Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin. Copyright: © 2014 Milutinovic et al

Single Cycle Structure-Based Humanization of an Anti-Nerve Growth Factor Therapeutic Antibody

Most forms of chronic pain are inadequately treated by present therapeutic options. Compelling evidence has accumulated, demonstrating that Nerve Growth Factor (NGF) is a key modulator of inflammatory and nociceptive responses, and is a promising target for the treatment of human pathologies linked to chronic and inflammatory pain. There is therefore a growing interest in the development of therapeutic molecules antagonising the NGF pathway and its nociceptor sensitization actions, among which function-blocking anti-NGF antibodies are particularly relevant candidates

Anti-HIV-1 Activity of a New Scorpion Venom Peptide Derivative Kn2-7

For over 30 years, HIV/AIDS has wreaked havoc in the world. In the absence of an effective vaccine for HIV, development of new anti-HIV agents is urgently needed. We previously identified the antiviral activities of the scorpion-venom-peptide-derived mucroporin-M1 for three RNA viruses (measles viruses, SARS-CoV, and H5N1). In this investigation, a panel of scorpion venom peptides and their derivatives were designed and chosen for assessment of their anti-HIV activities. A new scorpion venom peptide derivative Kn2-7 was identified as the most potent anti-HIV-1 peptide by screening assays with an EC50 value of 2.76 µg/ml (1.65 µM) and showed low cytotoxicity to host cells with a selective index (SI) of 13.93. Kn2-7 could inhibit all members of a standard reference panel of HIV-1 subtype B pseudotyped virus (PV) with CCR5-tropic and CXCR4-tropic NL4-3 PV strain. Furthermore, it also inhibited a CXCR4-tropic replication-competent strain of HIV-1 subtype B virus. Binding assay of Kn2-7 to HIV-1 PV by Octet Red system suggested the anti-HIV-1 activity was correlated with a direct interaction between Kn2-7 and HIV-1 envelope. These results demonstrated that peptide Kn2-7 could inhibit HIV-1 by direct interaction with viral particle and may become a promising candidate compound for further development of microbicide against HIV-1

Ab-initio zkoumání elektronické struktury, chemické vazby a optických vlastností Ba2HgS5 polovodiče

V tomto rukopisu byla zkoumána elektronická struktura, vazebná povaha a optické vlastnosti ternární sloučeniny Ba2HgS5 pomocí teorie hustotních funkcí (DFT). K modelování výměnných a korelačních potenciálů byly použity generalizované gradientové aproximace (GGA), Engel a Vosko a generalizované gradientové aproximace (EV-GGA) a modifikovaná schémata Becke Johnson (mBJ). Výpočty pásové struktury ukazují, že tato sloučenina má hodnotu mezery přímého energetického pásma 2,34 eV, což ukazuje těsnou shodu s experimentální hodnotou mezery pásma 2,40 eV. Hodnota mezery v energetickém pásmu vypočtená pomocí formalismu mBJ je větší než hodnota získaná z přístupů GGA a EV-GGA. Z analýzy parciální elektronické energetické hustoty stavů bylo zjištěno, že valenčnímu pásmu dominují elektronické stavy Ba-p, S-s a Hg-d, zatímco vodivé pásmo je tvořeno orbitaly S-p a Ba-d. Kromě toho existuje silná hybridizace ve volném pásmu a ve vodivém pásmu mezi stavy S-p a Hg-s, Ba-s a Hg-f, Hg-s, S-p a S-p a Hg-p. Tato silná hybridizace vede k silné kovalentní vazbě mezi atomy Hg-S a Ba-S. Navíc byly vypočteny a podrobně diskutovány optické konstanty. Bylo zjištěno, že optické parametry závislé na energii jsou anizotropní s ohledem na polarizaci dopadající elektromagnetické vlny a vykazují vlastnosti v úplném souladu s výpočty struktury elektronických pásem. Sloučenina absorbuje ultrafialové záření poměrně silně. Ba2HgS5 má vysoký index lomu v širokém rozsahu frekvencí a má potenciál být použit jako antireflexní povlak a také ve fotonických zařízeních, jako jsou diody emitující světlo (LED).In this manuscript, the electronic structure, bonding nature and optical properties of the ternary Ba2HgS5 compound was investigated using the density functional theory (DFT). The generalised gradient approximation (GGA), Engel and Vosko generalised gradient approximation (EV-GGA) and the modified Becke Johnson (mBJ) schemes were used to model the exchange and correlation potentials. Band structure calculations indicate that this compound has a direct energy band gap value of 2.34 eV, showing a close agreement with the experimental band gap value of 2.40 eV. The energy band gap value calculated using the mBJ formalism is larger than those obtained from the GGA and the EV-GGA approaches. From the analysis of the partial electronic energy density of states, it was observed that the valence band is dominated by the Ba-p, S-s and Hg-d electronic states, while the conduction band is formed by the S-p and Ba-d orbitals. In addition, there exists a strong hybridisation in the valance band and in the conduction band between the S-p and Hg-s, Ba-s and Hg-f, Hg-s, S-p as well as the S-p and Hg-p states, respectively. This strong hybridisation leads to strong covalent bonding between the Hg-S and Ba-S atoms. Moreover, the optical constants were calculated and discussed in details. The energy dependent optical parameters were found to be anisotropic with respect to the polarisation of the incident electromagnetic wave and exhibit features in complete agreement with the electronic band structure calculations. The compound absorbs ultraviolet radiation quite strongly. Ba2HgS5 possesses high refractive index over a wide range of frequency and has potential to be used as anti-reflective coating and also in photonic devices like in light emitting diodes (LEDs)

Multicenter observational study of erlotinib therapy (OBSTAR) for non small-cell lung cancer: A GFPC study.

International audienceCONTEXT: Erlotinib therapy for non small-cell lung cancer (NSCLC) has mainly been evaluated in randomized trials. METHOD: OBSTAR was a multicenter, retrospective, observational study involving all patients treated with erlotinib in 18 French centers between June 2005 and September 2007. The analyses focused on the patients' characteristics, previous treatments, and treatment efficacy during a three-year follow-up period. RESULTS: 534 patients were included in this study. The median survival times were respectively 5.2 [3.7-7.4] and 4.7 [4.1-5.7] months, depending to whether erlotinib was used as second- (n=190), or ≥third-line treatment (n=305). The disease control rate were 39.1% [30.2-48.7] and 29.9% [29.6-36.9] according to the line of treatment. Factors predictive of an objective response were gender, age, and smoking status. Factors predictive of progression were age, sex, smoking status, the line of treatment, and the number of metastases. Treatment had to be interrupted for toxicity in 8.5% of cases. CONCLUSION: This study of erlotinib therapy in 2005-2007 confirms, in the general NSCLC patient population, the results of pivotal trials

Concordance entre la stratégie thérapeutique proposée en RCP initiale et le traitement effectivement réalisé pour les CBPNC de stade III non-résecables : résultats initiaux de l'étude OBSTINATE (GFPC 06-2019)

International audienceL'objectif principal de l'étude OBSTINATE (GFPC 06-2019) est d'évaluer prospectivement la Qualité de Vie (QdV) au cours de la prise en charge du CBNPC de stade III non-résecable en condition de pratique courante. Les CBNPC de stade III constituent un groupe très hétérogène de situations cliniques, pour lesquelles les prises en charge thérapeutiques sont souvent multimodales. La reproductibilité des décisions thérapeutiques validées en RCP a d'ailleurs été récemment mise en question dans ce contexte a. L'objet de la présente analyse est d'explorer la concordance entre la proposition validée en RCP initiale et les traitements reçus par les patients dans le cadre de l'étude nationale non-interventionnelle OBSTINATE (GFPC 06-2019)