As a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple ...genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor.
The expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC.
Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2.
The findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.
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.
BACKGROUNDPyroptosis is a form of inflammatory cell death. Although it is recognized that NLRP3 (nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3) ...inflammasome is involved in pyroptosis activation, the mechanism by which head and neck squamous cell carcinoma (HNSCC) inhibits pyroptotic cell death remains undefined. This study aims to delineate the role of calcium regulator CD38 in NLRP3 inflammasome-dependent pyroptosis in HNSCC. METHODSCD38 overexpressing HNSCC cell lines (SAS, CAL27, SNU899) were generated using lentiviral vectors. NLRP3 and gasdermin D (GSDMD) quantity were detected using Western blot. Caspase-1 activity changes were measured using the Caspase-Glo® 1 inflammasome assay. Cell death proportion was determined by flow cytometry analysis. Proliferation assay was performed using xCELLigence RTCA system. Mouse xenotransplantation was performed to evaluate the potential oncogenic or tumor-suppressive function of CD38. ChIP assay was conducted to verify whether transcription factor NFAT1-mediated NLRP3 expression. RESULTSExogenous calcium treatment can lead to a significant increase in caspase-1 activity in HNSCC. This feature was also observed in HNSCC cells with stable CD38 overexpression. CD38-overexpressing cell lines showed a significant reduction in proliferation. Further, expression of NLRP3 protein level was significantly increased in CD38-overexpressing cell lines. The N-terminal effector domain of GSDMD was remarkably increased in the CD38-overexpressing HNSCC. ChIP assay indicated that calcium-sensitive transcription factor NFAT1 was possibly involved in the transcriptional upregulation of NLRP3 observed in CD38-overexpressing HNSCC. The pre-clinical xenograft model revealed that CD38 expression had an inhibiting function on HNSCC progression. CONCLUSIONIn conclusion, our results suggested that activation of pyroptosis in HNSCC is a calcium-dependent process. Reduced expression of calcium ion regulator CD38 functions could prevent inflammasome-induced pyroptosis in HNSCC. CD38 may function as a tumor suppressor in HNSCC progression.
Oral tongue squamous cell carcinoma (OTSCC) has a distinctive cell sub-population known as tumor-initiating cells (TICs). CD271 is a functional TIC receptor in head and neck cancers. The molecular ...mechanisms governing CD271 up-regulation remains unclear. Oxidative stress is a contributing factor in TIC development. Here, we explored the potential role of NADPH oxidase 5 (NOX5) and its regulatory mechanism on the development of CD271-expressing OTSCC. Our results showed that the splice variant NOX5α is the most prevalent form expressed in head and neck cancers. NOX5α enhanced OTSCC proliferation, migration, and invasion. Overexpression of NOX5α increased the size of OTSCC xenograft significantly in vivo. The tumor-promoting functions of NOX5α were mediated through the reactive oxygen species (ROS)-generating property. NOX5α activated ERK singling and increased CD271 expression at the transcription level. Also, NOX5α reduces the sensitivity of OTSCC to cisplatin and natural killer cells. The findings indicate that NOX5α plays an important part in the development of TIC in OTSCC.
Thesis (M. L. A.)--University of Hong Kong, 2009.
Includes special report study entitled: 'When nature exploits man-made structures ... ' : a detailed study of wall trees in Hong Kong. Includes ...bibliographical references. Also available in print.
We reviewed the multiplex PCR results of 20,127 respiratory specimens tested in a hospital setting from January 2014 to April 2023. The seasonal oscillation patterns of 17 respiratory viruses were ...studied. Compared with 2014–2019, a prominent drop in PCR positivity (from 64.46–69.21% to 17.29–29.89%, p < 0.001) and virus diversity was observed during the COVID-19 pandemic, with predominance of rhinovirus/enterovirus, sporadic spikes of parainfluenza viruses 3 and 4, respiratory syncytial virus and SARS-CoV-2, and rare detection of influenza viruses, metapneumovirus, adenovirus and coronaviruses. The suppressed viruses appeared to regain activity from the fourth quarter of 2022 when pandemic interventions had been gradually relaxed in Hong Kong. With the co-circulation of SARS-CoV-2 and seasonal respiratory viruses, surveillance of their activity and an in-depth understanding of the clinical outcomes will provide valuable insights for improved public health measures and reducing disease burden.
