Positron Emission Tomography Techniques to Measure Active Inflammation, Fibrosis and Angiogenesis in Hypertensive Heart Failure

Heart failure, which is responsible for a high number of deaths worldwide, can develop due to chronic hypertension. Heart failure can involve and progress through several different pathways, including: fibrosis, inflammation, and angiogenesis. Early and specific detection of changes in the myocardium during the transition to heart failure can be made via the use of molecular imaging techniques, including positron emission tomography (PET). Traditional cardiovascular PET techniques, such as myocardial perfusion imaging and sympathetic innervation imaging, have been established at the clinical level but are often lacking in pathway and target specificity that is important for assessment of heart failure. Therefore, there is a need to identify new PET imaging markers of inflammation, fibrosis and angiogenesis that could aid diagnosis, staging and treatment of hypertensive heart failure. This review will provide an overview of key mechanisms underlying hypertensive heart failure and will present the latest developments in PET probes for detection of cardiovascular inflammation, fibrosis and angiogenesis. Currently, selective PET probes for detection of angiogenesis remain elusive but promising PET probes for specific targeting of inflammation and fibrosis are rapidly progressing into clinical use

SKOR1 mediates FER kinase-dependent invasive growth of breast cancer cells

High expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity of FER is essential for its oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MB-231 cells reduces migration and invasion, as well as metastasis when xenografted into a mouse model of breast cancer. Using the FERASKI system, we identified Ski family transcriptional corepressor 1 (SKOR1) as a direct FER kinase substrate. SKOR1 loss phenocopies FER inhibition, leading to impaired proliferation, migration and invasion, and inhibition of breast cancer growth and metastasis formation in mice. We show that SKOR1 Y234, a candidate FER phosphorylation site, is essential for FER-dependent tumor progression. Finally, our work suggests that the SKOR1 Y234 residue promotes Smad2/3 signaling through SKOR1 binding to Smad3. Our study thus identifies SKOR1 as a mediator of FER-dependent progression of high-risk breast cancers. Cancer Signaling networks and Molecular Therapeutic

Characterisation of an atherosclerotic micro-calcification model using ApoE-/- mice and PET/CT

Intraplaque calcification is a prominent feature of advanced atherosclerotic plaque development. Current clinical evidence suggests that the size of calcium deposit may confer different effects on plaque stability [1], [2], [3]. Macro-calcified deposits (CT detected) are thought to confer plaque stability whereas micro-calcification ([18F]NaF PET detected) are thought to be a feature of high-risk ‘vulnerable’ plaques which are prone to rupture. Following on from the emerging role of micro-calcification in high risk plaques within the clinic [4], there is now an urgent need for preclinical atherosclerotic models with this feature to gain mechanistic insights and assess the impact of calcification-targeted therapies. Using a combination of invasive and ex vivo methods, ApoE−/− mice placed on an atherogenic diet have been shown to develop intraplaque calcification [5]. Additionally, [18F]NaF PET/CT has been used to assess the impact of exercise on calcification in ApoE−/− mice on a western diet [6]. In this study, we set out to determine if [18F]NaF PET/CT could be used to non-invasively detect and quantify micro-calficiation in the ApoE−/− high cholesterol diet (HCD) mouse model, and examine the temporal nature of this process

Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors

Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance

Movements and site fidelity of killer whales (Orcinus orca) relative to seasonal and long-term shifts in herring (Clupea harengus) distribution

Predators specialising on migratory prey that frequently change migration route face the challenge of finding prey with an unpredictable distribution. Here, we used photo-identification data to investigate whether killer whales observed in herring overwintering and spawning grounds off Iceland follow herring year-round, as previously proposed, and have the ability to adapt to long-term changes in herring distribution. Of 327 identified whales seen more than once, 45% were seen in both grounds, and were thus presumed herring-specialists, likely following herring year-round, while others were only seen on one of the grounds, possibly following herring to unsampled grounds or moving to other locations and exploiting different prey. High seasonal site fidelity to herring grounds, long-term site fidelity to herring spawning grounds, and matches of individual whales between past and recently occupied herring overwintering grounds showed an ability to adapt to long-term changes in prey distribution as well as diversity of movement patterns which are maintained over time, likely as socially-learnt traditions. Such population structuring shows that the movement patterns and foraging ecology of herring-eating killer whales are more complex than previously assumed and must be taken into account in future population assessments. Identifying the factors driving these differences in movements and resource use will be relevant towards our understanding of how prey predictability may drive specialization in this and other top predator species

A multilevel society of herring-eating killer whales indicates adaptation to prey characteristics

This work was supported by the Fundação para a Ciência e a Tecnologia (grant numbers SFSFRH/BD/30303/2006 and SFRH/BD/84714/2012); Icelandic Research Fund (i. Rannsóknasjóđur, grant number 120248402); National Geographic Society Science and Exploration Europe (grant number GEFNE65-12); Office of Naval Research (grant number N00014-08-10984); and a Russell Trust Award from the University of St. Andrews.Non-social factors can influence animal social structure. In killer whales (Orcinus orca), fish- versus mammal-eating ecological differences are regarded as key ecological drivers of their multilevel society, including group size, but the potential importance of specific target prey remains unclear. Here, we investigate the social structure of herring-eating killer whales in Iceland and compare it to the described social structures of primarily salmon- and seal-eating populations in the Northeast Pacific, which form stable coherent basic units nested within a hierarchical multilevel society. Using 29023 photographs collected over 6 years, we examined the association patterns of 198 individuals combining clustering, social network structure, and temporal patterns of association analysis. The Icelandic population had largely weak but non-random associations, which were not completely assorted by known ranging patterns. A fission–fusion dynamic of constant and temporary associations was observed but this was not due to permanent units joining. The population-level society was significantly structured but not in a clear hierarchical tier system. Social clusters were highly diverse in complexity and there were indications of subsclusters. There was no indication of dispersal nor strong sex differences in associations. These results indicate that the Icelandic herring-eating killer whale population has a multilevel social structure without clear hierarchical tiers or nested coherent social units, different from other populations of killer whales. We suggest that local ecological context, such as the characteristics of the specific target prey (e.g., predictability, biomass, and density) and subsequent foraging strategies may strongly influence killer whale social association patterns.PostprintPeer reviewe

Draft Genome Sequence of Frankia sp. Strain CN3, an Atypical, Noninfective (Nod–) Ineffective (Fix–) Isolate from Coriaria nepalensis

We report here the genome sequence of Frankia sp. strain CN3, which was isolated from Coriaria nepalensis. This genome sequence is the first from the fourth lineage of Frankia, strains of which are unable to reinfect actinorhizal plants. At 10 Mb, it represents the largest Frankia genome sequenced to date