PLoS Med

Background In 2014, the government of Togo implemented a pilot unconditional cash transfer (UCT) program in rural villages that aimed at improving children’s nutrition, health, and protection. It combined monthly UCTs (approximately US$8.40 /month) with a package of community activities (including behavior change communication [BCC] sessions, home visits, and integrated community case management of childhood illnesses and acute malnutrition [ICCM-Nut]) delivered to mother–child pairs during the first “1,000 days” of life. We primarily investigated program impact at population level on children’s height-for-age z-scores (HAZs) and secondarily on stunting (HAZ < −2) and intermediary outcomes including household’s food insecurity, mother–child pairs’ diet and health, delivery in a health facility and low birth weight (LBW), women’s knowledge, and physical intimate partner violence (IPV). Methods and findings We implemented a parallel-cluster–randomized controlled trial, in which 162 villages were randomized into either an intervention arm (UCTs + package of community activities, n = 82) or a control arm (package of community activities only, n = 80). Two different representative samples of children aged 6–29 months and their mothers were surveyed in each arm, one before the intervention in 2014 (control: n = 1,301, intervention: n = 1,357), the other 2 years afterwards in 2016 (control: n = 996, intervention: n = 1,035). Difference-in-differences (DD) estimates of impact were calculated, adjusting for clustering. Children’s average age was 17.4 (± 0.24 SE) months in the control arm and 17.6 (± 0.19 SE) months in the intervention arm at baseline. UCTs had a protective effect on HAZ (DD = +0.25 z-scores, 95% confidence interval [CI]: 0.01–0.50, p = 0.039), which deteriorated in the control arm while remaining stable in the intervention arm, but had no impact on stunting (DD = −6.2 percentage points [pp], relative odds ratio [ROR]: 0.74, 95% CI: 0.51–1.06, p = 0.097). UCTs positively impacted both mothers’ and children’s (18–23 months) consumption of animal source foods (ASFs) (respectively, DD = +4.5 pp, ROR: 2.24, 95% CI: 1.09–4.61, p = 0.029 and DD = +9.1 pp, ROR: 2.65, 95% CI: 1.01–6.98, p = 0.048) and household food insecurity (DD = −10.7 pp, ROR: 0.63, 95% CI: 0.43–0.91, p = 0.016). UCTs did not impact on reported child morbidity 2 week’s prior to report (DD = −3.5 pp, ROR: 0.80, 95% CI: 0.56–1.14, p = 0.214) but reduced the financial barrier to seeking healthcare for sick children (DD = −26.4 pp, ROR: 0.23, 95% CI: 0.08–0.66, p = 0.006). Women who received cash had higher odds of delivering in a health facility (DD = +10.6 pp, ROR: 1.53, 95% CI: 1.10–2.13, p = 0.012) and lower odds of giving birth to babies with birth weights (BWs) <2,500 g (DD = −11.8, ROR: 0.29, 95% CI: 0.10–0.82, p = 0.020). Positive effects were also found on women’s knowledge (DD = +14.8, ROR: 1.86, 95% CI: 1.32–2.62, p < 0.001) and physical IPV (DD = −7.9 pp, ROR: 0.60, 95% CI: 0.36–0.99, p = 0.048). Study limitations included the short evaluation period (24 months) and the low coverage of UCTs, which might have reduced the program’s impact. Conclusions UCTs targeting the first “1,000 days” had a protective effect on child’s linear growth in rural areas of Togo. Their simultaneous positive effects on various immediate, underlying, and basic causes of malnutrition certainly contributed to this ultimate impact. The positive impacts observed on pregnancy- and birth-related outcomes call for further attention to the conception period in nutrition-sensitive programs

