No abstract

Intragenic deletions of TSG101, the human homolog of a mouse gene (tsg101) that acts to suppress malignant cell growth, were reported in human breast tumours. We screened TSG101 for somatic mutations in DNA and RNA samples isolated from a variety of common human malignancies, EBV-immortalised B-cells, and normal lung parenchyma. Intragenic TSG101 deletions in RNA transcripts were frequently found in all types of samples. Analysis of DNA failed to show genomic rearrangements corresponding to transcripts containing deletions in the same samples. The breakpoints of most transcript deletions coincide with genuine or cryptic splice site sequences, suggesting that they result from alternative or aberrant splicing. A similar spectrum of transcript deletions has previously been described in the putative tumour suppressor gene FHIT. We analysed FHIT in the same series of RNA samples and detected truncated FHIT transcripts frequently in both tumour and normal tissues. In addition, transcripts from TSG101, FHIT and seven other genes were analysed in RNA isolated from normal peripheral blood lymphocytes. Large TSG101 and FHIT intragenic transcript deletions were detected and these appeared to be the predominant transcript iǹ aged' lymphocytes. Similar alterations were not detected in transcripts of the other genes which were analysed. Our ®ndings demonstrate that truncated TSG101 and FHIT transcripts are commonly detected in both normal and malignant tissues and that a signi®cant fraction of these are likely to be the result of aberrant splicing. While we cannot exclude that alterations in TSG101 and FHIT occur during cancer development, our data indicate that in this context the commonly observed transcript abnormalities are misleading.

No abstract

Dengue virus (DENV) causes 390 million infections per year. Infections can be asymptomatic or range from mild fever to severe haemorrhagic fever and shock syndrome. Currently, no effective antivirals or safe universal vaccine is available. In the present work we tested different gold nanoparticles (Aunp) coated with ligands ω-terminated with sugars bearing multiple sulfonate groups. We aimed to identify compounds with antiviral properties due to irreversible (virucidal) rather than reversible (virustatic) inhibition. The ligands varied in length, in number of sulfonated groups as well as their spatial orientation induced by the sugar head groups. We identified two candidates, a glucose-and a lactose-based ligand showing a low ec 50 (effective concentration that inhibit 50% of the viral activity) for DENV-2 inhibition, moderate toxicity and a virucidal effect in hepatocytes with titre reduction of Median tissue culture infectious Dose log 10 tciD 50 2.5 and 3.1. Molecular docking simulations complemented the experimental findings suggesting a molecular rationale behind the binding between sulfonated head groups and DENV-2 envelope protein. Dengue virus (DENV) belongs to the family Flaviviridae which are usually transmitted by mosquitos or ticks and are responsible for a variety of human diseases mainly haemorrhagic fevers (Dengue, yellow fever, West Nile) but also encephalitis and jaundice and lately Zika 1. According to the WHO 4 serotypes of Dengue exist DENV1-4. The risk of dengue infections is now present in 128 countries affecting almost half of the world population and resulting in 390 million of infections per year 2,3. Infections lead to diseases with large variety of severity ranging from asymptomatic to mild dengue fever and to severe dengue haemorrhagic fever and dengue shock syndrome with about 500,000 people yearly requiring hospitalization 4,5. Currently, there is no effective antiviral or safe universal vaccine for DENV infections. The only available vaccine (DENGVAXIA), recently approved by FDA, presents high risk to unexposed individuals and is therefore administered to people with laboratory-confirmed previous dengue infection 4. The continuous increase of DENV infections in endemic areas as well as the lack of efficient countermeasures underline the need for new therapeutics. There are different routes to interrupt the DENV replication cycle: (i) inhibiting intracellular targets such as two of the main DENV enzymes, namely protease 6-8 and RNA-dependent RNA polymerase 9-18 or (ii) structural glycoprotein envelope (E) protein of the DENV 4,19. Inhibiting the entry step is an attractive approach to prevent viral infections 20. The search for DENV entry inhibitors focused on the main three domains on the E protein, the stem domain, hydrophobic pocket in the hinge domain and the receptor binding domain 19 .