Influence of N- methylation and conformation on almiramide anti-leishmanial activity

The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α‑amino γ‑lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

L'exploration de l'utilisation d'un robot-jouet mobile comme agent d'imitation chez les enfants autistes

L’autisme est une problématique complexe dont les causes sont encore inconnues (Ferrari, 2001). Les interventions basées sur l’observation des enfants autistes ne parviennent pas à déclencher chez eux le désir d’apprendre et d’initier la communication dans un but de partager avec l’autre (Doehring, 2001). Cette étude exploratoire et innovatrice vise à vérifier l’effet de l’utilisation d’un robot-jouet (objet animé s’apparentant à l’humain) sur le développement de la communication réciproque des enfants autistes de bas niveau de fonctionnement, et ce par des jeux d’imitation d’expressions faciales, de mouvements du corps et d’actions familières. Nous avons évalué les indices de partage d’attention et de conventions chez quatre enfants autistes de bas niveau de fonctionnement, âgés de cinq ans, sélectionnés au Centre de réadaptation le Florès des Laurentides. La procédure expérimentale expose deux paires d’enfants autistes à 20 activités : une paire en interaction avec le robot et une autre paire en interaction avec l’expérimentatrice. Contrairement à notre hypothèse, les résultats montrent que les formes de conventions telle l’imitation des mouvements du corps et d’actions familières sont plus nombreuses chez les deux enfants jumelés à l’expérimentatrice. Par contre, les deux enfants jumelés au robot attestent d’un meilleur partage d’attention (contact visuel, proximité physique) et imitent davantage les expressions faciales que les enfants jumelés à l’humain. Ces résultats suggèrent fortement la poursuite d’études dans ce domaine ou de répliquer la présente étude avec un plus grand nombre de sujets afin de conforter nos conclusions préliminaires

L'exploration de l'utilisation d'un robot-jouet mobile comme agent d'imitation chez les enfants autistes

L’autisme est une problématique complexe dont les causes sont encore inconnues (Ferrari, 2001). Les interventions basées sur l’observation des enfants autistes ne parviennent pas à déclencher chez eux le désir d’apprendre et d’initier la communication dans un but de partager avec l’autre (Doehring, 2001). Cette étude exploratoire et innovatrice vise à vérifier l’effet de l’utilisation d’un robot-jouet (objet animé s’apparentant à l’humain) sur le développement de la communication réciproque des enfants autistes de bas niveau de fonctionnement, et ce par des jeux d’imitation d’expressions faciales, de mouvements du corps et d’actions familières. Nous avons évalué les indices de partage d’attention et de conventions chez quatre enfants autistes de bas niveau de fonctionnement, âgés de cinq ans, sélectionnés au Centre de réadaptation le Florès des Laurentides. La procédure expérimentale expose deux paires d’enfants autistes à 20 activités : une paire en interaction avec le robot et une autre paire en interaction avec l’expérimentatrice. Contrairement à notre hypothèse, les résultats montrent que les formes de conventions telle l’imitation des mouvements du corps et d’actions familières sont plus nombreuses chez les deux enfants jumelés à l’expérimentatrice. Par contre, les deux enfants jumelés au robot attestent d’un meilleur partage d’attention (contact visuel, proximité physique) et imitent davantage les expressions faciales que les enfants jumelés à l’humain. Ces résultats suggèrent fortement la poursuite d’études dans ce domaine ou de répliquer la présente étude avec un plus grand nombre de sujets afin de conforter nos conclusions préliminaires

Investigating the use of a mobile robotic toy as an imitation agent for children with autism

Unpredictability and complexity of social interactions are important challenges for a low functioning autistic child. The objective of this research is to explore if a mobile robot could, by being more predictable, attractive and simple, facilitate reciprocal interaction such as imitation. By conducting an exploratory study involving four children, we found that forms of share conventions such as imitation of body movements and of familiar actions are higher with two children paired with a human mediator, compared to two children paired with a robot mediator. The two children paired with the robot mediator demonstrate better shared attention (visual contact, physical proximity) and imitate facial expressions more than the children paired with the human mediator. 1

2003. Characteristics of mobile robotic toys for children with pervasive developmental disorders

Abstract – Pervasive developmental disorders (PDD) refers to a group of disorders characterized by delays in the development of multiple basic functions including socialization and communication. Symptoms may include communication problems such as using and understanding language; difficulty relating to people, objects, and events; unusual play with toys and other objects; difficulty with changes in routine or familiar surroundings, and repetitive body movements or behavior patterns [1]. Autism is the most characteristic and best studied PDD. We are investigating the use of mobile robotic toys that can move in the environment and interact in various manners (vocal messages, music, visual cues, movement, etc.) with children with autism. The hypothesis is that mobile robots can serve as an appropriate pedagogical tool to help children with PDD develop social skills because they are more predictable and less intimidating. The objective is to see how such devices can be used to capture the child’s attention and contribute to helping him or her develop social skills. This paper outlines the design considerations for such robots, and presents experimental protocols that are being developed to study the impacts of using these robots on the development of the child

Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma

Background: An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB. Methods: We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR. Results: Median follow up was 16.6 months (range: 0.7–67.8). Median duration on therapy was 5.1 months (<1–61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3–42.4) at baseline and 4.1 (1.1–96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes. Conclusions: Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation