Comparative molecular field analysis of the antitumor activity of 9H-thioxanthen-9-one derivatives against pancreatic ductal carcinoma 03

The present study establishes correlations of in vivo growth inhibition of a solid tumor, pancreatic ductal adenocarcinoma (Panc03), of mice with the steric and electrostatic fields and the hydrophobic parameter log P of a series (32) of 1-[[2-(dialkylamino)alkyl]amino]- 9H-thioxanthen-9-ones by the 3D-QSAR method comparative molecular field analysis (CoMFA). The template molecular model was hycanthone methanesulfonate (19), the structure of which had been established previously by X-ray crystallography. The hycanthone base is protonated at the terminal nitrogen N(2), and an intramolecular hydrogen bond is present between the proximal nitrogen N(1) and carbonyl oxygen O(1) atoms. Crystallographic data also indicate a planar arrangement of bonds around N(1). However, the molecular geometry of 19, optimized by semiempirical molecular orbital methods (PM3, MNDO, AM1), showed the expected trigonal-pyramidal configuration for N(1). A comparison of MO and ab initio methods applied to a model compound, 1-amino-9H-thioxanthen-9-one, led to the selection of PM3 as the method for full geometry optimization of first the cationic and then the neutral forms of 1-32, whereas AM1 provided atomic charges for these same structures save those incorporating a sulfonamide moiety (5, 7, 20, 25, 26, 29, 31, and 32). Acceptable values for the latter were obtained from ab initio calculations. Structures were aligned by minimizing root-mean-square (rms) differences in the fitting of structures to 19 using the FIT option of SYBYL. An alternative strategy of alignment, steric and electrostatic alignment (SEAL), was invoked to provide a comparison of statistical data generated with the rms alignment. The rms-fit alignment of structures produced slightly better cross-validated and conventional r2 values than those generated with the SEAL method. In addition, the rms-fit data indicate that a shift in the lattice of one-half of its spacing has a much smaller effect on the CoMFA data for a lattice of 1 A than one of 2 A. Inclusion of log P in a CoMFA of the neutral structures effected a small (ca. 8-10%) but significant improvement in cross-validated r2 values. The relative contributions of the hydrophobic effects and the steric and electrostatic fields to the conventional r2 values were 16%, 42%, and 42%, respectively. By contrast, incorporation of frontier molecular orbital (HOMO and LUMO) energies or their gaps in the PLS analyses failed to enhance correlation coefficients derived for either the charged or uncharged compounds.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of acetylcholine and glutamate on isolated neurons of locomotory network of Clione

In Clione limacina, locomotory rhythm is produced in the central pattern generator by reciprocal activity of two groups of interneurons. Dorsal (D) and ventral (V) phase interneurons activate neurons of the same phase and inhibit neurons of the opposite phase. Which neurotransmitters are used by these interneurons is not clear. In this study, identified follower neurons to V and D interneurons were isolated, and their responses to the local application of potential neurotransmitters were examined. Acetylcholine exerted inhibitory action on the isolated D-phase neurons and excitatory action on V-phase neurons. Glutamate produced excitation in D-phase neurons, and inhibition in V-phase neurons. These results suggest that acetylcholine is the neurotransmitter of D-phase interneurons, while glutamate might be the neurotransmitter of V-phase interneurons.     

Routine use of ultrasound 24 hours before laparoscopic cholecystectomy can predict the need for intraoperative cholangiogram: results of a 12-month prospective audit

Progressive supranuclear palsy (PSP) is a progressive degenerative extrapyramidal disease that often masquerades as Parkinson's disease (PD). Similar to PD, dysphagia frequently complicates the course of PSP. Because there is only one published report characterizing dysphagia in PSP, we reviewed the neurologic features and dynamic videofluoroscopic swallowing function study results in 10 dysphagic PSP patients. Abnormalities during multiple stages of ingestion were recorded in each patient. Uncoordinated lingual movements, absent velar retraction or elevation, impaired posterior lingual displacement, and copious pharyngeal secretions were noted in all patients. Tongue-assisted mastication, noncohesive lingual transfer, excessive oral bolus lingual leakage to the pharynx prior to active transfer, vallecular bolus retention, abnormal epiglottic positioning, and hiatal hernias were noted in at least half of the cohort. Although ingestion abnormalities in PSP are similar to those previously reported in PD, the number of studied patients and observed differences were too few to clearly differentiate the two diseases.     

Allelic polymorphism of the DNA-loci met and D7S23, linked to the mucoviscidosis gene in human populations of the Volga-Ural region

Data on allelic polymorphism of MET and D7S23 DNA loci linked to the human cystic fibrosis gene studied in three Bashkir ethnic groups and some Volga-Ural populations (Tartars, Maris, Mordovians, Udmurts, Chuvashs, and Komis) are presented. Udmurts were found to be substantially different from Bashkirs, Tartars, Mordovians, and Chuvashs by the allele frequency distribution observed for MET, while Komis and Bashkirs differed by this parameter from Mordovians and Maris. Comparative analysis of restriction fragment length polymorphism (RFLP) at the D7S23 locus revealed statistically significant differences in genotype frequencies between Bashkirs of the Arkhangel' skii region and populations of Mordva and Udmurtia. In this respect, the Mordovian population appeared to be notably different from the populations of Bashkortostan, Tatarstan, Marii-El, Udmurtiya, Chuvashiya, and Komis. Genetic distances were calculated and corresponding dendrograms were constructed on the basis of data on Met-H, CS.7, and the ApoB locus hypervariable region allelic frequencies. Three ethnogeographic Bashkir groups belonging to one tree branch were found to be closely related to the populations of Tartars, Maris, Udmurts, and Chuvashs and substantially different from Komis and Mordovians. Thus, the position of Volga-Ural populations on the dendrogram corresponds to the degree of relationship between the Finno-Ugric and Turkic populations, confirming the usefulness of DNA polymorphism analysis for the study of the genetic structure of populations.     

Double-diffusive convection in a circular cylinder

Summary A theoretical study is made of the onset of steady double-diffusive convection in a circular cylinder of small to moderate aspect ratio. An eigenfunction expansion method is used to derive systems of amplitude equations for weakly nonlinear evolution of critical disturbances. It is shown that the nature of the convective solution near criticality depends strongly on the cylinder's aspect ratio; this is particularly the case at or near aspect ratios where two modes become unstable at the same Rayleigh number. There is also a strong dependence on Prandtl number, which is discussed.With 7 Figure     

Involvement of specific mechanism in plasmid DNA uptake by mouse peritoneal macrophages

Lamina-associated polypeptide (LAP)2, which directly interacts with B-type lamins and chromosomes, is an integral membrane protein specifically distributed along the inner nuclear membrane of the nuclear envelope. Multiple regions of its large nucleoplasmic domain promote this localization, including the first (residues 1-296) and the second (residues 298-409) halves of the LAP2 N terminus. The second half is involved in LAP2 association with the nuclear lamina [Furukawa, K., Panté, N., Aebi, U. & Gerace, L. (1995) EMBO J. 14, 1626-1636]. In this study to further define its role, we examined which domain of B-type lamin interacts with LAP2 by means of a binding assay with bacterially expressed proteins and a yeast two-hybrid system. We found that amino acids in the region of residues 78-258 of the lamin B1 rod domain directly bound with LAP2. The data suggest that LAP2 may modulate the assembly of nuclear lamins.     

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P = 0.0061), whereas cyclin D1 mRNA overexpression was not (P = 0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P = 0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P = 0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P = 0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P = 0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age > 50 years (P = 0.0001), postmenopausal status (P = 0.0008), lymph node negativity (P = 0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.