PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Beyond the boundaries in the island of Ireland

The review essay opens with positive attributes of Ireland but then considers that the island has been subject to centuries of bitter dispute and unrest. The historical background to this is outlined, particularly the interactions between Ireland and its neighbouring island, Great Britain, which dominated Irish affairs. One policy adopted by the British was to encourage migration of Protestants into the largely Catholic island in the vain hope that this would reduce unrest. The
two islands were then united from 1801 as the United Kingdom of Great Britain and Ireland but demands from indigenous Irish Catholics for independence continued, resisted by the Protestant minority who wished to remain inside the UK. After the Great War a solution was imposed that granted most of Ireland independence but left the largely Protestant northeast corner within the UK as Northern Ireland. Reaction to and life with the Irish border are considered and the paper concludes with musings about its future.

The geoarchaeology of Paleolithic rivers of southwest Britain

In Britain, the majority of Lower and Middle Paleolithic archaeological finds come from river terrace deposits. The impressive “staircase” terrace sequences of southeast England, and research facilitated by aggregate extraction have provided a considerable body of knowledge about the terrace chronology and associated archaeology in that area. Such research has been essential in considering rates of uplift, climatic cycles, archaeological chronologies, and the landscapes in which hominins lived. It has also promoted the view that southeast England was a major hominin route into Britain. By contrast, the terrace deposits of the southwest have been little studied. The Palaeolithic Rivers of South West Britain (PRoSWEB) project employed a range of geoarchaeological methodologies to address similar questions at different scales, focusing on the rivers Exe, Axe, Otter, and the paleo-Doniford, all of which were located south of the maximum Pleistocene glacial limit (marine oxygen isotope stage [MIS] 4–2). Preliminary analysis of the fieldwork results suggests that although the evolution of these catchments is complex, most conform to a standard staircase-type model, with the exception of the Axe, and, to a lesser extent, the paleo-Doniford, which are anomalous. Although the terrace deposits are less extensive than in southeast Britain, differentiation between terraces does exist, and new dates show that some of these terraces are of great antiquity (MIS 10+). The project also reexamined the distribution of artifacts in the region and confirms the distributional bias to the river valleys, and particularly the rivers draining southward to the paleo–Channel River system. This distribution is consistent with a model of periodic occupation of the British peninsula along and up the major river valleys from the paleo–Channel River corridor. These data have a direct impact on our understanding of the paleolandscapes of the southwest region, and therefore our interpretations of the Paleolithic occupation of the edge of the continental landmass.