Promising clinical performance of pretargeted immuno-PET with anti-CEA bispecific antibody and gallium-68-labelled IMP-288 peptide for imaging colorectal cancer metastases: a pilot study.

INTRODUCTION: This pilot study evaluated the imaging performance of pretargeted immunological positron emission tomography (immuno-PET) using an anti-carcinoembryonic antigen (CEA) recombinant bispecific monoclonal antibody (BsMAb), TF2 and the [68Ga]Ga-labelled HSG peptide, IMP288, in patients with metastatic colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients requiring diagnostic workup of CRC metastases or in case of elevated CEA for surveillance were prospectively studied. They had to present with elevated CEA serum titre or positive CEA tumour staining by immunohistochemistry of a previous biopsy or surgical specimen. All patients underwent endoscopic ultrasound (EUS), chest-abdominal-pelvic computed tomography (CT), abdominal magnetic resonance imaging (MRI) and positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET). For immuno-PET, patients received intravenously 120 nmol of TF2 followed 30 h later by 150 MBq of [68Ga]Ga-labelled IMP288, both I.V. The gold standard was histology and imaging after 6-month follow-up. RESULTS: Eleven patients were included. No adverse effects were reported after BsMAb and peptide injections. In a per-patient analysis, immuno-PET was positive in 9/11 patients. On a per-lesion analysis, 12 of 14 lesions were positive with immuno-PET. Median SUVmax, MTV and TLG were 7.65 [3.98-13.94, SD 3.37], 8.63 cm3 [1.98-46.64; SD 14.83] and 37.90 cm3 [8.07-127.5; SD 43.47] respectively for immuno-PET lesions. Based on a per-lesion analysis, the sensitivity, specificity, positive-predictive value and negative-predictive value were, respectively, 82%, 25%, 82% and 25% for the combination of EUS/CT/MRI; 76%, 67%, 87% and 33% for FDG-PET; and 88%, 100%, 100% and 67% for immuno-PET. Immuno-PET had an impact on management in 2 patients. CONCLUSION: This pilot study showed that pretargeted immuno-PET using anti-CEA/anti-IMP288 BsMAb and a [68Ga]Ga-labelled hapten was safe and feasible, with promising diagnostic performance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02587247 Registered 27 October 2015.

A numerical study of nonlinear infrasound propagation in a windy atmosphere.

Direct numerical simulations of the two-dimensional unsteady compressible Navier-Stokes equations are performed to study the acoustic field generated by an infrasonic source in a realistic atmosphere. Some of the main phenomena affecting the propagation of infrasonic waves at large distances from the source are investigated. The effects of thermal and wind-related refraction on the signals recorded at ground level are highlighted, with particular emphasis on the phase shift induced by the presence of caustics in the acoustic field. Nonlinear waveform steepening associated with harmonic generation, and period lengthening, both of which are typical of large source amplitudes, are illustrated, and the importance of thermoviscous absorption in the upper atmosphere is clearly demonstrated. The role of diffraction in the shadow zone, around caustics and at stratospheric altitudes is also pointed out. The Navier-Stokes equations are solved using high-order finite-differences and a Runge-Kutta time integration method both originally developed for aeroacoustic applications, along with an adaptive shock-capturing algorithm which allows high-intensity acoustic fields to be examined. An improvement to the shock detection procedure is also proposed in order to meet the specificities of nonlinear propagation at long range. The modeling as well as the numerical results are reported in detail and discussed.

Prognostic value of metabolic parameters and clinical impact of ¹8F-fluorocholine PET/CT in biochemical recurrent prostate cancer.

PURPOSE: To evaluate the therapeutic impact of (18)F-fluorocholine (FCH) PET/CT in biochemical recurrent prostate cancer (PC) and to investigate the value of quantitative FCH PET/CT parameters in predicting progression-free survival (PFS). METHODS: This retrospective study included 172 consecutive patients with PC who underwent FCH PET/CT for biochemical recurrence. Mean rising PSA was 10.7 ± 35.0 ng/ml. Patients with positive FCH PET were classified into three groups: those with uptake only in the prostatic bed, those with locoregional disease, and those with distant metastases. Referring physicians were asked to indicate the hypothetical therapeutic strategy with and without the FCH PET/CT results. Clinical variables and PET parameters including SUVmax, SUVpeak, SUVmean, total lesion choline kinase activity (TLCKA) and standardized added metabolic activity (SAM) were recorded and a multivariate analysis was performed to determine the factors independently predicting PFS. RESULTS: In 137 of the 172 patients, the FCH PET/CT scan was positive, and of these, 29.9 % (41/137) had prostatic recurrence, 42.3 % (58/137) had pelvic lymph node recurrence with or without prostatic recurrence, and 27.7 % (38/137) had distant metastases. The FCH PET/CT result led to a change in treatment plan in 43.6 % (75/172) of the 172 patients. Treatment was changed in 49.6 % (68/137) of those with a positive FCH PET/CT scan and in 20 % (7/35) of those with a negative FCH PET/CT scan. After a median follow-up of 29.3 months (95 % CI 18.9 - 45.9 months), according to multivariate analysis age <70 years, SAM ≥23 and SUVmean ≥3 were parameters independently predicting PFS. A nomogram constructed using the three parameters showed 49 months of PFS in patients with the best scores (0 or 1) and only 11 months in patients with a poor score (score 3). CONCLUSION: This study indicates that a positive FCH PET result in PC patients with biochemical recurrence predicts a shorter PFS and confirms the major impact of the FCH PET result on the management of biochemical recurrent PC.

Glutathione redox state, tocochromanols, fatty acids, antioxidant enzymes and protein carbonylation in sunflower seed embryos associated with after-ripening and ageing.

BACKGROUND AND AIMS: Loss of seed viability has been associated with deteriorative processes that are partly caused by oxidative damage. The breaking of dormancy, a seed trait that prevents germination in unfavourable seasons, has also been associated with oxidative processes. It is neither clear how much overlap exists between these mechanisms nor is the specific roles played by oxygen and reactive oxygen species. METHODS: Antioxidant profiles were studied in fresh (dormant) or after-ripened (non-dormant) sunflower (Helianthus annuus) embryos subjected to controlled deterioration at 40 °C and 75 % relative humidity under ambient (21 %) or high O2 (75 %). Changes in seed vigour and viability, dormancy, protein carbonylation and fatty acid composition were also studied. KEY RESULTS: After-ripening of embryonic axes was accompanied by a shift in the thiol-based cellular redox environment towards more oxidizing conditions. Controlled deterioration under high O2 led to a faster loss of seed dormancy and significant decreases in glutathione reductase and glutathione peroxidase activities, but viability was lost at the same rate as under ambient O2. Irrespective of O2 concentration, the overall thiol-based cellular redox state increased significantly over 21 d of controlled deterioration to strongly oxidizing conditions and then plateaued, while viability continued to decrease. Viability loss was accompanied by a rapid decrease in glucose-6-phosphate-dehydrogenase, which provides NADPH for reductive processes such as required by glutathione reductase. Protein carbonylation, a marker of protein oxidation, increased strongly in deteriorating seeds. The lipid-soluble tocochromanols, dominated by α-tocopherol, and fatty acid profiles remained stable. CONCLUSIONS: After-ripening, dormancy-breaking during ageing and viability loss appeared to be associated with oxidative changes of the cytosolic environment and proteins in the embryonic axis rather than the lipid environment. High O2 concentrations accelerated dormancy alleviation but, surprisingly, did not accelerate the rate of viability loss.

A study of infrasound propagation based on high-order finite difference solutions of the Navier-Stokes equations.

The feasibility of using numerical simulation of fluid dynamics equations for the detailed description of long-range infrasound propagation in the atmosphere is investigated. The two dimensional (2D) Navier Stokes equations are solved via high fidelity spatial finite differences and Runge-Kutta time integration, coupled with a shock-capturing filter procedure allowing large amplitudes to be studied. The accuracy of acoustic prediction over long distances with this approach is first assessed in the linear regime thanks to two test cases featuring an acoustic source placed above a reflective ground in a homogeneous and weakly inhomogeneous medium, solved for a range of grid resolutions. An atmospheric model which can account for realistic features affecting acoustic propagation is then described. A 2D study of the effect of source amplitude on signals recorded at ground level at varying distances from the source is carried out. Modifications both in terms of waveforms and arrival times are described.

Elastic modulus of halloysite nanotubes.

This work reports measurements of the elastic modulus of halloysite nanotubes. Nanoscale three-point bending tests were performed on individual nanotubes using an atomic force microscope. Nanotubes exhibit elastic behaviour at small deformations. The stiffness of the tubes, and hence their elastic modulus, was deduced from force curve measurements using an appropriate mechanical model. The boundary conditions were also identified by recording the stiffness profile of a tube along its suspended length. An average elastic modulus of 140 GPa is obtained for a set of tubes with outer diameters ranging between 50 and 160 nm. Moreover, the elastic modulus increases with decreasing outer diameter, with a steep jump below 50 nm. The size dependence of the elastic modulus may be attributed to: (i) surface tension effects for thinner tubes and (ii) a non-negligible contribution of shear deformations to the total deflection for larger tubes.

Femoral fracture during breech vaginal delivery: A case report.

Femoral fracture is a rare but significant foetal injury, more frequent and likely to happen when the foetus is malpositioned or in a breech presentation. Cesarian section does not appear to be protective and all recent publications report cases occurring during cesarian section. We report a case that occurred in a vaginal delivery of a single footling breech presentation. This complication allows us to remind that femur fracture is a complication of breech delivery whatever the modality. The prognosis is good with early diagnosis.

High performance recycled CFRP composites based on reused carbon fabrics through sustainable mild solvolysis route.

A novel environmentally friendly recycling method is developed for large carbon-fibers reinforced-polymers composite panels whose efficiency is demonstrated through a proof-of-concept fabrication of a new composite part based on recycled fibers. The recycling process relies on formic acid as separation reagent at room temperature and atmospheric pressure with efficient recycling potential of the separating agent. Electron microscopy and thermal analysis indicate that the recycled fibers are covered by a thin layer of about 10wt.% of residual resin, alternating with few small particles, as compared to the smooth virgin fibers. The recycled composites show promising shear strength and compression after impact strength, with up to 93% retention of performance depending on the property as compared to the reference. The recycled carbon fibers can thus be reused for structural applications requiring moderate to high performances. The loss of properties is attributed to a lower adhesion between fresh epoxy resin and recycled carbon fibers due to the absence of sizing, partly compensated by a good interface between fresh and residual cured epoxy thanks to mechanical anchoring as well as chemical reactions. The room temperature and atmospheric pressure operating conditions combined to the recyclability of the forming acid contribute to the sustainability of the entire approach.

Uranium retention in a Callovo-Oxfordian clay rock formation: From laboratory-based models to in natura conditions.

For the performance assessment of radioactive waste disposal, it is critical to predict the mobility of radionuclides in the geological barrier that hosts it. A key challenge consists of assessing the transferability of current knowledge on the retention properties deduced from model systems to in natura situations. The case of the redox-sensitive element uranium in the Callovo-Oxfordian clay formation (COx) is presented herein. Extensive experimental work was carried out with respect to parameters affecting uranium speciation (pH, PCO2, [Ca] and redox potential) with illite, COx clay fraction and raw COx claystone. The "bottom-up" approach implemented, with illite and montmorillonite as reactive phases, quantitatively explains the adsorption results of U(VI) and U(IV) on COx. While retention is high for U(IV) (Rd∼104 L kg-1), it remains very low for U(VI) (Rd∼4 L kg-1) due to the formation of soluble ternary Ca(Mg)-U(VI)-carbonate complexes. The applicability of the sorption model was then assessed by comparing predictive analyses with data characterizing the behavior of naturally-occurring U (<3 mg kg-1). The COx clay phase is the largest reservoir of naturally-occurring U (∼65%) but only a small fraction appears to be adsorbed (∼1%). Under representative site conditions (especially with respect to reducing conditions), we have concluded that ternary U(VI) complexes control U speciation in solution while U(IV) surface species dominate U adsorption, with Rd values > 70 L kg-1.

Role of relative humidity, temperature, and water status in dormancy alleviation of sunflower seeds during dry after-ripening.

The effect of various combinations of temperature and relative humidity on dormancy alleviation of sunflower seeds during dry after-ripening was investigated. The rate of dormancy alleviation depended on both temperature and embryo moisture content (MC). Below an embryo MC of 0.1 g H(2)O g(-1) dw, dormancy release was faster at 15 °C than at higher temperatures. This suggests that dormancy release at low MC was associated with negative activation energy, supported by Arrhenius plots, and low Q(10) values. At higher MC, the rate of dormancy alleviation increased with temperature, correlating well with the temperature dependence of biochemical processes. These findings suggests the involvement of two distinct cellular mechanisms in dormancy release; non-enzymatic below 0.1 g H(2)O g(-1) dw and associated with active metabolism above this value. The effects of temperature on seed dormancy release above the threshold MC were analysed using a population-based thermal time approach and a model predicting the rate of dormancy alleviation is provided. Sunflower embryo dormancy release was effective at temperatures above 8 °C (the base temperature for after-ripening, Tb(AR), was 8.17 °C), and the higher the after-ripening temperature above this threshold value, the higher was the rate of dormancy loss. Thermodynamic analyses of water sorption isotherms revealed that dormancy release was associated with less bound water and increased molecular mobility within the embryonic axes but not the cotyledons. It is proposed that the changes in water binding properties result from oxidative processes and can, in turn, allow metabolic activities.

Differential apoptosis-like cell death in amastigote and trypomastigote forms from Trypanosoma cruzi-infected heart cells in vitro.

Apoptosis, type-I of programmed cell death (PCD-I), is not restricted to multicellular organisms since many apoptotic features have been described in different trypanosomatids, including Trypanosoma cruzi. Our present aim was to monitor, by different morphological markers, the occurrence of apoptosis-like death in amastigotes and trypomastigotes of T.cruzi (Y strain) during the infection of heart culture cells. We documented the differential occurrence of PCD-I in amastigotes and trypomastigotes, with distinct death rates noticed between these two parasite-distinct forms. Fluorescence microscopy and flow cytometry analysis using different hall markers of apoptosis (phosphatidylserine exposure, collapse of mitochondrial membrane potential and DNA fragmentation) showed that amastigotes present higher levels of apoptosis-like cell death as compared to trypomastigotes. It is possible that the higher levels of PCD-I in these highly multiplicative forms may contribute to the control of the parasite burden within the host cells. On the other hand, the apoptosis-like occurrence in the infective but non-proliferative stage of the parasite (trypomastigotes) may play a role in parasite evasion mechanisms as suggested for other parasites.

Role of family history and clinical screening in the identification of families with idiopathic dilated cardiomyopathy in Johannesburg, South Africa.

