Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders ...the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
Abstract
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, ...combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing
TGFBR2
promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of
CDKN2A/CDKN2B
deletion breakpoints reveals homozygous
MTAP
deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.
Women with atrial fibrillation are at a higher risk of stroke, despite treatment with warfarin. It is unclear if women treated with direct oral anticoagulants (DOACs) have better clinical outcomes, ...especially when considering the quality of anticoagulation control of warfarin.
This study compared the effectiveness and safety outcomes of DOACs versus warfarin in men and women with stratifications for anticoagulation control.
Patients newly diagnosed with atrial fibrillation and prescribed oral anticoagulants during 2010 to 2015 were identified using the Hong Kong clinical database. Propensity score matching was performed in men and women separately. Further analysis was conducted to stratify warfarin users according to their anticoagulation control. Cox regression was used to compare the risk of ischemic stroke or systemic embolism, intracranial hemorrhage (ICH), gastrointestinal bleeding, and all-cause mortality in the specific sex.
There were 4,972 men and 4,834 women successfully matched in our cohort. Compared with warfarin, DOAC use was associated with a lower risk of ICH (hazard ratio HR: 0.16; 95% confidence interval CI: 0.06 to 0.40) and all-cause mortality (HR: 0.55; 95% CI: 0.39 to 0.77) in women but not in men. The treatment by sex interaction was significant for ICH only, and a significantly lower risk of ICH remained in the DOAC group when compared with warfarin users with good anticoagulation control (HR: 0.13; 95% CI: 0.02 to 1.00) among women only. The risks of ischemic stroke or systemic embolism and gastrointestinal bleeding with DOACs versus warfarin were comparable in both sexes.
DOACs were associated with a lower risk of ICH and all-cause mortality in women only, where the association of lower ICH risk remained when compared with warfarin users with good anticoagulation control.
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Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders ...the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
In most urban public transit rail systems, passengers may need to make several interchanges between different lines to reach their destination. The design of coordinated timetables that enable smooth ...interchanges with minimal delay for all passengers is a very difficult task. This paper presents a mixed-integer-programming optimization model for this schedule synchronization problem for nonperiodic timetables that minimizes the interchange waiting times of all passengers. A novelty in our formulation is the use of binary variables that enable the correct representation of the waiting times to the "next available" train at the interchange stations.
By adjusting trains' run times and station dwell times during their trips and their dispatch times, turnaround times at the terminals, and headways at the stations, our model can construct high-quality timetables that minimize transfer waiting times. We also discuss an optimization-based heuristic for the model. We have tested our algorithm for the Mass Transit Railway (MTR) system in Hong Kong, which runs six railway lines with many cross-platform interchange stations. Preliminary numerical results indicate that our approach improves the synchronization significantly compared with the current practice of using fixed headways and trip times. We also explore the trade-offs among different operational parameters and flexibility and their impact on overall passenger waiting times.
Celotno besedilo
Dostopno za:
BFBNIB, CEKLJ, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose: There is a rising prevalence in undetected perinatal depression in many countries, more effort in screening and early identification of perinatal depression is needed. While the Whooley ...questionnaire is the recommended case-finding strategy for perinatal depression, there is no validated Chinese version. The aim was to evaluate the diagnostic accuracy and stability of the translated Chinese Whooley questionnaire against gold standard measurement during and early after pregnancy.
Materials and Methods: This observational study recruited 131 pregnant women from an antenatal clinic in Hong Kong from September 2019 to May 2020. We translated the Whooley questionnaire in Chinese and evaluated self-reported responses against an interviewer-assessed diagnostic standard (DSM-IV criteria) in 107 women at 26-28 gestational weeks. We calculated sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio, with DSM-IV diagnosis as the gold standard.
Results: The Chinese Whooley questions had a sensitivity of 79% (95% CI 54.4-93.9), a specificity of 97% (95% CI 90.4-99.3), a positive likelihood ratio of 23.2 (95% CI 7.4-72.1) and a negative likelihood ratio of 0.2 (95% CI 0.1-0.5) in identifying perinatal depression.
Conclusion: The translated Chinese Whooley questionnaire has an acceptable diagnostic accuracy in identifying perinatal depression. It can be implemented in health services among Cantonesespeaking Chinese population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower ...morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic (n = 78) and asymptomatic (n = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n = 61, and asymptomatic n = 10), and negative controls (n = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population.
Adolescent idiopathic scoliosis (AIS) is a structural deformity of the spine affecting millions of children. As a complex disease, the genetic aetiology of AIS remains obscure. Here we report the ...results of a four-stage genome-wide association study (GWAS) conducted in a sample of 4,317 AIS patients and 6,016 controls. Overall, we identify three new susceptibility loci at 1p36.32 near AJAP1 (rs241215, Pcombined=2.95 × 10(-9)), 2q36.1 between PAX3 and EPHA4 (rs13398147, Pcombined=7.59 × 10(-13)) and 18q21.33 near BCL-2 (rs4940576, Pcombined=2.22 × 10(-12)). In addition, we refine a previously reported region associated with AIS at 10q24.32 (rs678741, Pcombined=9.68 × 10(-37)), which suggests LBX1AS1, encoding an antisense transcript of LBX1, might be a functional variant of AIS. This is the first GWAS investigating genetic variants associated with AIS in Chinese population, and the findings provide new insight into the multiple aetiological mechanisms of AIS.
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