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Accurate knowledge of the exact stopping location of ions inside the patient would allow full exploitation of their ballistic properties for patient treatment. The localized energy deposition of a pulsed particle beam induces a rapid temperature increase of the irradiated volume and leads to the emission of ionoacoustic (IA) waves. Detecting the time-of-flight (ToF) of the IA wave allows inferring information on the Bragg peak location and can henceforth be used for in-vivo range verification. A challenge for IA is the poor signal-to-noise ratio at clinically relevant doses and viable machines. We present a frequency-based measurement technique, labeled as ionoacoustic tandem phase detection (iTPD) utilizing lock-in amplifiers. The phase shift of the IA signal to a reference signal is measured to derive the ToF. Experimental IA measurements with a 3.5 MHz lead zirconate titanate (PZT) transducer and lock-in amplifiers were performed in water using 22 MeV proton bursts. A digital iTPD was performed in-silico at clinical dose levels on experimental data obtained from a clinical facility and secondly, on simulations emulating a heterogeneous geometry. For the experimental setup using 22 MeV protons, a localization accuracy and precision obtained through iTPD deviates from a time-based reference analysis by less than 15 μm. Several methodological aspects were investigated experimentally in systematic manner. Lastly, iTPD was evaluated in-silico for clinical beam energies indicating that iTPD is in reach of sub-mm accuracy for fractionated doses < 5 Gy. iTPD can be used to accurately measure the ToF of IA signals online via its phase shift in frequency domain. An application of iTPD to the clinical scenario using a single pulsed beam is feasible but requires further development to reach

International audience; In the cerebral cortex, GABAergic interneurons and oligodendrocyte lineage cells share different characteristics and interact despite being neurons and glial cells, respectively. These two distinct cell types share common embryonic origins and are born from precursors expressing similar transcription factors. Moreover, they highly interact with each other through different communication mechanisms during development. Notably, cortical oligodendrocyte precursor cells (OPCs) receive a major and transient GABAergic synaptic input, preferentially from parvalbumin-expressing interneurons, a specific interneuron subtype recently recognized as highly mye-linated. In this review, we highlight the similarities and interactions between GABAergic interneurons and oligodendrocyte lineage cells in the cerebral cortex and suggest potential roles of this intimate interneuron-oligodendroglia relationship in cortical construction. We also propose new lines of research to understand the role of the close link between interneurons and oligodendroglia during cortical development and in pathological conditions such as schizophrenia.

Aim To investigate the feasibility of dose escalation using rapid arc (RA) and Helical Tomotherapy (HT) for patients with upper, middle and distal esophageal carcinomas, even for large tumor volumes. Background In esophageal cancer, for patients with exclusive radio-chemotherapy, local disease control remains poor. Planning study with dose escalation was done for two sophisticated modulated radiotherapy techniques: Rapid arc against Tomotherapy. Materials and methods Six patients treated with a RA simultaneous integrated boost (SIB) of 60 Gy were re-planned for RA and HT techniques with a SIB dose escalated to 70 Gy. Dose volume histogram statistics, conformity indices and homogeneity indices were analyzed. For a given set of normal tissue constraints, the capability of each treatment modality to increase the GTV dose to 70 Gy was investigated. Results Either HT or VMAT may be used to escalate the dose delivered in esophageal tumors while maintaining the spinal cord, lung and heart doses within tolerance. Adequate target coverage was achieved by both techniques. Typically, HT achieved better lung sparing and PTV coverage than did RA. Conclusions Dose escalation for esophageal cancer becomes clinically feasible with the use of RA and HT. This promising result could be explored in a carefully controlled clinical study which considered normal tissue complications and tumor control as endpoints.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERK Thr188 autophosphorylation as a regulatory phosphorylation of ERK1/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERK Thr188 phosphorylation permits the impairment of ERK1/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERK Thr188 phosphorylation on cardiomyocyte hypertrophy and cell survival was analyzed in isolated cells and in mice using the mutant ERK2 T188A , which is dominant-negative for ERK Thr188 signaling. ERK2 T188A efficiently attenuated cardiomyocyte hypertrophic responses to phenylephrine and to chronic pressure overload, but it affected neither antiapoptotic ERK1/2 signaling nor overall physiological cardiac function. In contrast to its inhibition of pathological hypertrophy, ERK2 T188A did not interfere with physiological cardiac growth occurring with age or upon voluntary exercise. A preferential role of ERK Thr188 phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERK Thr188 phosphorylation was increased 8.5 ± 1.3-fold in high-gradient, rapidly progressing cases (≥40 mmHg gradient), whereas in low-gradient, slowly progressing cases, the increase was not significant. Because interference with ERK Thr188 phosphorylation ( i ) inhibits pathological hypertrophy and ( ii ) does not impair antiapoptotic ERK1/2 signaling and because ERK Thr188 phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERK Thr188 phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.

