Genetic contribution of breast cancer genes in women of black African origin

Breast cancer (BC) is an increasing public health issue worldwide. BC incidence and mortality rates are rising in transitioning countries in Africa, with the most rapid increase occurring in Sub-Saharan Africa (SSA). Female BC represents 25.8% of all cancer diagnosis in SSA. Early age at onset, high grade and triple negative tumors are hallmarks of BC in this region, associated with germline pathogenic variants in susceptibility genes. While several genes have been associated with genetic predisposition (BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, STK11, ATM, CHEK2, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, … ), most studies have reported contribution of BRCA1 and BRCA2 pathogenic variants. Genetic contribution of BRCA genes has been estimated at 27% in Caucasian women. Available data from population of African origin are scarce and have mainly focused on pathogenic variants of BRCA1 and BRCA2. Reports from main studies on large sample size highlighted that BRCA1 still the major gene associated with BC in SSA. In addition, BRCA2, PALB2, and P53, are also on the top major genes with high penetrance, associated with BC. Mutation spectrum of BC genes in black African women seems to be different from Caucasian with increasing number of founder mutations identified. We hypothesis that the genetic contribution of known BC genes may be different between women of black African origin compared to Caucasians. In this review we explore the genetic contribution of known breast cancer genes in women of African origin, and discuss perspectives for prevention and patients care strategies in the era of precision medicine

Effet de l’Incorporation de l’Acide Guanido Acétique (AGA - C3H7N3O2) Comme Précursseur de la Créatine sur l'ingestion et les Performances de Croissance de Poulets de Chair au Sénégal

Les éleveurs de volailles de chair au Sénégal sont confrontés à une baisse de performances du fait d’une alimentation de plus en plus végétale, rallongeant la durée d’élevage. Jouant un rôle important dans le métabolisme énergétique des animaux, la créatine ne se trouve pas dans les plantes. Une supplémentation en Acide Guanido Acétique (AGA), qui est le seul précurseur naturel de la créatine, pourrait permettre d’équilibrer la demande de l'animal pour ce nutriment semi-essentiel. Cette étude vise à déterminer le niveau d’ingestion ainsi que les performances de croissance de poulets de chair nourris avec un aliment incorporant de l’AGA sous la forme commerciale de CreAMINO® utilisé comme complément alimentaire pour la première fois au Sénégal. L'expérience de nutrition a duré quarante-deux (42) jours avec 400 poussins chair d’un jour, de souche Cobb 500, non sexés. Le dispositif expérimental utilisé est complètement aléatoire avec deux niveaux de supplémentation en AGA (0 et 600 g/tonne d’aliment) et quatre répétitions pour chaque traitement. Les données collectées ont été analysées selon une procédure ANOVA. Les résultats ont révélé que les animaux qui ont reçu le régime expérimental contenant de l’AGA ont obtenu, à la fin de l’expérience, un poids vif (2191,6±137,9 vs 2080,2±186,2 g/sujet) (P>0,05) et un gain pondéral moyen (51,6 vs 48,9 g/sujet) (P>0,05) numériquement un peu plus élevé que les animaux du groupe témoin. L’ingestion alimentaire, la consommation hydrique ainsi que l’indice de conversion alimentaire ont été, respectivement, pour le groupe expérimental et le groupe témoin de 95,2 g/sujet/jour et 90,6 g/sujet/jour, de 262,4 ml/sujet/jour et 249,0 ml/sujet/jour ainsi que de 1,8 et 1,9. Les animaux abattus à la fin de  l’étude ont présenté un poids carcasse moyen de 1649,7±166,4 g/sujet pour le groupe expérimental et 1566±106,4 g/sujet pour le groupe témoin avec un rendement carcasse moyen similaire de 75,3%. Les paramètres zootechniques cités n’ont pas montré de différence significative entre les deux groupes (P>0,05).   Broiler breeders in Senegal are facing a decrease in performance due to an increasingly plant-based diet that extends the breeding period. Creatin, which plays an important role in the energy metabolism of animals, is not found in plants. Supplementation with Guanido Acetic Acid (GAA), which is the only natural precursor of creatine, could help balance the animal’s demand for this semi-essential nutrient. This paper focuses on determining the level of intake as well as growth performance of broilers fed with a feed incorporating GAA in the commercial form of CreAMINO® used as a fedd supplement for the first time in Senegal. The feeding experiment lasted forty-two (42) days with 400 one-day-old unsexed Cobb 500 chicks. The experimental design used was completely randomized with two treatments (0 and 600 g/ton of feed) and four replicates for each treatment. The data collected were analyzed using an ANOVA procedure. The results revealed that animals fed with experimental diet containing GAA had a live weight (2191.6±137.9 vs. 2080.2±186.2 g/subject) (P>0.05) and average weight gain (51.6 vs. 48.9 g/subject) (P>0.05) numerically slightly higher than animals in the control group at the end of the experiment. The feed intake, the water consumption, as well as the food conversion index for the experimental group and the control group were 95.2 g/subject/day and 90.6 g/subject/day, 262.4 ml/subject/day and 249.0 ml/subject/day and 1.8 and 1.9, respectively. Animals slaughtered at the end of the study had an average carcass weight of 1649.7±166.4 g/subject for the experimental group and 1566±106.4 g/subject for the control group with a similar average carcass yield of 75.3%. The zootechnical parameters cited did not show any significant difference between the two groups (P>0.05)

