Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.

We report the results of a selection for single-stranded DNA oligonucleotide ligands to the serine protease thrombin using recently developed methods. This selection yielded a family of DNA sequences that conform to a consensus structure comprised of a unimolecular quadruplex motif and complementary flanking sequences capable of forming an additional Watson-Crick duplex motif. This novel quadruplex/duplex structure was not reported in a previous selection for DNA molecules which bind to thrombin [Bock et al. (1992) Nature 355, 564-566]. All quadruplex/duplex molecules tested bound to thrombin with higher affinity than quadruplex structures lacking the duplex structure. However, binding affinities did not always correlate with inhibitory potency since some molecules with high affinity were not potent inhibitors in vitro. 1H NMR spectroscopy studies demonstrated that the complementarity of bases in the duplex portion of a selected sequence allows it to form multimolecular structures. Constraining these molecules to the unimolecular quadruplex/duplex structure by bridging the 5' and 3' ends of the duplex motif with either triethylene glycol or disulfide bonds improved their thrombin inhibitory activity. All bridged quadruplex/duplex molecules were more potent inhibitors than molecules with only a quadruplex motif. Bridging the ends of these structures not only increased thrombin inhibition but also improved resistance to nucleases in serum more than 40-fold over the unbridged quadruplex. In addition, we have found that both the length and sequence of the duplex motif are important for inhibition.

Serial analysis of gene expression (SAGE) allows for a quantitative, representative, and comprehensive pro®le of gene expression. We have utilized SAGE technology to contrast the di erential gene expression pro®le in rat embryo ®broblast cells producing temperature-sensitive p53 tumor suppressor protein at permissive or nonpermissive temperatures. Analysis of *15 000 genes revealed that the expression of 14 genes (P50.001, 50.03% abundance) was dependent on functional p53 protein, whereas the expression of three genes was signi®cantly higher in cells producing non-functional p53 protein. Those genes whose expression was increased by functional p53 include RAS, U6 snRNA, cyclin G, EGR-1, and several novel genes. The expression of actin, tubulin, and HSP70 genes was elevated at the nonpermissive temperature for p53 function. Interestingly, the expression of several genes was dependent on a nontemperature-sensitive mutant p53 suggesting altered transcription pro®les dependent on speci®c p53 mutant proteins. These results demonstrate the utility of SAGE for rapidly and reproducibly evaluating global transcriptional responses within di erent cell populations.

Several size classes of small polydisperse circular (spc) DNA from the African green monkey cell line BSC1 have been cloned into the bacterial plasmid pBR322. Analysis of the cloned spc DNA fragments as well as total spc DNA reveals that (a) most or all cloned spc DNAs share homologies with chromosomal sequences, (b) both unique and repetitive chromosomal sequences are represented in spc DNA, (c) the repetitive sequences in spc DNA include two known major repeat families (the alpha and the Alu) as well as a third, as yet unidentified, set of interspersed repetitive sequences, and (d) the alpha-like sequences are present in an oligomeric series of circular DNA molecules within the spc DNA population. The organizational features of repetitive DNA sequence-carrying circles suggest a mechanism for their generation.