Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases

Natural antioxidants are a very large diversified family of molecules classified by activity (enzymatic or nonenzymatic), chemical-physical properties (e.g., hydrophilic or lipophilic), and chemical structure (e.g., vitamins, polyphenols, etc.). Research on natural antioxidants in various fields, such as pharmaceutics, nutraceutics, and cosmetics, is among the biggest challenges for industry and science. From a biomedical point of view, the scavenging activity of reactive oxygen species (ROS) makes them a potential tool for the treatment of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, dementia, and amyotrophic lateral sclerosis (ALS). In addition to the purified phytochemical compounds, a variety of natural extracts characterized by a complex mixture of antioxidants and anti-inflammatory molecules have been successfully exploited to rescue preclinical models of these diseases. Extracts derived from Ginkgo biloba, grape, oregano, curcumin, tea, and ginseng show multitherapeutic effects by synergically acting on different biochemical pathways. Furthermore, the reduced toxicity associated with many of these compounds limits the occurrence of side effects. The support of nanotechnology for improving brain delivery, controlling release, and preventing rapid degradation and excretion of these compounds is of fundamental importance. This review reports on the most promising results obtained on in vitro systems, in vivo models, and in clinical trials, by exploiting natural-derived antioxidant compounds and extracts, in their free form or encapsulated in nanocarriers

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Isolated intra-ocular relapses of primary central nervous system lymphoma

Abstract published in European Journal of Neurology 24(Suppl 1):52, 2017International audienceBackground and aims: Relapses in primary central nervous system lymphoma (PCNSL) are usually cerebral and severe. Isolated intraocular relapses (IIOR) are much rarer and have not been specifically studied so far.Methods: We retrospectively selected patients treated within the French national expert network on PCNSL (LOC network). The inclusion criteria were: histologically proven PCNSL with at least a cerebral localization, immunocompetent status, 1st line treatment based on high-dose methotrexate and isolated IIOR subsequently.Results: 47 patients met the inclusion criteria (median age: 64.5 years (32.8-79.7), median Karnofsky Performance Status (KPS): 70 (40-100)). Initially, 13 patients had an ocular involvement, 16 had no ocular involvement and 18 had unknown status. The IIOR was the first relapse in 80% of cases. Median time from PCNSL diagnosis to IIOR was 14 months (3-51). Median KPS at IIOR was 80 (70-90), the affection was symptomatic in 95%. Decreased visual acuity was the prominent symptom. 76% of the patients received systemic chemotherapy (CT): ifosfamide-based CT (25%), methotrexate-based CT (25%), temozolomide (19%), in association with rituximab in 47%. 32% received a local treatment (intraocular CT or ocular radiotherapy) alone or in association with systemic CT. 31% subsequently received high-dose CT with autologous stem cells rescue). 60% of patients relapsed subsequently (35% in the brain, 62% in the eye) with a median PFS of 10,8 months. 5-year survival rate from relapse was 53.6% (0.28-1).Conclusion: IIOR of PCNSL seem to have a better prognosis than brain relapses. That might be explained by a better KPS allowing intensification chemotherapy for up to the third of patients

Isolated intra-ocular relapses of primary central nervous system lymphoma

Abstract published in European Journal of Neurology 24(Suppl 1):52, 2017International audienceBackground and aims: Relapses in primary central nervous system lymphoma (PCNSL) are usually cerebral and severe. Isolated intraocular relapses (IIOR) are much rarer and have not been specifically studied so far.Methods: We retrospectively selected patients treated within the French national expert network on PCNSL (LOC network). The inclusion criteria were: histologically proven PCNSL with at least a cerebral localization, immunocompetent status, 1st line treatment based on high-dose methotrexate and isolated IIOR subsequently.Results: 47 patients met the inclusion criteria (median age: 64.5 years (32.8-79.7), median Karnofsky Performance Status (KPS): 70 (40-100)). Initially, 13 patients had an ocular involvement, 16 had no ocular involvement and 18 had unknown status. The IIOR was the first relapse in 80% of cases. Median time from PCNSL diagnosis to IIOR was 14 months (3-51). Median KPS at IIOR was 80 (70-90), the affection was symptomatic in 95%. Decreased visual acuity was the prominent symptom. 76% of the patients received systemic chemotherapy (CT): ifosfamide-based CT (25%), methotrexate-based CT (25%), temozolomide (19%), in association with rituximab in 47%. 32% received a local treatment (intraocular CT or ocular radiotherapy) alone or in association with systemic CT. 31% subsequently received high-dose CT with autologous stem cells rescue). 60% of patients relapsed subsequently (35% in the brain, 62% in the eye) with a median PFS of 10,8 months. 5-year survival rate from relapse was 53.6% (0.28-1).Conclusion: IIOR of PCNSL seem to have a better prognosis than brain relapses. That might be explained by a better KPS allowing intensification chemotherapy for up to the third of patients