Effet de L’incorporation de L’Acide Guanido Acétique (AGA) Comme Précursseur de la Créatinine sur L'ingestion et les Performances de Croissance de Poulets de Chair au Sénégal

Cette étude a été conduite pour déterminer l’ingestion et les performances de croissance de poulets de chair nourris avec un aliment commercial incorporant 600 g/tonne d’Acide Guanidino Acétique (AGA) sous forme de CreAMINO®. L’AGA est un précurseur de la créatine qui joue un rôle important dans le métabolisme cellulaire des oiseaux. L'expérience de nutrition a duré 42 jours avec 400 poussins chair d’un jour, de souche Cobb 500, non sexés. Le dispositif expérimental utilisé est complètement aléatoire avec 2 traitements (Témoin et Expérimental) et 4 répétitions pour chaque traitement. Les données collectées ont été analysées selon une procédure ANOVA. Les résultats ont révélé que les animaux qui ont reçu le régime expérimental contenant de l’AGA ont obtenu, à la fin de l’expérience, un poids vif (2191,6±137,9 vs 2080,2±186,2 g/sujet) (P>0,05) et un gain pondéral moyen (51,6 vs 48,9 g/sujet) (P>0,05) numériquement un peu plus élevé que les animaux du groupe témoin. L’ingestion alimentaire et la consommation hydrique ont été, respectivement, de 95,2 g/sujet/jour et 262,4 ml/sujet/jour pour le groupe expérimental ainsi que 90,6 g/sujet/jour et 249,0 ml/sujet/jour pour le groupe témoin avec un indice de conversion alimentaire moyen similaire de 1,8. Les animaux abattus à la fin de l’étude ont présenté un poids carcasse moyen de 1649,7±166,4 g/sujet pour le groupe expérimental et 1566±106,4 g/sujet pour le groupe témoin avec un rendement carcasse moyen similaire de 75,3%. De manière générale, l’analyse statistique des paramètres zootechniques cités n’a pas montré de différence significative entre les deux groupes.   This study was conducted to determine intake and growth performance of broilers fed with commercial feed incorporating 600 g/ton of Guanidino Acetic Acid (GAA) in the form of CreAMINO®. GAA is a creatine precursor that plays an important role in the cellular metabolism of birds. The feeding experiment lasted 42 days with 400 one-day-old unsexed Cobb 500 chicks. The experimental design used was completely randomized with 2 treatments (Control and Experimental) and 4 replicates for each treatment. The data collected were analyzed using an ANOVA procedure. The results revealed that animals fed with experimental diet containing GAA had a live weight (2191.6±137.9 vs. 2080.2±186.2 g/subject) (P>0.05) and average weight gain (51.6 vs. 48.9 g/subject) (P>0.05) numerically slightly higher than animals in the control group at the end of the experiment. Feed intake and water consumption were, respectively, 95.2 g/subject/day and 262.4 ml/subject/day for the experimental group and 90.6 g/subject/day and 249.0 ml/subject/day for the control group with a similar mean feed conversion ratio of 1.8. Animals slaughtered at the end of the study had an average carcass weight of 1649.7±166.4 g/subject for the experimental group and 1566±106.4 g/subject for the control group with a similar average carcass yield of 75.3%. In general, the statistical analysis of the zootechnical parameters mentioned did not show any significant difference between two groups

Effet de L’incorporation de L’Acide Guanido Acétique (AGA) Comme Précursseur de la Créatinine sur L'ingestion et les Performances de Croissance de Poulets de Chair au Sénégal

