Noncoding RNAs in Cancer Medicine

Several signalling proteins involved in cell growth and differentiation represent attractive candidate targets for cancer diagnosis and/or therapy since they can act as oncogenes. Because of their high specificity and low immunogeneicity, using artificial small noncoding RNA (ncRNAs) as therapeutics has recently become a highly promising and rapidly expanding field of interest. Indeed, ncRNAs may either interfere with RNA transcription, stability, translation or directly hamper the function of the targets by binding to their surface. The recent finding that the expression of several genes is under the control of small single-stranded regulatory RNAs, including miRNAs, makes these genes as appropriate targets for ncRNA gene silencing. Furthermore, another class of small ncRNA, aptamers, act as high-affinity ligands and potential antagonists of disease-associated proteins. We will review here the recent and innovative methods that have been developed and the possible applications of ncRNAs as inhibitors or tracers in cancer medicine

Modern technologies for data storage, organization and managing in CRM systems

In our study we intend to emphasize the main targeted objectives for the implementation of CRM type platforms. According to these objectives, in order to provide the functionality of CRM platforms, we will make a reference to\ud the prime methods of collecting and organizing information: databases, data warehouses, data centers from Cloud Computing field. As a representative procedure of handling information we will exemplify the OLAP technique which\ud is implemented by means of SQL Server Analysis Service software instrument. Finally, we will try to look over some of the Cloud Computing based CRM platforms and how the OLAP techniques can be applied to them

IDENTIFICATION OF NOVEL INHIBITORS OF CDC25 PHOSPHATASES AS NEW ANTI-MELANOMA AGENTS BY LIGAND- AND STRUCTURE-BASED VIRTUAL SCREENING STUDIES

Cell division cycle 25 (CDC25) proteins are highly conserved dual specificity phosphatases that regulate the proper advancement of the cell cycle by activation of CDK/cyclin complexes. Overexpression of CDC25s, resulting in genomic instability and dysregulated cell growth, is frequently related to aggressiveness, high-grade tumors and poor prognosis. Thus, this family of enzymes represent an attractive target for drug discovery. Recently, compound 11, 3-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)- propanoic acid, and compound 19, 4-(2-carboxybenzoyl)phthalic acid, were identified as novel inhibitors of CDC25s with a different inhibition profile, by using a structure-based virtual screening approach. Both compounds arrested cells at the G0/G1 and G2/M phases of the cell cycle, increased Cdk1 hyperphosphorylation in K562 leukemia cells, and significantly suppressed the growth of human MCF-7 breast, PC-3 prostate cancer lines as well as K562 leukemia cells, thus representing novel interesting leads. This thesis project focused on the computer-assisted lead optimization of the initial hits 11 and 19. Firstly, in order to expand our understanding of structure-activity relationships within the 6-xanthone class of CDC25 inhibitors, we identified a series of structural analogs of compound 11 by ligand-based chemoinformatic approach. We examined their activity against melanoma cancer cell lines, as well as the mechanism of action involved. Nine compounds (3, 5–9, 21, 24, and 25) were identified with Ki values for CDC25A, -B and -C ranging from 0.01 to 4.4 μM. One of these analogs, 7, showed a high antiproliferative effect on human melanoma cell lines, A2058 and SAN, associated with an arrest in G2/M phase of the cell cycle. Furthermore, 7 induced apoptosis through intrinsic pathway. Interestingly, compound 7 decreased the protein levels of phosphorylated Akt and increased those of p53, thus contributing to the regulation of chemosensitivity through the control of downstream Akt pathways in melanoma cells. Secondly, a series of novel derivatives of compound 19 was rationally designed by using a structure-based approach, guided by preliminary docking studies, with the aim to improve its binding affinity, pharmacokinetic properties as well as to investigate its anti-melanoma effect. A focused library of 24 derivatives was synthesized: a preliminary screening of the inhibitory activities toward CDC25B showed that ten molecules (compounds 2, 3d, 4, 4a, 4b, 5f, 6, 6a, 6b, 7) acted as powerful inhibitors with Ki values ranging between 2.8–20.1 μM. Among them, compounds 2 and 6a showed good antiproliferative effects on melanoma cell line A2058. Taken together, our data emphasize that CDC25 could be considered as a possible oncotarget in melanoma cells and that the designed compounds represent small molecule CDC25 inhibitors that merit to be further evaluated as chemotherapeutic agents for melanoma, likely in combination with other therapeutic compounds

The Chromosomal Protein Sso7d of the CrenarchaeonSulfolobus solfataricus Rescues Aggregated Proteins in an ATP Hydrolysis-dependent Manner

In this work, we show that the nonspecific DNA-binding protein Sso7d from the crenarchaeon Sulfolobus solfataricus displays a cation-dependent ATPase activity with a pH optimum around neutrality and a temperature optimum of 70 degrees C. Measurements of tryptophan fluorescence and experiments that used 1-anilinonaphthalene-8-sulfonic acid as probe demonstrated that ATP hydrolysis induces a conformational change in the molecule and that the binding of the nucleotide triggers the ATP hydrolysis-induced conformation of the protein to return to the native conformation. We found that Sso7d rescues previously aggregated proteins in an ATP hydrolysis-dependent manner; the native conformation of Sso7d forms a complex with the aggregates, while the ATP hydrolysis-induced conformation is incapable of this interaction. Sso7d is believed to be the first protein isolated from an archaeon capable of rescuing aggregates

Percorsi di diritto comparato

The book Percorsi di diritto comparato (Paths of Comparative Law) is based on the papers delivered in 2020 as part of the course of the Comparative Law curriculum of the Doctorate School of Comparative, Private, Civil Procedure and Business Law at the University of Milan. The volume consists of twelve essays, which aim to offer a cross-section of some of the topics that animate the comparative law reflections, addressing issues of great topicality in the doctrinal debate, national and international.illustratorL’opera collettanea Percorsi di diritto comparato prende le mosse dagli interventi tenuti nel 2020 nell’ambito del corso del curriculum di Diritto Comparato della scuola di Dottorato di Diritto Comparato, Privato, Processuale Civile e dell’Impresa dell’Università degli Studi di Milano. Il volume si compone di dodici saggi, che vogliono offrire uno spaccato di alcuni dei temi che animano le riflessioni giuscomparatistiche, affrontando questioni di grande attualità nel dibattito dottrinale, nazionale ed internazionale

Proneural-Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma

Glioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12\u201315 months and just 3\u20135% of survival over 5 years. This is mainly because most patients suffer recurrence after treatment that currently consists in maximal resection followed by radio- and chemotherapy with temozolomide. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial\u2013mesenchymal transition associated with other aggressive cancers. In this review we frame this process in the high degree of phenotypic inter- and intra-tumor heterogeneity of GBM, which exists in different subtypes, each one characterized by further phenotypic variability in its stem-cell compartment. Under the selective pressure of different treatment agents PMT is induced. The mechanisms involved, as well as the significance of such event in the acquisition of a multitherapy resistance phenotype, are taken in consideration for future perspectives in new anti-GBM therapeutic options

Analysis of a fluvial groynes system on hydraulic scale model

River morphodynamics and sediment transportSediment-structure interactio

Split-appendix technique: Alternative urinary diversion for pediatric complete incontinence

We report our series of selected patients with complete incontinence in whom the appendix was divided and utilized for creating two continent catheterizable stomas. All patients were treated for urinary and fecal incontinence by split appendix technique. The appendix was divided into two different parts preserving adequate perfusion and used for creating an appendicocecostomy (ACE) and an appendicovesicostomy at the same time. After a clinical and radiological follow up, our patients referred a good acceptance and an easily management of the stomas in order to stay dry for all day from urine and feces with improving of their quality of life. The combination of ACE and Mitrofanoff principle have revolutionized the management of urinary and fecal incontinence in patients who are unable to utilize their urethra to keep themselves dry