Phenotypic Diversity of Vascular Smooth Muscle Cells in Pulmonary Arterial Hypertension: Implications for Therapy.

Pulmonary arterial hypertension (PAH) is a progressive incurable condition that is characterized by extensive remodeling of the pulmonary circulation, leading to severe right-sided heart failure and death. Similar to other vascular contractile cells, pulmonary arterial smooth muscle cells play central roles in physiological and pathologic vascular remodeling because of their remarkable ability to dynamically modulate their phenotype to ensure contractile and synthetic functions. The dysfunction and molecular mechanisms underlying their contribution to the various pulmonary vascular lesions associated with PAH have been a major focus of research. The aim of this review is to describe the medial and nonmedial origins of contractile cells in the pulmonary vascular wall and present evidence of how they contribute to the onset and progression of PAH. We also highlight specific potential target molecules and discuss future directions that are being explored to widen the therapeutic options for the treatment of PAH

Control electronics for the CIME RF system

International audienceThe paper describes the characteristics of the amplitude and phase loops for the accelerating voltage, thecontrol system which manages securities, sparks and multipactor problems for the cavities. Design methods andresults during first power tests are presented

Status report on GANIL-SPIRAL1

International audienceThe GANIL facility (Caen, France) (Figure 1) is dedicated to the acceleration of heavy ion beams for nuclear physics, atomic physics, radiobiology and material irradiation. The production of radioactive ion beams for nuclear physics studies represents the main part of the activity. Two complementary methods are used: the Isotope Separation On-Line (ISOL, the SPIRAL1 facility) and the In-Flight Separation techniques (IFS). SPIRAL1, the ISOL facilty, is running since 2001, producing and post-accelerating radioactive ion beams. The energy range available goes from 1.2 MeV/A to 25 MeV/A with a compact cyclotron (CIME, K=265). The running mode of this machine will be recalled as well as a review of the operation from 2001 to 2006. A point will be done on the past, present and future projects which allow to continue to develop the capacities of this equipment and to answer the new demands from the physicists, such as new beamlines for low or high energy experiments, new diagnotics of control or the adaptation of an identification system using Silicon, Germanium or plastic detectors in the requirements of the operation evironnement

Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets

Tuberculosis remains a serious threat to human health world-wide, and improved efficiency of medical treatment requires a better understanding of the pathogenesis and the discovery of new drugs. In the present study, we performed a whole-cell based screen in order to complete the characterization of 168 compounds from the GlaxoSmithKline TB-set. We have established and utilized novel previously unexplored host-model systems to characterize the GSK compounds, i.e. the amoeboid organisms D. discoideum and A. castellanii, as well as a microglial phagocytic cell line, BV2. We infected these host cells with Mycobacterium marinum to monitor and characterize the anti-infective activity of the compounds with quantitative fluorescence measurements and high-content microscopy. In summary, 88.1% of the compounds were confirmed as antibiotics against M. marinum, 11.3% and 4.8% displayed strong anti-infective activity in, respectively, the mammalian and protozoan infection models. Additionally, in the two systems, 13-14% of the compounds displayed pro-infective activity. Our studies underline the relevance of using evolutionarily distant pathogen and host models in order to reveal conserved mechanisms of virulence and defence, respectively, which are potential "universal" targets for intervention. Subsequent mechanism of action studies based on generation of over-expresser M. bovis BCG strains, generation of spontaneous resistant mutants and whole genome sequencing revealed four new molecular targets, including FbpA, MurC, MmpL3 and GlpK

Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer.

Genomic alterations in cancer cells result in vulnerabilities that clinicians can exploit using molecularly targeted drugs, guided by knowledge of the tumour genotype. However, the selective activity of these drugs exerts an evolutionary pressure on cancers that can result in the outgrowth of resistant clones. Use of rational drug combinations can overcome resistance to targeted drugs, but resistance may eventually develop to combinatorial therapies. We selected MAPK- and PI3K-pathway inhibition in colorectal cancer as a model system to dissect out mechanisms of resistance. We focused on these signalling pathways because they are frequently activated in colorectal tumours, have well-characterised mutations and are clinically relevant. By treating a panel of 47 human colorectal cancer cell lines with a combination of MEK- and PI3K-inhibitors, we observe a synergistic inhibition of growth in almost all cell lines. Cells with KRAS mutations are less sensitive to PI3K inhibition, but are particularly sensitive to the combined treatment. Colorectal cancer cell lines with inherent or acquired resistance to monotherapy do not show a synergistic response to the combination treatment. Cells that acquire resistance to an MEK-PI3K inhibitor combination treatment still respond to an ERK-PI3K inhibitor regimen, but subsequently also acquire resistance to this combination treatment. Importantly, the mechanisms of resistance to MEK and PI3K inhibitors observed, MEK1/2 mutation or loss of PTEN, are similar to those detected in the clinic. ERK inhibitors may have clinical utility in overcoming resistance to MEK inhibitor regimes; however, we find a recurrent active site mutation of ERK2 that drives resistance to ERK inhibitors in mono- or combined regimens, suggesting that resistance will remain a hurdle. Importantly, we find that the addition of low concentrations of the BCL2-family inhibitor navitoclax to the MEK-PI3K inhibitor regimen improves the synergistic interaction and blocks the acquisition of resistance

Design of the MEBT rebunchers for the SPIRAL 2 driver

International audienceThe SPIRAL 2 project uses normal conducting rebunchers to accelerate high intensity beams of protons , deuterons and heavier ions. All cavities work at 88 Mhz , the beta is 0,04 and 3 rebunchers are located in the MEBT line, which accepts ions with A/q up to 6. The paper describes the RF design and the technological solutions proposed for an original 3 gap cavity , characterised by very large beam holes (60mm) and providing up to 120 kV of effective voltag

Refurbishment of the the DEE on a Cavity for a Compact Cyclotron

International audienceThis project relates to the restoration of the copper electrode of a resonator at GANIL. It makes following important problems of corrosion of the copper pipes.• Refurbishment of the DEE of a cavity in cooper for a compact cyclotron• Thermal computation• Implementation• Manufacturing• Three axe control• RF qualifications• Commissionnin

Que faire quand une pneumonie persiste? [How to handle a non-resolving pneumonia?]

Persistent pneumonias are frequent both in hospital and primary care settings. Several parameters have to be taken into account. Firstly the appropriateness of treatment; secondly the immune status of the host; and finally infectious complications need to be ruled out. Several non-infectious diagnoses can mimic a persistent infiltrate, such as neoplastic disorders, organising pneumonias, interstitial disorders and drug - or radiation-induced lung diseases. Uncommon pathogens will not respond to common treatment, for instance atypical bacteria, mycobacteria, fungi including Pneumocystis as well as viruses. Referral to a pulmonologist should be considered to perform a fiberoptic bronchoscopy

Pneumologie : ce qui a changé en 2022 [Pneumology: what's new in 2022]

This selection of pneumological novelties of the year 2022 is not limited to pharmacological acquisitions but also includes progress in diagnostic strategies and the global management of respiratory diseases. We have chosen three pneumological issues. As cannabis is the most consumed illegal substance in Switzerland, it is important to know its impact on pulmonary physiology. An update of the international guidelines on pulmonary fibrosis as well as the European guidelines on pulmonary hypertension provides practical answers to the many clinical problems encountered in the management of these diseases. The key messages from these two consensus documents are reported here