CA repeat polymorphism of the COL6A3 gene on chromosome 2q37

A CA dinucleotide repeat has been identified in an intron of the human alpha3(VI) collagen gene (COL6A3) located on chromosome 2q37. Analysis of 100 chromosomes in unrelated Caucasians has demonstrated the existence of eight alleles, and the allelic frequencies have been determined.     

Leucovorin modulation of 5-iododeoxyuridine radiosensitization: a phase I study

Evidence for clinically significant radiosensitization by the halogenated pyrimidine 5-iododeoxyuridine (IdUrd) continues to accumulate. In vitro radiosensitization has been demonstrated in human colon tumor cell lines following exposure to 1-10 micrometer. Coadministration of leucovorin (LV) increases radiosensitization, which correlates directly with increased IdUrd DNA incorporation. Clinical data regarding proliferation rates and thymidine kinase levels in tumors versus normal tissues suggest selective incorporation of IdUrd into gastrointestinal tumors may occur. The objectives of this Phase I study were: (a) to assess the feasibility of LV modulation of IdUrd radiosensitization by determining the maximum tolerated dose (MTD) of IdUrd plus LV; and (b) to perform correlative laboratory studies to investigate the potential of IdUrd plus LV to increase radiosensitization in vivo. Seventeen patients with unresectable or recurrent gastrointestinal adenocarcinomas received a 14-day course of continuous i.v. infusion of IdUrd prior to initiation of radiotherapy. Two additional 14-day infusions of IdUrd with LV were given during the course of radiotherapy (60 Gy in 6 weeks). The initial dose of IdUrd was 250 mg/m2/day and was escalated in subsequent patients to 400 and 600 mg/m2/day. The LV dose remained fixed at 250 mg/m2/day. Leukopenia was the dose-limiting toxicity, and 400 mg/m2/day was the MTD for this trial. At the MTD, the mean +/- SD steady-state plasma concentration of IdUrd during the infusion, measured by high-performance liquid chromatography, was 0.66 +/- 0.23 micrometer. There was no significant influence of LV on IdUrd DNA incorporation in peripheral blood granulocytes as measured by high-performance liquid chromatography. Based on toxicity data and correlative laboratory studies, a meaningful increase in radiosensitization would not be achieved with the IdUrd infusion schedule and dose of LV investigated compared with IdUrd alone.     

Site-specific oxidation of histidine residues in glycated insulin mediated by Cu2+

The site-specific oxidation of histidine residues in glycated insulin mediated by copper ions and the relationship between the oxidation sites and the steric conformation of insulin are discussed in this study. Glycated insulin was prepared by incubating native insulin with glucose in 67 mM sodium phosphate, pH 7.5, at 37 degrees C for 30 h. In the presence of micromolar concentrations of Cu2+, glycated insulin was oxidized and its fragmentation or aggregation was detected. Accompanying the fragmentation, new N-termini were generated. The residues in these N-termini were identified as alanine, proline, valine, leucine and isoleucine by comparing dansyl derivatives with standard dansyl-amino acid products. Furthermore, several oxidized products of glycated insulin were isolated using reverse-phase HPLC (P1-P3). From amino acid composition and sequence analyses, it was determined that His10 on the insulin B-chain was modified in each of these peptides, while His5 was also modified in P3. The difference in susceptibility of His10 and His5 to oxidative modification is considered to be due to easier coordination of Cu2+ with His10, which further forms a complex with the Amadori compound at B-chain Phe1 that is vicinal to His10 in the steric conformation of insulin. This complex may generate an active oxygen species, which induces the degradation of the imidazole ring at His10, leading to aggregation or fragmentation of insulin.     

Epidemiological analysis of poliomyelitis cases in 1994, China

In 1994, the number of reported polio cases was 307 in China. This number was 53% lower than that in 1993, and was the lowest record ever in China. In 1994, the distribution of polio cases was highly dispersed and the number of outbreak was reduced obviously. Of 225 counties which reported polio cases in 1994, polio outbreak occured in 2 counties. Cases due to polio outbreak accounted for 4.2% of the total cases. The distribution of polio wild virus was narrow but the regional difference still existed. In the southeast, high risk region for polio consisting Guangdong, Hainan, Fujian three provinces, the number of polio cases decreased remarkably in 1994. On the contrary, in the southwest region which, consisting Guangxi, Yunnan, Guizhou, Sichuan four provinces, the number of polio cases increased obviously, accounted for approximately a half of the total number in 1994. During the coming 1 to 2 years, we should emphasis on these regions and provinces where high incidence was noticed in our polio eradication program. Those provinces should include Xinjiang, Fujian. Hubei three provinces that polio wild virus was identified in 1994, and Guangxi, Sichuan, Guizhou, Yunnan in the south west region as well. We should further increase Polio vaccination coverage of children especially floating and unplanned ones through strengthening routine immunization and carring out new national immunization day activity.     