BACKGROUND: Familial disease is implicated in 20 - 50% of cases of idiopathic dilated cardiomyopathy (IDCM) worldwide. The contribution of familial factors to IDCM in the Johannesburg area, South Africa, is unknown. OBJECTIVES: To describe the demographic details of patients with IDCM who presented at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), and to determine if there is evidence of familial disease through family history assessment and clinical screening of relatives. METHODS: This was a single-centre, cohort study performed at a quaternary care centre at CMJAH. Fifty unrelated probands diagnosed with IDCM and available first- and second-degree relatives were included in the study. A three-generation family pedigree was drawn up for all 50 probands. The pedigrees were analysed to identify the presence or absence of familial disease and categorised as positive, intermediate, negative or unreliable according to the family history obtained. From the 50 proband cases, there were 21 family members available for screening for features of IDCM. Eighty-two family members (55 first-degree and 27 second-degree relatives) were screened clinically. Screening included a personal history, full physical examination, electrocardiogram (ECG) and echocardiogram. RESULTS: The mean age at diagnosis of IDCM in the probands was 41.7 (standard deviation (SD) 12.4) years. The majority of probands were males (n=38; 76%). Of 50 pedigrees analysed, 14 (28%) were positive and likely to be indicative of familial dilated cardiomyopathy (DCM), and 9 (18%) patients were at intermediate risk of familial disease. Eighty-two asymptomatic family members were screened, with a median age of 33 (range 11 - 76) years. No asymptomatic family members were identified with features of DCM or presymptomatic DCM. Eleven of the 21 families screened had relatives with possible presymptomatic DCM identified by abnormalities on the echocardiogram in 3 families (14.3%) (4 individuals; all first-degree relatives of the index case) or identified on the basis of a conduction defect (an arrhythmia or first-/ second-/third-degree heart block) in 8 families (72.7%) (11 individuals; 9 first-degree and 2 second-degree relatives). CONCLUSIONS: Screening for IDCM should include a three-generation family history and clinical screening of all first-degree family members. As IDCM has an age-related penetrance, at-risk family members should receive follow-up for screening to assess symptoms and signs of IDCM. Genetic testing would potentially identify family members at high risk, who would benefit from screening; this might be a less expensive option.

[Lemierre syndrome: a complication of an oropharyngeal infection]. / Syndrome de Lemierre : une infection oropharyngée compliquée.

We report a case of Lemierre syndrome in a healthy infant, initially presenting with otitis media and angina. Lemierre syndrome is a disease that every pediatrician must know. Early diagnosis and treatment with antibiotics are necessary to decrease mortality. A review of the history and the complications of Lemierre syndrome is presented.

Plasma-activation of tap water using DBD for agronomy applications: Identification and quantification of long lifetime chemical species and production/consumption mechanisms.

Cold atmospheric plasmas are weakly ionized gases that can be generated in ambient air. They produce energetic species (e.g. electrons, metastables) as well as reactive oxygen species, reactive nitrogen species, UV radiations and local electric field. Their interaction with a liquid such as tap water can hence change its chemical composition. The resulting "plasma-activated liquid" can meet many applications, including medicine and agriculture. Consequently, a complete experimental set of analytical techniques dedicated to the characterization of long lifetime chemical species has been implemented to characterize tap water treated using cold atmospheric plasma process and intended to agronomy applications. For that purpose, colorimetry and acid titrations are performed, considering acid-base equilibria, pH and temperature variations induced during plasma activation. 16 species are quantified and monitored: hydroxide and hydronium ions, ammonia and ammonium ions, orthophosphates, carbonate ions, nitrite and nitrate ions and hydrogen peroxide. The related consumption/production mechanisms are discussed. In parallel, a chemical model of electrical conductivity based on Kohlrausch's law has been developed to simulate the electrical conductivity of the plasma-activated tap water (PATW). Comparing its predictions with experimental measurements leads to a narrow fitting, hence supporting the self-sufficiency of the experimental set, I.e. the fact that all long lifetime radicals of interest present in PATW are characterized. Finally, to evaluate the potential of cold atmospheric plasmas for agriculture applications, tap water has been daily plasma-treated to irrigate lentils seeds. Then, seedlings lengths have been measured and compared with untreated tap water, showing an increase as high as 34.0% and 128.4% after 3 days and 6 days of activation respectively. The interaction mechanisms between plasma and tap water are discussed as well as their positive synergy on agronomic results.

Cyclic guanosine monophosphate is the mediator of platelet-activating factor inhibition on transport by the mouse kidney thick ascending limb.

