In hospitalized older adults, a CAS-based pharmacist-physician intervention, compared to usual clinical care, resulted in significant higher number of drug cessation and dosage reductions for targeted PIMs.

Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and spread to cervical lymph nodes, with distant metastases developing in 30-40% of cases. HPV-16 is an important risk factor for HNSCC. How HPV enhances susceptibility to HNSCC is not fully understood, but seems to involve cofactors. In this study, we examined the effect of the cooperation between HPV-16 and the tyrosine kinase receptor ErbB-2 on E-cadherin/catenin complex patterns and neoplastic transformation of human normal oral epithelial (NOE) cells. We report that overexpression of ErbB-2 or E6/E7 alone does not affect E-cadherin/catenin complex patterns nor does it induce cell transformation of NOE cells. In contrast, coexpression of E6/E7 and ErbB-2 downregulates E-cadherin and catenin expression. This is accompanied by cytoplasmic localization of E-cadherin, as well as nuclear translocation of a, b, and c-catenins. Furthermore, we demonstrate that E6/E7 cooperate with overexpressed ErbB-2 to induce tumor formation in nude mice and to upregulate cyclin D1 and c-myc expression. Our data suggest that E6/E7 cooperate with ErbB-2 in head and neck carcinogenesis, at least in part, via the conversion of b-catenin from a cell adhesion to a nuclear function, that is, to act as a potential transcriptional regulator. This conversion leads to the upregulation of cyclin D1, c-myc and other oncoproteins necessary for alteration of the E-cadherin/catenin complex and cell transformation of NOE cells.

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Previous studies have shown that the reovirus 1 core protein harbors a putative nucleotide-binding motif and exhibits an affinity for nucleic acids. In addition, a nucleoside triphosphate phosphohydrolase activity present in reovirus cores has been recently assigned to 1 using gene reassortment analysis. In this study, it was demonstrated that the recombinant 1 protein, expressed in the yeast Pichia pastoris, is able to hydrolyze nucleoside 5-triphosphates or deoxynucleoside 5-triphosphates. This activity was absolutely dependent on the presence of a divalent cation, Mg 2؉ or Mn 2؉. The protein can also unwind double-stranded nucleic acid molecules in the presence of a nucleoside 5-triphosphate or deoxynucleoside 5-triphosphate. These results provide the first biochemical evidence that the reovirus 1 protein is a nucleoside triphosphate phosphohydrolase/helicase and strongly support the idea that 1 participates in transcription of the viral genome.Mammalian reoviruses are members of the Reoviridae family, and since their genome is made up of 10 segments of double-stranded RNA (dsRNA) 1 and replicates in the cytoplasm, they must encode their own transcriptional and replicative enzymes (1). During reovirus infection, the viral genome remains in the inner capsid (core) of the virus, composed of two major (1 and 2) and two minor (3 and 2) proteins. Gene reassortment experiments have resulted in the assignment of transcriptase activity to 3 (2). Although functions of other core proteins have not been firmly established, it is suspected that additional enzymatic functions are needed to achieve transcription and replication of the viral genome. For example, it has been postulated, by analogy with other viruses, that a helicase function could be present in the viral core (1).Nucleic acid helicases unwind double-stranded DNA and/or RNA, a process energetically coupled to the hydrolysis of nucleoside 5Ј-triphosphates (NTPs) or deoxynucleoside 5Ј-triphosphates (dNTPs) (3, 4). Helicases play a key role in nucleic acid replication, transcription, splicing, translocation, recombination, and repair (5-8). Helicases of prokaryotic, eukaryotic, and viral origins have been isolated and classified into defined superfamilies (9 -14). These proteins are characterized by seven conserved motifs designated I, Ia, and II-VI (15). Motifs I and II are very well conserved and correspond to the A and B consensus sequences of a nucleotide-binding domain (16). Superfamily II includes an expanding group of DNA and RNA helicases that harbor a DEA(D/H) sequence in motif II (17). The sequences present in motifs III-V are less strictly conserved, and their roles are not clearly defined, whereas motif VI is supposed to be involved in nucleic acid binding given its high content of positively charged amino acids (13).The 1 protein, a major component of the reovirus core, exhibits an affinity for dsRNA and dsDNA in filter binding assays and can also bind single-stranded RNA in gel retardation assays (18).2 Furthermore, analysis of gene reassortment ha...

Nucleotide excision repair (NER) is a multi-enzyme DNA repair pathway in eukaryotes. Several NER genes in this pathway including XPB, XPD, XPA and ERCC-1 have been implicated in anticancer drug resistance in human tumor cells. In this study, we assessed the levels of the above-mentioned proteins in the NCI panel of 60 human tumor cell lines in relation to the cytotoxicity patterns of 170 compounds that constitute the standard agent (SA) database. The database consists of drugs used in the clinic for which a mechanism of action has been at least partially defined. The ERCC-1, XPD and XPB protein expression patterns yielded significant negative Pearson correlations with 13, 32 and 17 out of the 170 compounds, respectively (using p<0.05). XPA produced a random assortment of negative and positive correlations, and did not appear to confer an overall resistance or sensitivity to these drugs. Protein expression was also compared with a pre-defined categorization of the standard agents into six mechanism-of-action groups resulting in an inverse association between XPD and alkylating agent sensitivity. Our present data demonstrate that XPD protein levels correlate with resistance to alkylating agents in human tumor cell lines suggesting that XPD is implicated in the development of this resistance. NER activity, using the in vitro cell-free system repair assay, revealed no correlation between NER activity and the level of XPD protein in four cell lines with widely varying XPD protein levels. This lack of correlation may be due to the contribution of XPD to other functions including interactions with the Rad51 repair pathway.