RESUMEN
Control of fire is one of the most important technological innovations within the evolution of humankind. The archaeological signal of fire use becomes very visible from around 400,000 y ago onward. Interestingly, this occurs at a geologically similar time over major parts of the Old World, in Africa, as well as in western Eurasia, and in different subpopulations of the wider hominin metapopulation. We interpret this spatiotemporal pattern as the result of cultural diffusion, and as representing the earliest clear-cut case of widespread cultural change resulting from diffusion in human evolution. This fire-use pattern is followed slightly later by a similar spatiotemporal distribution of Levallois technology, at the beginning of the African Middle Stone Age and the western Eurasian Middle Paleolithic. These archaeological data, as well as studies of ancient genomes, lead us to hypothesize that at the latest by 400,000 y ago, hominin subpopulations encountered one another often enough and were sufficiently tolerant toward one another to transmit ideas and techniques over large regions within relatively short time periods. Furthermore, it is likely that the large-scale social networks necessary to transmit complicated skills were also in place. Most importantly, this suggests a form of cultural behavior significantly more similar to that of extant Homo sapiens than to our great ape relatives.
RESUMEN
A subgroup of head and neck squamous cell carcinomas (HNSCCs) contains high-risk human papillomavirus-type 16 (HPV16). The viral E6 and E7 oncoproteins inactivate the p53 and pRb proteins, respectively. We examined the causative effect of HPV16 E6 and E7 expression on the immortalization of normal oral keratinocytes (OKCs) and compared the resulting phenotype with alternative ways of p53- and pRb-pathway abrogation frequently found in HNSCCs without HPV. Primary OKCs were conditionally immortalized with temperature-sensitive SV40 large T-antigen and human telomerase, allowing these cells to return to their senescent primary state after temperature shift. HPV16 E6 and E7 were introduced to overcome senescence, determined with population doubling (PD) as read-out. For comparison, we downregulated p53 and p16 by short hairpin RNA genes and expressed mutant p53R(175)H and cyclinD1. Expression of HPV16 E6 caused an extended life span similar to expression of mutant p53R(175)H or p53 knockdown. Expression of mutant p53R(175)H seemed to cause additional activation of the hypoxia and WNT signaling pathways. HPV16 E7 expression had no direct effect on lifespan, similar to p16 knockdown or cyclinD1 expression. In combination with HPV16 E6 or other functional inactivations of p53, abrogation of the pRb-pathway by either HPV16 E7 or other manipulations caused an immortal phenotype. Our data show the causative role of HPV16 E6/E7 in early squamous carcinogenesis. Activity of each gene could be mimicked by other genetic events frequently found in HNSCC without HPV. This data provides the experimental proof of causal association of HPV in HNSCC carcinogenesis and further support the crucial role of the p53- and pRb-pathways.