11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours

Two distinct etiologies of head and neck squamous cell carcinoma (HNSCC) have been proposed, DNA damage owing to tobacco and alcohol exposure and human papillomavirus (HPV) oncogene-mediated transformation. Common genetic alterations in HNSCC include TP53 mutations, 11q13 amplification (amp) and CDKN2A/p16 mutations or promoter methlyation. However, in HPV+ HNSCC it is frequent to observe wild-type TP53 and expression of p16. The relationship of this unusual pattern with 11q13 amp has not been tested. In a retrospective study on 125 HNSCC patients, only 17% (five out of 30) of HPV+ vs 44% (39 out of 89) of HPV − tumours expressed 11q13 amp (adjusted odds ratio (OR)=0.2, 95% confidence interval (CI)=0.1–0.6). A subpopulation of tumours (n=69) were classified according to the three molecular markers, TP53, p16 and 11q13 amp. In addition to wild-type TP53, and p16 expression, HPV+ tumours were more likely not to be amplified at 11q13 (OR=6.5, 95% CI=1.8–23.9). As HPV+ HNSCC lack the genetic alterations which are common in other tumours, we hypothesise that HPV infection may represent an early event in the HNSCC carcinogenic process, thus suggesting a distinct molecular pathway

New infant cranium from the African Miocene sheds light on ape evolution

The evolutionary history of extant hominoids (humans and apes) remains poorly understood. The African fossil record during the crucial time period, the Miocene epoch, largely comprises isolated jaws and teeth, and little is known about ape cranial evolution. Here we report on the, to our knowledge, most complete fossil ape cranium yet described, recovered from the 13 million-year-old Middle Miocene site of Napudet, Kenya. The infant specimen, KNM-NP 59050, is assigned to a new species of Nyanzapithecus on the basis of its unerupted permanent teeth, visualized by synchrotron imaging. Its ear canal has a fully ossified tubular ectotympanic, a derived feature linking the species with crown catarrhines. Although it resembles some hylobatids in aspects of its morphology and dental development, it possesses no definitive hylobatid synapomorphies. The combined evidence suggests that nyanzapithecines were stem hominoids close to the origin of extant apes, and that hylobatid-like facial features evolved multiple times during catarrhine evolution

Antifungal Efficacy of GM237354, a Sordarin Derivative, in Experimental Oral Candidiasis in Immunosuppressed Rats

GM237354 is a novel sordarin derivative with a broad spectrum of potent activity against a wide range of fungi. The members of this new class of antifungal agents act as potent inhibitors of fungal protein synthesis. In this study, the therapeutic effects of GM237354 were investigated in a novel experimental oral Candida albicans infection model in immunosuppressed rats. The animals were immunosuppressed with dexamethasone in their drinking water and infected on three alternate days. GM237354 was given three times per day for seven consecutive days at 1.25, 2.5, 5, or 10 mg/kg of body weight per dose. In addition, to provide a preliminary idea of the correlation between regimen administration and therapeutic efficacy, GM237354 was administered to two additional groups of rats at 5 mg/kg once or twice a day for 7 days. The drug efficacy was assessed microbiologically, histologically, and by a morphometric study of lesions. Evident agreement was observed among results obtained by the different methods in all of the animals studied. Microbiologically, the efficacy of GM237354 was determined by measuring the number of C. albicans organisms in the oral cavities of rats in the middle (day 4) and at the end (day 7) of the treatment. GM237354 administered at 5, 7.5, 10, 15, or 30 mg/kg/day for 7 days significantly reduced the number of CFU in the oral cavities of treated rats compared with the number of CFU in the oral cavities of the untreated controls. A significant reduction was also observed when GM237354 was administered at 7.5, 10, 15, or 30 mg/kg/day for 4 days. Furthermore, C. albicans was not detected in oral swabs from any infected rats after 1 week of treatment when GM237354 was administered at 15 or 30 mg/kg/day or after 4 days of treatment at 30 mg/kg/day. Histologically, untreated control animals showed extensive colonization of the epithelium of the dorsal tongue by numerous hyphae. Animals treated with GM237354 at 7.5 mg/kg/day showed small areas with superficial hyphal penetration into the epithelium that produced intraepithelial microabscesses. However, animals treated with GM237354 at 15 mg/kg/day showed multiple regenerative areas of the covering epithelium, and only focalized zones of the tongue surface were occupied by hyphae. No hyphal colonization of the epithelium was seen in rats treated with GM237354 at 30 mg/kg/day and which showed extensive areas of epithelial regeneration of the tongue. The histopathology findings were confirmed by morphometry studies, and the percentage of epithelium occupied by C. albicans hyphae decreased from 17.5% in the control group to 4.8 and 0.1% in animals treated with GM237354 at 7.5 and 15 mg/kg/day, respectively. These results demonstrated that the sordarin derivative GM237354 was effective against experimental oral candidiasis in immunosuppressed rats, and further studies are needed to determine the potential of GM237354 for use in the treatment of this infection in humans