EZH2-Mediated H3K27me3 Is Involved in Epigenetic Repression of Deleted in Liver Cancer 1 in Human Cancers

Enhancer of zeste homolog 2 (EZH2), the histone methyltransferase of the Polycomb Repressive complex 2 catalyzing histone H3 lysine 27 tri-methylation (H3K27me3), is frequently up-regulated in human cancers. In this study, we identified the tumor suppressor Deleted in liver cancer 1 (DLC1) as a target of repression by EZH2-mediated H3K27me3. DLC1 is a GTPase-activating protein for Rho family proteins. Inactivation of DLC1 results in hyper-activated Rho/ROCK signaling and is implicated in actin cytoskeleton reorganization to promote cancer metastasis. By chromatin immunoprecipitation assay, we demonstrated that H3K27me3 was significantly enriched at the DLC1 promoter region of a DLC1-nonexpressing HCC cell line, MHCC97L. Depletion of EZH2 in MHCC97L by shRNA reduced H3K27me3 level at DLC1 promoter and induced DLC1 gene re-expression. Conversely, transient overexpression of GFP-EZH2 in DLC1-expressing Huh7 cells reduced DLC1 mRNA level with a concomitant enrichment of EZH2 on DLC1 promoter. An inverse relation between EZH2 and DLC1 expression was observed in the liver, lung, breast, prostate, and ovarian cancer tissues. Treating cancer cells with the EZH2 small molecular inhibitor, 3-Deazaneplanocin A (DZNep), restored DLC1 expression in different cancer cell lines, indicating that EZH2-mediated H3K27me3 epigenetic regulation of DLC1 was a common mechanism in human cancers. Importantly, we found that DZNep treatment inhibited HCC cell migration through disrupting actin cytoskeleton network, suggesting the therapeutic potential of DZNep in targeting cancer metastasis. Taken together, our study has shed mechanistic insight into EZH2-H3K27me3 epigenetic repression of DLC1 and advocated the significant pro-metastatic role of EZH2 via repressing tumor and metastasis suppressors.published_or_final_versio

香港華人多發性硬化症的流行病學研究：問卷調查

OBJECTIVE: To study the epidemiology of multiple sclerosis in Hong Kong Chinese. DESIGN: Cross-sectional questionnaire survey. SETTING: Neurology and paediatric neurology departments in Hong Kong from January through June 1999. PARTICIPANTS: All confirmed multiple sclerosis patients. MAIN OUTCOME MEASURES: Demographic data, investigation results, Kurtzke's Expanded Disability Status Scale during the last follow-up visit, number of relapses between 1997 and 1998, and treatments used/currently in use. RESULTS: Fifty-three Chinese multiple sclerosis patients were identified. The prevalence was thus estimated to be 0.77 per 100,000 population. This low prevalence was also noted in other multiple sclerosis studies from South-East Asia (range, 0.8-4 per 100,000 population). The female to male ratio among the Chinese multiple sclerosis sufferers was 9.6:1, a figure somewhat higher than that reported in the other studies from South-East Asia (range, 3.2-6.6:1). The Chinese multiple sclerosis patients in this study also had a high spinal cord involvement (66%) and a low presence of cerebrospinal fluid oligoclonal banding (40%). These findings were different from those in Caucasian multiple sclerosis patients. CONCLUSION: Multiple sclerosis in Hong Kong Chinese has a low prevalence, a high female to male ratio, and a low cerebrospinal fluid oligoclonal banding presence.published_or_final_versio

One-Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke

Previous studies conducted between 1997 and 2003 estimated that the risk of stroke or an acute coronary syndrome was 12 to 20% during the first 3 months after a transient ischemic attack (TIA) or minor stroke. The TIAregistry.org project was designed to describe the contemporary profile, etiologic factors, and outcomes in patients with a TIA or minor ischemic stroke who receive care in health systems that now offer urgent evaluation by stroke specialists.We recruited patients who had had a TIA or minor stroke within the previous 7 days. Sites were selected if they had systems dedicated to urgent evaluation of patients with TIA. We estimated the 1-year risk of stroke and of the composite outcome of stroke, an acute coronary syndrome, or death from cardiovascular causes. We also examined the association of the ABCD(2) score for the risk of stroke (range, 0 [lowest risk] to 7 [highest risk]), findings on brain imaging, and cause of TIA or minor stroke with the risk of recurrent stroke over a period of 1 year.From 2009 through 2011, we enrolled 4789 patients at 61 sites in 21 countries. A total of 78.4% of the patients were evaluated by stroke specialists within 24 hours after symptom onset. A total of 33.4% of the patients had an acute brain infarction, 23.2% had at least one extracranial or intracranial stenosis of 50% or more, and 10.4% had atrial fibrillation. The Kaplan-Meier estimate of the 1-year event rate of the composite cardiovascular outcome was 6.2% (95% confidence interval, 5.5 to 7.0). Kaplan-Meier estimates of the stroke rate at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. In multivariable analyses, multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD(2) score of 6 or 7 were each associated with more than a doubling of the risk of stroke.We observed a lower risk of cardiovascular events after TIA than previously reported. The ABCD(2) score, findings on brain imaging, and status with respect to large-artery atherosclerosis helped stratify the risk of recurrent stroke within 1 year after a TIA or minor stroke

Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis

link_to_subscribed_fulltex

Cerebral augmentation effect induced by external counterpulsation is not related to impaired dynamic cerebral autoregulation in ischemic stroke

202307 bcchVersion of RecordRGCOthersNational Natural Science Foundation of China; National Key Research and Development Program of ChinaPublishe

MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility

MicroRNAs (miRNAs), an important class of small non-coding RNAs, regulate gene expression at the post-transcriptional level. miRNAs are involved in a wide range of biological processes and implicated in different diseases, including cancers. In this study, miRNA profiling and qRT-PCR validation revealed that miR-142-3p and miR-142-5p were significantly downregulated in hepatocellular carcinoma (HCC) and their expression levels decreased as the disease progressed. The ectopic expression of miR-142 significantly reduced HCC cell migration and invasion. Overexpression of either miR-142-3p or miR-142-5p suppressed HCC cell migration, and overexpression of both synergistically inhibited cell migration, which indicated that miR-142-3p and miR-142-5p may cooperatively regulate cell movement. miR-142-3p and miR-142-5p, which are mature miRNAs derived from the 3'- and 5'-strands of the precursor miR-142, target distinct pools of genes because of their different seed sequences. Pathway enrichment analysis showed a strong association of the putative gene targets of miR-142-3p and miR-142-5p with several cell motility-associated pathways, including those regulating actin cytoskeleton, adherens junctions, and focal adhesion. Importantly, a number of the putative gene targets were also significantly upregulated in human HCC cells. Moreover, overexpression of miR-142 significantly abrogated stress fiber formation in HCC cells and led to cell shrinkage. This study shows that mature miR-142 pairs collaboratively regulate different components of distinct signaling cascades and therefore affects the motility of HCC cells

Cost-effectiveness of pembrolizumab compared to ipilimumab and chemotherapy as a first line treatment for patients with advanced melanoma in Hong Kong

This journal suppl. entitled: Abstract Book of ESMO Asia Congress Singapore ... 2016BACKGROUND: Pembrolizumab (Pembro) has been shown to improve overall survival (OS) and progression free survival (PFS) compared with ipilimumab (Ipi) in patients with Ipi naïve advanced melanoma; however, there are no published data on the cost-effectiveness for Pembro compared with treatments currently used in Hong Kong for advanced melanoma. METHODS: A partitioned-survival model based on data from a recent randomized phase 3 study (KEYNOTE-006) was used to derive cost and time in PFS, OS, and post-progression survival for Pembro and Ipi. Other comparators include dacarbazine (DTIC), temozolomide (TMZ), and the paclitaxel-carboplatin combination (PC). A combination of clinical trial data, literature data, results of meta-analysis, and melanoma registry data was used to derive PFS and OS curves. The base-case time horizon for the model was 10 years with costs and health outcomes discounted at a rate of 5% per year. Individual patient level data on utilities and frequencies of adverse events were obtained from an interim analysis of the KEYNOTE-006 (cut-off date: 3-Mar-15) for Pembro and Ipi. Cost data included drug acquisition, treatment administration, adverse event management, and clinical management of advanced melanoma. Cost information was obtained. The distribution of patient weight from the Hong Kong population was applied to calculate the drug costs. The incremental cost effectiveness ratio (ICER) expressed as cost in US Dollars (USD) per quality-adjusted life years (QALYs) was the main outcome. Sensitivity analyses (probabilistic and one-way) were performed to test the robustness of the results. RESULTS: The ICER for Pembro as a 1L treatment for advanced melanoma was USD 8,034 compared with Ipi and USD 53,123 compared to DTIC. Results comparing Pembro to TMZ and to PC were similar to that of comparing with DTIC. CONCLUSIONS: Pembro is cost effective relative to Ipi for the treatment of advanced melanoma in Hong Kong. When compared with chemotherapy (DTIC, TMZ and PC), the resulting ICER is also lower than the WHO threshold of three times gross domestic product (GDP) per capita, which, for Hong Kong, is currently at USD 119,274

Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese

There is accumulating evidence to suggest that overexpression of efflux drug transporters at the blood-brain barrier, by reducing antiepileptic drug (AED) accumulation in the seizure foci, contributes to drug resistance in epilepsy. P-glycoprotein, encoded by the ABCB1 gene, is the most studied drug transporter. There are conflicting data as to whether the CC genotype of the ABCB1 3435C > T polymorphism is associated with drug resistance in Caucasian patients with epilepsy. We investigated this association in ethnic Chinese. ABCB1 3435C > T was genotyped in 746 Han Chinese patients with epilepsy and 179 controls. Patients with drug-resistant epilepsy were more likely to have the TT genotype compared with those with drug-responsive epilepsy (16.7% vs 7.4%, odds ratio = 2.5, 95% confidence interval = 1.4-4.6, P = 0.0009). Our results contrast with those of studies of Caucasians, and highlight the complexity of the possible role of this polymorphism in AED response in different ethnic populations. © 2007 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex