A Markov model for analysing cancer markers and disease states in survival studies

In studies of serial cancer markers or disease states and their relation to survival, data on the marker or state are usually obtained at infrequent time points during follow-up. A Markov model is developed to assess the dependence of risk of death on marker level or disease state and inferences within this model are based directly on data collected in this haphazard way. An application relating changing levels of serum alpha-fetoprotein to death in hepatocellular carcinoma is discussed in detail.     

Dictyostelium mutants lacking DIF,a putative morphogen

DIF is an endogenous extracellular signal that may control differentiation of D. discoideum cells. It is a dialyzable, lipid-like factor that induces stalk cell formation among isolated amebae incubated in vitro with cAMP. To examine the consequences of DIF deprivation, we have isolated several mutant strains that are impaired in DIF accumulation, and whose inability to make stalk cells in vitro and during normal development on agar can be corrected by the addition of exogenous DIF. Little DIF is made by the mutants, and morphological development on agar stops after the cells have aggregated, but before a slug forms. In these DIF-deprived conditions, prespore cells can differentiate, but prestalk cells cannot.     

Different requirements for productive interaction between the active site of HIV-1 proteinase and substrates containing -hydrophobic*hydrophobic- or -aromatic*pro- cleavage sites.

The sequence requirements for HIV-1 proteinase catalyzed cleavage of oligopeptides containing two distinct types of junctions (-hydrophobic*hydrophobic- or -aromatic*Pro-) has been investigated. For the first type of junction (-hydrophobic*hydrophobic-) the optimal residues in the P2 and P2' positions were found to be Val and Glu, respectively, in accord with recent statistical analysis of natural cleavage sites [Poorman, R. A., Tomasselli, A. G., Heinrikson, R. L., & Kézdy, F. J. (1991) J. Biol. Chem. 266, 14554-14561]. For the -aromatic*Pro- type of junction, in the specific sequence context studied here, the value of Glu in the P2' position was again observed. An explanation for the inefficient cleavage observed for peptides with the sequence -Val-Tyr*Pro- has been provided from molecular modeling of the putative enzyme-substrate complex. A significant effect upon cleavage rates due to the amino acid in the P5 position has also been documented. While lysine in the P5 position in one sequence of the -hydrophobic*hydrophobic- type produces a peptide cleaved very efficiently (kcat greater than 15 s-1 for Lys-Ala-Arg-Val-Nle*p-nitrophenylalanine-P2'-Ala-Nle-NH2, for P2' = Glu, Gln, Ile, Val, or Ala), for substrates of the -aromatic*Pro- type, the P5 residue can exert either a positive or negative effect on cleavage rates. These results have again been interpreted in light of molecular modeling. We suggest that interaction of the substrate sequence on the periphery of the active site cleft may influence the match of the enzyme-substrate pair and, hence, control the efficiency of catalysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

The prion protein gene is dispensable for the development of spongiform myeloencephalopathy induced by the neurovirulent Cas-Br-E murine leukemia virus.

The Cas-Br-E murine leukemia virus (MuLV) induces paralysis in susceptible mice that is accompanied by a severe spongiform myeloencephalopathy. These neurodegenerative lesions are very similar to those observed in prion diseases. To determine whether the prion protein gene (Prn-p) product was a downstream effector of this neurovirulent MuLV, we inoculated Prn-p(-/-) knockout homozygote and control heterozygote or wild-type mice with this retrovirus. All groups developed typical paralysis and spongiform encephalopathy, and no differences in clinical or histological phenotypes were observed between these groups. These results indicate that the Cas-Br-E MuLV does not require the prion protein to induce lesions. Thus, MuLV and prion proteins may induce a very similar disease through distinct pathways, or the viral Env protein, which harbors the primary determinant of pathogenicity, may act in a common pathway but downstream of the prion protein.