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Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells., info:eu-repo/semantics/published

The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis., Author summary Cell death allows elimination of supernumerary cells during development or of abnormal cells throughout life. Physiological cell death is tightly regulated to prevent pathologies such as degenerative diseases or cancers, which often occur due to excessive or absent cell death, respectively. Understanding the mechanisms of cell death pathways is thus crucial for fighting various diseases. The best studied form of cell death, apoptosis, has classically been considered the sole form of cell death during development, while other forms of cell death, referred to as necrosis, were considered accidental. Here, we show that a regulated form of necrosis controls germ cell number during Drosophila spermatogenesis, thus demonstrating that necrosis can play a key role in controlling cell number in physiological conditions. This regulated form of necrosis involves p53, a protein frequently mutated in cancer. Furthermore, we demonstrate that this pathway prevents tissue hyperplasia, a condition that can lead to cancer. We also provide evidence that the same pathway is operational in mammals, as shown in the testes of mice subjected to mild heat stress. These findings expand the possible mechanisms by which cell death could be targeted to treat human pathologies.

Regulated necrosis occurs in pathologies such as cerebral stroke and myocardial infarction, however the underlying mechanisms and its physiological relevance remain unclear. Here, we report a role for p53 in regulating necrosis in Drosophila spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs physiologically in mitotic germ cells during spermatogenesis. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. Drosophila spermatogenesis will thus be a useful model to identify inducers of necrosis to treat cancers that are refractory to apoptosis.

Regulated necrosis occurs in pathologies such as cerebral stroke and myocardial infarction, however the underlying mechanisms and its physiological relevance remain unclear. Here, we report a role for p53 in regulating necrosis in Drosophila spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs physiologically in mitotic germ cells during spermatogenesis. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. Drosophila spermatogenesis will thus be a useful model to identify inducers of necrosis to treat cancers that are refractory to apoptosis.

The counterfactual impact analysis of fair use amendments in Singapore undertaken here demonstrates that flexible fair use policy positively influences growth rates in private copying technology industries. In 2010, five years after the policy intervention, Singapore’s fair use amendments are correlated with a 3.33% increase in value-added (as % of GDP) for private copying technology industries. Prior to the amendment of fair use policies, private copying technology industries experienced - 1.97% average annual growth. After the changes were introduced, the same industries enjoyed a 10.18% average annual growth rate. This resulted in a total increase of € 2.27 billion in value-added for private copying technology industries in that period. The results show that, prior to fair use amendments, the private copying industries in Singapore were in recession. After fair use amendments, this group experienced a rapid increase in growth rates and continued to exhibit strong growth over the five year period. Crucially, the control group, a set of technology manufacturers/services, was not significantly affected by the fair use amendments in Singapore. The counterfactual impact of fair use policies on the control group, five years after the amendment, is shown to be correlated with a 0.01% increase in value-added (as % of GDP). Despite experiencing fluctuating growth rates, the control group exhibited steady, albeit small, recession relative to the entire economy both before and after the fair use amendments. Though the year-on-year growth rates of the control group fluctuated significantly, the period-averages were closer in magnitude than the other two groups (3.89% pre-amendment growth and -0.22% post-amendment growth). This suggests that the control group was not significantly affected by the fair use amendments. This is a positive finding that enables us to better isolate the impact of fair use on the two industrial groups of interest. The counterfactual impact analysis results in Singapore indicate that the growth of private copying technologies has had a negligible impact on copyright industry revenue. For 2010, fair use policy was correlated with a -0.23% reduction in value-added (as % of GDP) for copyright industries. The copyright group enjoyed an average growth rate of 14.16% before the amendments were introduced (a total increase of over € 274 million in value-added). This slowed to 6.68% for the period after the amendments were introduced and resulted in a total increase of over € 158 million in value-added. There was no significant change in growth rates for the copyright group before and after fair use amendments when measured in terms of real economic growth (value added as % of GDP). While growth certainly slowed down in absolute terms, the industry group nevertheless continued to grow after the intervention. Moreover, the magnitude of the change was minimal in comparison to the private copying group. The results indicate that the growth rate of copyright industries leveled out after the fair use policy intervention and consequently that the value-added (as % of GDP) of the copyright industry group remained relatively constant over the entire period. While copyright industry growth rates slowed to a limited extent, copyright markets did not experience a significant negative impact. Moreover, this impact was offset by substantially higher growth rates in private copying technology industries. We suggest fair use amendments in Singapore did not negatively affect the copyright industries significantly because private copying technologies, which experienced high growth as an industry group after the fair use amendments, increase the value of copyrighted works to consumers. While one might expect a rise in private copying technology industries to result in a significant recession for the copyright industries, this has not been the case in Singapore since the introduction of more flexible fair use policy in 2005. The counterfactual impact analysis results for the Singapore case study show that fair use policy is correlated with higher growth rates in private copying technology industries while having a very limited impact on copyright industries.