Isolated intra-ocular relapses of primary central nervous system lymphoma

Abstract published in European Journal of Neurology 24(Suppl 1):52, 2017International audienceBackground and aims: Relapses in primary central nervous system lymphoma (PCNSL) are usually cerebral and severe. Isolated intraocular relapses (IIOR) are much rarer and have not been specifically studied so far.Methods: We retrospectively selected patients treated within the French national expert network on PCNSL (LOC network). The inclusion criteria were: histologically proven PCNSL with at least a cerebral localization, immunocompetent status, 1st line treatment based on high-dose methotrexate and isolated IIOR subsequently.Results: 47 patients met the inclusion criteria (median age: 64.5 years (32.8-79.7), median Karnofsky Performance Status (KPS): 70 (40-100)). Initially, 13 patients had an ocular involvement, 16 had no ocular involvement and 18 had unknown status. The IIOR was the first relapse in 80% of cases. Median time from PCNSL diagnosis to IIOR was 14 months (3-51). Median KPS at IIOR was 80 (70-90), the affection was symptomatic in 95%. Decreased visual acuity was the prominent symptom. 76% of the patients received systemic chemotherapy (CT): ifosfamide-based CT (25%), methotrexate-based CT (25%), temozolomide (19%), in association with rituximab in 47%. 32% received a local treatment (intraocular CT or ocular radiotherapy) alone or in association with systemic CT. 31% subsequently received high-dose CT with autologous stem cells rescue). 60% of patients relapsed subsequently (35% in the brain, 62% in the eye) with a median PFS of 10,8 months. 5-year survival rate from relapse was 53.6% (0.28-1).Conclusion: IIOR of PCNSL seem to have a better prognosis than brain relapses. That might be explained by a better KPS allowing intensification chemotherapy for up to the third of patients

Isolated intra-ocular relapses of primary central nervous system lymphoma

Abstract published in European Journal of Neurology 24(Suppl 1):52, 2017International audienceBackground and aims: Relapses in primary central nervous system lymphoma (PCNSL) are usually cerebral and severe. Isolated intraocular relapses (IIOR) are much rarer and have not been specifically studied so far.Methods: We retrospectively selected patients treated within the French national expert network on PCNSL (LOC network). The inclusion criteria were: histologically proven PCNSL with at least a cerebral localization, immunocompetent status, 1st line treatment based on high-dose methotrexate and isolated IIOR subsequently.Results: 47 patients met the inclusion criteria (median age: 64.5 years (32.8-79.7), median Karnofsky Performance Status (KPS): 70 (40-100)). Initially, 13 patients had an ocular involvement, 16 had no ocular involvement and 18 had unknown status. The IIOR was the first relapse in 80% of cases. Median time from PCNSL diagnosis to IIOR was 14 months (3-51). Median KPS at IIOR was 80 (70-90), the affection was symptomatic in 95%. Decreased visual acuity was the prominent symptom. 76% of the patients received systemic chemotherapy (CT): ifosfamide-based CT (25%), methotrexate-based CT (25%), temozolomide (19%), in association with rituximab in 47%. 32% received a local treatment (intraocular CT or ocular radiotherapy) alone or in association with systemic CT. 31% subsequently received high-dose CT with autologous stem cells rescue). 60% of patients relapsed subsequently (35% in the brain, 62% in the eye) with a median PFS of 10,8 months. 5-year survival rate from relapse was 53.6% (0.28-1).Conclusion: IIOR of PCNSL seem to have a better prognosis than brain relapses. That might be explained by a better KPS allowing intensification chemotherapy for up to the third of patients

A research agenda for improving national Ecological Footprint accounts

Nation-level Ecological Footprint accounts are currently produced for more than 150 nations, with multiple calculations available for some nations. The data sets that result from these national assessments typically serve as the basis for Footprint calculations at smaller scales, including those for regions, cities, businesses, and individuals. Global Footprint Network's National Footprint Accounts, supported and used by more than 70 major organizations worldwide, contain the most widely used national accounting methodology today. The National Footprint Accounts calculations are undergoing continuous improvement as better data becomes available and new methodologies are developed. In this paper, a community of active Ecological Footprint practitioners and users propose key research priorities for improving national Ecological Footprint accounting. For each of the proposed improvements, we briefly review relevant literature, summarize the current state of debate, and suggest approaches for further development. The research agenda will serve as a reference for a large scale, international research program devoted to furthering the development of national Ecological Footprint accounting methodology.Ecological Footprint Biocapacity Productivity Nation Accounts Research Improvement