Comparative analysis of latrotoxin channels of different conductance in planar lipid bilayers. Evidence for cluster organization

It has been established that channels induced by Latrodectus tredicimguttatus alpha-toxin (LT) in lipid bilayers have a cluster organisation. So far as: (i) the LT-channels had practically identical sizes of its water pores (r = 9.4 +/- 0.6 A) independently on the lipid composition of planar bilayer lipid membrane (BLM) although their conductances might differ from each other more than 10 times (100 mM KCl (pH 7.5)). (ii) affinity of permeable ions to channels had a small variation with distinct group of BLM, although LT-channels conductances varied from 112 +/- 8 pS till 1110 +/- 40 pS for phosphatidylcholine-BLM and from 75 +/- 6 pS till 170 +/- 14 pS for phosphatidylserine-BLM. (iii) Ca/K selectivity was greater in negatively charged membranes but did not also depend on the channel amplitude for the same BLM. Cation-anionic selectivity was identical for all studied channels.     

Comparison of the kinetics of injectable testosterone in eugonadal and hypogonadal men

Serum reproductive hormone levels were measured serially after eugonadal and hypogonadal men had received either a 200-mg or a 100-mg intramuscular injection of testosterone enanthate. The calculated mean integrated testosterone and estradiol levels indicated that the 200-mg testosterone enanthate injection in the hypogonadal subjects maintained eugonadal levels of these hormones through day 11. The 100-mg dose maintained eugonadal levels of these hormones through day 11. The 100-mg dose maintained eugonadal testosterone levels through day 7. The testosterone:estradiol ratios in both groups following the 200-mg injection remained above or at the eugonadal baseline trough day 21. The authors recommend that replacement therapy for hypogonadal men should be 200 mg of testosterone enanthate every 10 to 14 days. A similar dosage would be recommended if testosterone enanthate were to be used as an experimental inhibitor of spermatogenesis (contraceptive agent).     

Rapid synthesis of new DNMT inhibitors derivatives of procainamide

DNA methyltransferases (DNMTs) are responsible for DNA methylation, an epigenetic modification involved in gene regulation. Families of conjugates of procainamide, an inhibitor of DNMT1, were conceived and produced by rapid synthetic pathways. Six compounds resulted in potent inhibitors of the murine catalytic Dnmt3A/3L complex and of human DNMT1, at least 50 times greater than that of the parent compounds. The inhibitors showed selectivity for C5 DNA methyltransferases. The cytotoxicity of the inhibitors was validated on two tumour cell lines (DU145 and HCT116) and correlated with the DNMT inhibitory potency. The inhibition potency of procainamide conjugated to phthalimide through alkyl linkers depended on the length of the linker; the dodecane linker was the best.     

Inhibition of growth of MDA-MB-231 human breast cancer xenografts in nude mice by bombesin/gastrin-releasing peptide (GRP) antagonists RC-3940-II and RC-3095

We have previously demonstrated that diphtheria toxin (DT) fused to human GM-CSF effectively eliminates human long-term leukemia initiating cells in SCID mice. However, because huGM-CSF does not react with the murine GM-CSF receptor possible side-effects to nonleukemic tissues could not be analyzed in the AML/SCID model. To overcome this problem, we used murine GM-CSF fused to DT and studied the therapeutic index in the rat leukemia model BNML/LT12. In DT-mGM-CSF dose escalation experiments, severe dose-dependent toxicity to organs such as liver, kidney and lung was observed. Therefore, the antileukemic effects were evaluated with the lower doses. Daily intraperitoneal bolus injections of 75 microg/kg/day for 7 days induced a 3 log leukemic cell kill. The dose of 75 microg/kg/day had no effect on the hemopoietic progenitor cell subsets. These in vivo studies show that the DT-GM-CSF fusion protein can be used for specifically targeting leukemic cells and thus has potential as a therapeutic agent in the treatment of AML.