Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.     

A bisexually reproducing all-triploid vertebrate

Green toads are common in the Palaearctic region, where they have differentiated into several taxa. The toads exist with variable amounts of ploidy, similar to other anuran species or reptiles. In vertebrate biology, the very rare occurrence of triploidy is coupled with infertility or unisexuality, or requires the coexistence of individuals of different ploidy in a reproductive community. The reproduction of naturally occurring triploids has been reported to occur only through parthenogenesis, gynogenesis or hybridogenesis. The bisexual reproduction of pure triploids has been considered to be impossible because of the problem of equally distributing three chromosome sets in meiosis. Here we report geographically isolated populations of green toads (Bufo viridis complex) that are all-triploid and reproduce bisexually.     

Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling

B-cell antigen receptor (BCR) expression is an important feature of chronic lymphocytic leukaemia (CLL), one of the most prevalent B-cell neoplasias in Western countries. The presence of stereotyped and quasi-identical BCRs in different CLL patients suggests that recognition of specific antigens might drive CLL pathogenesis. Here we show that, in contrast to other B-cell neoplasias, CLL-derived BCRs induce antigen-independent cell-autonomous signalling, which is dependent on the heavy-chain complementarity-determining region (HCDR3) and an internal epitope of the BCR. Indeed, transferring the HCDR3 of a CLL-derived BCR provides autonomous signalling capacity to a non-autonomously active BCR, whereas mutations in the internal epitope abolish this capacity. Because BCR expression was required for the binding of secreted CLL-derived BCRs to target cells, and mutations in the internal epitope reduced this binding, our results indicate a new model for CLL pathogenesis, with cell-autonomous antigen-independent signalling as a crucial pathogenic mechanism.     

Kuhn and coherentist epistemology

The paper challenges a recent attempt by Jouni-Matti Kuukkanen to show that since Thomas Kuhn’s philosophical standpoint can be incorporated into coherentist epistemology, it does not necessarily lead to: (Thesis 1) an abandonment of rationality and rational interparadigm theory comparison, nor to (Thesis 2) an abandonment of convergent realism. Leaving aside the interpretation of Kuhn as a coherentist, we will show that Kuukkanen’s first thesis is not sufficiently explicated, while the second one entirely fails. With regard to Thesis 1, we argue that Kuhn’s view on inter-paradigm theory comparison allows only for (what we shall dub as) ‘the weak notion of rationality’, and that Kuukkanen’s argument is thus acceptable only in view of such a notion. With regard to Thesis 2, we show that even if we interpret Kuhn as a coherentist, his philosophical standpoint cannot be seen as compatible with convergent realism since Kuhn’s argument against it is not ‘ultimately empirical’, as Kuukkanen takes it to be.     

Rationality and irrationality in the history of continental drift: Was the hypothesis of continental drift worthy of pursuit?

The revolution in geology, initiated with Alfred Wegener’s theory of continental drift, has been the subject of many philosophical discussions aiming at resolving the problem of rationality underlying this historical episode. Even though the debate included analyses in terms of scientific methodology, applications of concrete accounts of epistemic justification to this case study have been rare. In particular, the question as to whether Wegener’s theory was epistemically worthy of pursuit in the first half of the twentieth century, that is, in its early development, remained open or inadequately addressed. The aim of this paper is to offer an answer to this question. The evaluation of Drift will be done by means of an account of theory evaluation suitable for the context of pursuit, developed in ?e?elja and Straßer (accepted for publication). We will argue that pursuing the theory of continental drift was rational, i.e., that it was irrational to reject its pursuit as unworthy.