A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism

A microPET comparison of the effects of etifoxine and diazepam on [11C]flumazenil uptake in rat brains

International audienceUsing positron emission tomography (PET), the present study assessed the binding of [11C]flumazenil to GABA-A receptors in anesthetized rats following a single intravenous injection of an active dose of either etifoxine (25 mg/kg) or diazepam (1 mg/kg), which are both anxiolytic drugs. [11C]flumazenil binding was measured in five discrete brain structures, namely the caudate putamen, hippocampus, cerebellum, occipital cortex and parietal cortex. As expected, diazepam injection produced a significant decrease in [11C]flumazenil binding, which was interpreted as benzodiazepine GABA-A receptor occupancy, whereas etifoxine increased the binding of [11C]flumazenil. This first use of in vivo imaging after etifoxine administration revealed the activated binding pattern of [11C]flumazenil and highlighted the pharmacological differences between etifoxine and benzodiazepines. Using the same [11C]flumazenil radiotracer, PET neuroimaging could be applied to larger animals and, ultimately, to human subjects, thus providing new perspectives for better defining the molecular pharmacology of etifoxine

Differential effects of amyloid-beta 1–40 and 1–42 fibrils on 5-HT1A serotonin receptors in rat brain

International audienceEvidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT1AR) after intrahippocampal injections of amyloid-beta 1–40 (Aβ40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [18F]MPPF revealing an overexpression of 5-HT1AR in the hippocampus of patients with mild cognitive impairment. Because Aβ40 and Aβ42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT1AR reactivity by injecting them, separately, into the hippocampus or striatum of rats. [18F]MPPF in vitro autoradiography revealed that Aβ40 fibrils, but not Aβ42, were triggering an overexpression of 5-HT1AR in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aβ42 fibrils caused more pathophysiological damages than Aβ40 fibrils. The mechanisms of Aβ40 fibrils–induced 5-HT1AR expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed

Ventricular muscarinic receptor remodeling in patients with and without primary ventricular fibrillation. An imaging study

International audienc

Evaluation of Myelin Radiotracers in the Lysolecithin Rat Model of Focal Demyelination: Beware of Pitfalls!

International audienceThe observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. e lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. e in uence of these side e ects on imaging ndings has never been carefully assessed. e present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. e prototypical amyloid radiotracer [ 11 C]PIB was used to show that in vivo PET does not provide su cient sensitivity to reliably track myelin changes and may be sensitive to LPC side e ects instead of demyelination as such. Ex vivo autoradiography with a uorine radiotracer should be preferred, to adequately evaluate and compare radiotracers for the assessment of myelin content

Imaging Dopamine and Serotonin Systems on MPTP Monkeys: A Longitudinal PET Investigation of Compensatory Mechanisms

International audienceIt is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measured in vivo longitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([ 18 F]DOPA), dopamine D 2 /D 3 receptors ([ 11 C]raclopride), and serotonin transporter 11 C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio) benzylamine ([ 11 C]DASB) and serotonin 1A receptor ([ 18 F]MPPF) levels between four different states (baseline, early symptomatic, full symptomatic and recovered). During the early symptomatic state, we observed increases of [ 18 F]DOPA uptake in the anterior putamen, [ 11 C]raclopride binding in the posterior striatum, and 2-methoxyphenyl-(N-2-pyridinyl)-p-[ 18 F]fluoro-benzamidoethylpiperazine [ 18 F]MPPF uptake in the orbitofrontal cortex and dorsal ACC. After recovery from motor symptoms, the results mainly showed decreased [ 11 C]raclopride binding in the anterior striatum and limbic ACC. In addition, our findings supported the importance of pallidal dopaminergic neurotransmission in both the early compensatory mechanisms and the functional recovery mechanisms , with reduced aromatic L-amino acid decarboxylase (AAAD) activity closely related to the appearance or perseveration of motor symptoms. In parallel, this study provides preliminary evidence of the role of the serotonergic system in compensatory mechanisms. Nonetheless, future studies are needed to determine whether there are changes in SERT availability in the early symptomatic state and if [ 18 F]MPPF PET imaging might be a promising biomarker of early degenerative changes in PD. The present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms

Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate

International audienceSerotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/ serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the L-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms