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

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

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

Measuring neural entrainment to beat and meter in infants : effects of music background

Caregivers often engage in musical interactions with their infants. For example, parents across cultures sing lullabies and playsongs to their infants from birth. Behavioral studies indicate that infants not only extract beat information, but also group these beats into metrical hierarchies by as early as 6 months of age. However, it is not known how this is accomplished in the infant brain. An EEG frequency-tagging approach has been used successfully with adults to measure neural entrainment to auditory rhythms. The current study is the first to use this technique with infants in order to investigate how infants' brains encode rhythms. Furthermore, we examine how infant and parent music background is associated with individual differences in rhythm encoding. In Experiment 1, EEG was recorded while 7-month-old infants listened to an ambiguous rhythmic pattern that could be perceived to be in two different meters. In Experiment 2, EEG was recorded while 15-month-old infants listened to a rhythmic pattern with an unambiguous meter. In both age groups, information about music background (parent music training, infant music classes, hours of music listening) was collected. Both age groups showed clear EEG responses frequency-locked to the rhythms, at frequencies corresponding to both beat and meter. For the younger infants (Experiment 1), the amplitudes at duple meter frequencies were selectively enhanced for infants enrolled in music classes compared to those who had not engaged in such classes. For the older infants (Experiment 2), amplitudes at beat and meter frequencies were larger for infants with musically-trained compared to musically-untrained parents. These results suggest that the frequency-tagging method is sensitive to individual differences in beat and meter processing in infancy and could be used to track developmental changes

Design et calibration de chemcatcher pour la surveillance de butylétains dans les zones portuaires

International audienc

Evaluating polar pesticide pollution with a combined approach: a survey of agricultural practices and POCIS passive samplers in a Tunisian lagoon watershed

A study of pesticides in the Bizerte lagoon watershed on the Mediterranean coast of Tunisia showed that herbicides and fungicides are the most commonly used compounds. A survey was made of selected farmers. Pesticide contamination was monitored in the water column and sediments at four selected sampling sites (lagoon (A) and in three ouedsChegui (B), Garaa (C), and Tinja (D)). Polar organic chemical integrative samplers (POCIS) were used to assess pesticide contamination. Thirty-two pesticides were investigated; the total concentration of active ingredients ranged from 35.9ngL(-1) in Tinja oued to 1246ngL(-1) in Chegui oued. In the lagoon, the total concentration of pesticides was 67.7ngL(-1). In the sediments, the highest concentration was measured in Chegui oued in the spring (31ngg(-1) dw). The main compounds found in the analyzed sediments were prosulfocarb and tebuconazole molecules

Study of passive sampler calibration (Chemcatcher®) for environmental monitoring of organotin compounds: Matrix effect, concentration levels and laboratory vs in situ calibration

International audienceApplication of Chemcatcher® to monitor organotin compounds [monobutyltin (MBT), dibutyltin (DBT) and tributlytin (TBT)] in sea water has been little developed. Prior to the measurement of the time-weighted average water concentrations (TWAC), a calibration step is required to determine sampling rates (Rs) which is usually assessed in a flow-through laboratory pilot where experimental conditions are well controlled. This paper investigates the effect of the water matrix (tap water vs real sea water from the harbor of Port Camargue in France) and organotin concentrations on the uptake rates of organotin compounds. Laboratory calibrations provided sampling rates in the range of 66–225 mL.day−1 in high concentration (usually used for laboratory calibrations) and in the range of 30–56 mL.day−1 at low concentrations (environmental range). When the tank is filled with real sea water, sampling rates were found to be in the range of 38–177 mL.day−1. In order to demonstrate the efficiency of Chemcatcher® in real conditions, in situ calibration was done in the harbor of Port Camargue. This calibration has been done in order to replicate environmental conditions: compounds concentrations, hydrodynamic and water matrix effects. To compare the impact of calibration procedures on TWAC determination, Chemcatcher® was deployed in the harbor of Port Camargue and spot sampling was performed to monitor the concentrations of organotins in water throughout the exposure period. Results obtained using the field Rs determined by in situ calibration were more reliable. In this case, TWAC is in agreement with spot sampling concentration

Synthèse d'un polymère à empreinte moléculaire spécifique aux organoétains pour l'échantillonnage passif des organoétains dans l'eau de mer

International audienceEnvironmental contaminations can sometimes be difficult to measure, particularly in complex matrices such as seawater. This is the case of organotin compounds (OSn) such as the monobutyltin (MBT), dibutyltin (DBT), and tributyltin (TBT), whose range of polarity is wide. These compounds, mostly coming from antifouling paints used on ship shell, can be found in water and sediments where they are stable and can persist for years. Passive sampling is gaining in interest to offer solutions to monitor these kinds of compounds even in low concentrations. However, due to the diversity of pollutants present in the environment nowadays, it is important to propose solutions that allow a specific sampling. This work aims to highlight the usability of molecularly imprinted polymers (MIPs) in passive sampling for the monitoring of OSn. MIPs were synthetized using three synthesis ways (bulk, suspension, and mini-emulsion processes) and kinetics were realized in order to estimate the retention of OSn by the solid MIP phase. Results highlighted a good retention of OSn with mean retention kinetic constants near 10−5, 10−6 and 10−7 L.ng.s−1 for DBT, TBT and MBT respectively. The synthesis mode showed no impact on retention kinetics, therefore, bulk synthesis is recommended because of its simplicity. If the elimination of OSn from MIPs is to be optimized, the retention of OSn on MIPs has been demonstrated, and is very promising for their use in specific passive samplers.Les contaminations environnementales peuvent parfois être difficiles à mesurer, en particulier dans des matrices complexes comme l'eau de mer. C'est le cas des composés organostanniques (OSn) tels que le monobutylétain (MBT), le dibutylétain (DBT), et le tributylétain (TBT), dont la gamme de polarité est large. Ces composés, provenant principalement des peintures antisalissures utilisées sur les coques des navires, se retrouvent dans l'eau et les sédiments où ils sont stables et peuvent persister pendant des années. L'échantillonnage passif gagne en intérêt car il offre des solutions pour surveiller ces types de composés, même en faibles concentrations. En raison de la diversité des polluants présents dans l'environnement de nos jours, il est important de proposer des solutions qui permettent un échantillonnage spécifique. Ce travail vise à mettre en évidence l'utilité des polymères à empreintes moléculaires (MIPs) dans l'échantillonnage passif pour le suivi des OSn. Des MIPs ont été synthétisés selon trois voies de synthèse (procédés en vrac, en suspension et en mini-émulsion) et des cinétiques ont été réalisées afin d'estimer la rétention de l'OSn par la phase solide des MIPs. Les résultats ont mis en évidence une bonne rétention des OSn avec des constantes cinétiques de rétention moyennes proches de 10-5, 10-6 et 10-7 L.ng.s-1 pour DBT, TBT et MBT respectivement. Le mode de synthèse n'a montré aucun impact sur la cinétique de rétention, par conséquent, la synthèse en vrac est recommandée en raison de sa simplicité. Si l'élimination des OSn des MIPs doit être optimisée, la rétention des OSn sur les MIPs a été démontrée, et est très prometteuse pour leur utilisation dans des échantillonneurs passifs spécifiques