Canine Mammary Tumours Are Affected by Frequent Copy Number Aberrations,including Amplification of MYC and Loss of PTEN

BackgroundCopy number aberrations frequently occur during the development of many cancers. Such events affect dosage of involved genes and may cause further genomic instability and progression of cancer. In this survey, canine SNP microarrays were used to study 117 canine mammary tumours from 69 dogs.ResultsWe found a high occurrence of copy number aberrations in canine mammary tumours, losses being more frequent than gains. Increased frequency of aberrations and loss of heterozygosity were positively correlated with increased malignancy in terms of histopathological diagnosis. One of the most highly recurrently amplified regions harbored the MYC gene. PTEN was located to a frequently lost region and also homozygously deleted in five tumours. Thus, deregulation of these genes due to copy number aberrations appears to be an important event in canine mammary tumour development. Other potential contributors to canine mammary tumour pathogenesis are COL9A3, INPP5A, CYP2E1 and RB1. The present study also shows that a more detailed analysis of chromosomal aberrations associated with histopathological parameters may aid in identifying specific genes associated with canine mammary tumour progression.ConclusionsThe high frequency of copy number aberrations is a prominent feature of canine mammary tumours as seen in other canine and human cancers. Our findings share several features with corresponding studies in human breast tumours and strengthen the dog as a suitable model organism for this disease.     

Chemoselective synthesis of erythromycin A ketolides substituted in the C10-methyl group

The substrate for selective substitution in the C10-methyl group in erythromycin A derivatives was 10,11-anhydro-6O-methyl-descladinosylerythromycin. The latter, as an N-oxide, was reacted with NBS in acetic acid to form an allylic acetate. Nucleophilic substitutions and carbylation by Pd-catalysed cross-coupling reactions provided products substituted in the C10-methyl group. Methods for the preparation of 10-methylene derivatives of 11N,12O-cyclocarbamate 3-ketolides are described. The methylene group is part of an alpha,beta-unsaturated carbonyl system involving the 9-keto group. The products from conjugated addition are substituted in the C10-methyl group.     

Fish Oil Supplementation Alters the Plasma Lipidomic Profile and Increases Long-Chain PUFAs of Phospholipids and Triglycerides in Healthy Subjects

Background

While beneficial health effects of fish and fish oil consumption are well documented, the incorporation of n-3 polyunsaturated fatty acids in plasma lipid classes is not completely understood. The aim of this study was to investigate the effect of fish oil supplementation on the plasma lipidomic profile in healthy subjects.

Methodology/Principal Findings

In a double-blinded randomized controlled parallel-group study, healthy subjects received capsules containing either 8 g/d of fish oil (FO) (1.6 g/d EPA+DHA) (n = 16) or 8 g/d of high oleic sunflower oil (HOSO) (n = 17) for seven weeks. During the first three weeks of intervention, the subjects completed a fully controlled diet period. BMI and total serum triglycerides, total-, LDL- and HDL-cholesterol were unchanged during the intervention period. Lipidomic analyses were performed using Ultra Performance Liquid Chromatography (UPLC) coupled to electrospray ionization quadrupole time-of-flight mass spectrometry (QTOFMS), where 568 lipids were detected and 260 identified. Both t-tests and Multi-Block Partial Least Square Regression (MBPLSR) analysis were performed for analysing differences between the intervention groups. The intervention groups were well separated by the lipidomic data after three weeks of intervention. Several lipid classes such as phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, sphingomyelin, phosphatidylserine, phosphatidylglycerol, and triglycerides contributed strongly to this separation. Twenty-three lipids were significantly decreased (FDR<0.05) in the FO group after three weeks compared with the HOSO group, whereas fifty-one were increased including selected phospholipids and triglycerides of long-chain polyunsaturated fatty acids. After seven weeks of intervention the two intervention groups showed similar grouping.

Conclusions/Significance

In healthy subjects, fish oil supplementation alters lipid metabolism and increases the proportion of phospholipids and triglycerides containing long-chain polyunsaturated fatty acids. Whether the beneficial effects of fish oil supplementation may be explained by a remodeling of the plasma lipids into phospholipids and triglycerides of long-chain polyunsaturated fatty acids needs to be further investigated.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01034423","term_id":"NCT01034423"}}NCT01034423     

Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimer's Disease

Background

Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral β-amyloidosis, one of the characteristic hallmarks of Alzheimer''s disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.

Methodology/Principal Findings

The transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APP_swe) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral β-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a γ-secretase inhibitor we show a dose dependent reduction of soluble amyloid β levels in the brain.

Conclusions

ARTE10 mice develop a cerebral β-amyloidosis closely resembling the β-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD.     