Optimizing the care management of patients is a major issue for our society. In Brittany-Pays-de-la-Loire (almost 10% of French population), an observatory of cancer has been created in 2003. Its main objective was the follow-up of expensive drugs. The knowledge of the use of these drugs in clinical practice has led to development of a thesaurus of good use. Thus, regular exchanges between clinicians have almost totally reduced not medically justified prescriptions by the thesaurus after and before administration to patient. The thesaurus has given away to national guidelines from 2007. For example, in these two regions, optimization of the use of gemcitabine and bevacizumab has allowed to save respectively 2.5 millions euros between 2005 and 2008 and 3 millions euros between 2009 and 2010 (breast cancer only). Optimizing the use of anticancer drugs has allowed a real health economy without any bad impact on patient management. Respecting medical ethics, the main objective remains to optimize health care. This highly participation of clinicians currently allows to reflect together on the relevance of the last chemotherapy.

Oligodendrocytes are the myelin-forming cells of the vertebrate CNS. Little is known about the molecular control of region-specific oligodendrocyte development. Here, we show that oligodendrogenesis in the mouse rostral hindbrain, which is organized in a metameric series of rhombomere-derived (rd) territories, follows a rhombomere-specific pattern, with extensive production of oligodendrocytes in the pontine territory (r4d) and delayed and reduced oligodendrocyte production in the prepontine region (r2d, r3d). We demonstrate that segmental organization of oligodendrocytes is controlled byHoxgenes, namelyHoxa2andHoxb2. Specifically,Hoxa2loss of function induced a dorsoventral enlargement of theOlig2/Nkx2.2-expressing oligodendrocyte progenitor domain, whereas conditionalHoxa2overexpression in theOlig2+domain inhibited oligodendrogenesis throughout the brain. In contrast,Hoxb2deletion resulted in a reduction of the pontine oligodendrogenic domain. CompoundHoxa2−/−/Hoxb2−/−mutant mice displayed the phenotype ofHoxb2−/−mutants in territories coexpressingHoxa2andHoxb2(rd3, rd4), indicating thatHoxb2antagonizesHoxa2during rostral hindbrain oligodendrogenesis. This study provides the firstin vivoevidence thatHoxgenes determine oligodendrocyte regional identity in the mammalian brain.

Aims Activation of the β1-adrenergic receptor and its G protein, Gs, induces cardiac hypertrophy. However, activation of classic Gαs effectors, adenylyl cyclases (AC) and protein kinase A, is not sufficient for induction of hypertrophy, which suggests the involvement of additional pathway(s) activated by Gs. Recently, we discovered that βγ subunits of Gq induce phosphorylation of the extracellular regulated kinases 1 and 2 (Erk1/2) at threonine188 and thereby induce hypertrophy. Here we investigated whether β-adrenergic receptors might also induce cardiac hypertrophy via ErkThr188 phosphorylation. Methods and results β-Adrenergic receptor activation induced ErkThr188 phosphorylation in mouse hearts and in neonatal cardiomyocytes. Inhibition of Erk1/2 or overexpression of ErkThr188 phosphorylation-deficient mutants (Erk2T188A and Erk2T188S) significantly attenuated β–adrenergic cardiomyocyte hypertrophy in vitro . Erk activity was stimulated by both isoproterenol and the direct AC activator forskolin, but only isoproterenol induced ErkThr188 phosphorylation. ErkThr188 phosphorylation required Gβγ released from Gs and was prevented by Gβγ inhibition. Similarly, isoproterenol, but not forskolin, induced nuclear accumulation of Erk and cardiomyocyte hypertrophy. Long-term application of isoproterenol in mice caused left ventricular hypertrophy and cardiac remodelling, and this was reduced in Erk2T188S transgenic mice, supporting the physiological relevance of ErkThr188 phosphorylation. Conclusions Activation of Gs by β-adrenergic receptors leads to (i) canonical Erk1/2 activation via AC, and (ii) release of Gβγ, which then associates with activated Erk1/2 and induces ErkThr188 phosphorylation, causing nuclear accumulation of Erk and ultimately cardiomyocyte hypertrophy. These findings reveal a new pathway critically involved in β-adrenergically mediated cardiac hypertrophy and may yield new therapeutic strategies against hypertrophic remodelling.

