Frequent loss of heterozygosity and altered expression of the candidate tumor suppressor gene 'FAT' in human astrocytic tumors

Background: We had earlier used the comparison of RAPD (Random Amplification of Polymorphic DNA) DNA fingerprinting profiles of tumor and corresponding normal DNA to identify genetic alterations in primary human glial tumors. This has the advantage that DNA fingerprinting identifies the genetic alterations in a manner not biased for locus. Methods: In this study we used RAPD-PCR to identify novel genomic alterations in the astrocytic tumors of WHO grade II (Low Grade Diffuse Astrocytoma) and WHO Grade IV (Glioblastoma Multiforme). Loss of heterozygosity (LOH) of the altered region was studied by microsatellite and Single Nucleotide Polymorphism (SNP) markers. Expression study of the gene identified at the altered locus was done by semi-quantitative reverse-transcriptase-PCR (RT-PCR). Results: Bands consistently altered in the RAPD profile of tumor DNA in a significant proportion of tumors were identified. One such 500 bp band, that was absent in the RAPD profile of 33% (4/12) of the grade II astrocytic tumors, was selected for further study. Its sequence corresponded with a region of FAT, a putative tumor suppressor gene initially identified in Drosophila. Fifty percent of a set of 40 tumors, both grade II and IV, were shown to have Loss of Heterozygosity (LOH) at this locus by microsatellite (intragenic) and by SNP markers. Semi-quantitative RT-PCR showed low FAT mRNA levels in a major subset of tumors. Conclusion: These results point to a role of the FAT in astrocytic tumorigenesis and demonstrate the use of RAPD analysis in identifying specific alterations in astrocytic tumors

Appropriateness of acute admissions and last in-patient day for patients with long term neurological conditions

<p>Abstract</p> <p>Background</p> <p>To examine the appropriateness of admissions and in-patient stay for patients with long term neurological conditions (LTNCs). To identify variables predictive of appropriateness and explore management alternatives.</p> <p>Methods</p> <p>Adults admitted as acute patients to Derby Hospitals NHS Foundation Trust (England). Data were collected prospectively and examined by a multi-disciplinary expert panel to determine the appropriateness of admission and length of stay (LoS). Management alternatives were discussed.</p> <p>Results</p> <p>A total of 119 participants were recruited. 32 admissions were inappropriate and 83 were for an inappropriate duration. Whether a participant lived in their own home was predictive of an inappropriate admission. The number of LTNCs, number of presenting complaints and whether the participant lived alone in their own home were predictive of an inappropriate LoS. For admissions judged to be inappropriate, the panel suggested management alternatives.</p> <p>Conclusion</p> <p>Patients with LTNCs are being admitted to hospital when other services, e.g. ambulatory care, are available which could meet their needs. Inefficiencies in hospital procedures, such as discharge planning and patient transfers, continue to exist. Recognition of the need to plan for discharge at admission and to ensure in-patient services are provided in a timely manner may contribute towards improved efficiency.</p

Key-music: an expert system environment for music composition

In this paper we briefly explain the main concepts underlying the Key-Music system, a prototype of Artificial Intelligence tool for music knowledge representation and music composition. Key-Music is based on the Petri nets theory in conjunction with Knowledge Representation for storing general definitions about musical timed process, under the form of semantic frame-based multiple inheritance networks; representations of actual, individual music process can be generated as instances of a general definition, and Petri nets are automati cally derived to describe and perform them. Presently, the output of the system can be both a midi and a cmusic file

An OPS5 implementation of qualitative reasoning about physical systems

This paper describes the implementation of WQMS, a general-purpose qualitative modeling environment that integrates the process-centered approach and the constraint-centered approach. A new simulation algorithm is presented in which, owing to this integration, some drawbacks of QSIM are overcome using a depth-first strategy in the assessment of the qualitative states and a reduced set of input variables. With this algorithm it is possible to achieve qualitative simulations in cases in which simulations by QSIM are not feasible, because in some complex systems it is possible neither to specify the initial conditions for all required variables nor to handle the amount of branching that arises with normal computer facilities. An implementation of modeling and simulation of two biological systems is shown; to the best of the authors' knowledge, WQMS is the only environment with which a qualitative simulation can be achieved for these system

Human sirtuins: an overview of an emerging drug target in age-related diseases and cancer.

Sir2-like proteins (Sirtuins) are a class of enzymes conserved throughout the kingdoms of life. In fact, from Archaea to Mammals, these (class III) NAD+-dependent deacetylases catalyse the removal of the acetyl moiety from a substrate protein. Sirtuins show a conserved central catalytic domain with two more variable amino- and carboxy-terminal flanking regions. Amino acid comparison of these central conserved catalytic core sequences allows us to divide Sirtuins into five different classes (I, II, III, IV and U). These proteins differ in their subcellular localization (i.e. in Eukaryotes they can be found in the nucleus, cytoplasm or mitochondria). In humans there are seven Sirtuins (SIRT1-7) that are implicated in various physiological processes including aging and age-related disorders such as neoplasms, cardiovascular, metabolic and neurodegenerative diseases, and inflammation. Nowadays, the estimated life expectancy is definitely longer than in the past thus, we may consider all aging-related problems as having a strong social impact. Consequently, Sirtuins are emerging, particularly from a pharmacological point of view, as new and valuable drug targets

Crystal structures of HIV-1 reverse transcriptase in complexes with thiocarbamate non-nucleoside inhibitors

O-Phthalimidoethyl-N-arylthiocarbamates (TCs) have been recently identified as a new class of potent HIV-1 reverse transcriptase (RT) non-nucleoside inhibitors (NNRTIs), by means of computer-aided drug design techniques. To elucidate the atomic details of RT/TC interaction and validate an earlier TC docking model, the structures of three RT/TC complexes were determined at 2.8-3.0 Armstrong resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs

STRUCTURAL FUNCTIONALIZATION OF TRI-SUBSTITUTED PYRAZOLE DERIVATIVES AND PRELIMINARY EVALUATION OF THEIR ANTIMALARIAL ACTIVITY

The increasing prevalence of drug-resistant Plasmodium falciparum strains led to an urgent priority in the development of new antimalarial drugs. In this scenario, several pyrazole derivatives have been reported as antimalarial agents in the last years. Recently, novel Tri- and Tetrasubstituted pyrazole derivatives showed interesting antimalarial properties being endowed with micromolar IC50 values against Chloroquine (CQ)-sensitive D10 and CQ-resistant W2 Plasmodium strains. To further extend the structure activity relationships around these promising compounds, we designed and synthesized a new series of 3-phenyl-4-cyano pyrazoles bearing different basic chains at position 5. Briefly, the novel derivatives were prepared by sequentially reacting benzoylacetonitrile with carbon disulfide and iodomethane in the presence of sodium hydride. The so obtained thioketal A was substituted with the proper amine, leading to the formation of intermediates B, that were cyclized with hydrazine to afford the desired pyrazoles. All the newly isolated compounds were tested against D10 and W2 Plasmodium strains and their cytotoxicity was evaluated on normal fibroblast cells. Interestingly, the novel pyrazoles 2 showed micromolar IC50 values especially against CQ resistant W2 strain, resulting more effective than their analogues 1. Additionally, in preliminary tests the novel derivatives did not show any significant cytotoxicity on fibroblast cell lin

Bicyclic basic merbarone analogues as antiproliferative agents

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase II\u3b1. To further extend the structure\u2013activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3\u20136 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure\u2013activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase II\u3b1-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation