Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS-TIMI 54

Aims In PEGASUS-TIMI 54, ticagrelor significantly reduced the risk of the composite of major adverse cardiovascular (CV) events by 15–16% in stable patients with a prior myocardial infarction (MI) 1–3 years earlier. We report the efficacy and safety in the subpopulation recommended for treatment in the European (EU) label, i.e. treatment with 60 mg b.i.d. initiated up to 2 years from the MI, or within 1 year after stopping previous adenosine diphosphate receptor inhibitor treatment. Methods and results Of the 21 162 patients enrolled in PEGASUS-TIMI 54, 10 779 patients were included in the primary analysis for this study, randomized to ticagrelor 60 mg (n = 5388) or matching placebo (n = 5391). The cumulative proportions of patients with events at 36 months were calculated by the Kaplan–Meier (KM) method. The composite of CV death, MI, or stroke occurred less frequently in the ticagrelor group (7.9% KM rate vs. 9.6%), hazard ratio (HR) 0.80 [95% confidence interval (CI) 0.70–0.91; P = 0.001]. Ticagrelor also reduced the risk of all-cause mortality, HR 0.80 (0.67–0.96; P = 0.018). Thrombolysis in myocardial infarction major bleeding was more frequent in the ticagrelor group 2.5% vs. 1.1%; HR 2.36 (1.65–3.39; P < 0.001). The corresponding HR for fatal or intracranial bleeding was 1.17 (0.68–2.01; P = 0.58). Conclusion In PEGASUS-TIMI 54, treatment with ticagrelor 60 mg as recommended in the EU label, was associated with a relative risk reduction of 20% in CV death, MI, or stroke. Thrombolysis in myocardial infarction major bleeding was increased, but fatal or intracranial bleeding was similar to placebo. There appears to be a favourable benefit-risk ratio for long-term ticagrelor 60 mg in this population. Clinical trial registration http://www.clinicaltrials.gov NCT0122556

Positron emission tomography imaging studies of dopamine receptors in primate models of addiction

Animal models have provided valuable information related to trait and state variables associated with vulnerability to drug addiction. Our brain imaging studies in monkeys have implicated D2 receptors in cocaine addiction. For example, an inverse relationship between D2 receptor availability and rates of cocaine self-administration has been documented. Moreover, environmental variables, such as those associated with formation of the social hierarchy, can impact receptor availability and sensitivity to the abuse-related effects of cocaine. Similarly, both D2 receptor availability and cocaine self-administration can be altered by chronic drug administration and fluctuations in hormone levels. In addition, cocaine self-administration can be altered in an orderly fashion by presentation of an acute stressor, such as acting as an intruder into an unfamiliar social group, which can shift the cocaine dose–response curve to the left in subordinate monkeys and to the right in dominant animals, suggesting an interaction between social variables and acute stressors. Conversely, irrespective of social rank, acute environmental enrichment, such as increasing the size of the living space, shifts the cocaine dose–response curve to the right. These findings highlight a pervasive influence of the environment in modifying the reinforcing effects of cocaine and strongly implicate brain D2 receptors

Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.Charles C. Bell, Katie A. Fennell, Yih-Chih Chan, Florian Rambow, Miriam M. Yeung, Dane Vassiliadis, Luis Lara, Paul Yeh, Luciano G. Martelotto, Aljosja Rogiers, Brandon E. Kremer, Olena Barbash, Helai P. Mohammad, Timothy M. Johanson, Marian L. Burr, Arindam Dhar, Natalie Karpinich, Luyi Tian, Dean S. Tyler, Laura MacPherson, Junwei Shi, Nathan Pinnawala, Chun Yew Fong, Anthony T. Papenfuss, Sean M. Grimmond, Sarah-Jane Dawson, Rhys S. Allan, Ryan G. Kruger, Christopher R. Vakoc, David L. Goode, Shalin H. Naik, Omer Gilan, Enid Y.N. Lam, Jean-Christophe Marine, Rab K. Prinjha, Mark A. Dawso

Trans-oceanic and endemic origins of the small minnow mayflies (Ephemeroptera, Baetidae) of Madagascar

We investigated the relative importance of dispersal and vicariance in forming the Madagascar insect fauna, sequencing approximately 2300 bp from three rRNA gene regions to investigate the phylogeny of Afrotropical small minnow mayflies (Ephemeroptera: Baetidae). Six lineages contained trans-oceanic sister taxa, and variation in genetic divergence between sister taxa revealed relationships that range from very recent dispersal to ancient vicariance. Dispersal was most recent and frequent in species that spend the larval stage in standing water, adding to evidence that these evolutionarily unstable habitats may select for ecological traits that increase dispersal in insects. Ancestral state likelihood analysis suggested at least one Afrotropical lineage had its origin in Madagascar, demonstrating that unidirectional dispersal from a continental source may be too simplistic. We conclude that the Malagasy mayfly fauna should be considered in a biogeographical context that extends beyond Madagascar itself, encompassing trans-oceanic dispersal within multiple lineages

Distance Factors in the Foreign Market Entry of Software SMEs

Recent studies have indicated that the internationalization process of software SMEs is somewhat independent on the effect of psychic or geographic distance. However, these studies have analyzed the general pattern of entries where software SMEs not commonly follow a step-wise entry route from nearby countries to distant ones. Thus, it remains unknown what the effect of psychic and geographical distance is when these firms enter a distant foreign market. The findings in this case study reveal that psychic and geographic distance inhibited the foreign market entry of software SMEs. However, the distant foreign market entry of these firms was facilitated by distance-bridging and distance-compressing factors enabling foreign business operations despite the significant distance between the home and target country.peerReviewe