Risk factors for cancer of the oral cavity and oro-pharynx in Cuba

In terms of worldwide levels, Cuba has an intermediate incidence of cancer of the oral cavity and oro-pharynx. We studied 200 cases of cancer of the oral cavity and pharynx, of whom 57 women (median age = 64) and 200 hospital controls, frequency matched with cases by age and sex, in relation to smoking and drinking history, intake of 25 foods or food groups, indicators of oral hygiene and sexual activity, and history of sexually transmitted diseases. Odds ratios (OR) and 95% confidence intervals (CI) were obtained from unconditional multiple logistic regressions and adjusted for age, sex, area of residence, education, and smoking and drinking habits. In the multivariate model, high educational level and white-collar occupation, but not white race, were associated with halving of oral cancer risk. Smoking ≥30 cigarettes per day showed an OR of 20.8 (95% CI: 8.9–48.3), similar to smoking ≥4 cigars daily (OR = 20.5). Drinking ≥ 70 alcoholic drinks per week showed an OR of 5.7 (95% CI: 1.8–18.5). Hard liquors were by far the largest source of alcohol. Increased risk was associated with the highest tertile of intake for maize (OR = 1.9), meat (OR = 2.2) and ham and salami (OR = 2.0), whereas high fruit intake was associated with significantly decreased risk (OR = 0.4). Among indicators of dental care, number of missing teeth and poor general oral condition at oral inspection showed ORs of 2.7 and 2.6, respectively. Number of sexual partners, marriages or contacts with prostitutes, practice of oral sex and history of various sexually transmitted diseases, including genital warts, were not associated with oral cancer risk. 82% of oral cancer cases in Cuba were attributable to tobacco smoking, 19% to smoking cigars or pipe only. The fractions attributable to alcohol drinking (7%) and low fruit intake (11%) were more modest. Thus, decreases in cigarette and cigar smoking are at present the key to oral cancer prevention in Cuba. © 2001 Cancer Research Campaign http://www.bjcancer.co

Alterations in the insulin-like growth factor system during treatment with diethylstilboestrol in patients with metastatic breast cancer

Alterations in the insulin-like growth factor (IGF)-system were evaluated in 16 patients treated with diethylstilboestrol 5 mg 3 times daily. Fasting blood samples were obtained before treatment and after 2 weeks, 1 month and/or 2–3 months on therapy. Insulin-like growth factor (IGF)-I, IGF-II, free IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3 were measured by radioimmuno-/immunoradiometric-assays. All samples were subjected to Western ligand blotting as well as immunoblotting for IGFBP-3. We observed a significant decrease (percentage of pretreatment levels with 95 confidence intervals of the mean) in IGF-I [2 weeks 63% (49–79); 1 month 56% (44–73); 2–3 months 66% (53–82)], IGF-II [2 weeks 67% (56–80); 1 month 60% (52–68); 2–3 months 64% (55–75)], free IGF-I [2 weeks 29% (19–42); 1 month 25% (18–36); 2–3 months 31% (21–46)], IGFBP-2 [2 weeks 53% (18–156); 1 month 69% (61–78); 2–3 months 66% (57–78)], IGFBP-3 [2 weeks 74% (63–85); 1 month 69% (62–76); 2–3 months 71% (63–80)], as well as IGFBP-3 protease activity [2 weeks 71% (54–95); 1 month 78% (64–94); 2–3 months 71% (54–93)]. Contrary, the plasma levels (percentage of pretreatment levels with 95 confidence intervals of the mean) of IGFBP-1 [2 weeks 250% (127–495); 1 month 173% (138–542); 2–3 months 273% (146–510)] and IGFBP-4 [2 weeks 146% (112–192); 1 month 140% (116–169); 2–3 months 150% (114–198)] increased significantly. While this study confirms previous observations during treatment with oral oestrogens in substitution doses, the reduction in plasma IGF-II, free IGF-I, IGFBP-2 and -3 are all novel findings. A profound decrease in free IGF-I suggests a reduced bioavailability of IGFs from plasma to the tissues. These observations may be of significance to understand the mechanisms of the antitumour effect of diethylstilboestrol in pharmacological doses. © 2001 Cancer Research Campaign http://www.bjcancer.co

Structural analysis of the ParR/parC plasmid partition complex

Accurate DNA partition at cell division is vital to all living organisms. In bacteria, this process can involve partition loci, which are found on both chromosomes and plasmids. The initial step in Escherichia coli plasmid R1 partition involves the formation of a partition complex between the DNA-binding protein ParR and its cognate centromere site parC on the DNA. The partition complex is recognized by a second partition protein, the actin-like ATPase ParM, which forms filaments required for the active bidirectional movement of DNA replicates. Here, we present the 2.8 Å crystal structure of ParR from E. coli plasmid pB171. ParR forms a tight dimer resembling a large family of dimeric ribbon–helix–helix (RHH)2 site-specific DNA-binding proteins. Crystallographic and electron microscopic data further indicate that ParR dimers assemble into a helix structure with DNA-binding sites facing outward. Genetic and biochemical experiments support a structural arrangement in which the centromere-like parC DNA is wrapped around a ParR protein scaffold. This structure holds implications for how ParM polymerization drives active DNA transport during plasmid partition

Sequential N- to C-terminal SNARE complex assembly drives priming and fusion of secretory vesicles

During exocytosis a four-helical coiled coil is formed between the three SNARE proteins syntaxin, synaptobrevin and SNAP-25, bridging vesicle and plasma membrane. We have investigated the assembly pathway of this complex by interfering with the stability of the hydrophobic interaction layers holding the complex together. Mutations in the C-terminal end affected fusion triggering in vivo and led to two-step unfolding of the SNARE complex in vitro, indicating that the C-terminal end can assemble/disassemble independently. Free energy perturbation calculations showed that assembly of the C-terminal end could liberate substantial amounts of energy that may drive fusion. In contrast, similar N-terminal mutations were without effects on exocytosis, and mutations in the middle of the complex selectively interfered with upstream maturation steps (vesicle priming), but not with fusion triggering. We conclude that the SNARE complex forms in the N- to C-terminal direction, and that a partly assembled intermediate corresponds to the primed vesicle state