Cette étude a été conduite pour déterminer l’ingestion et les performances de croissance de poulets de chair nourris avec un aliment commercial incorporant 600 g/tonne d’Acide Guanidino Acétique (AGA) sous forme de CreAMINO®. L’AGA est un précurseur de la créatine qui joue un rôle important dans le métabolisme cellulaire des oiseaux. L'expérience de nutrition a duré 42 jours avec 400 poussins chair d’un jour, de souche Cobb 500, non sexés. Le dispositif expérimental utilisé est complètement aléatoire avec 2 traitements (Témoin et Expérimental) et 4 répétitions pour chaque traitement. Les données collectées ont été analysées selon une procédure ANOVA. Les résultats ont révélé que les animaux qui ont reçu le régime expérimental contenant de l’AGA ont obtenu, à la fin de l’expérience, un poids vif (2191,6±137,9 vs 2080,2±186,2 g/sujet) (P>0,05) et un gain pondéral moyen (51,6 vs 48,9 g/sujet) (P>0,05) numériquement un peu plus élevé que les animaux du groupe témoin. L’ingestion alimentaire et la consommation hydrique ont été, respectivement, de 95,2 g/sujet/jour et 262,4 ml/sujet/jour pour le groupe expérimental ainsi que 90,6 g/sujet/jour et 249,0 ml/sujet/jour pour le groupe témoin avec un indice de conversion alimentaire moyen similaire de 1,8. Les animaux abattus à la fin de l’étude ont présenté un poids carcasse moyen de 1649,7±166,4 g/sujet pour le groupe expérimental et 1566±106,4 g/sujet pour le groupe témoin avec un rendement carcasse moyen similaire de 75,3%. De manière générale, l’analyse statistique des paramètres zootechniques cités n’a pas montré de différence significative entre les deux groupes.   This study was conducted to determine intake and growth performance of broilers fed with commercial feed incorporating 600 g/ton of Guanidino Acetic Acid (GAA) in the form of CreAMINO®. GAA is a creatine precursor that plays an important role in the cellular metabolism of birds. The feeding experiment lasted 42 days with 400 one-day-old unsexed Cobb 500 chicks. The experimental design used was completely randomized with 2 treatments (Control and Experimental) and 4 replicates for each treatment. The data collected were analyzed using an ANOVA procedure. The results revealed that animals fed with experimental diet containing GAA had a live weight (2191.6±137.9 vs. 2080.2±186.2 g/subject) (P>0.05) and average weight gain (51.6 vs. 48.9 g/subject) (P>0.05) numerically slightly higher than animals in the control group at the end of the experiment. Feed intake and water consumption were, respectively, 95.2 g/subject/day and 262.4 ml/subject/day for the experimental group and 90.6 g/subject/day and 249.0 ml/subject/day for the control group with a similar mean feed conversion ratio of 1.8. Animals slaughtered at the end of the study had an average carcass weight of 1649.7±166.4 g/subject for the experimental group and 1566±106.4 g/subject for the control group with a similar average carcass yield of 75.3%. In general, the statistical analysis of the zootechnical parameters mentioned did not show any significant difference between two groups

Gene expression profiling in blood from cerebral malaria patients and mild malaria patients living in Senegal

International audienceBACKGROUND:Plasmodium falciparum malaria remains a major health problem in Africa. The mechanisms of pathogenesis are not fully understood. Transcriptomic studies may provide new insights into molecular pathways involved in the severe form of the disease.METHODS:Blood transcriptional levels were assessed in patients with cerebral malaria, non-cerebral malaria, or mild malaria by using microarray technology to look for gene expression profiles associated with clinical status. Multi-way ANOVA was used to extract differentially expressed genes. Network and pathways analyses were used to detect enrichment for biological pathways.RESULTS:We identified a set of 443 genes that were differentially expressed in the three patient groups after applying a false discovery rate of 10%. Since the cerebral patients displayed a particular transcriptional pattern, we focused our analysis on the differences between cerebral malaria patients and mild malaria patients. We further found 842 differentially expressed genes after applying a false discovery rate of 10%. Unsupervised hierarchical clustering of cerebral malaria-informative genes led to clustering of the cerebral malaria patients. The support vector machine method allowed us to correctly classify five out of six cerebral malaria patients and six of six mild malaria patients. Furthermore, the products of the differentially expressed genes were mapped onto a human protein-protein network. This led to the identification of the proteins with the highest number of interactions, including GSK3B, RELA, and APP. The enrichment analysis of the gene functional annotation indicates that genes involved in immune signalling pathways play a role in the occurrence of cerebral malaria. These include BCR-, TCR-, TLR-, cytokine-, FcεRI-, and FCGR- signalling pathways and natural killer cell cytotoxicity pathways, which are involved in the activation of immune cells. In addition, our results revealed an enrichment of genes involved in Alzheimer's disease.CONCLUSIONS:In the present study, we examine a set of genes whose expression differed in cerebral malaria patients and mild malaria patients. Moreover, our results provide new insights into the potential effect of the dysregulation of gene expression in immune pathways. Host genetic variation may partly explain such alteration of gene expression. Further studies are required to investigate this in African populations

NCR3 polymorphism, haematological parameters, and severe malaria in Senegalese patients

Background Host factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria. Methods Blood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed. Results We evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients. Conclusions Our results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes

Genetic Determination and Linkage Mapping of Plasmodium falciparum Malaria Related Traits in Senegal

Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p<10−4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved

Differential antibody responses to Plasmodium falciparum glycosylphosphatidylinositol anchors in patients with cerebral and mild malaria.

