Oncogene-blocking therapies: new insights from conditional mouse tumor models.

Identification of oncogene dependent signaling pathways controlling aggressive tumor growth has led to the emergence of a new era of oncogene-blocking therapies, including Herceptin and Gleevec. In the recent years conditional mouse tumor models have been established that allow switching-off the expression of specific oncogenes controlling tumor growth. The results may have two important implications for oncogene-blocking therapies: (i) downregulation of oncogenes, for instance HER2, MYC, RAS, RAF, BCR-ABL or WNT1, usually leads to a rapid tumor remission. However, it was observed that the initial remission was followed by recurrent tumor growth in most studies. Interestingly, different oncogenes controlled tumor growth in the recurrent than in the primary tumors. This could explain the astonishing clinical observation that inhibitors of a broader spectrum of protein kinases (so-called: "dirty inhibitors") may be superior over highly specific substances. Due to their additional "unspecific" inhibition of a broader spectrum of kinases, they may hamper the escape mechanisms by antagonizing also the pathways controlling recurrent tumor growth. (ii) Experiments with cell systems that allow switching-on oncogene expression point to a so far possibly underestimated cancer drug target: the dormant tumor cell. Oncogene expression (for instance: NeuT or RAS) led to a phenomenon named oncogene-induced senescence or dormancy. Dormant cells are unresponsive to mitogenic stimuli. Importantly, such cells are not at all ready to die, but can remain viable for extended periods of time. Recently, dormant tumor cells have been shown to be more resistant to stresses such as hypoxia or exposure to cytostatic drugs. It still is a matter of debate if and under which conditions dormant tumor cells can be "kissed to life". If these cells contribute to carcinogenesis, it will be important to identify substances specifically killing senescent cells. This review will focus on the possible relevance of senescence both as a pre-oncogenic condition and also for therapy.

Recognition of bacteriophage Qbeta plus strand RNA as a template by Qbeta replicase: role of RNA interactions mediated by ribosomal proteins S1 and host factor.

RNA-protein interactions between bacteriophage Qbeta plus strand RNA and the components of the Qbeta replicase system were studied by deletion analysis. Internal, 5'-terminal and 3'-terminal deletions were assayed for template activity with replicase in vitro. Of the two internal binding sites previously described for replicase, we found that the S-site (map position 1247 to 1346) could be deleted without any significant effect on template activity, whereas deletion of the M-site (map position 2545 to 2867) resulted in a strong inactivation and a high salt sensitivity of the residual activity. Binding complexes of the deletion mutant RNAs with the different proteins involved in Qbeta RNA replication were analysed by electron microscopy. The formation of looped complex structures, previously reported and explained as simultaneous interactions with replicase at the S and the M-site, was abolished by deleting the S-site but, surprisingly, not by deleting the M-site. The same types of complexes observed with replicase were also formed with purified protein S1 (the alpha subunit of replicase), suggesting that these internal interactions with Qbeta RNA are mediated by the S1 protein. The Qbeta host factor, a protein required for the template activity of the Qbeta plus strand, was reported earlier to form similar complexes by binding to the S and M-sites (or adjacent sites) and in addition to the 3'-end, resulting in double-looped structures. The patterns of looped complexes observed with the deletion mutant RNAs suggest that the binding of host factor might not involve the S and M-sites themselves but adjacent downstream sites. An additional internal host factor interaction near map position 2300 was detected with several mutant RNAs. Qbeta RNA molecules with 3'-truncations formed 3'-terminal loops with similar efficiency as wild-type RNA, indicating that recognition of the 3'-end by host factor is not dependent on a specific 3'-terminal base sequence.

A retrospective clinical and radiologic study of teeth re-implanted following traumatic avulsion.

Re-implantation is the recommended therapeutic procedure following traumatic exarticulation of teeth though its long-term prognosis remains controversial. The purpose of the following study was to evaluate the periodontal healing of 33 reimplanted incisors lost after trauma. The sample, which included 24 upper and 9 lower incisors, was divided in two groups: 15 teeth were reimplanted within 1 hour (=Group A) and 21 teeth after 3 hours or more (=Group B). The reimplanted teeth were followed for different radiographic evaluation periods up to 5 years (mean=2-9 years). The results showed a high rate of periodontal healing in Group A (66.7%), while Group B demonstrated a high percentage (83.3%) of both inflammatory and replacement resorption. Thus, even if the whole sample was prevented from drying before reimplantation, the teeth were affected by different rates of root resorption. Among the various prognostic factors suggested by the literature, bacterial contamination during extra-alveolar storage seemed the most critical.

[Dental and dentoalveolar injuries: their etiology, incidence and distribution in a specialized university service]. / Traumatologie dentaire et dento-alvéolaire: étiologie, fréquence et distribution dans un service universitaire spécialisé.

From 1987 to 1992, 520 patients presenting with traumatic injuries were referred to the Department of Orthodontics and Pedodontics at the University of Geneva. The sample consisted of 949 injuries, involving 556 primary and 393 permanent teeth. They concerned mostly upper primary (56%) or permanent (35%) incisors, and were more frequent in boys (60.6%) than girls (39.4%). Various epidemiological observations concerning etiology, age distribution and seasonal variations are discussed. Given the limits assigned by data derived from a selected sample, they are compared with other studies dealing with traumatic injuries.