Gram-scale synthesis of pinusolide and evaluation of its antileukemic potential

Pinusolide (1), a known platelet-activating factor (PAF) receptor binding antagonist, was synthesized from lambertianic acid (2), a labdane-type diterpene readily accessible in multigram quantities from the Siberian pine tree. It was shown that 1 not only decreases the proliferation activity of tumor cells at relatively low concentrations but specifically induces apoptosis at 100 microM via the mitochondrial pathway in the Burkitt lymphoma cell line BJAB. Also, using primary lymphoblasts and leukemic cells from children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), a significant DNA fragmentation in pinusolide-treated cells could be detected in an ex vivo apoptosis assay.     

Spontaneous asymmetric circling behavior in hemi-parkinsonism; a human equivalent of the lesioned-circling rodent behavior

When induced experimentally in rodents, hemispheric asymmetry in basal ganglia dopamine results in spontaneous asymmetric circling toward the hemisphere with the lower level of dopamine. A similar asymmetry has long been thought to exist in the brains of hemi-Parkinsonian patients. Using an electronic turn counter, we demonstrated that, like unilaterally lesioned rats, and without being aware of it, five ambulating outpatients with hemi-Parkinson's disease exhibit spontaneous rotation toward the hemisphere containing less striatal dopaminergic activity.     

Patterns of circulating hepatitis B surface antigen variants among vaccinated children born to hepatitis B surface antigen carrier and non-carrier mothers

Hepatitis B virus (HBV) variants that possessed missense mutation within the neutralization epitope of the major S antigen as defined by amino acid residues (aa#) 124–147, termed the a determinant variants, were identified through a population-based serosurvey of 2,305 children of the vaccinated birth cohorts born after 1986. Data on the 678 nucleotides encoding the S antigen of HBV were available for 75 HBV strains that were collected from 63 vaccinated children and 12 unvaccinated or incompletely vaccinated children, and 21 HBV strains from 25 unvaccinated adults. Among the diverse patterns of one to three amino acid substitutions within the a determinant, 145-Arg occurred most frequently (5/14); other variants were: 126-Ala, 127-Thr, 126-Ser/131-Asn/133-Thr, 129-His, 129-Arg, 123-Asn/131-Ile, 133-Leu, 141-Glu, and 141-Arg/144-Ala. Only one of these variants occurred in the 16 hepatitis B surface antigen (HBsAg)-carrier children born to HBsAg-negative mothers, whereas 12 of these variants occurred in the 20 (50%) children born to HBsAg-positive mothers. In addition, early administration of HBV vaccine within the noenatal period increased the likelihood of the emergence of these variants to 64.7% (11/17). Five of the 21 (23.8%) unvaccinated HBsAg-carrier adults harbored the a determinant variants possessing mutations within aa# 125–136, i.e. the putative first loop formed by the cysteine disulfide bonds. Vaccinated children were likely to harbor HBV variants possessing mutations involving altered charge of side chains and/or its hydrophobicity of amino acid residues within the putative second loop between aa#140 and 146. Our data suggest that emergence of these HBV S gene mutants in the phase of HBV vaccination program would be most common among populations in whom perinatal/vertical transmission of HBV is most common, i.e. southeast Asian and the Taiwanese.     

p53 gene status modulates the chemosensitivity of non-small cell lung cancer cells

This study examined the effects of p53 gene status on DNA damage-induced cell death and chemosensitivity to various chemotherapeutic agents in non-small cell lung cancer (NSCLC) cells. A mutant p53 gene was introduced into cells carrying the wild-type p53 gene and also vice versa to introduce the wild-type p53 gene into cells carrying the mutant p53 gene. Chemosensitivity and DNA damage-induced apoptosis in these cells were then examined. This study included five cell lines, NCI-H1437, NCI-H727, NCI-H441 and NCI-H1299 which carry a mutant p53 gene and NCI-H460 which carries a wild-type p53 gene. Mutant p53-carrying cells were transfected with the wild-type p53 gene, while mutant p53 genes were introduced into NCI-H460 cells. These p53 genes were individually mutated at amino acid residues 143, 175, 248 and 273. The representative cell line NCI-H1437 cells transfected with wild-type p53 gene (H1437/wtp53) showed a dramatic increase in susceptibility to three anticancer agents (7-fold to cisplatin, 21-fold to etoposide, and 20-fold to camptothecin) compared to untransfected or neotransfected H1437 cells. An increase in chemosensitivity was also observed in wild-type p53 transfectants of H727, H441, H1299 cells. The results of chemosensitivity were consistent with the observations on apoptotic cell death. H1437/wtp53 cells, but not H1437 parental cells, exhibited a characteristic feature of apoptotic cell death that generated oligonucleosomal-sized DNA fragments. In contrast, loss of chemosensitivity and lack of p53-mediated DNA degradation in response to anticancer agents were observed in H460 cells transfected with mutant p53. These observations suggest that the increase in chemosensitivity was attributable to wild-type p53 mediation of the process of apoptosis. In addition, our results also suggest that p53 gene status modulates the extent of chemosensitivity and the induction of apoptosis by different anticancer agents in NSCLC cells.     

Effects of pH and predation by Chaoborus larvae on the plankton of a shallow and acidic forest lake

1. Eutrophic acid lakes are not common. Delamere Lake in Cheshire, U.K. is shallow and acid (mean pH 4.5) with a very high phytoplankton crop (mean 290 μg chlorophyll a L^?1), dominated by Dictyosphaerium pulchellum. Rotifers were dominant in the pelagic waters but small cladocerans (Alona guttata, Chydorus sphaericus and Scapholeberis mucronata) were occasional in the littoral waters. Chaoborus flavicans larvae were the top predators in this fishless lake. Two mesocosm experiments were carried out in which pH and Chaoborus populations were manipulated. 2. Progressively higher concentrations of D. pulchellum were maintained in the elevated pH treatments (pH 6 and 8; P < 0.001) with increased amounts of a Chlamydomonas species at the end of the experiment. Highest species richness was seen at ambient pH. Thus the low pH of Delamere Lake alone did not control the structure of the phytoplankton community. Keratella quadrata showed significantly higher abundance at pH 6 than in other pH treatments (P < 0.001). Species richness of rotifers was unaffected by pH. 3. Most Cladocera were C. sphaericus. Although never seen in the open lake, Daphnia pulex appeared in all the pH treatments. Low pH did not control small Cladocera abundance in Delamere Lake, but probably hampered reproduction in Daphnia. Negative correlations between chlorophyll a concentrations and Daphnia in the mesocosms (r² = 0.215, P < 0.05), however, indicated the potential of large‐bodied daphniids in controlling phytoplankton. 4. Neither different combinations of Chaoborus instars (none, instars 1 and 2 and instars 3–5) nor different densities of instars 3–5 (0.15, 0.5 and 1.0 L^?1) had a negative impact on Cladocera. Daphnia pulex remained unaffected in the experiment, perhaps because of its large size, and C. sphaericus because of its high reproductive rate compensating predatory losses. 5. Very low pH in Delamere Lake might suppress Daphnia by hampering its reproduction. Consequently, Daphnia may be vulnerable to invertebrate predation even at low predator density in the lake.     

Interferon-α, interferon-γ and sizofiran in the adjuvant therapy in ovarian cancer — a preliminary trial

The study included 24 cases of negative second-look laparotomy (SLL) after operation on ovarian cancer. 12 cases were treated with sizofiran and recombinant interferon-gamma before and after SLL and then with human lymphoblastoid interferon-alpha. The remaining 12 cases (controls) were followed up without any drug therapy after SLL. There were no recurrences in the treated group, but in 3 cases of the control group. Also significant difference in survival was noted in the treated group.