The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

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

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Etude du rôle de la protéine QN1/KIAA1009, une nouvelle molécule motrice de la famille des kinésines, au cours de la prolifération et de la différenciation neuronale

Les molécules motrices telles que les kinésines sont impliquées dans divers processus fondamentaux comme la mitose, le transport vésiculaire, la transcription ou la réparation de l'ADN. Dans ce travail, nous montrons pour la première fois que la protéine QN1 appartient à la famille des kinésines et a pour orthologue la protéine humaine KIAA1009. Nous démontrons, par stratégie siRNA, l'implication de cette protéine au cours de deux processus cellulaires majeurs : la prolifération et la différenciation. En effet, la protéine QM1/KIAA1009 joue un rôle décisif dans le déroulement normal de la mitose et plus particulièrement dans la ségrégation correcte des chromosomes. De plus, nous démontrons que la protéine QN1/KIAA1009 participe à la voie de signalisation du NGF au cours de la différenciation des cellules PC12. L' ensemble de ces résultats montre que la protéine QN1/KIAA1009 est un nouvel acteur clé de la mitose.PARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

Prévalence et identifications des mycoplasmes respiratoires équins en France

National audienceIntroduction : Les bactéries du genre Mycoplasma sont de petites bactéries sans paroi dont lediagnostic est rendu complexe de par leur croissance fastidieuse et le peu de voiesmétaboliques exprimées. Pourtant plus de cent espèces ont été décrites, qu’elles soientcommensales, opportunistes ou pathogènes, avec un tropisme essentiellement urogénital ourespiratoire pour ces dernières Chez les chevaux, trois espèces, Mycoplasma (M.) equirhinis,M. pulmonis et M. felis, ont été détectées de façon récurrente dans des prélèvementsrespiratoires1,2. Leur présence est suspectée par les vétérinaires chez les chevaux présentantune toux chronique et en absence de réponse après un traitement antibiotique3. Cependant, l'implication des mycoplasmes dans les troubles respiratoires chez le cheval n'est pas clairement documentée4. Parmi les échantillons respiratoires équins (lavages bronchoalvéolaires [LBA] et majoritairement lavages trachéaux [LT]), analysés au laboratoire, 15% paran se sont révélés positifs par PCR en temps réel (rt-PCR) à Mycoplasma spp. Cependant, lesespèces associées n'ont pas encore été explorées. Objectifs : Cette étude vise à i) développeret valider des outils pour détecter, isoler et identifier les différentes espèces de Mycoplasmadans les échantillons cliniques respiratoires équins et ii) définir ensuite leur prévalence enFrance en fonction du type de prélèvement et des caractéristiques des chevaux (âge, sexe etrace). Matériel et méthodes : Des échantillons négatifs dopés avec des souches dénombrées(M. equirihinis, felis et pulmonis) et/ou une gamme de dilution d'ADN ont été utilisés pourcaractériser les méthodes de culture et de rt-PCR. La prévalence des espèces de mycoplasmea été déterminée sur une population de 630 chevaux, prélevés en France en 2020, etprésentant des troubles respiratoires. Les souches isolées et les extraits d'ADN positifs ont étéidentifiés par séquençage de l'ARNr 16S ou par PCR spécifique d'espèce. Résultats : Nosméthodes (culture et PCR permettent de détecter de façon équivalente), à partird’échantillons qualifiés, les trois espèces de mycoplasmes respiratoires équines. Sur notrepanel test, cent-sept chevaux (17%) sont positifs au genre Mycoplasma spp. par au moins unedes deux méthodes utilisées. Les mycoplasmes sont davantage détectés dans les LT (19,5%)que dans les LBA (8,4%). L'espèce M. equirhinis est retrouvée dans 81% des échantillonspositifs par rt-PCR et 98% des 43 souches isolées. Discussion et Conclusion : La prévalence desmycoplasmes dans les échantillons respiratoires est confirmée et affinée. M. equirhinis estl'espèce prédominante. Sa prévalence varie selon le type d'échantillon, l'âge et la conditiond’athlète du cheval

Some genetic and biochemical aspects of myoclonus

peer reviewedCan a gene defect be responsible for the occurrence in an individual, at a particular age, of such a muscle twitch followed by relaxation called: "myoclonus" and defined as sudden, brief, shock-like movements? Genetic defects could indeed determine a subsequent cascade of molecular events (caused by abnormal encoded proteins) that would produce new aberrant cellular relationships in a particular area of the CNS leading to re-builded "myoclonogenic" neuronal networks. This can be illustrated reviewing some inherited neurological entities that are characterized by a predominant myoclonic picture and among which a clear gene defect has been identified. In the second part of this chapter, we will also propose a new point of view on how some structural genes could, under certain conditions, when altered, produced idiopathic generalized epilepsy with myoclonic jerks, taking juvenile myoclonic epilepsy (JME) and the myoclonin (EFHC-1) gene as examples. (c) 2007 Elsevier Masson SAS. All rights reserved

29Si and 27Al MAS NMR Characterization of the Structural Evolution of a Lateritic Clay under Acidic and Alkaline Treatments

International audienc

Highly labeled methylene blue-ds DNA silica nanoparticles for signal enhancement of immunoassays: application to the sensitive detection of bacteria in human platelet concentrates

The authors would like to express their sincere gratitude to Gaelle-Anne Cremer for furnishing the streptavidin-antibody conjugates, Patrice Sarfati and Pierre Sonigo for their expert supervision of the work, François Rieunier and Stephane Rihet for their pertinent advices on the work.International audienceA nanoparticle-based electrochemical sandwich immunoassay was developed for bacteria detection in platelet concentrates. For the assay, magnetic beads were functionalized with antibodies to allow the specific capture of bacteria from the complex matrix, and innovative methylene blue-DNA/nanoparticle assemblies provided the electrochemical response for amplified detection. This nanoparticular system was designed as a temperature-sensitive nano-tool for electrochemical detection. First, oligonucleotide-functionalized nanoparticles were obtained by direct synthesis of the DNA strands on the nanoparticle surface using an automated oligonucleotide synthesizer. Densely packed DNA coverage was thus obtained. Then, DNA duplexes were constructed on the NP surface with a complementary strand bearing a 3 methylene blue tag. This strategy ultimately produced highly functionalized nanoparticles with electrochemical markers. These assemblies enabled amplification of the electrochemical signal, resulting in a very good sensitivity. A proof-of-concept was carried out for E. coli detection in human platelet concentrates. Bacterial contamination of this complex biological matrix is the highest residual infectious risk in blood transfusion. The development of a rapid assay that could reach 10–102 CFU mL−1 sensitivity is a great challenge. The nanoparticle-based electrochemical sandwich immunoassay carried out on a boron doped diamond electrode proved to be sensitive for E. coli detection in human platelets. Two antibody pairs were used to develop either a generic assay against certain Gram negative strains or a specific assay for E. coli. The methylene blue-DNA/nanoparticles amplify sensitivity ×1000 compared with the assay run without NPs for electrochemical detection. A limit of detection of 10 CFU mL−1 in a biological matrix was achieved for E. coli using the highly specific antibody pair