Boundary cap cells (BC), which express the transcription factor Krox20, participate in the formation of the boundary between the central nervous system and the peripheral nervous system. To study BC stemness, we developed a method to purify and amplify BC in vitro from Krox20 Cre/+ , R26R YFP/+ mouse embryos. We show that BC progeny are EGF/FGF2-responsive, form spheres, and express neural crest markers. Upon growth factor withdrawal, BC progeny gave rise to multiple neural crest and CNS lineages. Transplanted into the developing murine forebrain, they successfully survived, migrated, and integrated within the host environment. Surprisingly, BC progeny generated exclusively CNS cells, including neurons, astrocytes, and myelin-forming oligodendrocytes. In vitro experiments indicated that a sequential combination of ventralizing morphogens and glial growth factors was necessary to reprogram BC into oligodendrocytes. Thus, BC progeny are endowed with differentiation plasticity beyond the peripheral nervous system. The demonstration that CNS developmental cues can reprogram neural crest-derived stem cells into CNS derivatives suggests that BC could serve as a source of cell type-specific lineages, including oligodendrocytes, for cell-based therapies to treat CNS disorders.

During development, boundary cap cells (BC) and neural crest cell (NCC) derivatives generate Schwann cells (SC) of the spinal roots and a subpopulation of neurons and satellite cells in the dorsal root ganglia. Despite their stem-like properties, their therapeutic potential in the diseased central nervous system (CNS) was never explored. The aim of this work was to explore BC therapeutic potential for CNS remyelination. We derived BC from Krox20Cre × R26RYfp embryos at E12.5, when Krox20 is exclusively expressed by BC. Combining microdissection and cell fate mapping, we show that acutely isolated BC are a unique population closely related but distinct from NCC and SC precursors. Moreover, when grafted in the demyelinated spinal cord, BC progeny expands in the lesion through a combination of time-regulated processes including proliferation and differentiation. Furthermore, when grafted away from the lesion, BC progeny, in contrast to committed SC, show a high migratory potential mediated through enhanced interactions with astrocytes and white matter, and possibly with polysialylated neural cell adhesion molecule expression. In response to demyelinated axons of the CNS, BC progeny generates essentially myelin-forming SC. However, in contact with axons and astrocytes, some of them generate also myelin-forming oligodendrocytes. There are two primary outcomes of this study. First, the high motility of BC and their progeny, in addition to their capacity to remyelinate CNS axons, supports the view that BC are a reservoir of interest to promote CNS remyelination. Second, from a developmental point of view, BC behavior in the demyelinated CNS raises the question of the boundary between central and peripheral myelinating cells.

Over the past two decades, basic research has revealed a complex network of regulatory mechanisms that control the ERK1/2-signaling cascade. ERK1/2 mediate cardiac hypertrophy, a major risk factor for the development of arrhythmias, heart failure and sudden death, but also beneficial effects, e.g. protection of the heart from cell death and ischemic injury. Selective targeting of these ambiguous ERK functions could provide a powerful tool in the treatment of cardiac disease. This short review will discuss new mechanistic insights into ERK1/2-dependent development of cardiac hypertrophy and the prospect to translate this knowledge into future therapeutic strategies.

Given the ongoing decline of both pollinators and plants, it is crucial to implement effective methods to describe complex pollination networks across time and space in a comprehensive and high-throughput way. Here we tested if metabarcoding may circumvent the limits of conventional methodologies in detecting and quantifying plant-pollinator interactions. Metabarcoding experiments on pollen DNA mixtures described a positive relationship between the amounts of DNA from focal species and the number of trnL and ITS1 sequences yielded. The study of pollen loads of insects captured in plant communities revealed that as compared to the observation of visits, metabarcoding revealed 2.5 times more plant species involved in plant-pollinator interactions. We further observed a tight positive relationship between the pollen-carrying capacities of insect taxa and the number of trnL and ITS1 sequences. The number of visits received per plant species also positively correlated to the number of their ITS1 and trnL sequences in insect pollen loads. By revealing interactions hard to observe otherwise, metabarcoding significantly enlarges the spatiotemporal observation window of pollination interactions. By providing new qualitative and quantitative information, metabarcoding holds great promise for investigating diverse facets of interactions and will provide a new perception of pollination networks as a whole.