International audienceGlycosylphosphatidylinositol (GPI) membrane anchors of Plasmodium falciparum surface proteins are thought to be important factors contributing to malaria pathogenesis, and anti-GPI antibodies have been suggested to provide protection by neutralizing the toxic activity of GPIs. In this study, IgG responses against P. falciparum GPIs and a baculovirus recombinant MSP1p19 antigen were evaluated in two distinct groups of 70 patients each, who were hospitalized with malaria. Anti-GPI IgGs were significantly lower in patients hospitalized with confirmed cerebral malaria compared to those with mild malaria (P < 0.01) but did not discriminate for fatal outcome. In contrast, a specific marker of the anti-parasite immunity, as monitored by the anti-MSP1p19 IgG response, was similar in both cerebral and mild malaria individuals, although it was significantly lower in a subgroup with fatal outcomes. These results are consistent with a potential anti-toxin role for anti-GPI antibodies associated with protection against cerebral malaria

The use of crude Plasmodium falciparum antigens for comparison of antibody responses in patients with mild malaria vs. cerebral malaria.

analysis of Ab responses in cerebral malaria using basic tools as Ags. IgM Ab responses are of interest.International audienceBackground: Cerebral malaria (CM) is one of the major causes of death in African populations infected with Plasmodium falciparum. Only 1% of infected subjects develop CM. The reasons for these differences are not fully understood, but it is likely that the host humoral response against blood-stage antigens plays a role in protection from malaria, although the precise targets and mechanisms mediating immunity remain unclear. Objective: The purpose of this study was to distinguish between defined P. falciparum-specific Ab response patterns in patients presenting with mild malaria (MM) vs. CM. Methods: We used a panel of P. falciparum conserved antigens including crude blood-stage extracts schizont, merozoite and parasitised erythrocyte membranes and MSP-1p19, PfEB200, R23 and GST-5 recombinant antigens in a retrospective case-control study of symptomatic adults, one group presenting confirmed CM without fatal outcome and another group with MM. We further matched P. falciparum-specific Ab responses with those from individuals living in an endemic setting known to have protective immunity and considered them as "immune control" subjects (IC). Total IgG, IgM and IgG subclass Ab responses were determined using ELISA method. Results: Substantial Ab responses were found in symptomatic patients, significantly lower than the "immune control" subjects, and with a limited quantitative difference between MM versus CM. Interestingly, asynchronous IgM response was evidenced in CM contrary to MM. Conclusion: Our results suggest that the contribution of an efficient IgG response against parasite multiplication is of importance in the evolution towards CM manifestation without fatal outcome and deserves further analysis for vaccine candidates

Cytokine response during non-cerebral and cerebral malaria: evidence of a failure to control inflammation as a cause of death in African adults

Background. With 214 million cases and 438,000 deaths in 2015, malaria remains one of the deadliest infectious diseases in tropical countries. Several species of the protozoan Plasmodium cause malaria. However, almost all the fatalities are due to Plasmodium falciparum, a species responsible for the severest cases including cerebral malaria. Immune response to Plasmodium falciparum infection is mediated by the production of pro-inflammatory cytokines, chemokines and growth factors whose actions are crucial for the control of the parasites. Following this response, the induction of anti-inflammatory immune mediators downregulates the inflammation thus preventing its adverse effects such as damages to various organs and death. Methods. We performed a retrospective, nonprobability sampling study using clinical data and sera samples from patients, mainly adults, suffering of non-cerebral or cerebral malaria in Dakar, Sénégal. Healthy individuals residing in the same area were included as controls. We measured the serum levels of 29 biomarkers including growth factors, chemokines, inflammatory and anti-inflammatory cytokines. Results. We found an induction of both pro- and anti-inflammatory immune mediators during malaria. The levels of pro-inflammatory biomarkers were higher in the cerebral malaria than in the non-cerebral malaria patients. In contrast, the concentrations of anti-inflammatory cytokines were comparable in these two groups or lower in CM patients. Additionally, four pro-inflammatory biomarkers were significantly increased in the deceased of cerebral malaria compared to the survivors. Regarding organ damage, kidney failure was significantly associated with death in adults suffering of cerebral malaria. Conclusions. Our results suggest that a poorly controlled inflammatory response determines a bad outcome in African adults suffering of cerebral malaria