Induced pluripotent stem cells (iPSC) created from skin fibroblasts of patients with Prader-Willi syndrome (PWS) retain the molecular signature of PWS

AbstractPrader-Willi syndrome (PWS) is a syndromic obesity caused by loss of paternal gene expression in an imprinted interval on 15q11.2-q13. Induced pluripotent stem cells were generated from skin cells of three large deletion PWS patients and one unique microdeletion PWS patient. We found that genes within the PWS region, including SNRPN and NDN, showed persistence of DNA methylation after iPSC reprogramming and differentiation to neurons. Genes within the PWS minimum critical deletion region remain silenced in both PWS large deletion and microdeletion iPSC following reprogramming. PWS iPSC and their relevant differentiated cell types could provide in vitro models of PWS

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Socialisation alimentaire des enfants avec le Syndrome de Prader-Willi : une problématisation interdisciplinaire

International audienceEating “disorders” of people with Prader-Willi syndrome are frequently reported in the biomedical literature. The eating behaviors are presented as a syndrome-specific trajectory over the course of a lifetime. Infants initially show anorexic behavior, which then develops into hyperphagia that lasts from childhood to adulthood and is characterized by strong cravings for food and relentless thinking about it. However, the sociocultural determinants of these food practices are not fully understood. In the first section of this article, we carry out a literature review of medical articles published on disordered eating in children with PWS. The second section draws on a social science perspective and offers an interdisciplinary problematization using the concept of food socialization. To conclude, the third section explores the challenges facing research and new questions that emerge from the alternative problematization that is the PWS Food Social Norms Internalization (FSNI) theory

Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture

International audienceThe passage of substances across the blood-brainbamer is regulated by cerebral capillaries which possess certain distinctly different morphological and enzymatic properties compared to capillaries of other organs. Investigations of the functional characteristics of brain capillaries have been facilitated by the use of cultured brain endothelial cells, but in most studies a number of characteristics of the in vivo system are lost. To provide an in vitro system for studies of brain capillary functions, we developed a method of isolating and producing a large number of bovine brain capillary endothelialcells. These cells, absolutely free of pericyte contamination,are subcultured, at the split ratio of 1:20 (20-fold increase of the cultured surface), with no apparent changes in cell morphology up to the fiftieth generation (10 passages). Retention of endothelial-specific characteristics (factor VIII-related antigen, angiotensin-converting enzyme, and nonthrombogenic surface) is shown for brain capillaryderivedendothelial cells up to passage 10, even after frozenstorage at passage 3. Furthermore, we showed that bovinebrain capillary endothelial cells retain, up to the fiftieth generation, some of the characteristics of the blood-brain bamer: occurrence of tight junctions, paucity of pinocytotic vesicles, and monoamine oxidase activity

Enhancing histopathological image classification of invasive ductal carcinoma using hybrid harmonization techniques

International audienceThis study aims to develop a robust pipeline for classifying invasive ductal carcinomas and benign tumors in histopathological images, addressing variability within and between centers. We specifically tackle the challenge of detecting atypical data and variability between common clusters within the same database. Our feature engineering-based pipeline comprises a feature extraction step, followed by multiple harmonization techniques to rectify intra- and inter-center batch effects resulting from image acquisition variability and diverse patient clinical characteristics. These harmonization steps facilitate the construction of more robust and efficient models. We assess the proposed pipeline’s performance on two public breast cancer databases, BreaKHIS and IDCDB, utilizing recall, precision, and accuracy metrics. Our pipeline outperforms recent models, achieving 90-95% accuracy in classifying benign and malignant tumors. We demonstrate the advantage of harmonization for classifying patches from different databases. Our top model scored 94.7% for IDCDB and 95.2% for BreaKHis, surpassing existing feature engineering-based models (92.1% for IDCDB and 87.7% for BreaKHIS) and attaining comparable performance to deep learning models. The proposed feature-engineering-based pipeline effectively classifies malignant and benign tumors while addressing variability within and between centers through the incorporation of various harmonization techniques. Our findings reveal that harmonizing variabilities between patches from different batches directly impacts the learning and testing performance of classification models. This pipeline has the potential to enhance breast cancer diagnosis and treatment and may be applicable to other diseases

Identification of a Region Critical for Proteolysis of the Human Growth Hormone Receptor

