling opposing signaling pathways [4]. So far, a large amount of studies has clarified the complexity of the interplay between S1P, Cer and sphingolipid metabolism and these implications in the etiology of several human diseases. Effectively, deregulation of sphingolipid metabolism is implicated in numerous diseases, and accumulating evidence has shown a clear indication that sphingolipids have important role in the pathogenesis of diabetes and cancer [5]. Very recently, it is emerging a pivotal role of Cer traffic from the Endoplasmic Reticulum (ER) to the Golgi apparatus in the regulation of sphingolipid metabolism. In fact, Cer transport is a highly regulated step in the sphingolipid biosynthesis. Two main mechanisms are involved in Cer transport from ER to the Golgi apparatus: a protein-mediated transport, operated by CERT [6, 7] and a CERT-independent vesicular transport. Moreover, several studies reported that ER is a critical intracellular organelle involved in the control of cell fate [8, 9]. In this light, Cer accumulation in the ER appears to be a key element in the promotion of cell death in different human diseases, as well as in glioblastoma and diabetes. In light of these findings, in my Ph.D. course I wanted to evaluate in cellular models of glioblastoma (GBM) and type 2 diabetes (T2D) the role of Cer transport in the regulation of cell fate. Part 1: Glucolipotoxicity impairs ceramide flow from the ER to the Golgi apparatus in INS-1 -cells T2D is the most common form of diabetes characterized by insulin resistance and β-cell dysfunction. The etiology of T2D is not well established but it is know that loss of insulin secretion is directly linked to a loss of function and death of pancreatic β-cells [10]. Glucolipotoxicity is a condition determined by the combined action of elevated glucose and free fatty acids (FFAs) levels that exerts deleterious effects on pancreatic -cell function and survival. Several mechanisms have been proposed for glucolipotoxicity-induced β-cell dysfunction, and, among them, ER stress and elevations of the proapoptotic sphingolipid Cer appear to play key roles. Moreover, Cer accumulation due to glucolipotoxicity can be associated to the induction of ER… Advisors/Committee Members: docente guida: P. Viani, coordinator: M. Locati, VIANI, PAOLA, LOCATI, MASSIMO.

Subjects/Keywords: SPHINGOLIPID, CELL FATE, CERAMIDE, TRAFFIC, GLIOBLASTOMA, TYPE 2 DIABETES, SPHINGOSINE 1-PHOSPHATE; Settore BIO/10 - Biochimica

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Brioschi, L. (2016). SPHINGOLIPID SIGNALING AND DISEASE: THE KEY ROLE OF CERAMIDE TRAFFIC IN CELL FATE REGULATION. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/362927

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Brioschi, L.. “SPHINGOLIPID SIGNALING AND DISEASE: THE KEY ROLE OF CERAMIDE TRAFFIC IN CELL FATE REGULATION.” 2016. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/362927.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Brioschi, L.. “SPHINGOLIPID SIGNALING AND DISEASE: THE KEY ROLE OF CERAMIDE TRAFFIC IN CELL FATE REGULATION.” 2016. Web. 16 Jan 2021.

Vancouver:

Brioschi L. SPHINGOLIPID SIGNALING AND DISEASE: THE KEY ROLE OF CERAMIDE TRAFFIC IN CELL FATE REGULATION. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/362927.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Brioschi L. SPHINGOLIPID SIGNALING AND DISEASE: THE KEY ROLE OF CERAMIDE TRAFFIC IN CELL FATE REGULATION. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/362927

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

27. A. Cinque. PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING.

Degree: 2016, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/364862

► Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant tumor of the central nervous system in adults. Despite decades of experimentation to improve the… (more)

