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Fuster, V.

Publications and source records attributed to Fuster, V..

2 recordsLinked to original sources

A White Matter Atlas and Common Connectivity Space Facilitate the Pig as a Translational Model in Neuroscience

Neuroimagings capability to quickly and rapidly phenotype the cortical organization of the whole brain brings with it the possibility to extend our understanding of cortical organization across the mammalian lineage. However, neuroimaging has thus far generally limited itself to a small number of species, with most animal studies being performed in either rodents or Non-Human Primates. Here we perform a first pass characterization of an animal which has recently seen its stock rise in the neuroscience community with the development of new models of neurological disease; the domestic pig. Characterizing the structural connectome of the pig, we create a white matter atlas, and an anatomical template which we use to build a horizontal translation between the pig and human based on a connectivity blueprint approach. We find that conserved trends of structural connectivity across species enabled spatial prediction of regions of interest between the pig and human, showing the potential horizontal translations have as a tool to assess the translational validity of porcine models of neurological disease. Releasing the anatomical template, white matter atlas, and connectivity blueprints, we hope to ease and promote the acceptance of the pig as an alternative large-animal model by the neuroimaging community.

neuroscience

Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity

AimsAnthracycline-induced cardiotoxicity (AIC) is a serious adverse effect in a significant proportion of cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and ResultsForty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischemic pre-conditioning (RIPC, 3 cycles of 5 min leg ischemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each of five intracoronary doxorubicin injections (0.45 mg/kg) given at weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at weeks 6, 8, 12, and 16. After 16-week CMR, pigs were sacrificed and tissue samples collected. In study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed 2 weeks after the third dose. In Study 1, LVEF remained unchanged in doxorubicin-treated pigs until week 6 (time of the fourth doxorubicin injection). From there on, LVEF progressively declined, but LVEF depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5{+/-}9.1% vs 32.5{+/-}8.7%, p=0.04). Preserved LVEF was mainly due to conserved contractile function, as evidenced by smaller LVESV, and better regional contractile function. In Study 2, transmission electron microscopy (TEM) after 3 doxorubicin doses showed fragmented mitochondria with severe morphological abnormalities in RIPC+Doxo pigs, together with upregulation of fission proteins and autophagy markers on western blot. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was significantly less severe in the RIPC+Doxo pigs. ConclusionIn a translatable large animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from the early stages of AIC. RIPC is a promising intervention for testing in clinical trials in AIC.

molecular biology