Animal Models of Human Pathology 2012

[No abstract available

E2F1 activation is responsible for pituitary adenomas induced by HMGA2 gene overexpression

The High Mobility Group protein HMGA2 is a nuclear architectural factor that plays a critical role in a wide range of biological processes including regulation of gene expression, embryogenesis and neoplastic transformation. Several studies are trying to identify the mechanisms by which HMGA2 protein is involved in each of these activities, and only recently some new significant insights are emerging from the study of transgenic and knock-out mice. Overexpression of HMGA2 gene leads to the onset of prolactin and GH-hormone induced pituitary adenomas in mice, suggesting a critical role of this protein in pituitary tumorigenesis. This was also confirmed in the human pathology by the finding that HMGA2 amplification and/or overexpression is present in human prolactinomas. This review focuses on recent data that explain the mechanism by which HMGA2 induces the development of pituitary adenomas in mice. This mechanism entails the activation of the E2F1 protein by the HMGA2-mediated displacement of HDAC1 from pRB protein

The Tumor Suppressive Role of PATZ1 in Thyroid Cancer: A Matter ofEpithelial-Mesenchymal Transition

PATZ1 is a chromatin-regulating factor with emerging roles in stemness and cancer. It has been suggested to play a dual oncogene/tumor suppressor role depending on the cellular context, but its function in human tumor biology is still far to be completely elucidated. We have recently identified its tumor suppressive role in thyroid carcinogenesis, possibly through the association between PATZ1 and p53 to oppose epithelial-mesenchymal transition and cell migration. These are major processes in tumor progression, local invasion, metastasis, and therapeutic resistance and play a recognized role in the development of thyroid cancer, particularly anaplastic thyroid carcinoma, but many questions about how they are orchestrated remain opened. Elucidation of the mechanisms regulating epithelial-mesenchymal transition and cell migration can suggest new candidates for antimetastatic drug development that could lead to more effective therapies for highly aggressive and lethal thyroid cancers

Hydrodynamic impacts of short laser pulses on plasmas

We determine conditions allowing to simplify the description of the impact of a short and arbitrarily intense laser pulse onto a cold plasma at rest. If both the initial plasma density and pulse profile have plane simmetry, then suitable matched upper bounds on the maximum and the relative variations of the initial density, as well as the intensity and duration of the pulse, ensure a strictly hydrodynamic evolution of the electron fluid (without wave-breaking or vacuum-heating) during its whole interaction with the pulse, while ions can be regarded as immobile. We use a recently developed fully relativistic plane model whereby the system of the (Lorentz-Maxwell and continuity) PDEs is reduced into a family of highly nonlinear but decoupled systems of non-autonomous Hamilton equations with one degree of freedom, with the light-like coordinate $\xi=ct\!-\!z$ instead of time $t$ as an independent variable, and new apriori estimates (eased by use of a Liapunov function) of the solutions in terms of the input data (initial density and pulse profile). If the laser spot radius $R$ is finite but not too small the same conclusions hold for the part of the plasma close to the axis $\vec{z}$ of cylindrical symmetry. These results may help in drastically simplifying the study of extreme acceleration mechanisms of electrons.Comment: 29 pages, 8 figures. To appear in the Journal "Mathematics

Optimization of Short RNA Aptamers for TNBC Cell Targeting

Triple-negative breast cancer (TNBC) is an aggressive cancer with limited targeted therapies. RNA aptamers, suitably chemically modified, work for therapeutic purposes in the same way as antibodies. We recently generated 2′ Fluoro-pyrimidines RNA-aptamers that act as effective recognition elements for functional surface signatures of TNBC cells. Here, we optimized three of them by shortening and proved the truncated aptamers as optimal candidates to enable active targeting to TNBC. By using prediction of secondary structure to guide truncation, we identified structural regions that account for the binding motifs of the full-length aptamers. Their chemical synthesis led to short aptamers with superb nuclease resistance, which specifically bind to TNBC target cells and rapidly internalize into acidic compartments. They interfere with the growth of TNBC cells as mammospheres, thus confirming their potential as anti-tumor agents. We propose sTN145, sTN58 and sTN29 aptamers as valuable tools for selective TNBC targeting and promising candidates for effective treatments, including therapeutic agents and targeted delivery nanovectors.Fil: Camorani, Simona. Institute Of Experimental Endocrinology And Oncology; ItaliaFil: D'Argenio, Annachiara. Institute Of Experimental Endocrinology And Oncology; ItaliaFil: Agnello, Lisa. Institute Of Experimental Endocrinology And Oncology; ItaliaFil: Nilo, Roberto. Institute Of Experimental Endocrinology And Oncology; ItaliaFil: Zanetti, Antonella. Institute Of Biostructures And Bioimaging; ItaliaFil: Ibarra, Luis Exequiel. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Universidad Nacional de Rio Cuarto. Facultad de Cs.exactas Fisicoquimicas y Naturales. Instituto de Biotecnologia Ambiental y Salud. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Cordoba. Instituto de Biotecnologia Ambiental y Salud.; ArgentinaFil: Fedele, Monica. Institute Of Experimental Endocrinology And Oncology; ItaliaFil: Cerchia, Laura. Institute Of Experimental Endocrinology And Oncology; Itali

