Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal ...carcinoma (NPC).
To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data.
In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55).
Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion.
This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Diabetes mellitus (DM) is now a global health problem, however, its pathogenesis has not yet been fully deciphered. Even though modern medicine has great contribution to the control and treatment of ...DM, it is still far from success to completely cure the disease.
Panax ginseng C.A. Meyer (ginseng) is a well-recognized traditional Chinese medicine for treating DM in Asia. In this study, high throughput proteomic approach has been adopted to investigate the antidiabetic action of 2 weeks’ ginsenoside Re (Re, a major component of ginseng) administration to streptozotocin-induced diabetic rats. Employing surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) and bioinformatics, 432 cluster peaks were detected in the samples, among them 293 potential biomarkers were found to have significant differentiations between the DM and control normal rats. When the Re-treated diabetic rats were compared to the untreated ones, a protein peak was detected to have significant alteration corresponding to Re treatment. This specific protein was found to match with C-reactive protein (CRP) in the protein database, and was subsequently validated by ELISA. This is the first study demonstrated that CRP could be altered by Re treatment, indicating that Re may improve diabetes and its complications by alleviation of inflammation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Applications of low-cost single-frequency continuous GPS receivers for monitoring volcano and landslide activities as well as to complement dual-frequency receivers have been demonstrated to produce ...stable and accurate positioning. In studies of crustal deformation, the relative distance between monitoring stations may vary from several kilometers to tens of kilometers, hence the differential single-frequency observations cannot model the ionospheric delay or other distance dependent errors. The 55 low-cost single-frequency continuous stations have been deployed together with 52 continuous dual-frequency stations in southeastern Taiwan since 2008. All of the single-frequency stations have applied corrections using dual-frequency stations to eliminate the distance dependent errors. Comparing velocity estimates from 8 co-located, the differences in horizontal and vertical components are less than 3 mm/yr and 6 mm/yr, respectively. Our study shows that the combination of single- and dual-frequency GPS data can provide robust results to study the fault slip behavior on the Longitudinal Valley fault.
Full text
Available for:
BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Activation of the hepatic stellate cells (HSCs) is a key pathogenic event in liver fibrosis. Protein
-glutathionylation (PSSG) of cysteine residues is a distinct form of oxidative response that ...modifies protein structures and functions. Glutaredoxin-1 (GLRX) reverses PSSG by liberating glutathione (GSH). In this study, we showed that pirfenidone (PFD), an anti-lung fibrosis drug, inhibited HSC activation and liver fibrosis in a GLRX-dependent manner. Glrx depletion exacerbated liver fibrosis, and decreased GLRX and increased PSSG were observed in fibrotic mouse and human livers. In contrast, overexpression of GLRX inhibited PSSG and liver fibrosis. Mechanistically, the inhibition of HSC activation by GLRX may have been accounted for by deglutathionylation of Smad3, which inhibits Smad3 phosphorylation, leading to the suppression of fibrogenic gene expression. Our results have established GLRX as the therapeutic target of PFD and uncovered an important role of PSSG in liver fibrosis. GLRX/PSSG can be both a biomarker and a therapeutic target for liver fibrosis.
Current international guidelines recommend non-vitamin K oral anticoagulants (NOACs) for stroke prevention among patients with non-valvular atrial fibrillation (AF) at significant ischaemic stroke ...risk given the superior safety and comparable efficacy of NOACs over warfarin. Nonetheless, the safety and effectiveness of NOACs have not been evaluated in patients with AF with underlying moderate or severe mitral stenosis (MS), hence the recommended stroke prevention strategy remains warfarin therapy.
