Interpreting clinical assays for histone deacetylase inhibitors

As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all development steps. When “imprinted” early by the environment, epigenetic changes influence the organism at an early stage and can be transmitted to the progeny. Together with DNA sequence alterations, DNA aberrant cytosine methylation and microRNA deregulation, epigenetic modifications participate in the malignant transformation of cells. Their reversible nature has led to the emergence of the promising field of epigenetic therapy. The efforts made to inhibit in particular the epigenetic enzyme family called histone deacetylases (HDACs) are described. HDAC inhibitors (HDACi) have been proposed as a viable clinical therapeutic approach for the treatment of leukemia and solid tumors, but also to a lesser degree for noncancerous diseases. Three epigenetic drugs are already arriving at the patient’s bedside, and more than 100 clinical assays for HDACi are registered on the National Cancer Institute website. They explore the eventual additive benefits of combined therapies. In the context of the pleiotropic effects of HDAC isoforms, more specific HDACi and more informative screening tests are being developed for the benefit of the patients

Revealing the correlation between real-space structure and chiral magnetic order at the atomic scale

We image simultaneously the geometric, electronic and magnetic structure of a buckled iron bilayer film that exhibits chiral magnetic order. We achieve this by combining spin-polarized scanning tunneling microscopy and magnetic exchange force microscopy (SPEX), to independently characterize the geometric as well as the electronic and magnetic structure of non-flat surfaces. This new SPEX imaging technique reveals the geometric height corrugation of the reconstruction lines resulting from strong strain relaxation in the bilayer, enabling the decomposition of the real-space from the eletronic structure at the atomic level, and the correlation with the resultant spin spiral ground state. By additionally utilizing adatom manipulation, we reveal the chiral magnetic ground state of portions of the unit cell that were not previously imaged with SP-STM alone. Using density functional theory (DFT), we investigate the structural and electronic properties of the reconstructed bilayer and identify the favorable stoichiometry regime in agreement with our experimental result

Geochemical evidence (C, N and Pb isotopes) of recent anthropogenic impact in south-central Chile from two environmentally distinct lake sediment records

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in Journal of Quaternary Science 25 (2010): 1100-1112, doi:10.1002/jqs.1364.In this paper, we compare the elemental and isotopic (C, N, Pb) geochemistry of lake sediments from two contrasted environments in South-Central Chile. The first lake, Laguna Chica de San Pedro (LCSP), is situated in the urbanized area of the Biobio Region (36°S). The second lake, Lago Puyehue (40°S), is located 400 km to the southeast of LCSP and belongs to an Andean national park. Our aim is to identify environmental impacts associated with increasing industrial activities and land-degradation during the last 150 years. In LCSP, shifts in C/N atomic ratios, δ13C and δ15N from 1915–1937 to the late 80’s are attributed to successive land-degradation episodes in the lake watershed. Based on a Pb isotopic mixing model, we estimate that up to 20% of lead in LCSP sediments is supplied from urban atmospheric pollution. By contrast, human impact in the watershed of Lago Puyehue is very limited. We observe no change in organic geochemistry during the last 150 years and lead contamination remains lower than 5%, even during the last decades. Although contamination levels are much higher in LCSP than in Lago Puyehue, a peak in anthropogenic Pb is recorded during the same period (1974–1976) at both sites. This maximum contamination level is consistent with increased industrial activity in the vicinity of Concepción.This research was partly supported by the Belgian OSTC project EV/12/10B "A continuous Holocene record of ENSO variability in southern Chile", by the Scientific Co-operation Exchange Program between University of Concepción (Chile) and University of Liège (Belgium) funded by the Belgian CGRI (Commissariat Général aux relations internationales de la Communauté Française de Belgique), and by Fondecyt project Nº 1070508. S.B. is supported by a BAEF fellowship (Belgian American Educational Foundation), and by an EU Marie Curie Outgoing Fellowship under the FP6 programme

Inflammatory Mediators Increase Nav1.9 Current and Excitability in Nociceptors through a Coincident Detection Mechanism

Altered function of Na+ channels is responsible for increased hyperexcitability of primary afferent neurons that may underlie pathological pain states. Recent evidence suggests that the Nav1.9 subunit is implicated in inflammatory but not acute pain. However, the contribution of Nav1.9 channels to the cellular events underlying nociceptor hyperexcitability is still unknown, and there remains much uncertainty as to the biophysical properties of Nav1.9 current and its modulation by inflammatory mediators. Here, we use gene targeting strategy and computer modeling to identify Nav1.9 channel current signature and its impact on nociceptors' firing patterns. Recordings using internal fluoride in small DRG neurons from wild-type and Nav1.9-null mutant mice demonstrated that Nav1.9 subunits carry the TTX-resistant “persistent” Na+ current called NaN. Nav1.9−/− nociceptors showed no significant change in the properties of the slowly inactivating TTX-resistant SNS/Nav1.8 current. The loss in Nav1.9-mediated Na+ currents was associated with the inability of small DRG neurons to generate a large variety of electrophysiological behaviors, including subthreshold regenerative depolarizations, plateau potentials, active hyperpolarizing responses, oscillatory bursting discharges, and bistable membrane behaviors. We further investigated, using CsCl- and KCl-based pipette solutions, whether G-protein signaling pathways and inflammatory mediators upregulate the NaN/Nav1.9 current. Bradykinin, ATP, histamine, prostaglandin-E2, and norepinephrine, applied separately at maximal concentrations, all failed to modulate the Nav1.9 current. However, when applied conjointly as a soup of inflammatory mediators they rapidly potentiated Nav1.9 channel activity, generating subthreshold amplification and increased excitability. We conclude that Nav1.9 channel, the molecular correlate of the NaN current, is potentiated by the concerted action of inflammatory mediators that may contribute to nociceptors' hyperexcitability during peripheral inflammation

Corrosion rate determination of rare-earth Mg alloys in a Na2SO4 solution by electrochemical measurements and inductive coupled plasma-optical emission spectroscopy

The corrosion resistance of three Mg alloys containing rare-earth elements (WE43, EV31 and ZE41) was studied and compared to that of two Mg– Al alloys (AZ31 and AZ91) and of pure Mg (99.95 wt.%). Current-voltage curves and electrochemical impedance measurements were performed with rotating disk electrodes in an aerated 0.1 M Na 2 SO 4 solution. For all the alloys, it was confirmed that the intermetallic particles acted as local cathodes and that more protective films were formed on the alloys surface by comparison with the pure Mg. Corrosion rates were determined from inductive coupled plasma-optical emission spectroscopy measurements and from the electrochemical measurements. Higher corrosion rates were observed for the rare-earth Mg alloys compared to the AZ series alloys. These data allowed the corrosion mechanisms to be discussed

On the stability of the oxides film formed on a magnesium alloy containing rare-earth elements

The electrochemical behaviour of a commercial magnesium alloy containing rare-earth elements, the WE43, was investigated by electrochemical techniques in both sulphate and chloride solutions and compared to that of pure magnesium (99.95 wt %). A particular attention was paid to the oxides film that formed during the corrosion process. Electrochemical impedance data analysis allowed the oxides films thickness to be determined. The film was thinner and more protective for the WE43 Mg alloy than for the pure Mg. ToF-SIMS analysis showed the incorporation of alloying elements, mainly yttrium and zirconium in the corrosion products layer. A higher compactness due to a higher Pilling-Bedworth ratio can explain the electrochemical results

Cellular immune response to Plasmodium falciparum after pregnancy is related to previous placental infection and parity

BACKGROUND: Malaria in pregnancy is characterised by the sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous spaces. Placental parasites express a specific phenotype, which allows them to cytoadhere to chondroitin sulfate A expressed by syncytiotrophoblasts. Malaria infection during pregnancy allows the acquisition of antibodies against placental parasites, these antibodies are thought to be involved in protection during subsequent pregnancies. METHODS: To investigate the development of a cellular response to placental parasites during pregnancy, peripheral blood mononuclear cells were collected from women at the time of their confinement. The study was performed in Cameroon where malaria transmission is perennial. In vitro cell proliferation and cytokine production were measured in response to non-malarial activators (concanavalin A and PPD), a recombinant protein from P. falciparum MSP-1, and erythrocytes infected by two P. falciparum lines, RP5 and W2. Like placental parasites, the RP5 line, but not W2, adheres to chondroitin sulfate A and to syncytiotrophoblasts. RESULTS: The proliferative response to all antigens was lower for cells obtained at delivery than 3 months later. Most interestingly, the cellular response to the RP5 line of P. falciparum was closely related to parity. The prevalence rate and the levels of response gradually increased with the number of previous pregnancies. No such relationship was observed with W2 line, or MSP-1 antigen. CONCLUSIONS: This suggests the occurrence of an immune response more specific for the RP5 line in women having had multiple pregnancies, and who are likely to develop immunity to pregnancy-associated parasites. Both humoral and cellular mechanisms may account for the lower susceptibility of multigravidae to malaria

The Relationship between Visceral Adiposity and Nonalcoholic Fatty Liver Disease Diagnosed by Controlled Attenuation Parameter in People with HIV: A Pilot Study