PATZ Attenuates the RNF4-mediated Enhancement of Androgen Receptor-dependent Transcription *

PATZ is a transcriptional repressor affecting the basal activity of different promoters, whereas RNF4 is a transcriptional activator. The association of PATZ with RNF4 switches the activation to repression of selected basal promoters. Because RNF4 interacts also with the androgen receptor (AR) functioning as a coactivator and, in turn, RNF4 associates with PATZ, we investigated whether PATZ functions as an AR coregulator. We demonstrate that PATZ does not influence directly the AR response but acts as an AR corepressor in the presence of RNF4. Such repression is not dependent on histone deacetylases. A mutant RNF4 that does not bind PATZ but enhances AR-dependent transcription is not influenced by PATZ, demonstrating that the repression by PATZ occurs only upon binding to RNF4. We also demonstrate that RNF4, AR, and PATZ belong to the same complex in vivo also in the presence of androgen, suggesting that repression is not mediated by the displacement of RNF4 from AR. Finally, we show that the repression of endogenous PATZ expression by antisense expression plasmids in LNCaP cells results in a stronger androgen response. Our findings demonstrate that PATZ is a novel AR coregulator that acts by modulating the effect of a coactivator. This could represent a novel and more general mechanism to finely tune the androgen response

PO-038 PDGFRβ as a new biomarker for metastatic triple-negative breast cancer: development of a theranostic anti-PDGFRβ aptamer for imaging and suppression of metastases

Introduction Triple-negative breast cancers (TNBCs) are a heterogeneous group of aggressive tumours lacking oestrogen and progesterone receptors and HER2 receptor, thus excluding the possibility of using targeted therapy against these proteins. Mesenchymal-like (ML) subtype, characterised by a stem-like, undifferentiated phenotype, is more invasive and metastatic than other TNBC subtypes and has a strong tendency to form vasculogenic mimicry (VM). Recently, platelet derived growth factor receptor β (PDGFRβ) has been shown to play a role in VM of TNBC. Regrettably, therapies targeting PDGFRβ with tyrosine kinase inhibitors are not effective in treating TNBCs, thus developing new strategies to target PDGFRβ in TNBC patients is crucial to improve their chances of survival. Here, we describe the characterisation of the Gint4.T anti-PDGFRβ nuclease-resistant RNA aptamer as high efficacious theranostic tool for imaging and suppression of ML TNBC metastases. Material and methods Immunohistochemical analyses on a human TNBC tissue microarray was performed to correlate PDGFRβ expression with clinical and molecular features of different subtypes. Functional assays were conducted on PDGFRβ-positive ML BT-549 and MDA-MB-231 cells to investigate the effect of Gint4.T in interfering with cell growth in 3D conditions, migration, invasion and VM formation. Gint4.T was conjugated with near-infrared (NIR) fluorescent VivoTag-S680 and its binding specificity to receptor was confirmed both in vitro (confocal microscopy and flow cytometry analyses of TNBC cells) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). MDA-MB-231 cells were i.v. injected in nude mice and Gint4.T-NIR was used to detect lung metastases in mice untreated or i.v. injected with Gint4.T or a scrambled aptamer. Results and discussions The expression of PDGFRβ was observed in human TNBC samples characterised by higher metastatic behaviour. Treatment of TNBC cell lines with Gint4.T aptamer blocked their invasive growth and vasculogenic properties in 3D culture conditions, and strongly reduced cell migration/invasion in vitro and metastases formation in vivo. The Gint4.T-NIR was able to specifically bind to TNBC xenografts and detect lung metastases in vivo. Therefore, the aptamer revealed a high efficacious theranostic tool for imaging and suppression of TNBC metastases. Conclusion These studies indicate PDGFRβ as a new biomarker for ML and metastatic TNBC subtype and propose a novel targeting agent for the diagnosis and treatment of metastatic TNBCs