Positron emission tomography ligand activation studies in the sports sciences: measuring neurochemistry in vivo

Functional neuroimaging with magnetic resonance imaging (fMRI) or positron emission tomography (PET) provides the methodology to unravel some of the fascinating, but hitherto largely unresolved interactions between physical exercise and brain function. Phenomena such as raised mood, pain modulation, and sport addiction associated with physical exercise are highly interesting psychophysical models that require further in depth understanding at the neurotransmitter level. PET ligand displacement studies allow in vivo monitoring of endogenous transmitter trafficking in the entire brain and, thereby, to identify the link between exercise-induced behavioral measures and the endogenous neurotransmitter release. This review focuses on the methodology of ligand displacement in the opioidergic system, which together with the dopaminergic system has been considered as a central neurotransmitter system underlying diverse sport-induced psychophysical effects. Understanding the basic principles of exercise-induced transmitter release in the brain will potentially aid clinical applications of endurance training, both as a preventative or therapeutic intervention.     

DISPERSAL and BYCATCH MORTALITY IN GRAY, HALICHOERUS GRYPUS, AND HARBOR, PHOCA VITULINA, SEALS TAGGED AT THE NORWEGIAN COAST

Between 1975 and 1998, 3,571 gray and 630 harbor seal pups were tagged along the Norwegian coast, and 259 (7%) gray and 80 (13%) harbor seal tags were returned. Incidental mortality, mainly in bottom-set nets, accounted for the majority of deaths (79% in gray and 48% in harbor seals, respectively). Seals were most vulnerable to incidental mortality in fishing gear during the first three months after birth, but high incidental mortality prevailed during the first 8–10 mo. Gray seals dispersed more widely (mean distance: 120 km) than harbor seals (mean distance: 69 km). Both species dispersed most widely during the two first months after tagging. The maximum distance moved was 739 km for gray and 463 km for harbor seals. Strong fidelity for their place of birth was observed in adult gray seals during breeding season. No significant difference in incidental mortality was detected between the areas of tagging. However, for 37 harbor seals tagged in a 724 km nature reserve no returns were reported.     

Muscle fibers,ubiquinone and exercise capacity in effort angina

Seventeen male patients with ischaemic heart disease (IHD) and effort angina performed OBLA exercise stress tests (set to 2.0 mmol × 1^–1). They had muscle biopsies from the vastus lateralis muscle the day before coronary by-pass grafting, and from the internal and external intercostal, diaphragm and gastrocnemius muscles during surgery. They had a low W_OBLA (83 ± 6 W, mean ± 1 S.E.M), W_OBLA corresponded to 79 ± 4% (% W_OBLA) of W_SL (symptom limited or maximal capacity = 111 ± 11 W). Peak blood lactate concentration averaged 2.9 mmol × 1^–1. Muscle fibre composition disclosed a depressed percent slow twitch (ST or red) muscle fibres in the vastus lateralis and intercostal muscles (%ST). The diaphragm and gastrocnemius muscles had normal %ST. Intercostal muscles had elevated values for the fast twitch muscle fibre (FT) subgroup FTa indicative of endurance adaptation. The vastus lateralis, gastrocnemius and diaphragm muscles had normal muscle ubiquinone (UQ) contents, whereas the intercostals were depleted. Plasma contents of the antioxidants UQ and -tocopherol were low as compared to healthy man.The study was carried out by the Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden.     

Muscle ubiquinone in male effort angina patients

Seven (7) males with effort angina and listed for coronary by-pass surgery had muscle biopsies taken from their vastus lateralis muscle for determination of muscle fiber types (%ST), ubiquinone (vitamin Q, UQ), oxidative and fermentative enzyme activities. Graded cycle ergometer exercise to determine intensities corresponding to onset of blood lactate accumulation set to 2.0 nimol × 1^–1 (W_OSLA) and symptom limited exercise (maximal, W_SL) were also undertaken. W_OBLA was positively related to %ST (r = 0.92, p < 0.001). %ST was on the other hand inversely related to UQ (r =–0.82, p < 0.05), the heart specific LD subunit LD-H (r =–0.96, p < 0.001), the isozyme LD₃ as the fraction of LD (%LD3) (r=–0.93, p < 0.01), and the CK isozyme CKMB as the fraction of CK (%CKMB) (r = –0.88, p < 0.05). It was suggested that muscle UQ depletion in the patients was related to molecular oxygen and free oxygen radical formation. The lack of antioxidants then caused a radical trauma specifically to the ST fiber and their mitochondria. This could be a cause and-effect explanation for the selective ST fiber downregulation in effort angina and heart failure in general.