Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.

EAEPC v. Commission: Final Curtain for the GSK Spain Saga on so-called ‘dual-pricing’ for medicines

Following the CoJ’s 2009 judgment in the so-called GSK ‘dual-pricing’ case, the umbrella association of parallel traders complained to the Commission and requested a re-opening of the case. The Commission rejected the complaint and the General Court has now upheld that decision.

Verdi-paper

Background. To describe and compare love-related mortality in German and Italian operas of the 19th century, as operas are perfectly suited as a setting to study the relationship between love and premature death.Method. This is a historic cohort study of named characters in the 19th century operas by Italian and German composers included in a modern reference work. Follow-up lasted from the start of the opera until the final curtain. We calculated overall and cause-specific (e.g. love, violence) mortality, and proportional mortality ratios.Results: Among 76 eligible operas (23 German and 53 Italian) with 614 named characters, we recorded 118 deaths. The risk of dying young in opera is substantial, accounting for 94 of the 118 deaths. Violence was the main direct cause of death (62.7%) and love the main indirect cause (39.8%). The risk of dying of love was almost twice as high in Italian operas compared to German ones (46.8% versus 26.8%). Women experienced an almost double risk of dying of love compared to men (54.8% versus 31.6%).Discussion: This is the first empirical study on the contribution of passionate love to premature mortality. Its novelty lies in the use of opera as a source of epidemiological data. Our findings support the hypothesis that Italians are more passionate than Germans, resulting in proportionately more young people dying because of love in Italian operas. These findings provide further evidence for a link between emotion and mortality.