Epstein–Barr virus infection and nasopharyngeal carcinoma Tsao, Sai Wah; Tsang, Chi Man; Lo, Kwok Wai
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
10/2017, Volume:
372, Issue:
1732
Journal Article
Peer reviewed
Open access
Epstein–Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated ...nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways.
This article is part of the themed issue ‘Human oncogenic viruses’.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Critical Thermal maximum (CTmax) is often used to characterize the upper thermal limits of organisms and represents a key trait for evaluating the fitness of ectotherms. The lack of standardization ...in CTmax assays has, however, introduced methodological problems in its measurement, which can lead to questionable estimates of species' upper thermal limits. Focusing on ants, which are model organisms for research on thermal ecology, we aim to obtain a reliable ramping rate that will yield the most rigorous measures of CTmax for the most species. After identifying three commonly used ramping rates (i.e., 0.2, 0.5 and 1.0°C min-1) in the literature, we experimentally determine their effects on the CTmax values of 27 species measured using dynamic assays. Next, we use static assays to evaluate the accuracy of these values in function of the time of exposure. Finally, we use field observations of species' foraging activities across a wide range of ground temperatures to identify the most biologically relevant CTmax values and to develop a standardized method. Our results demonstrate that the use of a 1°C min-1 ramping rate in dynamic assays yields the most reliable CTmax values for comparing ant species' upper thermal limits, which are further validated in static assays and field observations. We further illustrate how methodological biases in physiological trait measurements can affect subsequent analyses and conclusions on community comparisons between strata and habitats, and the detection of phylogenetic signal (Pagel's λ and Bloomberg's K). Overall, our study presents a methodological framework for identifying a reliable and standardized ramping rate to measure CTmax in ants, which can be applied to other ectotherms. Particular attention should be given to CTmax values obtained with less suitable ramping rates, and the potential biases they may introduce to trait-based research on global warming and habitat conversion, as well as inferences about phylogenetic conservatism.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Patients with a history of Helicobacter pylori–negative idiopathic bleeding ulcers have an increased risk of recurring ulcer complications.
Aim
To build a machine learning model to ...identify patients at high risk for recurrent ulcer bleeding.
Methods
Data from a retrospective cohort of 22 854 patients (training cohort) diagnosed with peptic ulcer disease in 2007‐2016 were analysed to build a model (IPU‐ML) to predict recurrent ulcer bleeding. We tested the IPU‐ML in all patients with a diagnosis of gastrointestinal bleeding (n = 1265) in 2008‐2015 from a different catchment population (independent validation cohort). Any co‐morbid conditions which had occurred in >1% of study population were eligible as predictors.
Results
Recurrent ulcer bleeding developed in 4772 patients (19.5%) in the training cohort, during a median follow‐up period of 2.7 years. IPU‐ML model built on six parameters (age, baseline haemoglobin, and presence of gastric ulcer, gastrointestinal diseases, malignancies, and infections) identified patients with bleeding recurrence within 1 year with an area under the receiver operating characteristic curve (AUROC) of 0.648. When we set the IPU‐ML cutoff value at 0.20, 27.5% of patients were classified as high risk for rebleeding with a sensitivity of 41.4%, specificity of 74.6%, and a negative predictive value of 91.1%. In the validation cohort, the IPU‐ML identified patients with a recurrence ulcer bleeding within 1 year with an AUROC of 0.775, and 84.3% of overall accuracy.
Conclusion
We developed a machine‐learning model to identify those patients with a history of idiopathic gastroduodenal ulcer bleeding who are not at high risk for recurrent ulcer bleeding.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Omicron generally causes milder disease than previous strains of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), especially in fully vaccinated individuals. However, incompletely ...vaccinated children may develop Omicron‐related complications such as those affecting the central nervous system. To characterize the spectrum of clinical manifestations of neuro‐COVID and to identify potential biomarkers associated with clinical outcomes, we recruited 15 children hospitalized for Omicron‐related neurological manifestations in three hospitals in Hong Kong (9 boys and 6 girls aged 1–13 years). All were unvaccinated or incompletely vaccinated. Fourteen (93.3%) were admitted for convulsion, including benign febrile seizure (n = 7), complex febrile seizure (n = 2), seizure with fever (n = 3), and recurrent breakthrough seizure (n = 2), and the remaining nonconvulsive patient developed encephalopathic state with impaired consciousness. None of the seven children with benign febrile seizure and six of eight children with other neurological manifestations had residual deficits at 9‐month follow‐up. SARS‐CoV‐2 RNA was undetectable in the cerebrospinal fluid (CSF) specimens of seven patients who underwent lumbar puncture. Spike‐and‐wave/sharp waves affecting the frontal lobes were detected in four of seven (57.1%) patients who underwent electroencephalogram. Children with Omicron‐related neurological manifestations had significantly higher blood levels of IL‐6 (p < 0.001) and CHI3L1 (p = 0.022) than healthy controls, and higher CSF levels of IL‐6 (p = 0.002) than children with non‐COVID‐19‐related febrile illnesses. Higher CSF‐to‐blood ratios of IL‐8 and CHI3L1 were associated with longer length of stay, whereas higher ratios of IL‐6 and IL‐8 were associated with higher blood tau level. The role of CSF:blood ratio of IL‐6, IL‐8, and CHI3L1 as prognostic markers for neuro–COVID should be further evaluated.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
The outbreak caused by the novel coronavirus SARS-CoV-2 has been declared a global health emergency. G-quadruplex structures in genomes have long been considered essential for regulating a ...number of biological processes in a plethora of organisms. We have analyzed and identified 25 four contiguous GG runs (G2NxG2NyG2NzG2) in the SARS-CoV-2 RNA genome, suggesting putative G-quadruplex-forming sequences (PQSs). Detailed analysis of SARS-CoV-2 PQSs revealed their locations in the open reading frames of ORF1 ab, spike (S), ORF3a, membrane (M) and nucleocapsid (N) genes. Identical PQSs were also found in the other members of the Coronaviridae family. The top-ranked PQSs at positions 13385 and 24268 were confirmed to form RNA G-quadruplex structures in vitro by multiple spectroscopic assays. Furthermore, their direct interactions with viral helicase (nsp13) were determined by microscale thermophoresis. Molecular docking model suggests that nsp13 distorts the G-quadruplex structure by allowing the guanine bases to be flipped away from the guanine quartet planes. Targeting viral helicase and G-quadruplex structure represents an attractive approach for potentially inhibiting the SARS-CoV-2 virus.
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Cancer‐associated fibroblasts (CAFs) are important in tumor microenvironment (TME) driven cancer progression. However, CAFs are heterogeneous and still largely underdefined, better understanding ...their origins will identify new therapeutic strategies for cancer. Here, the authors discovered a new role of macrophage‐myofibroblast transition (MMT) in cancer for de novo generating protumoral CAFs by resolving the transcriptome dynamics of tumor‐associated macrophages (TAM) with single‐cell resolution. MMT cells (MMTs) are observed in non‐small‐cell lung carcinoma (NSCLC) associated with CAF abundance and patient mortality. By fate‐mapping study, RNA velocity, and pseudotime analysis, existence of novel macrophage‐lineage‐derived CAF subset in the TME of Lewis lung carcinoma (LLC) model is confirmed, which is directly transited via MMT from M2‐TAM in vivo and bone‐marrow‐derived macrophages (BMDM) in vitro. Adoptive transfer of BMDM‐derived MMTs markedly promote CAF formation in LLC‐bearing mice. Mechanistically, a Smad3‐centric regulatory network is upregulated in the MMTs of NSCLC, where chromatin immunoprecipitation sequencing(ChIP‐seq) detects a significant enrichment of Smad3 binding on fibroblast differentiation genes in the macrophage‐lineage cells in LLC‐tumor. More importantly, macrophage‐specific deletion and pharmaceutical inhibition of Smad3 effectively block MMT, therefore, suppressing the CAF formation and cancer progression in vivo. Thus, MMT may represent a novel therapeutic target of CAF for cancer immunotherapy.
Here, the authors discovered a direct mechanism of tumor‐associated macrophages for de novo generating protumoral cancer‐associated fibroblasts (CAF) via macrophage‐myofibroblast transition (MMT) by resolving their transcriptome dynamics at single‐cell resolution. Encouragingly, targeting the MMT key regulator Smad3 effectively blocked the production and protumoral actions of CAF, evidencing its translational potential as a novel therapeutic target in the tumour microenvironment for cancer.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of ...acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination.
This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for coronavirus disease 2019 (COVID-19) vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine adverse event response and evaluation program. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analyzed.
Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. In total, 29 (87.88%) were male and 4 (12.12%) were female, with a median age of 15.25 years. And 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management. The overall incidence of acute myocarditis/pericarditis was 18.52 (95% confidence interval CI, 11.67-29.01) per 100 000 persons vaccinated. The incidence after the first and second doses were 3.37 (95% CI, 1.12-9.51) and 21.22 (95% CI, 13.78-32.28 per 100 000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI, 2.38-12.53) and 37.32 (95% CI, 26.98-51.25) per 100 000 persons vaccinated.
There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose.
Abnormal metabolism and uncontrolled angiogenesis are two important characteristics of malignant tumors. The occurrence of both events involves many key molecular changes including miRNA. However, ...EBV encoded miRNAs are rarely mentioned as capable of regulating tumor metabolism and tumor angiogenesis. Here, we reported that one of the key miRNAs encoded by EBV, EBV-miR-Bart1-5P, can significantly promote nasopharyngeal carcinoma (NPC) cell glycolysis and induces angiogenesis in vitro and in vivo. Mechanistically, EBV-miR-Bart1-5P directly targets the α1 catalytic subunit of AMP-activated protein kinase (AMPKα1) and consequently regulates the AMPK/mTOR/HIF1 pathway which impelled NPC cell anomalous aerobic glycolysis and angiogenesis, ultimately leads to uncontrolled growth of NPC. Our findings provide new insights into metabolism and angiogenesis of NPC and new opportunities for the development of targeted NPC therapy in the future.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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