Estramustine and estrone analogs rapidly and reversibly inhibit deoxyribonucleic acid synthesis and alter morphology in cultured human glioblastoma cells

Estramustine is an estradiol-based agent that has been shown to accumulate in human glioma cells, resulting in a concentration-dependent alteration in cell size and shape within minutes and an inhibition of proliferation over 3 to 6 days. We evaluated human glioblastoma cultures with [3H]thymidine incorporation assays to determine estramustine's early effects on deoxyribonucleic acid synthesis in these tumors. Because estramustine shares a common structural motif with other antimicrotubule drugs, we synthesized four A-ring conjugates of estrone that contained a carbamate moiety but lacked nitrogen mustard. These analogs were examined by [3H]thymidine incorporation and compared with vinblastine. Greater than 70% inhibition of [3H]thymidine incorporation occurred within 1 hour of treatment with estramustine at 10(-5) mol/L, which increased to 80% inhibition at 4 hours. Ethyl carbamate JE208 was nearly as effective as estramustine in inhibiting deoxyribonucleic acid synthesis, and both were more effective than vinblastine. The inhibitory effects of estramustine and estrone analogs were reversible; vinblastine was not reversible. Although estramustine and JE208 induced similar antiproliferative and morphological changes in glioblastoma cells that persisted for at least 4 days, there was a modest recovery of morphology and thymidine incorporation with JE208 after prolonged treatment. The common findings with estramustine and JE208 suggest that these agents may have a similar mechanism of action and form the basis for the investigation of new agents that may rapidly and reversibly inhibit glioblastoma.     

The apolipoprotein E allele epsilon 4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease

We determined apolipoprotein E (ApoE) genotypes in 122 autopsied demented patients. The frequency of the ApoE epsilon 4 allele was 39.6% in Alzheimer's disease (AD), 29.0% in the Lewy body variant of AD (LBV), and 6.25% in diffuse Lewy body disease. For AD and LBV patients, the epsilon 4 frequency was significantly higher than that reported in nondemented controls (10 to 15%). Therefore, LBV and AD share ApoE epsilon 4 as a genetic risk factor, providing further evidence that these conditions overlap.     

Molecular cloning of human Frizzled-6

The Frizzled genes encode receptors for WNTs, secreted glycoproteins implicated in development as well as in carcinogenesis. In this paper, we report molecular cloning of Hfz6, the human homologue of Mfz6. Nucleotide sequence analysis showed that the Hfz6 gene encodes the 706 amino-acid protein with seven transmembrane domains, a cystein-rich domain in the N-terminal extracellular region, two N-linked glycosylation sites, and two cystein residues in the second and third extracellular loops. Hfz6 mRNA 4.4-kb in size was detected in various normal adult and fetal tissues, and a larger amount of Hfz6 mRNA was detected in both fetal lung and fetal kidney. The Hfz6 gene has been mapped to human chromosome 8q22.3-q23.1. In conclusion, we have cloned Hfz6, which encodes a seven-transmembrane receptor with the cystein-rich domain in the N-terminal extracellular region, but without the Ser/Thr-X-Val motif in the C-terminus.     

Radiation therapy for stage I-II non-small cell lung cancer in patients aged 75 years and older

Vaccination with peptides that induce a specific immune response is a potential prophylactic or therapeutic strategy against viral infections and tumors. Because of the extensive polymorphism of the HLA loci, synthetic peptide vaccines must consist of a cocktail of peptides that bind specifically to different HLA molecules. Such cocktails should be optimized for the target population as each population has its specific HLA gene frequencies. To achieve maximum population coverage with a minimum number of peptides, information is needed on the ranking of the most frequent HLA phenotypes. We introduce the minimal phenotype panel, which is the smallest combination of HLA antigens selected so that the proportion of individuals in a population that express at least one of the antigens in the panel exceeds a desired minimum value. We developed a method for assembling minimal phenotype panels based on known HLA class I gene frequencies. We give an example based on a set of 2446 well-defined HLA-typed, random, healthy, unrelated, Dutch Caucasoid individuals. In addition, we discuss the possibility of assembling minimal phenotype panels based on two-locus haplotypes, which enables the assembly of phenotype panels from the antigens of both loci.     

Fabrication of 1.55 μm VCSELs on Si using metallic bonding

Using AuGeNiCr multilayered metals as the wafer bonding medium, long-wavelength GaInAsP/InP vertical cavity surface emitting lasers employing Al-oxide/Si as the upper and lower distributed Bragg reflectors were fabricated on Si substrate with the bonding interface formed outside the vertical cavity surface emitting laser cavity. Laser emission at 1.545 μm was measured under pulsed operations near room temperature. The low-temperature metallic bonding process demonstrates a great potential in device fabrication