MS remains disproportionately prevalent in Asian countries compared with the developed countries. This prospective, randomised, open-label trial with blinded endpoint adjudication aims to evaluate the safety and efficacy of dabigatran for stroke prevention in AF patients with moderate or severe MS. Patients with AF aged ≥18 years with moderate or severe MS not planned for valvular intervention in the coming 12 months will be randomised in a 1:1 ratio to receive dabigatran 110 mg or 150 mg two times per day or warfarin with international normalised ratio 2-3 in an open-label design. Patients with estimated creatinine clearance <30 mL/min, or with a concomitant indication for antiplatelet therapy will be excluded. The primary outcome is a composite of stroke and systemic embolism. Secondary outcomes are ischaemic stroke, systemic embolism, haemorrhagic stroke, intracranial haemorrhage, major bleeding and death. The estimated required sample size is approximately 686 participants.
The study protocol has been approved by the Institutional Review Board of the University of Hong Kong and Hong Kong West Cluster, Hospital Authority, Hong Kong for Fung Yiu King Hospital, Grantham Hospital, Queen Mary Hospital and Tung Wah Hospital in Hong Kong. Results will be published in peer-reviewed journals.
ClinicalTrials.gov Registry (NCT04045093); pre-results.
Background/Purpose In 2003, the severe acute respiratory syndrome (SARS) outbreak resulted in 8096 probable cases and 774 deaths in 26 countries. The purpose of this study was to explore the effect ...of the SARS outbreak on hospitalization for chronic ambulatory-care-sensitive conditions (ACSCs) in Taiwan. Methods We applied a population-based interrupted time series study design and used the time series auto-regressive integrated moving-average model to compare the actual and predicted admission rates of seven selected chronic ACSCs. The analyses were based on National Health Insurance hospital inpatient claims data from 1997 to 2003. Results The impact of SARS on ACSCs after the outbreak varied among seven selected chronic conditions. Hospitalization for respiratory conditions was significantly lower than the predicted values, whereas hospitalization for diabetes was significantly higher than the predicted values after the outbreak. Conclusion Admission rates for most ACSCs, except for diabetes, did not change in the post-SARS period. The reductions in outpatient utilization during the SARS outbreak did not appear to affect adversely admissions for most ACSCs.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
High‐magnetization materials play crucial roles in various applications. However, the past few decades have witnessed a stagnation in the discovery of new materials with high magnetization. ...In this work, Ni/NiO nanocomposites are fabricated by depositing Ni and NiO thin layers alternately, followed by annealing at specific temperatures. Both the as‐deposited samples and those annealed at 373 K exhibit low magnetization. However, the samples annealed at 473 K exhibit a significantly enhanced saturation magnetization exceeding 607 emu cm
−3
at room temperature, surpassing that of pure Ni (480 emu cm
−3
). Material characterizations indicate that the composite comprises NiO nanoclusters of size 1–2 nm embedded in the Ni matrix. This nanoclustered NiO is primarily responsible for the high magnetization, as confirmed by density functional theory calculations. The calculations also indicate that the NiO clusters are ferromagnetically coupled with Ni, resulting in enhanced magnetization. This work demonstrates a new route toward developing artificial high‐magnetization materials using the high magnetic moments of nanoclustered antiferromagnetic materials.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
To examine the relationship between medical home transformation and patient experience of chronic illness care.
Study Setting
Thirteen safety net clinics located in five states enrolled in ...the Safety Net Medical Home Initiative.
Study Design
Repeated cross‐sectional surveys of randomly selected adult patients were completed at baseline (n = 303) and postintervention (n = 271).
Data Collection Methods
Questions from the Patient Assessment of Chronic Illness Care (PACIC) (100‐point scale) were used to capture patient experience of chronic illness care. Generalized estimating equation methods were used to (i) estimate how differential improvement in patient‐centered medical home (PCMH) capability affected differences in modified PACIC scores between baseline and postintervention, and (ii) to examine cross‐sectional associations between PCMH capability and modified PACIC scores for patients at completion of the intervention.
Principal Findings
In adjusted analyses, high PCMH improvement (above median) was only marginally associated with a larger increase in total modified PACIC score (adjusted β = 7.7, 95 percent confidence interval CI: −1.1 to 16.5). At completion of the intervention, a 10‐point higher PCMH capability score was associated with an 8.9‐point higher total modified PACIC score (95 percent CI: 3.1–14.7) and higher scores in four of five subdomains (patient activation, delivery system design, contextual care, and follow‐up/coordination).
Conclusions
We report that sustained, 5‐year medical home transformation may be associated with modest improvement in patient experience of chronic illness care for vulnerable populations in safety net clinics.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Small extracellular vesicles (sEVs) play a key role in exchanging cargoes between cells in tumour microenvironment. This study aimed to elucidate the functions and mechanisms of hepatocellular ...carcinoma (HCC) derived sEV‐clathrin light chain A (CLTA) in remodelling microvascular niche. CLTA level in the circulating sEVs of HCC patients was analysed by enzyme‐linked immunosorbent assay (ELISA). The functions of sEV‐CLTA in affecting HCC cancerous properties were examined by multiple functional assays. Mass spectrometry was used to identify downstream effectors of sEV‐CLTA in human umbilical vein endothelial cells (HUVECs). Tube formation, sprouting, trans‐endothelial invasion and vascular leakiness assays were performed to determine the functions of sEV‐CLTA and its effector, basigin (BSG) in HUVECs. BSG inhibitor, SP‐8356, was tested in a mouse model of patient‐derived xenografts (PDXs). Circulating sEVs of HCC patients had markedly enhanced CLTA levels than control individuals and were reduced in patients after surgery. HCC derived sEV‐CLTA enhanced HCC cancerous properties, disrupted endothelial integrity and induced angiogenesis. Mechanistically, CLTA remodels microvascular niche by stabilizing and upregulating BSG. Last, SP‐8356 alone or in combination with sorafenib attenuated PDXs growth. The study reveals the role of HCC derived sEV‐CLTA in microvascular niche formation. Inhibition of CLTA and its mediated pathway may illuminate a new therapeutic strategy for HCC patients.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract only Background: Sex differences in the pathogenesis of hypertension exist. Whilst gut microbiota (GM) dysregulation is a novel risk factor of hypertension, studies using shotgun ...metagenomics sequencing and ambulatory 24-hour blood pressure (BP) monitoring to study the potential sex differences in the associations between the GM and BP are lacking. Methods: We recruited 241 asymptomatic Hong Kong Chinese (113 male, 128 female, mean age 54±6), who were not on anti-hypertensive agents, and studied their GM composition using shotgun sequencing. 24-hour ambulatory BP was recorded. GM-mediated short chain fatty acids (SCFAs) were quantified in stool and plasma by GC-MS. Statistical analysis was performed under covariate-adjusted models including age, sex, BMI, smoking, sodium-intake, fatty liver and menopause status. Results: Based on 24-hour BP, 36% (87 of 241) of the study population was hypertensive. Males had a higher mean BP than females (127±13/81±10mmHg vs. 117±12/71±8mmHg, p<0.001). GM β-diversity was significantly different in hypertensive vs. normotensive individuals, driven by females. A significant enrichment of Ruminococcus gnavus was observed in the hypertensive group whilst Oscillibacter sp. CAG:241 and Gemmiger formicilis was enriched in the normotensive group. These differences remained significant in females with no significant differential species found in males. Additionally, Dorea formicigenerans was negatively associated whilst Clostridium bolteae and Bacteroides ovatus were positively associated in female-specific hypertension. Repeated cross-validation machine-learning demonstrated microbial features were more predictive of hypertension in females than males, and the addition of microbial features to clinical features (age, BMI) improved the model’s prediction accuracy from 0.69 to 0.84 in females. Total plasma SCFAs and propionic acid were independent predictors of systolic and diastolic BP in females but not males. GM β-diversity was also significantly associated with total SCFAs and propionic acid levels. Conclusion: GM dysregulation appears to be more strongly associated with hypertension in females, which may be mediated through circulating plasma SCFAs.
PDF
