Assessing low laser damage densities of fused silica optics by means of a functional raster scan protocol.

The knowledge of the laser damage resistance of fused silica optics for their use in high-power lasers is of primary importance for the operation and maintenance of these facilities. Among the control procedures developed, one of the most relevant to date is the raster scan procedure [Lamaignère et al., Rev. Sci. Instrum. 78, 103105 (2007)]. This procedure is used to determine the damage density of optical components as a function of fluence. To date, this procedure takes into account all triggered damage sites, regardless of their size and/or morphology. We have added a step to this procedure, which consists in irradiating again all the damage sites with a series of shots to ascertain their ability to grow. This allows us to estimate the densities of growing damage sites, which are most critical for the safe operation of lasers. This pragmatic approach can be considered a functional test procedure. By applying this procedure to large optical areas, we were then able to measure extremely low damage densities (∼10-4 damage cm-2) over a wide range of fluences [0-18 J cm-2], corresponding to fluences to which the optics are irradiated during the operation of high-power lasers. We can then determine the damage law of a given set of optical components. This reference law makes it possible, on the one hand, to predict the lifetime of the optics. On the other hand, any deviation can then be analyzed with regard to this reference law. Thanks to the determination of confidence intervals, this functional procedure can also be used to delimit the reference law by upper and lower bounds.

High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells.

Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.

Flow cytometric detection of dyserythropoiesis: a sensitive and powerful diagnostic tool for myelodysplastic syndromes.

Several groups have published flow cytometry scores useful for the diagnosis or prognosis of myelodysplastic syndromes (MDS), mainly based on the detection of immunophenotypic abnormalities in the maturation of granulocytic/monocytic and lymphoid lineages. As anemia is the most frequent symptom of early MDS, the aim of this study was to identify markers of dyserythropoiesis relevant for the diagnosis of MDS analyzed by selecting erythroblasts in a whole no-lysis bone marrow strategy by using a nuclear dye. This prospective study included 163 patients, including 126 with cytopenias leading to MDS suspicion and 46 controls without MDS. In a learning cohort of 53 unequivocal MDS with specific markers, there was a significant difference between the coefficients of variation of mean fluorescence intensities of CD71 and CD36 in MDS patients compared with controls. These two parameters and the hemoglobin level were used to build a RED-score strongly suggestive of MDS if ≥ 3. Using the RED-score in the whole cohort, 80% of MDS or non-MDS patients were correctly classified. When combined with the flow score described by Ogata et al., this strategy allowed to reach a very high sensitivity of 88% of patients correctly classified.

[Anticoagulant clinics are they effective in France? Performance evaluation of six anticoagulant clinics concerning the management of vitamin K antagonists]. / Les cliniques d'anticoagulants sont-elles efficaces en France ? Évaluation des performances de six cliniques dans la gestion des traitements par antivitamines K.

PURPOSE: Recent data show that the quality of anticoagulation evaluated in patients receiving vitamin K antagonists (VKA) is not optimal in France. The aim of this retrospective study was to estimate the performances of six French anticoagulant clinics that manage VKA treatments over a 3-year period, from 2009 to 2011. METHODS: All clinics used the same rule based software. We determined the time spent in the therapeutic range (TTR), a surrogate end-point of quality of treatment with VKA. RESULTS: The overall duration of follow-up was 2755 patient-years concerning 2385 patients. The time spent in the therapeutic range 2 to 3 assigned for 89% of the patients, was 73%. On the other hand the time spent in the therapeutic range for the other two INR ranges (2.5-3.5 and 3-4.5) concerning 11% of patients with prosthetic heart valve was lower (63.7% and 68.8% respectively) with an imbalance in favour of the time below the range. In this study, warfarin (Coumadine(®)) and fluindione (Previscan(®)) allowed an equivalent quality of anticoagulation. The 1728 patients of age ranged from 60 to 100 years spent more time in TTR than the 651 younger patients. The percentage of time spent with an INR greater than 5 was extremely reduced which is a guarantee of safety. CONCLUSION: These results prove that anticoagulant clinics in France have the same good performances as their counterparts abroad. It can be assumed that a high TTR contributes to a low incidence of both bleedings and thrombosis.

A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse.

The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10-70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.

The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia.

The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.

Anti-Legionella activity of staphylococcal hemolytic peptides.

A collection of various Staphylococci was screened for their anti-Legionella activity. Nine of the tested strains were found to secrete anti-Legionella compounds. The culture supernatants of the strains, described in the literature to produce hemolytic peptides, were successfully submitted to a two step purification process. All the purified compounds, except one, corresponded to previously described hemolytic peptides and were not known for their anti-Legionella activity. By comparison of the minimal inhibitory concentrations, minimal permeabilization concentrations, decrease in the number of cultivable bacteria, hemolytic activity and selectivity, the purified peptides could be separated in two groups. First group, with warnericin RK as a leader, corresponds to the more hemolytic and bactericidal peptides. The peptides of the second group, represented by the PSMα from Staphylococcus epidermidis, appeared bacteriostatic and poorly hemolytic.

Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies.

Mammalian target of rapamycin (mTOR) is a protein kinase implicated in the regulation of various cellular processes, including those required for tumor development, such as the initiation of mRNA translation, cell-cycle progression and cellular proliferation. In a wide range of hematological malignancies, the mTORC1 signaling pathway has been found to be deregulated and has been designed as a major target for tumor therapy. Given that pre-clinical studies have clearly established the therapeutic value of mTORC1 inhibition, numerous clinical trials of rapamycin and its derivates (rapalogs) are ongoing for treatment of these diseases. At this time, although disease stabilization and tumor regression have been observed, objective responses in some tumor types have been modest. Nevertheless, some of the mechanisms underlying cancer-cell resistance to rapamycin have now been described, thereby leading to the development of new strategy to efficiently target mTOR signaling in these diseases. In this review, we discuss the rationale for using mTOR inhibitors as novel therapies for a variety of hematological, malignancies with a focus on promising new perspectives for these approaches.

Surveillance of avian influenza in the Caribbean through the Caribbean Animal Health Network: surveillance tools and epidemiologic studies.

The Caribbean region is considered to be at risk for avian influenza (AI) due to a large backyard poultry system, an important commercial poultry production system, the presence of migratory birds, and disparities in the surveillance systems. The Caribbean Animal Health Network (CaribVET) has developed tools to implement AI surveillance in the region with the goals to have 1) a regionally harmonized surveillance protocol and specific web pages for AI surveillance on www.caribvet.net, and 2) an active and passive surveillance for AI in domestic and wild birds. A diagnostic network for the Caribbean, including technology transfer and AI virus molecular diagnostic capability in Guadeloupe (real-time reverse transcription-polymerase chain reaction for the AI virus matrix gene), was developed. Between 2006 and 2009, 627 samples from four Caribbean countries were tested for three circumstances: importation purposes, following a clinical suspicion of AI, or through an active survey of wild birds (mainly waders) during the southward and northward migration periods in Guadeloupe. None of the samples tested were positive, suggesting a limited role of these species in the AI virus ecology in the Caribbean. Following low pathogenic H5N2 outbreaks in the Dominican Republic in 2007, a questionnaire was developed to collect data for a risk analysis of AI spread in the region through fighting cocks. The infection pathway of the Martinique commercial poultry sector by AI, through introduction of infected cocks, was designed, and recommendations were provided to the Caribbean Veterinary Services to improve cock movement control and biosecurity measures. The CaribVET and its organization allowed interaction between diagnostic and surveillance tools on the one hand and epidemiologic studies on the other, both of them developed in congruence with regional strategies. Together, these CaribVET activities contribute to strengthening surveillance of avian influenza virus (AIV) in the Caribbean region and may allow the development of research studies on both AI risk analysis and on AIV ecology.

[Diffusion-weighted MR imaging of liver pathology: principles and clinical applications]. / Imagerie par résonance magnétique de diffusion (IRMD) en pathologie hépatique: principe et applications cliniques.