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Radiomics prognostic analysis of PET/CT images in a multicenter head and neck cancer cohort: investigating ComBat strategies, sub-volume characterization, and automatic segmentation

International audiencePurposeThis study aimed to investigate the impact of several ComBat harmonization strategies, intra-tumoral sub-volume characterization, and automatic segmentations for progression-free survival (PFS) prediction through radiomics modeling for patients with head and neck cancer (HNC) in PET/CT images.MethodsThe HECKTOR MICCAI 2021 challenge set containing PET/CT images and clinical data of 325 oropharynx HNC patients was exploited. A total of 346 IBSI-compliant radiomic features were extracted for each patient’s primary tumor volume defined by the reference manual contours. Modeling relied on least absolute shrinkage Cox regression (Lasso-Cox) for feature selection (FS) and Cox proportional-hazards (CoxPH) models were built to predict PFS. Within this methodological framework, 8 different strategies for ComBat harmonization were compared, including before or after FS, in feature groups separately or all features directly, and with center or clustering-determined labels. Features extracted from tumor sub-volume clustering were also investigated for their prognostic additional value. Finally, 3 automatic segmentations (2 threshold-based and a 3D U-Net) were also compared. All results were evaluated with the concordance index (C-index).ResultsRadiomics features without harmonization, combined with clinical factors, led to models with C-index values of 0.69 in the testing set. The best version of ComBat harmonization, i.e., after FS, for feature groups separately and relying on clustering-determined labels, achieved a C-index of 0.71. The use of features extracted from tumor sub-volumes further improved the C-index to 0.72. Models that relied on the automatic segmentations yielded close but slightly lower prognostic performance (0.67–0.70) compared to reference contours.ConclusionA standard radiomics pipeline allowed for prediction of PFS in a multicenter HNC cohort. Applying a specific strategy of ComBat harmonization improved the performance. The extraction of intra-tumoral sub-volume features and automatic segmentation could contribute to the improvement and automation of prognosis modeling, respectively

Prader-Willi Syndrome as a Model of Human Hyperphagia

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Patients with PWS and related syndromes display differentially methylated regions involved in neurodevelopmental and nutritional trajectory

International audienceBackground Prader–Willi syndrome is a rare genetic neurodevelopmental disorder caused by a paternal deficiency of maternally imprinted gene expression located in the chromosome 15q11–q13 region. Previous studies have demonstrated that several classes of neurodevelopmental disorders can be attributed to either over- or under-expression of specific genes that may lead to impairments in neuronal generation, differentiation, maturation and growth. Epigenetic changes that modify gene expression have been highlighted in these disorders. One recent study focused on epigenetic analysis and compared patients with PWS with patients with other imprinting disorders. No study, however, has yet focused on epigenetics in patients with PWS specifically by comparing the mutations associated with this syndrome. Objective This study investigated the epigenetic modifications in patients with PWS and patients with PWS-related disorders caused by inactivation of two genes of the PWS chromosomal region , SNORD116 and MAGEL2 . Our approach also aimed to compare the epigenetic modifications in PWS and PWS-related disorders. Methods We compared genome-wide methylation analysis (GWAS) in seven blood samples from patients with PWS phenotype (five with deletions of the PWS locus, one with a microdeletion of SNORD116 and one with a frameshift mutation of MAGEL2 presenting with Schaaf–Yang syndrome), as well as two control patients. Controls were infants that had been studied for suspicion of genetic diseases that was not confirmed by the genetic analysis and the clinical follow-up. Results The analysis identified 29,234 differentially methylated cytosines, corresponding to 5,308 differentially methylated regions (DMRs), which matched with 2,280 genes. The DMRs in patients with PWS were associated with neurodevelopmental pathways, endocrine dysfunction and social and addictive processes consistent with the key features of the PWS phenotype. In addition, the separate analysis for the SNORD116 and MAGEL2 deletions revealed that the DMRs associated with the SNORD116 microdeletion were found in genes implicated in metabolic pathways and nervous system development, whereas MAGEL2 mutations mostly concerned genes involved in macromolecule biosynthesis. Conclusion The PWS is associated with epigenetic modifications with differences in SNORD116 and MAGEL2 mutations, which seem to be relevant to the different associated phenotypes