Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

TIC et Construction de ressources territoriales: Observations à partir de trois territoires d'étude : Diois, Maurienne, Vésubie

International audienceThe Development of the territories of mountain is based on logics of differentiation, resting on the construction of specific resources. In the case of tourism, the meeting of these resources in a "basket of goods" makes it a particular destination. From the study of three territories of French mountain: Diois, Maurienne, Vésubie, this article questions the place of the ICT in the construction of these territorial resources and in the constitution of the baskets of goods. From their capacity to look towards external glances on the territories, the TIC contribute to the revelation of these resources and then to their development. They also contribute to the formation of networks of actors differentiated around these resources. Lastly, in certain cases, the ICT and their uses, become a specific resource for the territories. The undertaken studies show that the local policy options induce very different positionings taking into consideration development of the ICT.Le Développement des territoires de montagne s'appuie sur des logiques de différenciation, reposant sur la construction de ressources spécifiques. Dans le cas du tourisme, la réunion de ces ressources dans un " panier de biens " en fait une destination particulière. A partir de l'étude de trois territoires de montagne français : Diois, Maurienne, Vésubie, le présent article interroge la place des TIC dans la construction de ces ressources territoriales et dans la constitution des paniers de biens. De par leur capacité à porter des regards extérieurs sur les territoires, les TIC contribuent à la révélation de ces ressources, puis à leur développement. Elles contribuent aussi à la formation de réseaux d'acteurs différenciés autour de ces ressources. Enfin, dans certains cas, les TIC et leurs usages, deviennent une ressource spécifique aux territoires. Les études menées montrent que les choix politiques locaux induisent des positionnements très différents au regard du développement des TIC

TIC et Construction de ressources territoriales: Observations à partir de trois territoires d'étude : Diois, Maurienne, Vésubie

International audienceThe Development of the territories of mountain is based on logics of differentiation, resting on the construction of specific resources. In the case of tourism, the meeting of these resources in a "basket of goods" makes it a particular destination. From the study of three territories of French mountain: Diois, Maurienne, Vésubie, this article questions the place of the ICT in the construction of these territorial resources and in the constitution of the baskets of goods. From their capacity to look towards external glances on the territories, the TIC contribute to the revelation of these resources and then to their development. They also contribute to the formation of networks of actors differentiated around these resources. Lastly, in certain cases, the ICT and their uses, become a specific resource for the territories. The undertaken studies show that the local policy options induce very different positionings taking into consideration development of the ICT.Le Développement des territoires de montagne s'appuie sur des logiques de différenciation, reposant sur la construction de ressources spécifiques. Dans le cas du tourisme, la réunion de ces ressources dans un " panier de biens " en fait une destination particulière. A partir de l'étude de trois territoires de montagne français : Diois, Maurienne, Vésubie, le présent article interroge la place des TIC dans la construction de ces ressources territoriales et dans la constitution des paniers de biens. De par leur capacité à porter des regards extérieurs sur les territoires, les TIC contribuent à la révélation de ces ressources, puis à leur développement. Elles contribuent aussi à la formation de réseaux d'acteurs différenciés autour de ces ressources. Enfin, dans certains cas, les TIC et leurs usages, deviennent une ressource spécifique aux territoires. Les études menées montrent que les choix politiques locaux induisent des positionnements très différents au regard du développement des TIC

Synthesis and Radioprotective Properties of Pulvinic Acid Derivatives

A high-throughput screening method has highlighted the marked antioxidant activity of some pulvinic acid derivatives (PADs) towards oxidation of thymidine, under γ and UV irradiation, and Fenton-like conditions. Here, we report the synthesis of a series of new hydrophilic PADs and the evaluation of their radioprotective efficacy in cell culture. Using a cell-based fluorescent assay, we show that some of these compounds have a pronounced ability to prevent cell death caused by radiation and to allow the subsequent resumption of proliferation. Thus, PADs may be considered as a novel class of radioprotective agents. © 2011 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim