Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer

We examined the genomic status of cyclin-dependent kinase-4 and -6 inhibitors, p16INK4,p15INK4B, and p18, in 40 primary lung cancers and 31 metastatic lung cancers. Alterations of the p16INK4 gene were detected in 6 (2 insertions and 4 homozygous deletions) of 22 metastatic non-small cell lung cancers (NSCLCs; 27%), but none were detected in 25 primary NSCLCs, 15 primary small cell lung cancers (SCLCs), or 9 metastatic SCLCs, indicating that mutation in the p16INK4 gene is a late event in NSCLC carcinogenesis. Although three intragenic mutations of the p15INK4B gene were detected in 25 primary NSCLCs (12%) and five homozygous deletions of the p15INK4B gene were detected in 22 NSCLCs (23%), no genetic alterations of the p15INK4B gene were found in primary and metastatic SCLCs. The p18 gene was wild type in these 71 lung cancers, except 1 metastatic NSCLC which showed loss of heterozygosity. We also examined alterations of these three genes and expression of p16INK4 in 21 human lung cancer cell lines. Alterations of the p16INK4 and p15INK4B genes were detected in 71% of the NSCLC cell lines (n = 14) and 50% of the NSCLC cell lines (n = 14), respectively, but there were none in the 7 SCLC cell lines studied. No p18 mutations were detected in these 21 cell lines. These results indicate that both p16INK4 and p15INK4B gene mutations are associated with tumor progression of a subset of NSCLC, but not of SCLC, and that p15INK4B mutations might also be an early event in the molecular pathogenesis of a subset of NSCLC.     

Abrasive particles in tobacco products: a possible factor in dental attrition

Tobacco products are known to cause oral soft-tissue lesions, but they may also directly affect the teeth. Abrasive particles contained in tobacco products may contribute to dental attrition. We studied tobacco samples from 16 brands of cigars, eight brands of snuff, four brands of chewing tobacco and several unprocessed tobacco leaves used as cigar wrappers. Insoluble particulate matter made up about 0.5 percent of the weight of an average tobacco sample.     

Extended induction of ovulation by human menopausal gonadotropins and a gonadotropin-releasing hormone analog in high responders for in vitro fertilization and oocyte donation

OBJECTIVE: To examine the efficacy of extending ovulation induction for the in vivo maturation of oocytes. STUDY DESIGN: Fifty-nine high responders underwent 72 in vitro fertilization (IVF) cycles with a conventional protocol of human menopausal gonadotropin and a gonadotropin-releasing hormone analog. These patients donated oocytes to 81 recipients. The same 59 patients underwent 90 subsequent cycles in which the duration of induction was extended by two to three days. The oocytes were also donated to 138 patients. RESULTS: With the extended protocol, significantly more oocytes were retrieved (29.1 vs. 20.6), and a greater proportion of them were mature. Fertilization rates were significantly higher for both donors (67.7% vs. 36.2%) and recipients (67.5% vs. 47.1%). Conception rates were also significantly higher for both donors (24.4% vs. 11.1%) and recipients (38.4% vs. 24.7%). CONCLUSION: Extending the duration of ovulation induction in high responders is associated with in vivo maturation of oocytes and improved success rates in IVF and ovum-donation programs.     

Volume contraction on photoexcitation of the reaction center from Rhodobacter sphaeroides R-26: internal probe of dielectrics

Reaction centers of Rhodobacter sphaeroides undergo a approximately 20 A3/mole volume contraction in < 50 ns after excitation. The rapid volume change is tentatively assigned to electrostriction. From its magnitude, we infer that the effective dielectric coefficient is 10-15 if the compressibility of the reaction center is similar to that of globular proteins. The volume contraction is not sensitive to replacement of the natural ubiquinone at the QA site by other quinones or to the occupancy of the QB site. The quenching caused by pressure on the reaction centers most likely occurs on a faster time scale than that of electron transfer.     

Expression and characterization of recombinant Manduca sexta serpin-1B and site-directed mutants that change its inhibitory selectivity

Hemolymph of Manduca sexta contains a number of serine proteinase inhibitors from the serpin superfamily. During formation of a stable complex between a serpin and a serine proteinase, the enzyme cleaves a specific peptide bond in an exposed loop (the reactive-site region) at the surface of the serpin. The amino acid residue on the amino-terminal side of this scissile bond, the P1 residue, is important in defining the selectivity of a serpin for inhibiting different types of serine proteinases. M. sexta serpin-1B, with alanine at the position predicted from sequence alignments to be the P1 residue, was previously named alaserpin. This alanyl residue was changed by site-directed mutagenesis to lysine (A343K) and phenylalanine (A343F). The serpin-1B cDNA and its mutants were inserted into an expression vector, H6pQE-60, and the serpin proteins were expressed in Escherichia coli. Affinity-purified recombinant serpins selectively inhibited mammalian serine proteinases: serpin-1B inhibited elastase; serpin-1B(A343K) inhibited trypsin, plasmin, and thrombin; serpin-1B(A343F) inhibited chymotrypsin as well as trypsin. All three serpins inhibited human cathepsin G. This insect serpin and its site-directed mutants associated with mammalian serine proteinases at rates similar to those reported for mammalian serpins. Serpin-1B and its mutants formed SDS-stable complexes with the enzymes they inhibited. The scissile bond was determined to be between residues 343 and 344 in wild-type serpin-1B and in serpin-1B with mutations at residue 343. These results demonstrate that the P1 alanine residue defines the primary selectivity of serpin-1B for elastase-like enzymes, and that this selectivity can be altered by mutations at this position.     

Effect of carbamazepine on agitation in Alzheimer's inpatients refractory to neuroleptics

BACKGROUND: Agitation in Alzheimer's disease remains a principal problem in the clinical management of elderly patients. Neuroleptic medication appears to have modest efficacy in controlling behavioral symptoms in dementia patients. Carbamazepine has been reported to decrease agitation associated with various psychiatric disorders and to reduce neuroleptic side effects. METHOD: In an open prospective study, the effects of carbamazepine on agitation, hostility, and uncooperativeness were investigated in 15 severely demented Alzheimer's inpatients who had failed to respond to prior treatment with neuroleptics. Depending on clinical efficacy and tolerability of carbamazepine treatment, concomitant medication with haloperidol was initiated. Severity of psychopathologic symptoms was assessed by the Brief Psychiatric Rating Scale during the study period of 4 weeks. RESULTS: In 2 subjects, carbamazepine treatment was discontinued because of leukopenia and allergic reactions. A significant improvement in factor scores activation and hostility was observed after 4 weeks. Ten patients received concomitant medication with haloperidol. CONCLUSION: Carbamazepine may be effective in treating agitation in severely demented Alzheimer's inpatients refractory to neuroleptic medication alone. The combination of carbamazepine and haloperidol seems to be promising in clinical management of elderly Alzheimer's patients.