Background: Fat alterations are frequent in people with HIV (PWH) and predict worse cardiometabolic outcomes. Visceral adipose tissue (VAT) is associated with ectopic fat accumulation in the liver. We aimed to investigate nonalcoholic fatty liver disease (NAFLD) diagnosed by controlled attenuation parameter (CAP) as a potential marker of visceral adiposity in PWH. Methods: We conducted a prospective pilot study of HIV mono-infected patients undergoing metabolic characterization and paired CAP measured by transient elastography with dual-energy X-ray absorptiometry (DEXA) scan. NAFLD was defined as CAP >= 285 dB/m, in absence of alcohol abuse. Excess visceral adiposity was defined as VAT > 1.32 Kg. Pairwise correlation, area under the curve (AUC) and logistic regression analysis were employed to study the association between VAT and CAP. Results: Thirty patients were included, of whom 50% had NAFLD. CAP was correlated with VAT (r = 0.650, p < 0.001) measured by DEXA scan. After adjusting for duration of HIV infection, body mass index and waist circumference, CAP remained the only independent predictor of excess VAT (adjusted odds ratio 1.05, 95% confidence interval [CI] 1.01-1.10). The AUC analysis determined CAP had excellent performance to diagnose excess VAT (AUC 0.92, 95% CI 0.81-1.00), higher than BMI and waist circumference. The optimized CAP cut-off to diagnose excess VAT was 266 dB/m, with a sensitivity of 88.3% and a specificity of 84.6%. Conclusions: NAFLD diagnosed by CAP is associated with VAT in PWH independently of anthropometric measures of obesity. CAP may be a potential diagnostic marker of visceral adiposity in the practice of HIV medicine

The EGIM, EMSO generic instrument module, step towards standardization

Peer ReviewedPostprint (published version

MR imaging of adult acute infectious encephalitis

International audienceBackground. – Imaging is a key tool for the diagnosis of acute encephalitis. Brain CT scan must be urgently performed to rule out a brain lesion with mass effect that would contraindicate lumbar puncture. Brain MRI is less accessible than CT scan, but can provide crucial information with patients presenting with acute encephalitis.Method. – We performed a literature review on PubMed on April 1, 2015 with the search terms " MRI " and " encephalitis ".Results. – We first described the various brain MRI abnormalities associated with each pathogen of acute encephalitis (HSV, VZV, other viral agents targeting immunocompromised patients or travelers; tuberculosis, listeriosis, other less frequent bacterial agents). Then, we identified specific patterns of brain MRI abnomalies that may suggest a particular pathogen. Limbic encephalitis is highly suggestive of HSV; it also occurs less frequently in encephalitis due to HHV6, syphillis, Whipple's disease and HIV primary infection. Rhombencephalitis is suggestive of tuberculosis and listeriosis. Acute ischemic lesions can occur in patients presenting with severe bacterial encephalitis, tuberculosis, VZV encephalitis, syphilis, and fungal infections. Conclusion. – Brain MRI plays a crucial role in the diagnosis of acute encephalitis. It detects brain signal changes that reinforce the clinical suspicion of encephalitis, especially when the causative agent is not identified by lumbar puncture; it can suggest a particular pathogen based on the pattern of brain abnormalities and it rules out important differential diagnosis (vascular, tumoral or inflammatory causes).Introduction. – L'imagerie cérébrale est essentielle au diagnostic d'encéphalite aiguë. Le scanner cérébral doit être réalisé en urgence afin d'exclure une lésion cérébrale avec effet de masse qui contre-indiquerait la ponction lombaire. L'IRM cérébrale est moins accessible que le scanner, mais peut apporter des informations importantes en cas d'encéphalite aiguë.Méthode. – Revue de la littérature sur PubMed le 1 er avril 2015 avec les mots clés « IRM » et « encéphalite ».Résultats. – Nous décrivons les différentes anomalies IRM associées à chaque agent pathogène de l'encéphalite aiguë (HSV, VZV, autres virus ciblant les patients immunodéprimés ou voyageurs ; tuberculose, listériose, autres agents bactériens moins fréquents). Nous identifions des patterns spécifiques d'anomalies IRM qui peuvent orienter vers un pathogène particulier. L'encéphalite limbique est très évocatrice de l'HSV ; elle survient aussi moins fréquemment dans les encéphalites dues au HHV6, à la syphilis, à la maladie de Whipple et à la primo-infection par le VIH. Une rhombencéphalite doit fait rechercher la tuberculose et la listériose. Des lésions ischémiques aiguës peuvent survenir chez des patients atteints d'encéphalite bactérienne grave, de tuberculose, d'encéphalite à VZV, de syphilis et d'infections fongiques