Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

Inhibition of dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities

Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. In the present study, we identified new compounds with anti-DENV replication activity by targeting viral replication enzymes – NS5, RNA-dependent RNA polymerase (RdRp) and NS3 protease, using cell-based reporter assay. Subsequently, we performed an enzyme-based assay to clarify the action of these compounds against DENV RdRp or NS3 protease activity. Moreover, these compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication. These results describe novel prototypical small anti-DENV molecules for further development through compound modification and provide potential antivirals for treating DENV infection and DENV-related diseases

Water-Soluble Ruthenium(III)-Dimethyl Sulfoxide Complexes: Chemical Behaviour and Pharmaceutical Properties

In this paper we report a review of the results obtained in the last few years by our group in the development of ruthenium(III) complexes characterized by the presence of sulfoxide ligands and endowed with antitumor properties. In particular, we will focus on ruthenates of general formula Na[trans-RuCl4(R1R2SO)(L)], where R1R2SO = dimethylsulfoxide (DMSO) or tetramethylenesulfoxide (TMSO) and L = nitrogen donor ligand. The chemical behavior of these complexes has been studied by means of spectroscopic techniques both in slightly acidic distilled water and in phosphate buffered solution at physiological pH. The influence of biological reductants on the chemical behavior is also described. The antitumor properties have been investigated on a number of experimental tumors. Out of the effects observed, notheworthy appears the capability of the tested ruthenates to control the metastatic dissemination of solid metastasizing tumors. The analysis of the antimetastatic action, made in particular on the MCa mammary carcinoma of CBA mouse, has demonstrated a therapeutic value for these complexes which are able to significantly prolong the survival time of the treated animals. The antimetastatic effect is not attributable to a specific cytotoxicity for metastatic tumor cells although in vitro experiments on pBR322 double stranded DNA has shown that the test ruthenates bind to the macromolecule, causing breaks corresponding to almost all bases, except than thymine, and are able to cause interstrand bonds, depending on the nature of the complex being tested, some of which results active as cisplatin itself

Parental species and hybrid descendants of Bacillus (Insecta Phasmatodea) show different patterns of highly amplified, colocalized ribosomal and telomeric sequences

We investigated by dual-color fluorescence in situ hybridization (FISH) with 28S ribosomal and (TTAGG)n telomeric probes all species of the circum-Mediterranean genus Bacillus encompassing bisexual and parthenogenetic taxa, namely the three parental species (B. grandii, B. atticus, B. rossius) and the two derived hybrids (B. whitei, B. lynceorum). Specimens were collected in Italian mainland, Sardinia and Sicily. In all species the presence of colocalized, highly amplified ribosomal and telomeric sequences was demonstrated by the double labelling of the cytological satellites. These satellites varied in size, number and location both among and within species. In B. grandii and B. atticus a maximum of two FISH-labeled locations were observed, whereas in B. rossius and in the two hybrids up to 11 different positions were recorded. Moreover, our investigations showed a significant occurrence of chromosome breakages and rearrangements. The overall meaning of the ribosomal and telomeric sequence colocalization as well as the Nucleolar Organizer Region mobility and activity are discussed in both the ancestors and their hybrid descendants. It is noteworthy that the same trait has been shown in seven additional phasmid species belonging to distantly related genera. This trait could be a shared ancestral character in phasmids

Use of mixed study techniques in the evaluation of coastline dynamics - the “Porto Cesareo” MPA case of study

In recent decades, the much-discussed climate changes with the consequent variations in sea and weather conditions and the rise of the mean sea level are causing an indisputable set of negative actions on the entire coastal system mainly due to the increase of the erosive phenomenon along the shorelines. These critical scenarios have a major impact even on a local scale, and because of that, we decided to study a well knows tract of rocky/sandy mixed coast, in a highly anthropized area, even if located inside the “Porto Cesareo” Marine Protected Area (MPA) (Ionian Sea, Gulf of Taranto, Puglia Region, Italy). The high naturalistic and archaeological value of this area calls for a greater institutional effort in the study of erosional phenomena. Several historical documents from other studies point out that this coastal area is an ideal place for this kind of research. The effects of coastal erosion and anthropic pressures along this tract of coast require adequate efforts for a consistent and rapid evaluation of the coastal dynamics. The methodologies proposed in this work are based on mixed techniques from different fields of study, integrating recent aero photogrammetry surveys with drones, aerial images acquired by the Italian Military Geographic Institute (IGM), elaboration of paleoshorelines related by underwater archaeological markers and their dating, and finally on the elaboration of satellite products useful for the study of vast areas. The monitoring of coastal areas and the evaluation of shoreline dynamics are core topics in the implementation of managing actions of decision makers on a local, regional, national, and international scale, above all in places like the chosen one, inside an MPA. Remote sensing through the use of RPAS (Remotely Piloted Aircraft Systems or Drones) has proved to be very useful for identifying phenomena that act on a small spatial scale and in supporting and implementing protective measures according to the adaptive management approach, through multi-year surveys on habitats of conservation interest [18]. For the implementation of fine-scale monitoring actions, we have chosen products from the Sentinel satellite of the Copernicus constellation (European Space Agency - ESA). In this context, the use of satellite products provides a recurrent view of the ground, useful in the short and long-term monitoring of changes in wide coastal areas, and in particular, offers a coastline positioning evaluation in near real-time. Local monitoring actions performed in recent years have already shown an erosive trend in the past decades, and even, negative forecasts for the next decade, so further surveys with mixed methodologies could be crucial in the evaluation of the evolution of this particular coastal area by local authorities