This study aimed to investigate the effects of caffeine on performances of simulated match, Wingate Anaerobic Test (WAnT), and cognitive function test of elite taekwondo athletes. Ten elite taekwondo ...athletes in Hong Kong volunteered to participate in two main trials in a randomized double-blinded crossover design. In each main trial, 1 h after consuming a drink with caffeine (CAF) or a placebo drink without caffeine (PLA), the participants completed two simulated taekwondo match sessions followed by the WAnT. The participants were instructed to complete three cognitive function tests, namely the Eriksen Flanker Test (EFT), Stroop Test, and Rapid Visual Information Processing Test, at baseline, before exercise, and immediately after the simulated matches. They were also required to wear functional near-infrared spectroscopy equipment during these tests. Before exercise, the reaction time in the EFT was shorter in the CAF trial than in the PLA trial (PLA: 494.9 ± 49.2 ms vs. CAF: 467.9 ± 38.0 ms, p = 0.035). In the WAnT, caffeine intake increased the peak power and mean power per unit of body weight (by approximately 13% and 6%, respectively, p = 0.018 & 0.042). The performance in the simulated matches was not affected by caffeine intake (p = 0.168). In conclusion, caffeine intake enhances anaerobic power and may improve certain cognitive functions of elite taekwondo athletes in Hong Kong. However, this may not be enough to improve the simulated match performance.
The Proximal Femur Maturity Index (PFMI) can be used to assess skeletal maturity on existing whole-spine radiographs without additional radiation. However, the relationship between the PFMI at the ...initiation of bracing for adolescent idiopathic scoliosis (AIS) and subsequent curve progression remains unknown. This study aimed to investigate the relationship between the PFMI and curve progression, and the predictability of risks to adulthood curve progression and surgical thresholds based on the PFMI grade at brace initiation.
This was a prospective study of 202 patients with AIS who were prescribed underarm bracing according to the Scoliosis Research Society criteria and had good brace-wear compliance. The patients were followed from brace initiation until complete skeletal maturity. Longitudinal data on the coronal Cobb angle and skeletal maturity assessments using Risser staging, Sanders staging, the distal radius and ulna classification, and the PFMI were collected. Each patient was assessed on whether the major curve progressed to ≥40° (adulthood deterioration) and ≥50° (the surgical threshold). Logistic regressions were used to predict probabilities of curve progression to the 2 thresholds, adjusted for factors that were significant in univariate analyses.
The PFMI correlated with the other skeletal maturity indices (r s Spearman rank correlation = 0.60 to 0.72, p < 0.001 for all). The pre-brace PFMI grade correlated with progression to ≥40° (r rb rank-biserial correlation = -0.30, p < 0.001) and to ≥50° (r rb = -0.20, p = 0.005). Based on regression models (p < 0.001) adjusted for the pre-brace major Cobb angle and curve type, brace initiation at PFMI grades 2 and 3 for a curve of ≥30° had predicted risks of 30% (95% confidence interval CI, 4% to 55%) and 12% (95% CI, 7% to 17%), respectively, for progression to the surgical threshold. Brace initiation at PFMI grade 5 had 0% progression risk.
The PFMI can be used for predicting curve progression and prognosticating brace outcomes in AIS. Patients with brace initiation at PFMI grade 4 for a curve of <30° or at grade 5 were unlikely to progress to the adulthood deterioration or surgical threshold. In comparison, skeletally immature patients initiating bracing at a PFMI grade of ≤3 for a major curve of ≥30° had a higher risk of progression despite compliant brace wear.
Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence.
Psoriasis is a common chronic immune-mediated inflammatory skin disease with the association of various comorbidities. Despite the introduction of highly effective biologic therapies over the past ...few decades, the exact trigger for an immune reaction in psoriasis is unclear. With the majority of immune cells residing in the gut, the effect of gut microbiome dysbiosis goes beyond the gastrointestinal site and may exacerbate inflammation and regulate the immune system elsewhere, including but not limited to the skin via the gut-skin axis. In order to delineate the role of the gut microbiome in Southern Chinese psoriasis patients, we performed targeted 16S rRNA sequencing and comprehensive bioinformatic analysis to compare the gut microbiome profile of 58 psoriasis patients against 49 healthy local subjects presumably with similar lifestyles.
and
were found to be enriched in psoriasis patients and in some of the healthy subjects, respectively. Metabolic functional pathways were predicted to be differentially abundant, with a clear shift toward SCFA synthesis in healthy subjects. The alteration of the co-occurrence network was also evident in the psoriasis group. In addition, we also profiled the gut microbiome in 52 of the 58 recruited psoriasis patients after taking 8 weeks of an orally administrated novel E3 probiotics formula (with prebiotics, probiotics and postbiotics). The Dermatological Life Quality Index (
= 0.009) and Psoriasis Area and Severity Index (
< 0.001) were significantly improved after taking 8 weeks of probiotics with no adverse effect observed. We showed that probiotics could at least partly restore gut dysbiosis via the modulation of the gut microbiome. Here, we also report the potential application of a machine learning-derived gut dysbiosis index based on a quantitative PCR panel (AUC = 0.88) to monitor gut dysbiosis in psoriasis patients. To sum up, our study suggests the gut microbial landscape differed in psoriasis patients at the genera, species, functional and network levels. Additionally, the dysbiosis index could be a cost-effective and rapid tool to monitor probiotics use in psoriasis patients.
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