Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Role of CRIPTO in epithelial-mesenchymal transition in prostate cancer and it impact on the modulation of the intercellular communication

Le cancer de la prostate (CaP) représente le premier cancer chez l'homme et la seconde cause de mortalité. Alors que la plupart des malades atteints de cancer de la prostate évoluent favorablement (forme indolente), une fraction non négligeable développera une maladie agressive avec l’apparition de métastases. La recherche des biomarqueurs tumoraux peut aider à différencier les CaP dits indolent et les CaP agressifs qui sont responsables du décès des patients. Ils permettront de mieux sélectionner des patients afin d’éviter le surtraitement. La protéine CRIPTO est le premier membre de la superfamille des protéines EGF-CFC. Ce facteur de croissance est largement impliqué dans le développement embryonnaire et s'exprime dans de nombreux types de cancers. Son rôle dans le CaP reste encore non élucidé. L’objectif de mon travail de thèse consiste à examiner le profil d'expression de CRIPTO et d'évaluer son impact potentiel sur l’agressivité du cancer de la prostate.Les résultats ont montré que CRIPTO est exprimé de manière significative dans 37,9% de CaP. Il est absent voire faiblement détecté dans les prostates hyperplasiques bénignes et dans les tissus sains. Nous avons montré ensuite que la surexpression de CRIPTO favorise une transition épithéliale-mésenchymateuse (TEM) associée à l’augmentation de la capacité de migration et de la survie des cellules tumorales. Les voies de signalisation régulées par CRIPTO impliquent l’activation des voies PI3K / AKT et FGFR1 / ERK.De manière très intéressante, les cellules tumorales mésenchymateuses surexprimant CRIPTO secrètent excessivement des vésicules. Nous avons tenté alors de découvrir le rôle de ces vésicules dans la progression du cancer de la prostate. Les vésicules extracellulaires (VEs) purifiés étaient capables de moduler la signalisation du récepteur des androgènes et d’activer la voie du TGFß. Les cellules tumorales prostatiques traitées par ces VEs deviennent plus agressive et acquierent des caractéristiques mésenchymateuses.En conclusion, nos résultats mettent en évidence une nouvelle fonction importante de CRIPTO dans le cancer de la prostate. Nous démontrons également que les cellules tumorales surexprimant ce facteur de croissance secrètent excessivement des vésicules qui participent activement dans la communication intercellulaire et promeuvent la progression du CaP. L’ensemble de nos travaux suggère que le ciblage thérapeutique de CRIPTO et le blocage de la sécrétion des VEs pourraient être des nouvelles approches thérapeutiques innovantes pour le traitement du cancer de la prostate.Prostate cancer (PCa) remains at the top of the list of the most common malignant tumors and the dominant cause of mortality and morbidity in men worldwide. Detection of tumor biomarkers to aid differentiate indolent from severe PCa cases and well-choose patients at high risk for intensive treatment. The founding member of EGF-CFC protein superfamily, CRIPTO, is widely implicated in embryonic development and is found to be expressed in a wide spectrum of human tumors. As its role in PCa was still unclear, we aimed to investigate expression profile of CRIPTO in PCa and relate its potential impact on prostate malignancy.Prostatic tissues and cell lines, both normal and cancerous, were engaged in experimental studies and design was based on techniques used in biochemistry, cellular and molecular biology.CRIPTO showed to be upregulated in 37.9% of PCas, while being absent or marginally detected in benign conditions. Our results displayed that CRIPTO overexpression promoted epithelial-mesenchymal transition (EMT) associated with enhanced migration capacity and survival under stress conditions due to propensity to stimulate PI3K/AKT and FGFR1/ERK signaling pathways.More interestingly, tumor mesenchymal like cells overexpressing CRIPTO secreted vesicles excessively. Thus we attempted to uncover the role of these vesicles in the progression of PCa. Extracellular vesicles derived from these cells were highly capable to modulate androgen receptor signaling through TGF-ß pathway and rendering the recipient prostatic cells more aggressive by acquisition of mesenchymal features.Our results highlight a new substantial function of CRIPTO in PCa and put in evidence its importance as a new promising target for PCa treatment. Moreover, we emphasize on an original role of mesenchymal extracellular vesicles in the interclonal communication to carry and transfer tumorigenic contents and enhance progression of PCa. This opens new scopes towards better understanding of vesicles secreted by prostate cancer cells and their impact to better cure the disease

CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities

Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors

Transcriptomic Analysis of Breast Cancer Stem Cells and Development of a pALDH1A1:mNeptune Reporter System for Live Tracking

International audienceMany solid cancers are hierarchically organized with a small number of cancer stem cells (CSCs) able to regrow a tumor, while their progeny lacks this feature. Breast CSC is known to contribute to therapy resistance. The study of those cells is usually based on their cell-surface markers like CD44high /CD24low/neg or their aldehyde dehydrogenase (ALDH) activity. However, these markers cannot be used to track the dynamics of CSC. Here, a transcriptomic analysis is performed to identify segregating gene expression in CSCs and non-CSCs, sorted by Aldefluor assay. It is observed that among ALDH-associated genes, only ALDH1A1 isoform is increased in CSCs. A CSC reporter system is then developed by using a far red-fluorescent protein (mNeptune) under the control of ALDH1A1 promoter. mNeptune-positive cells exhibit higher sphere-forming capacity, tumor formation, and increased resistance to anticancer therapies. These results indicate that the reporter identifies cells with stemness characteristics. Moreover, live tracking of cells in a microfluidic system reveals a higher extravasation potential of CSCs. Live tracking of non-CSCs under irradiation treatment show, for the first time, live reprogramming of non-CSCs into CSCs. Therefore, the reporter will allow for cell tracking to better understand the implication of CSCs in breast cancer development and recurrence