Single Event Effects in the Pixel readout chip for BTeV

In future experiments the readout electronics for pixel detectors is required to be resistant to a very high radiation level. In this paper we report on irradiation tests performed on several preFPIX2 prototype pixel readout chips for the BTeV experiment exposed to a 200 MeV proton beam. The prototype chips have been implemented in commercial 0.25 um CMOS processes following radiation tolerant design rules. The results show that this ASIC design tolerates a large total radiation dose, and that radiation induced Single Event Effects occur at a manageable level.Comment: 15 pages, 6 Postscript figure

Characterization of Prototype BTeV Silicon Pixel Sensors Before and After Irradiation

We report on measurements performed on silicon pixel sensor prototypes exposed to a 200 MeV proton beam at the Indiana University Cyclotron Facility. The sensors are of n+/n/p+ type with multi-guard ring structures on the p+-side and p-stop electrode isolation on the n+-side. Electrical characterization of the devices was performed before and after irradiation up to a proton fluence of 4E14 p/cm2. We tested pixel sensors fabricated from normal and oxygen-enriched silicon wafers and with two different p-stop isolation layouts: common p-stop and individual p-stop.Comment: 8 pages in postscript format. Presented at 2001 IEEE Nuclear Science Symposium 4-10 November 2001 San Diego, Californi

ATLAS RPC Quality Assurance results at INFN Lecce

The main results of the quality assurance tests performed on the Resistive Plate Chamber used by the ATLAS experiment at LHC as muon trigger chambers are reported and discussed. Since July 2004, about 270 RPC units has been certified at INFN Lecce site and delivered to CERN, for being integrated in the final muon station of the ATLAS barrel region. We show the key RPC characteristics which qualify the performance of this detector technology as muon trigger chamber in the harsh LHC enviroments. These are dark current, chamber efficiency, noise rate, gas volume tomography, and gas leakage.Comment: Comments: 6 pages, 1 table, 9 figures Proceedings of XXV Physics in Collision-Prague, Czech Republic, 6-9 July 200

Identification of two new repetitive elements and chromosomal mapping of repetitive DNA sequences in the fish Gymnothorax unicolor (Anguilliformes: Muraenidae)

Muraenidae is a species-rich family, with relationships among genera and species and taxonomy that have not been completely clarified. Few cytogenetic studies have been conducted on this family, and all of them showed the same diploid chromosome number (2n=42) but with conspicuous karyotypic variation among species. The Mediterranean moray eel Gymnothorax unicolor was previously cytogenetically studied using classical techniques that allowed the characterization of its karyotype structure and the constitutive heterochromatin and argyrophilic nucleolar organizer regions (Ag-NORs) distribution pattern. In the present study, we describe two new repetitive elements (called GuMboI and GuDdeI) obtained from restricted genomic DNA of G. unicolor that were characterized by Southern blot and physically localized by in situ hybridization on metaphase chromosomes. As they are highly repetitive DNA sequences, they map in heterochromatic regions. However, while GuDdeI was localized in the centromeric regions, the GuMboI fraction was distributed on some centromeres and was co-localized with the nucleolus organizer region (NOR). Comparative analysis with other Mediterranean species such as Muraena helena pointed out that these DNA fractions are species-specific and could potentially be used for species discrimination. As a new contribution to the karyotype of this species, we found that the major ribosomal genes are localized on acrocentric chromosome 9 and that the telomeres of each chromosome are composed of a tandem repeat derived from a poly-TTAGGG DNA sequence, as it occurs in most vertebrate species. The results obtained add new information useful in comparative genomics at the chromosomal level and contribute to the cytogenetic knowledge regarding this fish family, which has not been extensively studied

Efficacy of 5-FU Combined to Na[trans-RuCl4(DMSO)Im], A Novel Selective Antimetastatic Agent, on the Survival Time of Mice With P388 Leukemia, P388/DDP subline and MCa Mammary Carcinoma

The combinational treatment between the selective antimetastatic agent, sodium-trans-rutheniumtetrachloridedimethylsulfoxideimidazole, Na[trans-RuCl4(DMSO)Im], and the cytotoxic drug 5-fluorouracil (5-FU) on primary tumor growth and on the survival time of experimental tumors results in an effect significantly greater than that of each single agent used alone either with the solid metastasizing MCa mammary carcinoma of the CBA mouse or with the lymphocytic leukemia P388 and its platinum resistant P388/DDP subline. Thus the inorganic compound Na[trans-RuCl4(DMSO)Im], known for its potent and selective antimetastatic effects, positively interacts with the antitumor action of an organic anticancer agent such as 5-FU on both a solid metastasizing tumor and a tumor of lymphoproliferative type. In particular, the effects of the combinational treatment on the survival time of tumor bearing mice seem to be related to the selective antimetastatic activity of the ruthenium complex that joins the potent cytotoxicity of 5-FU for the tumor. Moreover, these data show that Na[trans-RuCl4(DMSO)Im] is almost as effective on the subline of P388 made resistant to cisplatin as it was on the parental line