Since we have previously shown a direct inhibitory effect of platelet-activating factor (PAF) on Cl reabsorption in the medullary thick ascending limb of Henle's loop (TAL), the aim of this study was to extend this effect to the whole TAL and to further investigate the signaling pathway involved. In microperfused cortical TALs, PAF significantly decreased Cl reabsorption by 50.3 +/- 6.5%. On the one hand, this effect was not modified in the presence of staurosporine and was not mimicked by phorbol ester; chelating cytosolic Ca by BAPTA/AM failed to suppress the inhibitory effect of PAF on Cl reabsorption; moreover, no significant increase in intracellular Ca concentration could be observed in the presence of PAF on isolated tubules. On the other hand, 8-bromo cyclic GMP mimicked the PAF effect on Cl reabsorption and prevented a further effect of this agent; the PAF effect was significantly reduced by H-8, a cyclic GMP-dependent protein kinase inhibitor; in medullary TALs, PAF significantly increased by twofold cyclic GMP content, an effect inhibited by the PAF antagonist BN 50730, whereas PAF did not significantly modify cAMP content in basal or stimulated conditions. Finally, inhibition of nitric oxide production by NAME or NMMA failed to prevent the effect of PAF on Cl reabsorption. It is concluded that the PAF-induced inhibition of Cl reabsorption in the TAL was mediated by cyclic GMP, likely independent of a nitric oxide synthesis.

Cl- absorption across the thick ascending limb is not altered in cystic fibrosis mice. A role for a pseudo-CFTR Cl- channel.

The cortical thick ascending limb (CTAL) absorbs Cl- via a Na+-K+-Cl- cotransport at the apical membrane and several Cl- channels at the basolateral membrane, including a 9-pS channel having several properties of the cystic fibrosis transmembrane conductance regulator (CFTR). Having checked that CFTR mRNA is present in the mouse CTAL, we investigated whether this channel is a CFTR molecule by applying the patch-clamp technique to CTALs microdissected from CFTR knockout mice (cftrm1Unc). The 9-pS channel was active in cell-attached patches from tubules of mice homozygous for the disrupted cftr gene [CFTR (-/-)] at the same frequency and with the same activity (NPo) as in normal [CFTR (+/+)] or heterozygous [CFTR (+/-)] mice. The conductive properties of the channel, studied on inside-out patches, were identical in CFTR (-/-), CFTR (+/+), and CFTR (+/-) tubules, as were the sensitivities to internal pH and internal ATP, two typical features of this channel. In addition, the Cl- absorption in isolated, microperfused CTALs and the Na+-K+-Cl- cotransport activity were identical in CFTR (-/-), CFTR (+/+), and CFTR (+/-) mice. These results show that the 9-pS Cl- channel is distinct from CFTR, and that the CFTR protein has no influence on the Cl- absorption in this part of the renal tubule.

Novel tetra-acridine derivatives as dual inhibitors of topoisomerase II and the human proteasome.

Acridine derivatives, such as amsacrine, represent a well known class of multi-targeted anti-cancer agents that generally interfere with DNA synthesis and inhibit topoisomerase II. But in addition, these tricyclic molecules often display secondary effects on other biochemical pathways including protein metabolism. In order to identify novel anti-cancer drugs, we evaluated the mechanism of action of a novel series of bis- and tetra-acridines. As expected, these molecules were found to interact with DNA and inhibit the topoisomerase II-mediated DNA decatenation. Interestingly when tested on human tumour cells either sensitive (HL-60) or resistant (HL-60/MX2) to topoisomerase II inhibitors, these molecules proved equicytotoxic against the two cell lines, suggesting that they do not only rely on topoisomerase II inhibition to exert their cytotoxic effects. In order to identify alternative targets, we tested the capacity of acridines 1-9 to inhibit the proteasome machinery. Four tetra-acridines inhibited the proteasome in vitro, with IC(50) values up to 40 times lower than that of the reference proteasome inhibitor lactacystin. Moreover, unlike peptide aldehydes used as reference inhibitors for the proteasome, these new acridine compounds demonstrated a good selectivity towards the proteasome, when tested against four unrelated proteases. A cellular assay based on the degradation of a proteasome protein substrate indicated that at least two of the tetra-acridines maintained this proteasome inhibition activity in a cellular context. This is the first report of tetra-acridines that demonstrate dual topoisomerase II and proteasome inhibition properties. This new dual activity could represent a novel anti-cancer approach to circumvent certain forms of tumour resistance.