▼ Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant tumor of the central nervous system in adults. Despite decades of experimentation to improve the outcome of patients with GBM, this type of neoplasm remains one of the most lethal human cancers.Therefore, the need to test different and new agents for efficacy and safety is urgent. Perifosine (PF) is a synthetic lipid analogue belonging to a relatively new class of structurally related antitumor agents: the alkylphospholipids (APLs). PF exhibits potent antineoplastic activity against a multitude of cancer cell lines and different tumor models and is currently being tested in phase II clinical trial against major human tumors. However, the effect of PF against gliomas is poorly investigated. PF can induce apoptosis and/or cell growth arrest in tumor cells, but the details of its molecular mechanism is still to be elucidated. To date, the Ser/Thr kinase Akt, which is a key regulator of multiple survival pathways, is considered as the most important molecular target of PF. However, PF can induce also Akt-independent effects and the contribution of Akt inhibition to the clinical activity of PF remains to be assessed. As other ALPs, PF may alter the structure and function of cell membranes directly by inducing a biophysical disturbance of cell membranes where it accumulates and/or indirectly by interfering with the metabolism and transport of membrane lipids. In particular, alterations in the properties of lipid rafts, ordered membrane lipid domains enriched in cholesterol and sphingolipids (SLs), could affect numerous signaling pathways crucial to cell survival and proliferation that are dependent on these structures. On these premises, the purpose of this study was to investigate the sensitivity of GBM cells to PF treatment and to provide a contribution to the understanding of its molecular mechanism by focusing on the ability of PF to target membrane lipid metabolism and content, and, as a consequence, membrane-related signaling pathways crucial in the regulation of cell demise. At first, we evaluated the effect of PF on cell survival in several human GBM cell lines. We demonstrated that in these cell lines PF inhibits cell viability in a dose-dependent manner and that its cytotoxic effects are not solely due to Akt inhibition. Furthermore, we found that in glioma cells PF maintains ERK in its phosphorylated/active state in a sustained manner over time. Treatment with the MAPK inhibitor PD98059 potentiates PF toxicity, and strongly reduces PF-induced LC3B-II increase. This could thus represent a molecular mechanism for self-defense from PF, at least in part due to the induction of protective autophagy. Moreover, in cells exposed to PF we found a time-dependent increase in the number of giant and multinucleated cells with an irregular shape, these morphological changes resembling those described for mitotic catastrophe, suggesting that this could be the mechanism of PF-induced cells death, while apoptosis was undetectable. Accumulating… Advisors/Committee Members: tutor: P. Viani, coordinatore: M. Locati, VIANI, PAOLA, LOCATI, MASSIMO.

Subjects/Keywords: Settore BIO/10 - Biochimica

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cinque, A. (2016). PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/364862

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Cinque, A.. “PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING.” 2016. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/364862.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Cinque, A.. “PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING.” 2016. Web. 16 Jan 2021.

Vancouver:

Cinque A. PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING. [Internet] [Thesis]. Università degli Studi di Milano; 2016. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/364862.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Cinque A. PLEIOTROPIC EFFECTS OF PERIFOSINE ON GLIOBLASTOMA CELLS SURVIVAL: ALTERED MEMBRANE LIPID METABOLISM AND CELL SIGNALING. [Thesis]. Università degli Studi di Milano; 2016. Available from: http://hdl.handle.net/2434/364862

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

28. M. Liguori. BIOLOGICAL ROLE OF OSTEOACTIVIN, A PROTEIN EXPRESSED BY TUMOR-CONDITIONED MACROPHAGES, IN THE PROCESSES OF TUMOR GROWTH AND TISSUE REPAIR.

Degree: 2017, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/481318

► Tumor-Associated Macrophages (TAM) are key orchestrators of the tumor microenvironment, directly affecting neoplastic cell growth, neo-angiogenesis, extracellular matrix remodeling and immunosuppression. In a gene profiling… (more)

▼ Tumor-Associated Macrophages (TAM) are key orchestrators of the tumor microenvironment, directly affecting neoplastic cell growth, neo-angiogenesis, extracellular matrix remodeling and immunosuppression. In a gene profiling analysis on tumor-conditioned macrophages cultured in vitro with tumor cell supernatants, we identified a number of up-regulated genes. One of the most expressed gene was Gpnmb, coding for a protein called Human Glycoprotein non-metastatic melanoma protein B (GPNMB), also named Osteoactivin (OA). Osteoactivin is a trans-membrane and shed molecule with diverse biological functions, spanning from cell adhesion and migration, to immune-suppression and tissue repair. This study investigates the modulation of this protein and its functional role in monocytes/macrophages and TAM, in the tumor context. In human monocytes, expression of OA is up-regulated by anti-inflammatory stimuli, in particular IL-10, and corticosteroids. Immunostimulatory cytokines (IFNγ, IL-1β) or LPS are not stimulating its production. Accordingly, in vitro M2-polarized macrophages express more OA than M1-macrophages. A spontaneous mutation of the Gpnmb gene occurred in the DBA/2J mouse strain. The mutation causes a premature stop codon and generation of a truncated non-functional protein. This strain, and the reconstituted DBA/2J-Gpnmb+ mice with functional OA, are commercially available. OA-defective mice do not have obvious major problems, with the exception of the known rapid onset of glaucoma. To clarify the role of this protein in the tumor microenvironment, we generated methylcolantrene-induced fibrosarcoma in these mice. Both mouse strains produced tumors with a similar incidence. We established and characterized 2 cell lines from DBA/2JGpnmb+ mice and 2 from DBA/2J mice. Tumors from DBA/2J mice grew earlier in DBA/2JGpnmb+ mice, indicating that the protein Osteoactivin produced by stromal cells, including TAM, enhanced tumor growth. To better understand the function of this protein, we generated isogenic cell lines expressing or not the functional OA protein (G2 OA and G2 MOCK cells). Osteoactivin -expressing cells grew faster in vitro and under serum-free conditions were able to survive and to form spheroids which go on proliferating in an anchorage-independent manner. OA-expressing cells present typical cancer stem cell markers on their membranes such as Sca1, CD117 and SOX-2 and they are able to self-renew. The in vivo experiments demonstrated that Osteoactivin expression is associated with a significantly more aggressive phenotype, both in terms of tumor-take and tumor growth compared to OA-defective cell lines. We further demonstrated that OA-expressing tumors have higher mRNA levels of specific stem markers and in particular Nanog, SOX-2 and Brachyury. From these data we can speculate that the production of Osteoactivin and its secretion by macrophages in the tumor microenvironment might be involved in the maintenance of cancer cell stemness and their proliferative potential. Advisors/Committee Members: relatore: M. Locati, correlatore: P. Allavena, C. Belgiovine, LOCATI, MASSIMO.