Due to ongoing technological advances, the range of clinical applications for diffusion-weighted MR imaging has expanded to now include abdominal pathology. Current applications for liver pathology include two main directions. First, oncologic imaging with detection, characterization and follow-up of lesions. Second, evaluation of diffuse liver diseases, including hepatic fibrosis. The diagnostic impact and role of diffusion-weighted MR imaging remain under investigation, but appear promising. Because of its short acquisition time, sensitivity, and additional information it provides, diffusion-weighted MR imaging should be included in routine liver imaging protocols.

Inter- and intraobserver consistency in assessing eligibility for bevacizumab (BVZ) in non-small-cell lung cancer (NSCLC) patients with centrally located tumors.

BACKGROUND: Bevacizumab (BVZ) combined with platinum-based therapy is registered for first-line treatment of nonsquamous non-small-cell lung cancer (NSCLC). Patients with centrally located tumors are stated ineligible for BVZ treatment. The goal of this study was to assess the consistency in evaluating eligibility of patients with central tumors for BVZ treatment. MATERIALS AND METHODS: The study group was composed of 150 NSCLC patients with centrally located tumors. Eligibility for BVZ was assessed by chest computed tomography (CT) scan. Eligibility was assessed independently using CT images reviewed on workstations. Inter- and intraobserver variations on 50 randomly extracted patients were estimated through a statistical modeling (multiple correspondence analysis). RESULTS: Discordance in eligibility was found for 82 patients (55%). The interobserver strength of agreement was fair to moderate (average kappa = 0.40). Contrarily, the intraobserver strength of agreement was good to very good (average kappa = 0.74). At multivariate analysis, the risk of discrepancy was essentially related to the assessment of the contact between the tumor and the vessels (odds ratio = 13.3, 95% confidence interval 2.8-62.6, P = 0.001). CONCLUSIONS: The consistency in evaluating eligibility of patients with central tumors for BVZ treatment is weak. The study group indicated more stringent criteria to help physicians in taking the best treatment choice that need however to be prospectively validated.

Universality of solar-wind turbulent spectrum from MHD to electron scales.

To investigate the universality of magnetic turbulence in space plasmas, we analyze seven time periods in the free solar wind under different plasma conditions. Three instruments on Cluster spacecraft operating in different frequency ranges give us the possibility to resolve spectra up to 300 Hz. We show that the spectra form a quasiuniversal spectrum following the Kolmogorov's law approximately k(-5/3) at MHD scales, a approximately k(-2.8) power law at ion scales, and an exponential approximately exp[-sqrt[k(rho)e]] at scales k(rho)e approximately [0.1,1], where rho(e) is the electron gyroradius. This is the first observation of an exponential magnetic spectrum in space plasmas that may indicate the onset of dissipation. We distinguish for the first time between the role of different spatial kinetic plasma scales and show that the electron Larmor radius plays the role of a dissipation scale in space plasma turbulence.

[Excellent performances of Wells' score and of the modified Wells' score for the diagnosis of proximal or distal deep venous thrombosis in outpatients or inpatients at Toulouse University Hospital: TVP-PREDICT study]. / Excellentes performances du score de Wells et du score de Wells modifié dans le diagnostic de thrombose veineuse profonde proximale ou distale chez des patients hospitalisés ou ambulatoires au CHU de Toulouse: étude TVP-PREDICT.

AIM OF THE STUDY: In order to validate a standardized strategy for the diagnosis of lower limb deep vein thrombosis (DVT) in the regional university hospital of Toulouse, we decided to study the performances of Wells' score and the modified Wells' score for the diagnosis of proximal and distal DVT. METHOD: Inpatients or outpatients referred to the vascular medicine department from April 2006 to March 2007 with suspected DVT were included prospectively and consecutively. Wells' score was determined for each patient and compared with the duplex ultrasound result. RESULTS: Two hundred and ninety-seven patients were included. The prevalence of DVT was 13.5%. The negative predictive values of Wells' score and the modified Wells' score were 99 and 97% respectively. Similar results were found for proximal or distal thrombosis. The performances of the modified Wells' score were not statistically better than those of the original score. In 48% of patients, the determination of the D-dimers would not have been contributory. In the group with low probability (70% of patients), the incidence of thrombosis was 0.6%. CONCLUSION: Wells' score and Wells' modified score have shown excellent performances. The value of the modified Wells' score is not superior and our preference, for practical reasons, goes to the original score. The widespread use of duplex ultrasound, the large proportion of patients in which D-dimers would not have been contributory and the excellent results of Wells score for patients with a low probability of DVT are encouraging arguments in favor of the development of an alternative strategy for these patients.

Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum.

Spontaneous apoptosis of bone marrow erythroid precursors accounts for the anemia that characterizes most low-grade myelodysplastic syndromes (MDS). We have shown that death of these precursors involved the Fas-dependent activation of caspase-8. To explore the pathway leading from caspase-8 activation to apoptosis, we transduced MDS bone marrow CD34(+) cells with a lentivirus encoding wild-type (WT) or endoplasmic reticulum (ER)-targeted Bcl-2 protein before inducing their erythroid differentiation. Both WT-Bcl-2 and ER-targeted Bcl-2 prevented spontaneous and Fas-dependent apoptosis in MDS erythroid precursors. ER-targeted Bcl-2 inhibited mitochondrial membrane depolarization and cytochrome c release in MDS erythroid precursors undergoing apoptosis, indicating a role for the ER in the death pathway, upstream of the mitochondria. MDS erythroid precursors demonstrated elevated ER Ca(2+) stores and these stores remained unaffected by ER-targeted Bcl-2. The ER-associated protein Bcl-2-associated protein (BAP) 31 was cleaved by caspase-8 in MDS erythroid precursors undergoing apoptosis. The protective effect of ER-targeted Bcl-2 toward spontaneous and Fas-induced apoptosis correlated with inhibition of BAP31 cleavage. A protective effect of erythropoietin against Fas-induced BAP31 cleavage and apoptosis was observed. We propose that apoptosis of MDS erythroid precursors involves the ER, downstream of Fas and upstream of the mitochondria, through the cleavage of the ER-associated BAP31 protein.

PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML.

The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways are frequently activated in acute myelogenous leukemia (AML). mTORC1 inhibition with RAD001 induces PI3K/Akt activation and both pathways are activated independently, providing a rationale for dual inhibition of both pathways. PI-103 is a new potent PI3K/Akt and mTOR inhibitor. In human leukemic cell lines and in primary blast cells from AML patients, PI-103 inhibited constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 was essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibited leukemic proliferation, the clonogenicity of leukemic progenitors and induced mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. In contrast, apoptosis was not induced with RAD001 and IC87114 association, which specifically inhibits mTORC1 and p110delta activity, respectively. PI-103 had additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. Interestingly, PI-103 did not induce apoptosis in normal CD34(+) cells and had moderate effects on their clonogenic and proliferative properties. Here, we demonstrate that multitargeted therapy against PI3K/Akt and mTOR with PI-103 may be of therapeutic value in AML.

[Imaging of incidental cystic lesions of the pancreas]. / Imagerie des lésions kystiques du pancréas de découverte fortuite.

Cystic lesions of the pancreas, with an estimated prevalence of 20%, frequently are incidental findings at imaging on asymptomatic patients. Pseudocysts, typically in a setting of pancreatitis, should first be excluded. Characterization of cystic tumors is more complicated. Still, it is important to differentiate between benign and malignant lesions. Multi-detector row CT and MRI allow characterization of such lesions in over 75% of cases. Indeterminate lesions should undergo endoscopic US with biopsy/aspiration and fluid analysis, especially for mucin producing tumors (rounded with thick enhancing wall). When imaging fails to fully characterize a lesion, follow-up may be proposed for lesions less than 3 cm in size, that are either unilocular with thin nonenhancing wall (simple cyst) or lobulated multilocular with thin nonenhancing wall (serous cystadenoma, isolated side branch IPMTP). Follow-up imaging shows that these tumors usually show very little change over time. Management is based on comparing estimated patient survival without treatment to surgical risks (morbidity, mortality, functional sequelae from the procedure).