Abstract
Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalence in southern China and Southeast Asia. It is well-known to be associated with latent Epstein-Barr ...virus (EBV) infection. By using small RNA sequencing, we previously established a comprehensive miRNA profile in a panel of NPC samples and revealed that the EBV-encoded miRNAs derived from BamHI-A rightward transcripts (miR-BARTs) are abundantly expressed. The important roles of miR-BARTs in cancer development have been reported extensively. In the present study, we identified multiple putative binding sites of miR-BART5-5p, BART7-3p, BART9-3p and BART14-3p on the 3'-UTR of a critical DNA double-strand break (DSB) repair gene, Ataxia-Telangiectasia-Mutant (ATM). Notably, the expression of these 4 miR-BARTs represented more than 10% of all EBV-encoded miRNAs in NPC cells while downregulation of ATM expression was observed in our local primary NPC samples in both qRT-PCR and immunohistochemical (IHC) staining analysis. In addition, the abilities of miR-BARTs to downregulate ATM expression were demonstrated in the transient transfection experiments. By manipulating the miR-BARTs expression in epithelial cell lines, we further revealed that these four viral miRNAs could inhibit both ionizing radiation (IR)-induced ATM kinase activity and BZLF1-induced viral lytic reactivation. In conclusion, our findings suggest that miR-BART5-5p, BART7-3p, BART9-3p and BART14-3p work co-operatively to modulate DNA damage response and to maintain viral latency, contributing to the NPC tumorigenesis. Acknowledgement: Theme-based Research Scheme (T12-401/13-R) and GRF (14104415 and 14138016), Research Grant Council, Hong Kong.
Citation Format: Raymond W. Lung, Po-Man Hau, Joanna H. Tong, Ka-Hei Lam, Anthony W. Chan, Kevin Y. Yip, George S. Tsao, Kwok-Wai Lo, Ka-Fai To. Epstein-Barr virus-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 482.
Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated epithelial malignancy. The high expression of BART‐miRNAs (miR‐BARTs) during latent EBV infection in NPC strongly supports ...their pathological importance in cancer progression. Recently, we found that several BART‐miRNAs work co‐operatively to modulate the DNA damage response (DDR) by reducing Ataxia‐telangiectasia‐mutated (ATM) activity. In this study, we further investigated the role of miR‐BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down‐regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2‐3p, BART12, BART17‐5p and BART19‐3p in BRCA1 expression. The ectopic expression of these four miR‐BARTs suppressed endogenous BRCA1 expression in EBV‐negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR‐BARTs activities in C666‐1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR‐BART17‐5p and miR‐BART19‐3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA‐damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR‐BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives
Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses ...with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS.
Methods
We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS.
Results
We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non‐specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%).
Conclusions
These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non‐specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.
Key points
What's already known about this topic?
The anomalies associated with Kabuki syndrome (KS) may be detectable on routine fetal ultrasound.
What does this study add?
This study provides comprehensive information on the prenatal manifestations of KS. Although the prenatal ultrasound findings are not specific for KS, recognition of the fetal abnormalities should alert clinicians to consider discussion regarding targeted fetal genetic testing using the KS panel or exome sequencing and provision of appropriate counselling to explain the findings.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Nasopharyngeal carcinoma (NPC) is common among southern Chinese including the ethnic Cantonese population living in Hong Kong. Epstein-Barr virus (EBV) infection is detected in all undifferentiated ...type of NPC in this endemic region. Establishment of stable and latent EBV infection in premalignant nasopharyngeal epithelial cells is an early event in NPC development and may contribute to its pathogenesis. Immortalized primary nasopharyngeal epithelial cells represent an important tool for investigation of EBV infection and its tumorigenic potential in this special type of epithelial cells. However, the limited availability and small sizes of nasopharyngeal biopsies have seriously restricted the establishment of primary nasopharyngeal epithelial cells for immortalization. A reliable and effective method to immortalize primary nasopharyngeal epithelial cells will provide unrestricted materials for EBV infection studies. An earlier study has reported that Bmi-1 expression could immortalize primary nasopharyngeal epithelial cells. However, its efficiency and actions in immortalization have not been fully characterized. Our studies showed that Bmi-1 expression alone has limited ability to immortalize primary nasopharyngeal epithelial cells and additional events are often required for its immortalization action. We have identified some of the key events associated with the immortalization of primary nasopharyngeal epithelial cells. Efficient immortalization of nasopharyngeal epithelial cells could be reproducibly and efficiently achieved by the combined actions of Bmi-1 expression, activation of telomerase and silencing of p16 gene. Activation of MAPK signaling and gene expression downstream of Bmi-1 were detected in the immortalized nasopharyngeal epithelial cells and may play a role in immortalization. Furthermore, these newly immortalized nasopharyngeal epithelial cells are susceptible to EBV infection and supported a type II latent EBV infection program characteristic of EBV-infected nasopharyngeal carcinoma. The establishment of an efficient method to immortalize primary nasopharyngeal epithelial cells will facilitate the investigation into the role of EBV infection in pathogenesis of nasopharyngeal carcinoma.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives: The present study aimed to develop and validate a Cantonese short version of the Zarit Burden Interview (CZBI-Short) for Hong Kong Chinese dementia caregivers.