Matern Child Nutr

Adequate complementary feeding (CF) practices are essential for achieving optimal growth but challenging to measure comprehensively. This paper describes CF practices in 2034 children aged 6-23 months, and investigates their relationships with length-for-age z-score (LAZ) and stunting, using cross-sectional data collected from May to July 2014 in rural northern Togo. The WHO Infant and Young Child Feeding (IYCF) indicators were computed, along with ancillary indicators on feeding style and timing of introduction of complementary foods. The associations between those indicators and children's LAZ and stunting were assessed using linear and logistic regressions, after stratification by age group and adjustment for children, maternal and household characteristics. CF practices were suboptimal and their associations with child's growth varied across indicators and age groups. In children aged 6-11 months, reaching the Minimum Dietary Diversity and the Minimum Acceptable Diet was associated with higher LAZ (p<0.05). In 18-23 month-old children, only the consumption of iron-rich food was associated with both LAZ (p=0.02) and stunting (p=0.05). The late introduction of family foods was associated with higher odds of being stunted and lower LAZ in children aged 12-17 months (p<0.001). The untimely introduction of porridge was associated with higher odds of stunting in children aged 9-23 months (p<0.05). Unexpectedly, helping the child to eat was negatively associated with linear growth in all age groups. These findings nurture the ongoing process of review of the WHO IYCF indicators showing that, in their current version, they hardly capture the links between CF and child's growth at different ages

The high protein expression of FOXO3, but not that of FOXO1, is associated with markers of good prognosis

To better define the role of FOXO1 and FOXO3 transcriptional factors in breast carcinogenesis, we performed a comparative study of their expression at both the RNA and protein levels in a series of human breast tumors. We used qRT-PCR assay to quantify mRNA expression and Reverse Phase Protein Arrays (RPPA) to quantify protein expression in 218 breast tumors from patients with known clinical/pathological status and outcome. Weak correlations were observed between mRNA and protein expressions for both FOXO1 and FOXO3 genes. High expression of FOXO3 protein, but not FOXO1 protein, was a good prognostic marker, negatively correlated with KI67 and markers of activity of the PI3K/AKT/mTOR oncogenic pathway, and positively correlated with p53, a marker of apoptosis. Moreover, FOXO3 protein expression, but not FOXO1 protein expression, was also negatively correlated with various proteins involved in different DNA repair mechanisms. FOXO3 protein, but not FOXO1 protein, appears to be a tumor suppressor that inhibits breast cancer by altering DNA damage response (DDR), thereby inducing p53-dependent apoptosis. This antitumor effect appears to be suppressed by excessive activity of the PI3K/AKT/mTOR pathway. High FOXO3 protein expression could be a biomarker of deficient DDR in breast tumors

Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers

Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancer

Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma

International audienceAnal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequencing of a homogeneous group of 20 treatment-naive ASCC. A total of 2422 somatic single nucleotide variations (SNV) were found, with an overall moderate rate of somatic mutations per tumour (median 105 relevant SNV per tumour) but a high mutational load in 3 tumours. The mutational signatures associated with age and APOBEC were observed in 100% and 60% of tumours respectively. The most frequently mutated genes were PIK3CA (25%) followed by FBXW7 (15%), FAT1 (15%), and TRIP12 (15%), the two last ones having never been described in ASCC. The main copy number alterations were gains of chromosome 3q (affecting PIK3CA) and losses of chromosome 11q (affecting ATM). The combined analysis of somatic mutations and copy number alterations show that recurrent alterations of the PI3K/AKT/mTOR pathway are frequent (60%) in these tumours, as well as potentially targetable alterations of other signalling pathways that have never been described in ASCC such as chromatin remodelling (45%) and ubiquitin mediated proteolysis (35%). These results highlight the possible implication of these aberrant signalling pathways in anal carcinogenesis and suggest promising new therapeutic approaches in ASCC. The high somatic mutation burden found in some tumours, suggesting an elevated neoantigen load could also predict sensitivity of ASCC to immunotherapy

Assessment of the functional impact of germline BRCA1/2 variants located in non-coding regions in families with breast and/or ovarian cancer predisposition

The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants.Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay.We identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C\ua0>\ua0T) and one BRCA2 promoter variants (c.-296C\ua0>\ua0T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A\ua0>\ua0G and c.4186-2022C\ua0>\ua0T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities.In this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants