p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment.

A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases in which tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS), which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease. Recently, we were able to show that the small molecule inhibitor PKC412 (midostaurin) shows strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR. In this study, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo. We provide evidence that the antitumor effect on combination treatment is achieved by VPA-induced reactivation of p21, which is downregulated in aRMS cells by destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

[Relevant publications in ambulatory general internal medicine in 2007]. / Médecine interne générate ambulatoire: quelques enseignements de la littérature.

Screening procedures for genital Chlamydia infection, cancer risks linked to oral contraceptives, indications and efficacy of HPV vaccination, and diagnostic tools for celiac disease in adults; these are just a few of the general practice themes that were reviewed and analysed in 2007 by residents and chief residents at the Community medicine and primary care Service of the Geneva University Hospitals. These commented summaries, intended for all our colleagues, constitute Geneva's contribution to the literature data base initiated in 2005 by chief residents in Lausanne.

Community risk indicators for dental caries in school children: an ecologic study.

A statewide survey of NC schoolchildren found wide variation in dental caries prevalence among sampled classrooms. This study examined factors associated with this variation using classrooms as a surrogate for the larger community, in order to identify community risk indicators (CRI). In all, 172 classrooms (3400 students) in Grades K-6 were available for analysis. Initially, 56 sociodemographic, environmental, health system, and clinical factors were evaluated for their association with caries prevalence (K-3: average dfs + DMFS; 4-6: average DMFS) using univariate and bivariate analyses. Of these, 21 factors met our criteria for evaluation using WLS multivariate regression. For Grades K-3 (n = 108), population density, parental education, and coastal residence were negatively associated with caries scores, while age, and medical and dental, Medicaid expenditures were positive. For Grades 4--6 (n = 64), age and fs:dfs ratio were positively associated with caries scores while population density, population:dentist ratio, and years of natural fluoride exposure were negative. CRIs for both models, when compared to individual models, explained a substantial portion of the variation in caries prevalence, 31% for Grades K-3 and 51% for Grades 4-6. Results suggest that a risk assessment model based on community rather than individual variables is feasible and further refinement may reveal factors useful in identifying high risk communities.

Perceived needs for dental continuing education within the Army dental care system.

Results of a worldwide survey examining the perceived needs for continuing education (CE) among Army general dentists and their supervisors are presented. Responses from 255 supervisors and 528 dentists were available for analysis. There was overall lack of agreement between supervisors and dentists concerning CE preferences; supervisors selected risk or clinic management topics and dentists chose patient care topics. Years of practice, practice location, and advanced general dentistry program participation strongly influenced dentists' perceived needs. Results suggest that in evaluating or planning for CE programs, differences in perceived needs between various groups within the dental care system must be considered.

Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer's disease.

It could be argued that clinical experience with cholinergic drugs in the therapy of AD has not yet shown relevant symptomatic improvements. The main reasons for this might be attributed to peripheral cholinergic effects and the liver toxicity of some of these drugs, which limit their use and prevent confirmation of the cholinergic hypothesis (Gray et al., 1989). The main disadvantages of the cholinesterase inhibitors used in clinical trials are the short duration of action in the case of physostigmine and the potential for liver toxicity seen with the aminoacridine derivatives. The results presented with SDZ ENA 713 indicate that the disadvantages of AChE inhibitors might be overcome by improving CNS selectivity and thereby decreasing the peripheral cholinergic effects and toxicity. Clinico-pharmacological studies with SDZ ENA 713 have been performed in healthy volunteers; while central activity was clearly demonstrated in an EEG-sleep study (Holsboer et al., 1992), no prohibitive peripheral side effects were seen, confirming in humans the results obtained in experimental animals (Enz et al., 1991). A multicentre clinical investigation in AD patients has been performed in Europe and is currently being evaluated.

Characterization of the irreversible inhibition of high-affinity choline transport produced by hemicholinium mustard.

The inhibition of high-affinity choline transport by hemicholinium mustard (HCM), an alkylating analogue of hemicholinium-3, was examined in rat brain synaptosomes and guinea pig myenteric plexus. In synaptosomes, 50% high-affinity choline transport inhibition occurs with an HCM concentration of 104 nM (4-min incubation). A 10-min preincubation with 10 microM HCM results in essentially complete (greater than 95%) inactivation that persists after washing. Low-affinity choline transport in synaptosomes is unaffected by HCM inhibition at all concentrations examined (1-50 microM). Time course experiments indicate that the maximum irreversible inhibition (58%) seen after a 1-min preincubation with 500 nM HCM decreases to 46% inhibition after a 15-min preincubation; however, analysis of variance reveals that this difference is not significant. HCM inhibition of acetylcholine release from myenteric plexus-longitudinal muscle preparations persists for at least 2 h after removal of drug from the incubation bath; this inactivation can be prevented by coincubation with a high choline concentration during treatment with the mustard. In contrast, inhibition produced by the parent compound hemicholinium-3 is largely reversed by washing in both preparations examined. The observed potency and selectivity of HCM suggest its usefulness as a covalent probe for high-affinity choline transport.

Muscarinic activity of the thiolactone, lactam, lactol, and thiolactol analogues of pilocarpine and a hypothetical model for the binding of agonists to the m1 receptor.

Pilocarpine isosteres have been synthesized and characterized with regard to their in vitro muscarinic properties. The results indicate that the carbonyl oxygen of the lactone function of pilocarpine is of primary importance for agonist activity with the ether oxygen being of lesser or secondary importance. An X-ray structure determination for the hydrogen O,O'-ditoluoyltartrate salt of thiolactone pilocarpine isostere 2a has been performed. This compound has an unusual pharmacological profile exhibiting M1-agonist selectivity as well ass presynaptic antagonism. As a result this compound is also viewed as having therapeutic potential for Alzheimer's disease. A model for the binding of pilocarpine and other muscarinic agonists to the third transmembrane helix of the human m1 muscarinic receptor has been developed.

Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogues. N-[4-(tertiary amino)-2-butynyl]-5-methyl-2-pyrrolidones.

The enantiomers of three 5-methyl-2-pyrrolidone analogues of the muscarinic agent oxotremorine (1) were synthesized. The pyrrolidine derivative (R)-13 was an antagonist to carbachol in the guinea pig ileum and also showed central and peripheral antimuscarinic activity in vivo. It was more potent and more selective than atropine in antagonizing the central effects of 1. The dimethylamino analogue (R)-14 and the trimethylammonium salt (R)-15 were potent agonists in the guinea pig ileum. (R)-14 showed both central muscarinic (hypothermia) and central antimuscarinic activity (antagonism of oxotremorine-induced tremor) in vivo. The R enantiomers of 13-15 were considerably more potent than the S enantiomers in vivo and in vitro irrespective of whether agonist or antagonist activity was measured. From a comparison of the contribution of the methyl group at the chiral center to the overall affinities, it is suggested that agonists and antagonists in this series bind in an essentially identical manner to the muscarinic receptor.