Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

Subependymal giant-cell astrocytomas (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5–10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumor-normal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2–46 Mb) was seen in 76% (16/21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0–7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFs IRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation

Trial by Dutch laboratories for evaluation of non-invasive prenatal testing. Part I—clinical impact

Objective: To evaluate the clinical impact of nationwide implementation of genome-wide non-invasive prenatal testing (NIPT) in pregnancies at increased risk for fetal trisomies 21, 18 and 13 (TRIDENT study). Method: Women with elevated risk based on first trimester combined testing (FCT ≥ 1:200) or medical history, not advanced maternal age alone, were offered NIPT as contingent screening test, performed by Dutch University Medical laboratories. We analyzed uptake, test performance, redraw/failure rate, turn-around time and pregnancy outcome. Results: Between 1 April and 1 September 2014, 1413/23 232 (6%) women received a high-risk FCT result. Of these, 1211 (85.7%) chose NIPT. One hundred seventy-nine women had NIPT based on medical history. In total, 1386/1390 (99.7%) women received a result, 6 (0.4%) after redraw. Mean turn-around time was 14 days. Follow-up was available in 1376 (99.0%) pregnancies. NIPT correctly predicted 37/38 (97.4%) trisomies 21, 18 or 13 (29/30, 4/4 and 4/4 respectively); 5/1376 (0.4%) cases proved to be false positives: trisomies 21 (n = 2), 18 (n = 1) and 13 (n = 2). Estimated reduction in invasive testing was 62%. Conclusion: Introduction of NIPT in the Dutch National healthcare-funded Prenatal Screening Program resulted in high uptake and a vast reduction of invasive testing. Our study supports offering NIPT to pregnant women at increased risk for fetal trisomy. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd

Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS: Results of the TRIDENT study

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin

Emancipation in and integration of elementary and nursery schools 1981

Attitudes of heads of elementary schools, nursery schools and experimental combinations of elementary and nursery schools ( basisschool ) regarding the future 'basisschool' and emancipation of women. Mail-survey sex school staff / full-time or part-time / nr. of working hours in week / function position / present division of functions and tasks between male and female teachers / use of educational material especially selected for its emancipatory value / type of school catholic, Dutch reformed-protestant, normal neutral or specific neutral/ nursery school, elementary school, integrated 'basisschool' / reason for appointment to head of school / sex of extra teachers for experimental 'basisschool' / opinion about policy to integrate all elementary and nursery schools into 'basisschool' / future head of 'basisschool' / intention to apply for position of head of 'basisschool' / present cooperation in experiment with other elementary and nursery schools. Interviews on attitudes towards emancipation and roles of men and women / division of tasks and functions between men and women in schools / chances of women / perceived influence of institutions or persons concerning division of tasks and functions and procedures for appointment of heads of integrated 'basisschool'. Background variables: basic characteristics/ household characteristics/ occupation/employment/ religio

Onderwijs emancipatie en integratie 1981

Attitudes of heads of elementary schools, nursery schools and experimental combinations of elementary and nursery schools ( basisschool ) regarding the future 'basisschool' and emancipation of women. Mail-survey sex school staff / full-time or part-time / nr. of working hours in week / function position / present division of functions and tasks between male and female teachers / use of educational material especially selected for its emancipatory value / type of school catholic, Dutch reformed-protestant, normal neutral or specific neutral/ nursery school, elementary school, integrated 'basisschool' / reason for appointment to head of school / sex of extra teachers for experimental 'basisschool' / opinion about policy to integrate all elementary and nursery schools into 'basisschool' / future head of 'basisschool' / intention to apply for position of head of 'basisschool' / present cooperation in experiment with other elementary and nursery schools. Interviews on attitudes towards emancipation and roles of men and women / division of tasks and functions between men and women in schools / chances of women / perceived influence of institutions or persons concerning division of tasks and functions and procedures for appointment of heads of integrated 'basisschool'. Background variables: basic characteristics/ household characteristics/ occupation/employment/ religio

Adherence to guideline-recommended therapy is associated with decreased major adverse cardiovascular events and major adverse limb events among patients with peripheral arterial disease.

10.1161/JAHA.113.000697Journal of the American Heart Association3

Trial by Dutch laboratories for evaluation of non-invasive prenatal testing. Part I-clinical impact

Contains fulltext : 171862.pdf (publisher's version ) (Open Access)OBJECTIVE: To evaluate the clinical impact of nationwide implementation of genome-wide non-invasive prenatal testing (NIPT) in pregnancies at increased risk for fetal trisomies 21, 18 and 13 (TRIDENT study). METHOD: Women with elevated risk based on first trimester combined testing (FCT >/= 1:200) or medical history, not advanced maternal age alone, were offered NIPT as contingent screening test, performed by Dutch University Medical laboratories. We analyzed uptake, test performance, redraw/failure rate, turn-around time and pregnancy outcome. RESULTS: Between 1 April and 1 September 2014, 1413/23 232 (6%) women received a high-risk FCT result. Of these, 1211 (85.7%) chose NIPT. One hundred seventy-nine women had NIPT based on medical history. In total, 1386/1390 (99.7%) women received a result, 6 (0.4%) after redraw. Mean turn-around time was 14 days. Follow-up was available in 1376 (99.0%) pregnancies. NIPT correctly predicted 37/38 (97.4%) trisomies 21, 18 or 13 (29/30, 4/4 and 4/4 respectively); 5/1376 (0.4%) cases proved to be false positives: trisomies 21 (n = 2), 18 (n = 1) and 13 (n = 2). Estimated reduction in invasive testing was 62%. CONCLUSION: Introduction of NIPT in the Dutch National healthcare-funded Prenatal Screening Program resulted in high uptake and a vast reduction of invasive testing. Our study supports offering NIPT to pregnant women at increased risk for fetal trisomy. (c) 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. (c) 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd

KAI407, a Potent Non-8-Aminoquinoline Compound That Kills Plasmodium cynomolgi Early Dormant Liver Stage Parasites In Vitro.

Contains fulltext : 138513.pdf (publisher's version ) (Open Access