Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained ...momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.
Summary Background Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is ...non-inferior to gefitinib in patients with non-small-cell lung cancer. Methods In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18–75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov , number NCT01040780 , and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. Findings 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67–1·05; median progression-free survival 4·6 months 95% CI 3·5–6·3 vs 3·4 months 2·3–3·8; p=0·13). The most common adverse events were rash (81 41% of 200 patients in the icotinib group vs 98 49% of 199 patients in the gefitinib group) and diarrhoea (43 22% vs 58 29%). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 61% vs 140 70%; p=0·046), especially drug-related diarrhoea (37 19% vs 55 28%; p=0·033). Interpretation Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer. Funding Zhejiang Beta Pharma (China), the Chinese National Key Special Program for Innovative Drugs, the 863 Project, and Zhejiang Provincial Key Special Program.
Discovery of magnetic Weyl fermions: Dirac fermions split into pairs of Weyl fermions by slow magnetic fluctuations.
Weyl fermions as emergent quasiparticles can arise in Weyl semimetals (WSMs) in ...which the energy bands are nondegenerate, resulting from inversion or time-reversal symmetry breaking. Nevertheless, experimental evidence for magnetically induced WSMs is scarce. Here, using photoemission spectroscopy, we observe that the degeneracy of Bloch bands is already lifted in the paramagnetic phase of EuCd
2
As
2
. We attribute this effect to the itinerant electrons experiencing quasi-static and quasi–long-range ferromagnetic fluctuations. Moreover, the spin-nondegenerate band structure harbors a pair of ideal Weyl nodes near the Fermi level. Hence, we show that long-range magnetic order and the spontaneous breaking of time-reversal symmetry are not essential requirements for WSM states in centrosymmetric systems and that WSM states can emerge in a wider range of condensed matter systems than previously thought.
The spatiotemporal variations of surface air pollutants (O3, NO2, SO2, CO, and PM10) with four land-use types, residence (R), commerce (C), industry (I) and greenbelt (G), have been investigated at ...283 stations in South Korea during 2002-2013, using routinely observed data. The volatile organic compound (VOC) data at nine photochemical pollutant monitoring stations available since 2007 were utilized in order to examine their effect on the ozone chemistry. The land-use types, set by the Korean government, were generally consistent with the satellite-derived land covers and with the previous result showing anti-correlation between O3 and NO2 in diverse urban areas. The relationship between the two pollutants in the Seoul Metropolitan Area (SMA) residence land-use areas was substantially different from that outside of the SMA, probably due to the local differences in vehicle emissions. The highest concentrations of air pollutants in the diurnal, weekly, and annual cycles were found in industry for SO2 and PMPM10, in commerce for NO2 and CO, and in greenbelt for O3. The concentrations of air pollutants, except for O3, were generally higher in big cities during weekdays, while O3 showed its peak in suburban areas or small cities during weekends. The weekly cycle and trends of O3 were significantly out of phase with those of NO2, particularly in the residential and commercial areas, suggesting that vehicle emission was a major source in those areas. The ratios of VOCs to NO2 for each of the land-use types were in the order of I (10.2) > C (8.7) > G (3.9) > R (3.6), suggesting that most areas in South Korea were likely to be VOC-limited for ozone chemistry. The pollutants (NO2, SO2, CO, and PMPM10 except for O3 have decreased, most likely due to the effective government control. The total oxidant values (OX = O3 + NO2) with the land-use types were analyzed for the local and regional (or background) contributions of O3, respectively, and the order of OX (ppb) was C (57.4) > R (53.6) > I (50.7) > G (45.4), indicating the greenbelt observation was close to the background.
Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. ...We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.
•Comprehensive in vitro and in vivo epigenomic profile of more than 3,100 HARs•Nearly half of all HARs have features of neurodevelopmental enhancers•Extensive human-specific rewiring of the cis-regulatory architecture of HARs•Primate- and human-specific change in PPP1R17 developmental expression patterns
Human accelerated regions (HARs) are the fastest-evolving regions of the human genome. By interrogating the in vitro enhancer activity and in vivo epigenetic landscapes of more than 3,100 HARs during human neurodevelopment, we demonstrate that nearly half of all HARs act as neurodevelopmental enhancers. Further, we demonstrate PPP1R17 to be a putative HAR-regulated gene likely involved in human-specific cortical neurodevelopment.
Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the ...specific mortality.
Retrospective multinational study including SCN diagnosed between 1990 and 2014.
2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1).
After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN.
IRB 00006477.
Summary Background Few effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide ...alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients. Methods This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1–21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1–4, 9–12, and 17–20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01311687 , and with EudraCT, number 2010-019820-30. Findings The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2–13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6–4·7) versus 1·9 months (1·9–2·2) with high-dose dexamethasone (hazard ratio 0·48 95% CI 0·39–0·60; p<0·0001). The most common grade 3–4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 48% of 300 vs 24 16% of 150, respectively), anaemia (99 33% vs 55 37%, respectively), and thrombocytopenia (67 22% vs 39 26%, respectively). Grade 3–4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 13% vs 12 8%, respectively), bone pain (21 7% vs seven 5%, respectively), and fatigue (16 5% vs nine 6%, respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group. Interpretation Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma. Funding Celgene Corporation.
Chronic urticaria (CU) is a debilitating skin disease that lasts for more than 6 weeks with wheals and/or angioedema, including chronic spontaneous urticaria (CSU) and chronic inducible urticaria ...(CIndU). In China, the prevalence of this disease is high, more than 1%, and on the rise. CU has a major impact on the quality of life (QoL) of patients who frequently experience sleep disturbance, depression, and anxiety. Nearly one-third of patients with CSU, in China, are resistant to second-generation H1-antihistamines (sgAHs), even at a fourfold dose (second line; off-label). Omalizumab is approved for the treatment of CSU treatment in Europe and shows remarkable efficacy and safety. In China, regulatory approval for the use of omalizumab is pending, and its use in clinical practice varies widely. Consensus on omalizumab CU treatment in China is urgently needed. The aim of this article is to propose a practical omalizumab treatment algorithm for the management of antihistamine-resistant CSU and CIndU in adults and special population including children and adolescents, and pregnant or breast feeding women, to guide daily clinical practice in China. In the development of this consensus, an expert group including mainly dermatologists, allergists, but also pulmonologists, ENTs, immunologists, and pediatricians in Allergic Disease Prevention and Control Committee, Chinese Preventive Medicine Association, reviewed the existing evidence and developed consensus on the use of omalizumab in CU patients from China. The goal of this consensus is to assist clinicians in making rational decisions in the management of refractory CU with omalizumab. The key clinical questions covered by the treatment algorithm are: 1) Omalizumab treatment routine strategy in both CSU and CIndU patients; 2) Recommended dose and treatment duration for different age stratification; 3) Treatment duration for CU patients with other allergic comorbidities; 4) Recommendation on omalizumab stopping strategy.
Objective We sought to evaluate performance of a noninvasive prenatal test for fetal trisomy 21 (T21) and trisomy 18 (T18). Study Design A multicenter cohort study was performed whereby cell-free DNA ...from maternal plasma was analyzed. Chromosome-selective sequencing on chromosomes 21 and 18 was performed with reporting of an aneuploidy risk (High Risk or Low Risk) for each subject. Results Of the 81 T21 cases, all were classified as High Risk for T21 and there was 1 false-positive result among the 2888 normal cases, for a sensitivity of 100% (95% confidence interval CI, 95.5–100%) and a false-positive rate of 0.03% (95% CI, 0.002–0.20%). Of the 38 T18 cases, 37 were classified as High Risk and there were 2 false-positive results among the 2888 normal cases, for a sensitivity of 97.4% (95% CI, 86.5–99.9%) and a false-positive rate of 0.07% (95% CI, 0.02–0.25%). Conclusion Chromosome-selective sequencing of cell-free DNA and application of an individualized risk algorithm is effective in the detection of fetal T21 and T18.
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