Liver metastases from colorectal cancer: regional intra-arterial treatment following failure of systemic chemotherapy.

This study was designed to determine response rate, survival and toxicity associated with combination chemotherapy delivered intra-arterially to liver in patients with hepatic metastases of colorectal origin refractory to standard systemic treatment. A total of 28 patients who failed prior systemic treatment with fluoropyrimidines received a median of 5 cycles of intra-arterial treatment consisting of 5-fluorouracil 700 mg/m(2)/d, leucovorin 120 mg/m(2)/d, and cisplatin 20 mg/m(2)/d for 5 consecutive days. Cycles were repeated at intervals of 5-6 weeks. A major response was achieved in 48% of patients: complete response in 8% and partial response in 40%. The median duration of response was 11.5 months. Median survival was 12 months at a median follow up of 12 months. On multivariate analysis, the only variables with a significant impact on survival were response to treatment and performance status. Toxicity was moderate: grades III-IV neutropenia occurred in 29% of patients. Most of the patients complained of fatigue lasting for a few days following each cycle. There were no cases of hepatobiliary toxicity. These findings indicate that regional intra-arterial treatment should be considered in selected patients with predominantly liver disease following failure of standard treatment.

Sequentially folded SV-11 RNA: metastability is relevant to biological function.

By simulating a Markov process comprising kinetically controlled elementary chain-growth steps and upstream refolding events, we compute the sequential folding of SV-11 RNA; a species capable of acting as a template instructing its own replication when folded into a metastable conformation. The predicted structure is endowed with available primers for replication and is identical within the regions of homology to the experimentally probed active structure of MNV-11 RNA, a species from which SV-11 RNA has evolved. The uneven rate of chain growth during SV-11 RNA replication and the pause sites along the replica sequence are determined. Such predictions are testable in pulse-chase kinetic experiments.

Evidence of a tertiary interaction functional in group I 3'-splicing.

It has been recently shown that the schedule of 3'-splicing events for yeast mitochondrial group I introns requires that conserved helix P10 materializes only after 5'-cleavage has taken place. A scenario compatible with experimental findings has been proposed [(1992) FEBS Lett. 297, 201-204; (1990) Proc. Natl. Acad. Sci. USA 87, 8192-8196] where the formation of P10 is postponed by competition for standard base-pairing with an extended P1 interaction engaging the same portion of the internal guide sequence (IGS) which is subsequently involved in P10. Although the formation of P10 in the fifth intron of yeast apocytochrome b gene (YCOB5) has been confirmed by site-directed mutagenesis, we cannot be confident that this interaction is merely stabilized by Watson-Crick base-pairing, involving the 3'-exon and the IGS, especially given that its formation requires closure of an intron loop of 159 unpaired bases. Thus, our aim is to establish the participation of the 5'-extremity of the intron in the formation of P10. By deoxyribose substitution at positions 1 and 2 of the 5'-extremity of the intron, we are able to confirm the existence of tertiary interactions stabilizing the 3'-splicing site. We show that selective deoxyribose substitution renders the intron inefficient for 3'-splicing when compared with wild type levels.

Preservation of a kinetically originated folding of the cis antirepressor sequence for transport of HIV-1 viral RNA.

We compute a metastable secondary structure for the cis antirepressor sequence (CAR) in the viral RNA of human immunodeficiency virus 1 (HIV-1) whose lifetime is long enough to allow for further stabilization by interaction with the ribosomal machinery. The structure emerges as the viral genome RNA is being synthesized by RNA polymerase II and corresponds to the biologically active structure sustained between units 7364 and in env RNA. It is the most probable among the fast-formed structures which emerge during transcription. No tertiary interactions appear to influence the statistical weight of this metastable state. The structure is predicted by means of a Monte Carlo simulation which computes refolding events occurring as the CAR portion of viral RNA is being assembled. The final emerging structure is preserved for transportation of viral RNA and spliced env RNA from the nucleus to the cytoplasm of the host cell.