Methods: The 12-item Zarit ...Burden Interview (ZBI) was translated into spoken Cantonese and back-translated by two bilingual research assistants and face validated by a panel of experts. Five hundred Chinese dementia caregivers showing signs of stress reported their burden using the translated ZBI and rated their depressive symptoms, overall health, and care recipients' physical functioning and behavioral problems. The factor structure of the translated scale was identified using principal component analysis and confirmatory factor analysis; internal consistency and item-total correlations were assessed; and concurrent validity was tested by correlating the ZBI with depressive symptoms, self-rated health, and care recipients' physical functioning and behavioral problems.
Results: The principal component analysis resulted in 11 items loading on a three-factor model comprised role strain, self-criticism, and negative emotion, which accounted for 59% of the variance. The confirmatory factor analysis supported the three-factor model (CZBI-Short) that explained 61% of the total variance. Cronbach's alpha (0.84) and item-total correlations (rho = 0.39-0.71) indicated CZBI-Short had good reliability. CZBI-Short showed correlations with depressive symptoms (r = 0.50), self-rated health (r = −0.26) and care recipients' physical functioning (r = 0.18-0.26) and disruptive behaviors (r = 0.36).
Conclusions: The 12-item CZBI-Short is a concise, reliable, and valid instrument to assess burden in Chinese dementia caregivers in clinical and social care settings.
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BFBNIB, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
We demonstrate fiber Bragg gratings written in polymer fiber for use in the THz window for the first time. A KrF excimer laser operating at 248 nm was used to inscribe notch-type gratings in single ...component Topas subwavelength fiber. A transmission loss at the centre wavelength of the grating of 60 dB is observed in short gratings containing only 192 notches. Experimental results and modeling are presented. The gratings are expected to find use in THz signal filtering and chemical or biosensing applications.
For the first time, an innovative concept of combining sponge-based moving bed (SMB) and an osmotic membrane bioreactor (OsMBR), known as the SMB-OsMBR hybrid system, were investigated using Triton ...X-114 surfactant coupled with MgCl2 salt as the draw solution. Compared to traditional activated sludge OsMBR, the SMB-OsMBR system was able to remove more nutrients due to the thick-biofilm layer on sponge carriers. Subsequently less membrane fouling was observed during the wastewater treatment process. A water flux of 11.38 L/(m2 h) and a negligible reverse salt flux were documented when deionized water served as the feed solution and a mixture of 1.5 M MgCl2 and 1.5 mM Triton X-114 was used as the draw solution. The SMB-OsMBR hybrid system indicated that a stable water flux of 10.5 L/(m2 h) and low salt accumulation were achieved in a 90-day operation. Moreover, the nutrient removal efficiency of the proposed system was close to 100%, confirming the effectiveness of simultaneous nitrification and denitrification in the biofilm layer on sponge carriers. The overall performance of the SMB-OsMBR hybrid system using MgCl2 coupled with Triton X-114 as the draw solution demonstrates its potential application in wastewater treatment.
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•A mixture of MgCl2 and Triton X-114 can serve as a novel draw solution.•The reverse flux of novel draw solution was 4.5 times lower than that of only MgCl2.•Low salt accumulation was achieved during 90-day SMB-OsMBR operation.•Approximately 100% NH4–N and 98% PO4–P were removed by the SMB-OsMBR hybrid system.•Moving free sponge carriers in the bioreactor continuously cleaned the FO membrane.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Acetaminophen is a commonly used drug for the treatment of patients with common cold and influenza. However, an overdose of acetaminophen may be fatal. In this study we investigated whether mice, ...administered intraperitoneally with a lethal dose of acetaminophen, when followed by oral administration of
Phyllanthus urinaria extract, may be prevented from death. Histopathological analysis of mouse liver sections showed that
Phyllanthus urinaria extract may protect the hepatocytes from acetaminophen-induced necrosis. Therapeutic dose of
Phyllanthus urinaria extract did not show any toxicological phenomenon on mice. Immunohistochemical staining with the cytochrome P450 CYP2E1 antibody revealed that
Phyllanthus urinaria extract reduced the cytochrome P450 CYP2E1 protein level in mice pre-treated with a lethal dose of acetaminophen.
Phyllanthus urinaria extract also inhibited the cytochrome P450 CYP2E1 enzymatic activity
in vitro. Heavy metals, including arsenic, cadmium, mercury and lead, as well as herbicide residues were not found above their detection limits. High performance liquid chromatography identified corilagin and gallic acid as the major components of the
Phyllanthus urinaria extract. We conclude that
Phyllanthus urinaria extract is effective in attenuating the acetaminophen induced hepatotoxicity, and inhibition of cytochrome P450 CYP2E1 enzyme may be an important factor for its therapeutic mechanism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We have investigated the potential
in vivo anti-tumour activity of corilagin using the Hep3B hepatocellular carcinoma cell line and an athymic nude mice xenograft model. The purity of corilagin was ...confirmed by high performance liquid chromatographic analysis. Corilagin was administrated intraperitoneally for a continuous period of 7 days at a concentration of 15
mg/kg of body weight per day. A significant inhibition of tumour growth was observed when treated mice are compared with control groups. Furthermore, analysis of enzymes markers of liver function, including alanine aminotransferase and asparate aminotransferase, suggested that current therapeutic dosage of corilagin did not exert adverse effect on liver. Our observations support the view that corilagin is considerably effective to retard the
in vivo growth of xenografted Hep3B hepatocellular carcinoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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