Subjects/Keywords: Settore MED/04 - Patologia Generale; Settore MED/06 - Oncologia Medica

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Liguori, M. (2017). BIOLOGICAL ROLE OF OSTEOACTIVIN, A PROTEIN EXPRESSED BY TUMOR-CONDITIONED MACROPHAGES, IN THE PROCESSES OF TUMOR GROWTH AND TISSUE REPAIR. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/481318

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Liguori, M.. “BIOLOGICAL ROLE OF OSTEOACTIVIN, A PROTEIN EXPRESSED BY TUMOR-CONDITIONED MACROPHAGES, IN THE PROCESSES OF TUMOR GROWTH AND TISSUE REPAIR.” 2017. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/481318.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Liguori, M.. “BIOLOGICAL ROLE OF OSTEOACTIVIN, A PROTEIN EXPRESSED BY TUMOR-CONDITIONED MACROPHAGES, IN THE PROCESSES OF TUMOR GROWTH AND TISSUE REPAIR.” 2017. Web. 16 Jan 2021.

Vancouver:

Liguori M. BIOLOGICAL ROLE OF OSTEOACTIVIN, A PROTEIN EXPRESSED BY TUMOR-CONDITIONED MACROPHAGES, IN THE PROCESSES OF TUMOR GROWTH AND TISSUE REPAIR. [Internet] [Thesis]. Università degli Studi di Milano; 2017. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/481318.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Liguori M. BIOLOGICAL ROLE OF OSTEOACTIVIN, A PROTEIN EXPRESSED BY TUMOR-CONDITIONED MACROPHAGES, IN THE PROCESSES OF TUMOR GROWTH AND TISSUE REPAIR. [Thesis]. Università degli Studi di Milano; 2017. Available from: http://hdl.handle.net/2434/481318

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

29. M. Massara. THE NEUTROPHIL ANTI-TUMORAL RESPONSE IN CANCER: ROLE OF ACKR2 AND CHEMOKINE RECEPTORS.

Degree: 2018, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/528533

► Chemokines are key mediators of inflammation and are involved in both extrinsic and intrinsic pathway of cancer. Their main function is to induce leukocyte migration… (more)

▼ Chemokines are key mediators of inflammation and are involved in both extrinsic and intrinsic pathway of cancer. Their main function is to induce leukocyte migration through the binding of specific seven transmembrane receptors. Beside canonical chemokine receptor a smaller family of atypical chemokine receptors was described. ACKR2 binds with high affinity a broad panel of CC inflammatory chemokines mediating their internalization and intracellular degradation. Due to its chemokine scavenging activity, ACKR2 plays a protective role in chronic inflammation and in the extrinsic pathway of cancer. The objective of my thesis was to investigate the role of ACKR2 in the intrinsic pathway of cancer using the NeuT (HER2) murine model of oncogene-driven breast cancer crossed with ACKR2 KO mice. In this model, we found that ACKR2 plays a dual an opposite role. It slows the primary tumor development while it promotes lung metastasis. We found the same phenotype on metastasis using the orthotopically transplanted 4T1 mammary carcinoma and melanoma B16F10 cell lines were we demonstrated that ACKR2 expression in the hematopoietic compartment acts as a negative regulator of the mobilization of neutrophils with anti-metastatic function. In the last part of my thesis we also investigated the phenotype of circulating and tumor associated neutrophils (TANs) in glioma patients, a tumor context characterized by blood neutrophilia and a general immunosuppressive state. We found a higher grade of neutrophilia and an increased rate of immature neutrophils in high grade comparing low grade glioma patients. Finally, we found that the relative abundance of circulating neutrophils on total leukocytes positively correlates with relative abundance of TANs. Collectively taken, these results indicate that neutrophils are a heterogeneous population with both pro and anti-tumoral functions. Targeting of neutrophils in cancer context represent a potential therapeutic approach that limit their pro-tumoral role unleashing the anti-tumoral and anti-metastatic potential. Advisors/Committee Members: tutor: M. Locati, supervisore: R. Bonecchi, LOCATI, MASSIMO, BONECCHI, RAFFAELLA.

Subjects/Keywords: Settore MED/04 - Patologia Generale

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Massara, M. (2018). THE NEUTROPHIL ANTI-TUMORAL RESPONSE IN CANCER: ROLE OF ACKR2 AND CHEMOKINE RECEPTORS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/528533

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Massara, M.. “THE NEUTROPHIL ANTI-TUMORAL RESPONSE IN CANCER: ROLE OF ACKR2 AND CHEMOKINE RECEPTORS.” 2018. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/528533.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Massara, M.. “THE NEUTROPHIL ANTI-TUMORAL RESPONSE IN CANCER: ROLE OF ACKR2 AND CHEMOKINE RECEPTORS.” 2018. Web. 16 Jan 2021.

Vancouver:

Massara M. THE NEUTROPHIL ANTI-TUMORAL RESPONSE IN CANCER: ROLE OF ACKR2 AND CHEMOKINE RECEPTORS. [Internet] [Thesis]. Università degli Studi di Milano; 2018. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/528533.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Massara M. THE NEUTROPHIL ANTI-TUMORAL RESPONSE IN CANCER: ROLE OF ACKR2 AND CHEMOKINE RECEPTORS. [Thesis]. Università degli Studi di Milano; 2018. Available from: http://hdl.handle.net/2434/528533

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

30. M. Manzoni. MOLECULAR HETEROGENEITY OF MULTIPLE MYELOMA: THE BIOLOGICAL AND CLINICAL RELEVANCE OF NOVEL GENE MUTATIONS BY NEXT GENERATION SEQUENCING.

Degree: 2018, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/546254

► Il mieloma multiplo (MM) è una proliferazione maligna fatale delle plasmacellule (PC) secernenti anticorpi del midollo osseo (BM), caratterizzata da un ampio spettro clinico e… (more)

Subjects/Keywords: MM; NGS; mutations; cfDNA; Settore MED/15 - Malattie del Sangue

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Manzoni, M. (2018). MOLECULAR HETEROGENEITY OF MULTIPLE MYELOMA: THE BIOLOGICAL AND CLINICAL RELEVANCE OF NOVEL GENE MUTATIONS BY NEXT GENERATION SEQUENCING. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/546254

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Manzoni, M.. “MOLECULAR HETEROGENEITY OF MULTIPLE MYELOMA: THE BIOLOGICAL AND CLINICAL RELEVANCE OF NOVEL GENE MUTATIONS BY NEXT GENERATION SEQUENCING.” 2018. Thesis, Università degli Studi di Milano. Accessed January 16, 2021. http://hdl.handle.net/2434/546254.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Manzoni, M.. “MOLECULAR HETEROGENEITY OF MULTIPLE MYELOMA: THE BIOLOGICAL AND CLINICAL RELEVANCE OF NOVEL GENE MUTATIONS BY NEXT GENERATION SEQUENCING.” 2018. Web. 16 Jan 2021.

Vancouver:

Manzoni M. MOLECULAR HETEROGENEITY OF MULTIPLE MYELOMA: THE BIOLOGICAL AND CLINICAL RELEVANCE OF NOVEL GENE MUTATIONS BY NEXT GENERATION SEQUENCING. [Internet] [Thesis]. Università degli Studi di Milano; 2018. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/2434/546254.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Manzoni M. MOLECULAR HETEROGENEITY OF MULTIPLE MYELOMA: THE BIOLOGICAL AND CLINICAL RELEVANCE OF NOVEL GENE MUTATIONS BY NEXT GENERATION SEQUENCING. [Thesis]. Università degli Studi di Milano; 2018. Available from: http://hdl.handle.net/2434/546254

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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